MXPA02012563A

MXPA02012563A - Fused cyclic modulators of nuclear hormone receptor function.

Info

Publication number: MXPA02012563A
Application number: MXPA02012563A
Authority: MX
Inventors: Mark E Salvati
Original assignee: Squibb Bristol Myers Co
Priority date: 2000-06-28
Filing date: 2001-06-20
Publication date: 2003-05-14
Also published as: WO2002000653A3; NZ523802A; EP1299385A2; CA2413683A1; NO20026167D0; HUP0303165A3; WO2002000653A2; HUP0303165A2; JP2004515462A; AU2002215609A1; NO20026167L; BR0111869A

Abstract

Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.

Description

CYCLIC COMPOUNDS FUSED AS MODULATORS OF A NUCLEAR HORMONE RECEIVER Field of the Invention The present invention relates to fused cyclic compounds, to methods of using the compounds in the treatment of conditions associated with the nuclear hormone receptor such as cancer, and to pharmaceutical compositions containing the compounds.

BACKGROUND OF THE INVENTION Nuclear hormone (RHN) receptors constitute a large super family of sequence-specific and ligand-dependent transcription factors. Members of this family have influence on transcription either directly, through specific binding to target promoter genes (Evans, in Sci ence 240: 889-895 (1988)), or indirectly, via protein-protein interactions with other transcription factors (Jonat et al., Cell 62: 1189-1204 (1990),? chuele et al., Cell 62: 1217-1226 (1990), and Yang-Yen et al., Cell 62: 1205-1215 (1990)). The super-fa of the nuclear hormone receptor (also known in the art as the super-family of the REF. 143513"steroid / thyroid" hormone receptor) includes receptors for a variety of hydrophobic ligands, including cortisol, aldosterone, estrogen, progesterone, tetosterone, vitamin D3, thyroid hormone, and retinoic acid (Evans, 1988, supra). In addition to these conventional nuclear hormone receptors, the superfamily contains a number of proteins that do not have known ligands, called orphan nuclear hormone receptors (Mangelsdorf et al., Cell 83: 835-839 (1995), O '). Malley et al., Mol.Endocrinol., 10: 1293 (1996), In ark et al., Mol.Endocpnol., 10, 1293-1307 (1996) and Giguere, Endocpn., Rev. 20, 689-725 (1999)) . The conventional nuclear hormone receptors are generally transactivators in the presence of the ligand, and can either be active repressors or inert transcriptionally in the absence of the ligand. Some of the orphan receptors behave as if they were transcriptionally inert in the absence of the ligand. Others, however, behave either as repressors or constitutive activators. These orphan nuclear hormone receptors are either under the control of ubiquitous ligands that have not been identified, or do not need to bind to the ligand to perform these activities. In common with other transcription factors, the nuclear hormone receptors have a modular structure, which is comprised of three distinct domains: an N-terminal domain of variable size that contains a trans-focal AF-1 activation function, a binding domain of highly conserved DNA and a moderately conserved ligand binding domain. The ligand binding domain is not only responsible for binding the specific ligand but also contains a transcriptional activation function called AE-2 and a dimentional domain (Wurtz et al., Na ture Struc. Biol. 3, 87-94 ( 1996), Parker et al., Na ture Struc. Biol. 3, 113-115 (1996) and Kumar et al., Steroids 64, 310-319 (1999)). Although, the total protein sequence of these receptors can vary significantly, all participate both in a common structural arrangement indicative of the divergence of an ancestral arcotype, and in substantial homology (especially, sequence identity) in the binding domain of ligand Nuclear hormone receptors that bind the spheroid (RHN-EE) comprise a sub-family of nuclear hormone receptors. These receptors are related because they participate in a stronger sequence homology with each other, particularly in the ligand binding domain (DEL), than the other members of the RHN super family (Evans, 1988, aupra) and all use steroid-based ligands. Some examples of this sub-family of RHN are the androgen receptor (AR), the estrogen receptor (ER), the progesterone receptor (RP), the glucocorticoid receptor (RG), the mineralocorticoid receptor (RM), the aldosterone receptor (RALD) and the spheroid and xenobiotic receptor (REX) (Evans et al., WO 99/35246). Based on strong sequence homology in the DEL, several orphan receptors can also be members of the RHN-EE sub-family. Consistent with the high sequence homology found in the DEL for each of the RHN-EEs, the natural ligands for each are derived from a common stereoinoid nucleus. Examples of some of the steroid-based ligands used by members of the RHN-EE include cortisol, aldosterone, estrogen, progesterone, testosterone and dihydrotestosterone. The specificity of a particular steroid-based ligand for one RHN-EE against another is obtained by the difference substitution near the spheroid nucleus. The high affinity binding of a particular RHN-SE, coupled with the high-level specificity for that particular RHN-SE, can only be achieved with minor structural changes near the steroid nucleus (eg, Waller et al., Toxicol. Pharma et al., 137, 219-227 (1996) and Mekenyan et al., Environ. Sci. Technol. 31, 3702-3711 (1997), binding affinity of progesterone to the androgen receptor when compared to testosterone. ). They have described numerous synthetically derived spheroidal and spheroidal antagonists and agonists for members of the RHN-EE family. Many of these antagonist ligands and agonists are used clinically in man to treat a variety of medical conditions. RU486 is an example of a synthetic agonist of RP, which is used as a birth control agent (Vegeto et al., Cell 69: 703-713 (1992)), and Flutamide is an example of an antagonist of the RA, which is used for the treatment of prostate cancer (Neri et al, Endo 91, 427-437 (1972)). Tamoxifen is an example of a tissue-specific modulator of ER function, which is used in the treatment of breast cancer (Smigel J- Na ti.Can cer Inst. 90, 647-648 (1998)). Tamoxifen can function as an ER antagonist in the breast tissue while acting as an ER agonist in bone (Grese et al., Proc. Na ti.Acid.Sci.USA 94, 14105-14110 (1997) ). Due to the selective tissue effects seen for Tamoxifen, this agent and similar agents are referred to as "partial agonist" or "partial antagonist". In addition to synthetically derived non-endogenous ligands, non-endogenous ligands for RHN can be obtained from food sources (Regal et al., Proc. Soc. Exp. Biol. Med. 223, 372-378 (2000) and Hempstock et al. al., J. Med. Food 2, 267-269 (1999)). Flavanoid phytoestrogens are an example of an unnatural ligand for RHN-EE that are readily obtained from a food source such as soybean (Quella et al., J. Cl in. Oncol. 18, 1068-1074 (2000) and Banz et al., J. Med. Food 2, 271-273 (1999)). The ability to modulate the transcriptional activity of the individual RHN by the addition of a small molecule ligand makes them ideal targets for the development of pharmaceutical agents for a variety of disease states. As mentioned above, non-natural ligands can be engineered in synthetic fashion to serve as modulators of RHN function. In the case of the RHN-EE, the genetic engineering design of an unnatural ligand can include the identification of a core structure which simulates the natural steroid core system. This can be achieved by randomization against several RHN-EE or through directed procedures using available crystal structures from a variety of RHN ligand binding domains (Bourguet et al., Na ture 375, 377-382 ( 1995), Brzozowski, et al., Na ture 389, 753-758 (1997), Shiau et al., Cell 95, 927-937 (1998) and Tanenbaum et al., Proc. Na ti. Acad. Sci. USA 95, 5998-6003 (1998)). The differential substitution near such a nucleus that simulates the steroid can provide agents with selectivity for one receptor against another. In addition, the modifications can be used to obtain agents with agonist or antagonist activity for a particular RHN-EE. The differential substitution near the nucleus that simulates the steroid can result in the formation of a series of high affinity antagonists and agonists with specificity for, for example, ER against RP against RA against RG against MR. Such a differential substitution procedure has been reported, for example, for the quinolim-based modulators of the steroid RHN in J. Med. Chem. , 41, 623 (1999); WO 9749709; US 5696133; US 5696130; US 5696127; US 5693647; US 5693646; US 5688810; US 5688808 and WO 9619458, all incorporated herein by reference. The compounds of the present invention comprise a core which serves as a steroid simulator, and are useful as modulators of the function of the nuclear hormone receptors that bind the spheroid, as well as other RHNs as described below.

Breva Description of the Invention The present invention provides fused cyclic compounds of the following formula I and salts thereof, the compounds are especially useful as modulators of the function of the nuclear hormone receptor: (D) As used in formula I, and throughout the specification, the symbols have the following meanings unless otherwise indicated, and are, for each case, independently selected: G is an aplo or heterocycle group (eg example, heteropole), wherein the group is mono- or polycyclic, and which is optionally substituted at one or more positions, preferably with hydrogen, substituted alkyl or alkyl, substituted alkenyl or alkenyl, alkynyl or substituted alkyl, halo, cycloalkyl or cycloalkyl substituted, substituted cycloalkenyl or cycloalkenyl, substituted aryl or aryl, substituted heterocycle or heterocycle, substituted substituted arylalkyl, heterocycloalkyl or substituted heterocyclealkyl, CN, R1OC = 0, R1C = 0, R "J>, R1HNC = 0, R ^ NC), HOCR3R3 ', nitro, R1OCH2, RX0, NHZ, NR4R5, SR1, SO2OR1, S02NR1R1', (R * O) (R ^ O) P = 0, (R1) (R1 ') P = 0, or (R1 ') (NHR1) P = 0; E is C = Z2, CR7R7 '(for example, CHR7), S02, P = OR2, or P = OOR2; Zi is O, S, NH, or NR6; Z2 is O, S, NH, or NR6; R? is CR7 or N; A2 is CR7 or N; And it is J-J'-J "where J is (CR7R7 ') nyn = 0-3, J' is a bond or O, S, S = 0, SO ,, NH, NR6, CO, OC = 0, NRY = 0, CR7R7 ', C = CR8R8', R2P = 0, 0PO0RJ OP02, OS02, CN, NHNH, NHNR6, NR6NH, N = N, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle or aplo or aryl substituted, and J "is (CR R) nyn = 0-3, where Y is not a link; W is CRR7'-CR7R7 ', CRR = CRN', CR7R7'-C = 0, NR9-CRR7 ', N = CR8, N = N, NR9-NRq', substituted cycloalkyl or cloalk, substituted cycloalkenyl or cycloalkenyl, heterocycle or substituted heterocycle, or substituted aryl or aryl; Q is H, alkyl or substituted alkyl, alquenllo or alquenllo substituted cycloalkyl or substituted cycloalkyl, cycloalkenyl oc cloalquenilo substituted heterocycloalkyl or substituted heterocycloalkyl, arylalkyl or substituted arylalkyl, alqumilo or substituted alkynyl, aryl or substituted aryl, heterocyclo (e.g., heteroaplo ) or substituted heterocycle (e.g., substituted heteroaryl), halo, CN, R '? C = 0, PJC = 0, R5R6NC = 0, H0CR7R7', nitro, R1OCH2, R * -0, NH2, C-OSR1, SO2R1 or NR4R5; M is a bond, 0, CR C pRT or NR, 10, and M 'is a bond or NR, with the proviso that at least one of M or M' must be a bond; L is a bond, (CR7R7 ') n, NH, NR5 or N (CR7R7') n, where n = 0-3; R1 and R1 'are each independently H, alkyl or substituted alkyl, cloalquilo c or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl , substituted or substituted arylalkyl; R is alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle substituted heterocycle, cycloalkylalkyl substituted cycloalkylalkyl, cicloalquemlalquilo or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, aplalqu it or substituted arylalkyl; R3 and R3 are each independently H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aplo or aryl, substituted aplalquilo or substituted arylalkyl, halo, CN, hydroxylamine, hydroxamide, alkoxy, or substituted alkoxy, mood, NRiR ^, thiol, alkylthio or substituted alkylthio; R4 is H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, aplo or aplo substituted arylalkyl or substituted arylalkyl, R1C = 0, R1NHC = 0,? O2OR1, or S02NR1R1 '; R is substituted alkyl or alkyl, substituted cycloalkyl cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, R1C = 0, R1NHC = 0,? O2R1, S020R "J or S02NR1R1 '; R6 is substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl , aryl or substituted aryl, arylalkyl or substituted arylalkyl, CN, OH, OR1, R1C = 0 # R1NHC = 0, SO2R1, S02ORJ O ? OiNR'R1 '; R and R7 'are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, cycloalkenylalkyl or. substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, halo, CN, OR1, nitro, hydroxylamine, hydroxylamide, amino, NHR4, NRR5, ÑOR1, thiol, alkylthio or substituted alkylthio, R1C = 0, R1OC = 0, R1NHC = 0, SO2R1, SOR1, P03R1R1 '. R1R1'NC = 0 C ^ SR1, SOL-R1,? OyOR1, or S02NR1R1 '; Ra and Rñ 'are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, nitro, halo, CN, OR1, amino, NHR4, ÑOR1, alkylthio or substituted alkylthio, C = OSR1, R1OC = 0, R ^ -O, R * NHC = 0, R1R1'NC = 0, SOOR1,? = OR1, SOzR1, P03R'R1 ', or SOzNRV; R9 and R9 'are each independently H, alkyl or substituted alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, CN, OH, OR1, R ^ O, RxOC = 0, R-'NHC-O, O SOINRV; and R 10 is H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, CN, OH, OR1, R1C = 0, R1OC = 0, R1R1'NC = 0, S02R * ", SO ^ OR1, O S02NR] R1 'The compounds of the formula I and the salts thereof, which comprise a nucleus which can serve as a spheroid simulator (and which does not require the presence of a steroid-like structure (eg, cyclopentaneperhydrophenanthrene analog)), are new except that: where E is C = 0, M and M 'are both a bond, Zi is O, Q is H and y A? are CH: (i) GL- is not phenyl, 4-chlorophenyl or benzyl when W is -CH = CH- and Y is -CH? -CH? -; (ii) GL- is not phenyl when W is -CH = CH- or -CH2-CH2- and Y is -CH2-; (iii) GL- is not phenyl, 4-methoxyphenyl, 4-chlorophenyl, or certain groups (optionally substituted aryl) - (C 1 -C 3) -akyl- (e.g., benzyl), when W and Y are -CH 2 -CH 2 -; and (iv) G-L- is not 4-chlorophenyl or benzyl when W and Y are phenylene; where E is C = 0, M and M 'are both a bond, Zi is 0, and Ai and; are CH: (i) G-L- is not benzyl when Q is -CO2CH3, W is -CH = CH- and Y is -CH2- or -CH? -CH2-; and (ii) G-L- is not phenyl when Q is methyl, W is -CH = CH- and Y is -CH2-; where E is C = S, M and M 'are both a bond, Z \ is O, Q is H, Ai and A are CH, W is -CH = CH- and Y is -CH2- or -CH2-CH2- , GL- is not phenyl; and where E is C = 0, M and M 'are both a bond, Zi is 0, Q is H, Y is -CH2-CH_-, and W is -CH = CH- or -CH-CH2-, GL- it is not 4-chlorophenyl (i) when Ai and A are C-CHj; and (ii) when A] is C-isopropyl and A ^ is C-CHj.

Additional Description of the Invention The following are definitions of terms used in the present specification. The initial definition provided for a group or term in it applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. The terms "alkyl" and "alk" refer to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one more of the following groups: halo (e.g., a single substituent halo or multiple halo substituents which, in the latter case, form groups such as a perfluoroalkyl group or an alkyl group carrying Cl 3 or CF3), alkoxy, alkylthio, hydroxy, carboxy (i.e., -COOH), alkoxycarbonyl, alkylcarbonyloxy, amino (i.e., -NH2), carbamoyl or substituted carbamoyl, carbamate or carbamate substituted, urea or substituted urea, amidinyl or amidinyl substituted, thiol (-SH), aryl, heterocycle, cycloalkyl, heterocycloalkyl, -S-aryl, -S-heterocycle, -S = 0 -aryl, -S = 0-heterocycle, -S (0) 2 -aryl, - S (0) 2-heterocycle, -NHS (O) z-aryl, -NHS (O '-heterocycle, -NHS (O) 2 NH-aryl, -NHS (0)? NH-heterocycle, -P (O) 2 -aryl, -P (O) 2-heterocycle, -NHP (O) 2-aryl, -NHP (0) 2-heterocycle, -NHP (O) 2 NH-aryl, -NHP (O) 2 NH-heterocycle, -O -aryl, -O-heterocycle, -NH-aryl, -NH-heterocycle, -NHC = 0-aryl, -NHC = 0-heterocycle, - OC = 0-aryl, -OC = 0-heterocycle, -NHC = ONH-aryl, -NHC = ONH-heterocycle, -OC = 00-aryl, -0C = 00-heterocycle, -OC = ONH-aryl, -OC = ONH-heterocyclic ?, -NHC = 00-aryl, -NHC = 00-heterocycle, -C = ONH-aryl, -C = ONH-heterocycle, -C = 00-aryl, -C = 00-heterocycle, -N (alkyl) S (O) 2-aryl, -N (alkyl) S (O) 2-heterocycle, - (alkyl)? (O) 2NH-aryl, N (alkyl)? (O) 2 NH-heterocycle, -N (alkyl) P (O) 2-aryl, -N (alkyl) P (O) 2-heterocycle, -N (alkyl) P (O) 2 NH-aryl, (alkyl) P (O) rNH-heterocycle, -N (alkyl) -aryl, -N (alkyl) -heterocycle, -N (alkyl) C = 0 -aryl, - (alkyl) C = 0-heterocycle, -N (alkyl) C = 0NH-aryl, -N (alkyl) C = ONH-heterocycle, -OC = ON (alkyl) -aryl, -OC = ON (alkyl) -heterocycle, -N (alkyl) C = 00-aryl, -N ( alkyl) C = 00-heterocycle, -C = ON (alkyl) -aryl, -C = O (alkyl) -heterocycle, -NHS (O) N (alkyl) -aryl, NH? (O) 2N (alkyl) -heterocycle, NHP (O) 2N (alkyl) -aryl, NHP (O) 2N (alkyl) -heterocycle, -NHC = ON (alkyl) -aryl, -NHC = ON (alkyl) - heterocycle, - (alkyl) S (O) 2 N (alkyl) -aryl, -N (alkyl) S (O) 2 N (alkyl) -heterocycle, -N (alkyl) P (O) 2 N (alkyl) -aryl, - N (alkyl) P (O) 2 N (alkyl) -heterocycle, - (alkyl) C = ON (alkyl) -aryl, and -N (alkyl) C = ON (alkyl) -heterocycle, as well as by OR13 where Rlj it is defined later in Reaction Scheme XV. In the aforementioned exemplary substituents, groups such as "aryl" and "heterocycle" may themselves be optionally substituted. The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary groups include ethenyl or allyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, alkyl or substituted alkyl, as well as the groups mentioned above as exemplary alkyl substituents. The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary groups include ethynyl. "Substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, alkyl or substituted alkyl, as well as those groups mentioned above as exemplary alkyl substituents. The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups recited above as exemplary alkyl substi ters, and as previously mentioned as preferred aryl substituents in the definition for G. Substituents examples also include fused or spiro-linked cyclic substituents, especially cycloalkemyl or substituted cycloalkenyl. The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary groups include c-clobutenyl, c-clopentenyl, cyclohexenyl, etc. "C substituted chloralkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, nitro, cyano, alkyl or substituted alkyl, as well as those groups mentioned above as exemplary alkyl substituents, and as previously mentioned as preferred aryl substituents in the definition for G. Exemplary substituents they also include fused or spiro-linked cyclic substituents, especially cycloalkyl or substituted cycloalkyl. The terms "alkoxy" or "alkylthio" refer to an alkyl group as described above linked through an oxygen bond (-0-) or a sulfur bond (-S-), respectively. The terms "substituted alkoxy" or "substituted alkylthio" refer to an alkyl group substituted as described above linked through an oxygen or sulfur link, respectively. The term "alkoxycarbonyl" refers to an alkoxy group linked through a carbonyl group. The term "alkylcarbonyl" refers to an alkyl group linked through a carbonyl group. The term "alkylcarbonyloxy" refers to an alkylcarbonyl group linked through an oxygen bond.

The terms "arylalkyl", "substituted arylalkyl", "cycloalkylalkyl", "substituted cycloalkylalkyl", "cycloalkylmetal", "substituted cycloalkylmetal", "heterocycloalkyl" and "substituted heterocycloalkyl" refer to aryl, cycloalkyl, cycloalkenyl and heterocycle groups bonded to through an alkyl group, substituted in the alkyl, cycloalkyl, cycloalkenyl or heterocycle and / or the alkyl group where indicated as "substituted". The term "aryl" refers to aromatic, cyclic hydrocarbon groups which have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where they contain two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be joined at a single point (for example, bife ilo), or fused (for example, naphthyl, fenantremlo and the like). "Substituted aplo" refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, substituted nitro, cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, cyano, S (0) m- (m = 0, 1 or 2), alkyl or substituted alkyl, as well as also those groups mentioned above as exemplary alkyl substituents and as previously mentioned as preferred aryl substituents in the definition for G. Exemplary substituents also include fused cyclic substituents, such as heterocycle or cycloalkenyl groups, or substituted heterocycle or cycloalkenyl. "Carbamoyl" refers to the group -CONH- which is linked at one end to the rest of the molecule and at the other to hydrogen or an organic portion (such as alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, alkylcarbonyl, hydroxyl) and substituted nitrogen). "Carbamate" refers to the group -O-CO-NH- which is linked at one end to the rest of the molecule and at the other to hydrogen or an organic portion (such as those listed above). "Urea" refers to the group -NH-CO-NH- which is linked at one end to the rest of the molecule and at the other to hydrogen or an organic portion (such as those listed above). "Amidinyl" refers to the group -C (= NH) (NHJ. "Substituted carbamoyl", "substituted carbamate", "substituted urea" and "substituted amidinyl" refer to carbamoyl, carbamate, urea or amidinyl groups as described above in which other of the hydrogen groups are replaced by an organic portion (such as those listed above.) The terms "heterocycle," "heterocyclic," and "heterocycle" refer to cyclic groups (e.g., monocyclic ring systems). to 7 elements, bicyclic of 7 to 11 elements or tricyclic of 10 to 16 elements) completely saturated, or partially or completely unsaturated, including aromatic (ie, "heteroaryl"), which have at least one heteroatom in at least one ring containing carbon atom Each ring of the heterocyclic group containing a heteroatom can have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatoms optionally quaternized. (The term "heteroaply" refers to a heteroaryl group that carries a quaternary nitrogen atom and therefore a positive charge). The heterocyclic group can be attached to the rest of the molecule at any carbon atom or heteroatom to the ring or ring system. Exemplary heterocyclic monocyclic groups include azetidyl, pyrrolidyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl., furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-? iperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like. The bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, onyl cro, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl , furopyridinyl (such as furo [2, 3-c] pyridinyl, furo [3, 2-b] pyridinyl] or furo [2, 3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3, -di idro-4) -oxo-quinazolinyl), triazinilazepinyl, tetrahydroquinolinyl and the like. Exemplary heterocyclic tricyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like, 'Substituted heterohexy substituted 2heterocyclic', and "substituted heterocycle" (such as "substituted heteroaryl") refer to heterocycle, heterocyclic groups or heterocycle substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment Exemplary substituents include, but are not limited to, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, nitro, oxo (i.e. = 0), cyano, alkyl-? (O) m- (m-0, 1 or 2), alkyl or substituted alkyl, as well as those groups mentioned above as exemplary alkyl substituents, and as previously mentioned as preferred heterocycle substituents in the definition for G. The term "quaternary nitrogen" refers to a positively charged nitrogen atom, tet ravalente which includes, for example, positively charged nitrogen in a tetraalkylammonium group (e.g., tetramethylammonium, N-methylpyridinium), positively charged nitrogen in the protonated ammonium species (e.g., methylmethylhydroammonium, N-hydropipimide), positively charged nitrogen in N-amine oxides (e.g., N-methyl-morpholin-N-oxide, pipdm-N-oxide), and nitrogen positively charged to an N-amino-ammonium group (e.g., N-aminopyridinium). The terms "halogen" or "halo" refer to chlorine, bromine, fluorine or iodine. The terms "hydroxylamine" and "hydroxylamide" refer to the groups OH-NH- and OH-NH-CO-, respectively. When a functional group is classified as "protected", this means that the group is in modified form to moderate, especially prevent, unwanted side reactions in the protected site. Suitable protecting groups for the methods and compounds described therein include, without limitation, those described in official textbooks, such as Greene, T.W. et al., Protective Groups in Organi c Synthesis, Wiley, N.Y. (1991). When a term such as "(CRR) n" is used, denotes an optionally substituted alkyl chain existing between the two fragments to which it is attached, the length of the chain is defined by the range described for the term n. An example of this is n = 0-3, which implies units from zero to three (CRR) existing between the two fragments, which are attached to the primary and terminal units (CRR). In the situation where the term n is set to zero (n = 0) then there is a link between the two fragments attached to (CRR). Unless otherwise indicated, any hetero atom with insufficient valencies is assumed to have sufficient hydrogen atoms to satisfy the valences. Divalent groups, such as those in the W definition (eg, NR-CR7R7), can be linked in any direction to the rest of the molecule (e.g., -ArN 9-CR7RT-Aro, -A? -CRRT-'NR9-A2- for the aforementioned group within the definition of W). Carboxylate anion refers to a negatively charged group -COOY Compounds of formula I form salts which are also within the scope of this invention. The reference to a compound of formula I herein is meant to include reference to salts thereof, unless otherwise indicated. The term "salt (s)", as used herein, denotes acidic and / or basic salts formed with organic and / or inorganic acids and bases. Further, when a compound of formula I contains both a basic portion, such as but not limited to a pyridine or imidazole, and an acid portion such as but not limited to a carboxylic acid, zwitterions ("internal salts") can be formed and they are included within the term "salt (s)" as used in this. Pharmaceutically acceptable (ie, physiologically acceptable, non-toxic) salts are preferred, although other salts are also useful, for example, in the isolation or purification steps which may be employed during the preparation. The salts of the compounds of the formula I can be formed, for example, by the reaction of a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt is precipitated or in an aqueous medium followed by lyophilization. The compounds of the formula I, which contain a basic portion, such as but not limited to an imidazole ring or an amine or a pyridine, can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, eg, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, canforates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulphates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydrodes, hydroxyethanesulfonates (for example, 2-hydroxyethanesulfonates), lactates, alloys, methanesulfonates, naphthalenesulfonates (for example, 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulphates, phenylpropionates (for example, 3-phenylpropionates), phosphates, picrates, pivalates , propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. The compounds of formula I, which contain an acidic portion, such as but not limited to a carboxylic acid, can form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as benzathines. , dicyclohexylamines, hydrabamines (formed with N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, Usin and the like . The basic groups containing nitrogen can be quaternized with agents such as lower alkyl halides (for example, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl sulfates, diethyl sulfates, dibutyl, and diamyl), long-chain halides (for example, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (for example, benzyl and phenethyl bromides), and others. The prodrugs and solvates of the compounds of the invention are also contemplated therein. The term "prodrug" as used in thisdenotes a compound which, up to administration to a subject, undergoes chemical conversion by metabolic or chemical processes to produce a compound of formula I, or a salt and / or solvate thereof. Solvates of the compounds of the formula I include, for example, hydrates. The compounds of the formula I, and salts thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All tautomeric forms are contemplated herein as part of the present invention. All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons in various substituents), including enantiomeric forms and diastereomeric forms are contemplated within the scope of this invention. The individual stereoisomers of the compounds of the invention can, for example, be substantially free of other isomers (for example, as a pure or substantially pure optical isomer having a specific activity), or can be mixed, for example, as racemates or with all the others, stereoisomers, or others selected. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC Recommendations of 1974. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives. or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. All isomers with figurative of the compounds of the present invention are contemplated, either in mixture or in pure or substantially pure form. The definition of compounds of the present invention encompasses both cis (2) and trans (-) alkene isomers, as well as cis and trans isomers of heterocycle or cyclic hydrocarbon rings. Throughout the specification, the groups and substituents thereof may be chosen to provide stable compounds and portions.

Methods of Preparation The compounds of the present invention can be prepared by methods such as those illustrated in the following Reaction Schemes I to XV. The solvents, temperatures, pressures and other reaction conditions can be easily selected by one of ordinary skill in the art. The starting materials are commercially available or are readily prepared by one of ordinary skill in the art or are prepared by the methods illustrated in Figures 1 to 3. Combinatorial techniques can be employed in the preparation of the compounds, for example, where the intermediaries have suitable groups for these techniques. See the following alternative methods, which may be employed in the preparation of the compounds of the present invention: Tetrahedron, 27, 3119 (1971); Tetrahedron, 30, 2977 (1974); Tetrahedron. Let, 31, 2631 (1969); J. Org. Chem., 35, 3097 (1970); Bull. Chem. Soc. Jpn. , 67, 3082 (1994); Bull. Chem. Soc. Jpn. , 65, 61 (1992); European Patent (EP) No. 406119; U.S. Patent No. 4,397,857; Pons et al. , Eur. J. Org. Chem., 853-859 (1998); Kucharczyk et al. , J. Med. Chem., 1654-1661 (1993); and German Patent (DE) Document No. 3227055. All documents cited in the present specification, such as those cited in these "Preparation Methods" as well as other sections herein, are incorporated herein by reference in their entirety. Such documents are not admitted as a prior art.

Reaction scheme I As illustrated in Reaction Scheme I, the compounds of formula I can be obtained from the azabicyclo-3-ethylcarboxylate intermediates of formula II. The intermediates of formula II can be prepared, for example, from the synthetic procedures described in Bull. Chem. Soc. Jpn. , 65, 61 (1992), Tetra? E ron Let. 31, 2603 (1990), Chem. Commun. 597 (1999), Tetrahedron Lett. 38, 4021, (1997), Tetrahedron Lett. 40, 7929 (1999), Synlett. 1, 29 (1991), J. Chem. Soc, Chem. Commun. 1601 (1988), J. Org.

Chem. 31, 1059 (1966), Synthesis 10, 925 (1990), Tetrahedron Lett. 40, 8447 (1999), U.S. Patent No. 4775668 and EP No. 266576 and references therein, by one of ordinary skill in the art (incorporated herein by reference in its entirety). In addition to a racemic mixture of a compound of formula II, individual antipodes can be synthesized, for example, in accordance with the procedures described in the above documents. Exemplary methods for the preparation of the compounds of the formula II are further described below in Figures 1 to 3. The treatment of II with an intermediate of formula Z2 = C = N = -LG, produces an intermediate of formula III . Intermediates of formula Z .. = C = N-L-G can be obtained, for example, from commercially available isocyanates, thioisocyanates and carbodiimides or can be easily prepared by one skilled in the art. An intermediate of formula III can be heated with or without the presence of a base, such as DBU or triethylamine, to produce a compound of formula IV, which is the compound of formula I wherein M 'and M are each a bond and E is C = Z. The individual optical isomers of a compound of Formula IV (also known as antipodes) can be obtained, for example, by the use of the corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. The individual a or β (endo or exo) isomers of a compound of formula IV can be obtained, for example, by separation of a resulting mixture by standard techniques.

Reaction scheme II vp Reaction Scheme II describes a method for preparing the compounds of formula I, wherein an intermediate of formula II was treated with a phosgene-like reagent of the formula Cl-E-Cl in the presence of a base, such as NaHCO 3, to produce an intermediate of formula V. Phosgene-like intermediates of formula Cl-E-Cl can be obtained from commercially available sources or can be easily prepared by one skilled in the art. Phosgene equivalents such as carbonyldiimidazoles may alternatively be employed in this step, and elsewhere in these reaction Schemes as appropriate, in place of Cl-E-Cl. The intermediate of formula V can be reacted with an amine of formula H2N-L-G in the presence of a base, such as diisopropylamine or triethylamine, with or without a coupling reagent, such as DMAP, to produce an intermediate of formula VI. The amine intermediates of formula H S.-L-G can be obtained from commercial sources or can be easily prepared by one skilled in the art. The intermediate of formula VI can be converted to a compound of formula VII by heating with or without the presence of a base, such as DBU or triethylamine. A compound of formula VII is a compound of formula I, where M and M 'are each a bond and E is C = Z ?,? 02, P = OR2 or P = OOR. "The individual antipodes of a compound of formula VII can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques The individual a or β isomers of a compound of formula VII can be obtained, example, by separating a resulting mixture by standard techniques.

Reaction scheme III VD Reaction Scheme III describes a method for preparing the compounds of formula I, wherein an intermediate of formula II is saponified with an acid of formula VIII by treatment with a base, such as sodium hydroxide. The acid can then be coupled to an amine of formula H2N-LG via a variety of coupling reagents, for example, as described in The Practice of Peptide? Ynthesis, Springer-Verlag, 2nd Ed., Bodanszy, Mi los, 1993 (incorporated herein by reference in its entirety), to produce an amide intermediate of formula IX. The intermediate of formula IX can be heated with or without the presence of a base such as triethylamine, with a phosgene-like reagent of formula Cl-E-Cl, to produce a compound of formula VII, which is a compound of formula I where M and M 'are each a bond and E is C = Z2, S02, P = OR2 or P = OOR. "Individual antipodes of a compound of formula VII can be obtained, for example, by the use of individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques The individual a or β isomers of a compound of formula VII can be obtained, for example, by separation of a resulting mixture by standard techniques.

Reaction scheme IV As shown in Reaction Scheme IV, a route for compounds of formula I, in which E is C = Z2 and Z2 = N-CN, involves the treatment of an intermediate of formula II with a substituted cyano-thiourea of formula NC-NH-C (S) -NH-LG, in the presence of a water-soluble coupling reagent (RASA), such as l- (3-dimethylammopropyl) -3-et? lcarbod? im? da hydrochloride , as described in Tetrahedron. Let. 30, 7313 (1989) (incorporated herein by reference in its entirety), to produce an intermediate of formula X. The substituted cyano-thioureas of the formula NC-NH-C (S) -NH-LG can be obtained from Commercially available sources or can be easily prepared by one skilled in the art. An intermediate of formula X can be heated with or without the presence of a base, such as DBU, to produce a compound of formula XI, which is a compound of formula I wherein, in addition to E being C = N-CN, M and M 'are each a link. Individual antipodes of a compound of formula XI can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of the formula XI can be obtained, for example, by separation of a resulting mixture by standard techniques.

Reaction scheme V As illustrated in reaction scheme V, a compound of formula XII, which is a compound of formula I in which Q = H, can be converted to a compound of formula I where Q is equal to substituents as defined in this different from H, by treatment with a base such as LDA and an alkyl halide such as methyl iodide, preferably in a solvent such as tetrahydrofuran at low temperatures (e.g., -78 ° C) to produce a compound of formula IV, which is a compound of formula I, where M and M 'are each a bond and E is C = Z2. Individual antipodes of a compound of formula IV can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula XII or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of formula IV can be obtained, for example, by use of the corresponding individual endo or exo isomers of a compound of formula XII or by separation of a resulting mixture by standard techniques. The compounds of formula XII can be obtained, for example, by using the procedure of Reaction Scheme I wherein Q = H.

Reaction scheme VI Z, "B,? Nü m. ' As shown in Reaction Scheme VI, the compounds of formula I can be synthesized by means of a solid support path As such, the above synthetic tute allows synthesis of combinatorial libraries of compounds of formula I via, example, standard automated solid phase synthesis procedures The treatment of a compound of formula II with a protective agent such as di-tert-butylcarbonate, followed by hydrolysis of the ester group by treatment with a base, such as sodium hydroxide, produces an intermediate of formula XIII The intermediate of formula XIII can be attached to a solid support, such as modified Merrifield resin, by treatment with a coupling reagent such as 2,6-dichloro-benzoyl chloride in the presence of pyridine and DMF, to produce an intermediate of formula XIV with solid support.The removal of the protective group can be achieved by treatment with an acid, such as acid tr iffluoroacetic in DMF with sonication, to provide a compound of formula XV, which can be reacted with an intermediate of formula Z2 = C = N-L-G, to produce a formula intermediate XVI. The final product IV can be formed and released from the solid support by heating the intermediate of formula XVI with or without a base, such as DBU. A compound of formula IV is a compound of formula I wherein M 'and M are each a bond and E is C = Z2. Individual antipodes of a compound of formula IV can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of formula IV can be obtained, for example, by separation of a resulting mixture by standard techniques.

Reaction scheme VII vu Reaction Scheme VII shows an alternative procedure for the synthesis of the compounds of the formula I in solid support. As described for Reaction Scheme VI, an intermediate of formula XV can be easily synthesized. The intermediate of formula XV can be treated, with or without the presence of a base such as triethylamine or NaHCO 3, with a phosgene-like reagent of formula Cl-E-Cl, to produce an intermediate of formula XVII. The intermediate of formula XVII can be reacted with an amine of formula HN-LG in the presence of a base, such as dnsopropylamine, with or without a coupling reagent, such as 4-d? Methammo pipdma, to produce a intermediary of formula XVIII. The final product VII can be formed and released from the solid support by heating the intermediate of formula XVIII with or without a base, such as DBU. A compound of formula VII is a compound of formula I wherein and M 'are each a bond and E is C = Z2, S02, P = 0R2 or P = 00R2. Individual antipodes of a compound of formula VII can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. Individual isomers or β of a compound of formula VII can be obtained, for example, by separation of a resulting mixture by standard techniques.

Reaction scheme VIII As described in Reaction Scheme II, an intermediate of formula VI can be easily synthesized. As shown in Reaction Scheme VIII, the treatment of an intermediate of formula VI with a substituted O-diphenylphosphinylhydroxylamine of the formula Ph 2 POONH-R 13, and potassium hydride as described in Synthesis, 7, 592 (1982) and Tetrahedron Let. , 29, 1777 (1988) (both incorporated herein by reference in their entirety), produces an intermediate of formula XXII. The intermediate of formula XXII can be heated with or without a base, such as triethylamine, to produce a compound of formula XXIII, which is a compound of formula I where M is a bond, M 'is NR10 and E is C = Zt, SO ?, P = OR2 or P = OOR2. Individual antipodes of a compound of formula XXIII can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of formula XXIII can be obtained, for example, by separation of a resulting mixture by standard techniques.

Scheme of reaction IX As described in Reaction Scheme VI, an intermediate of formula XIII can be easily synthesized. As shown in Reaction Scheme IX, the acid intermediate of formula XIII can be coupled to an amine of formula H2N-LG via the use of a variety of coupling reagents, as described in Reaction Scheme III, to produce an amide intermediate of formula XXIV. The treatment of an intermediate of formula XXIV with potassium hydride and a substituted O-diphenylphosphinylhydroxylamine of formula Ph2POONH-R10, as described in Reaction Scheme VIII, followed by removal of the BOC protecting group by treatment with an acid, such as trifluoroacetic acid, it produces an intermediate of formula XXV. The intermediate of formula XXV can be treated with a phosgene-like reagent of formula Cl-E-Cl, to produce an intermediate which can be heated with or without a base, such as triethylamine, to produce a compound of formula XXVI, which is a compound of formula I where M 'is a bond, M is NR10 and E is C = Z, SO ?, P = OR2 or P = OOR2. Individual antipodes of a compound of formula XXVI can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula XIII or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of formula XXVI can be obtained, for example, by separating a resulting mixture by standard techniques.

Reaction scheme X As described in Reaction Scheme IX, an intermediate of formula XXIV can be easily synthesized. As shown in Reaction Scheme X, treatment of an intermediate of formula XXIV with suitable agents to form a hydroxylamide moiety, such as TMS-Cl followed by MoOs (DMF) 2 as described in J. Org. Chem., 54, 5852 (1989) and J. Org. Chem., 59, 8065 (1994) (both incorporated herein by reference in its entirety), and for the deprotection of a BOC group, such as ethanol saturated with HCl gas, results in the generation of a hydroxylamide intermediate of formula XXVII . The intermediate of formula XXVII can be treated with a phosgene-like reagent of formula Cl-E-Cl, to produce a compound of formula XXVIII, which is a compound of formula I wherein M is O, M 'is a bond, and E is C = Z2,? 02, P = OR "" or P = OOR2. Individual antipodes of a compound of formula XXVIII can be obtained, for example, by use of the corresponding individual antipodes of a compound of formula XIII or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of formula XXVIII can be obtained, for example, by separation of a resulting mixture by standard techniques.

Reaction scheme XI E-C-Z1 > Sport. l > -? OR1 As shown in Reaction Scheme XI, the treatment of an intermediate of formula H2N-L-G with a phosgene-like reagent of formula Cl-E-Cl as described in Oppi. Bri efs 17, 235 (1985), results in an intermediate of formula XXXII. The intermediate of formula XXXII can be reacted with an intermediate of formula II to produce an intermediate of formula VI. As described in Reaction Scheme II, an intermediate of formula VI can be easily converted to an intermediate of formula VII, which is a compound of formula I where M and M 'are each a bond and E is C = Z ?,? 02, P = OR2 or P = OOR2. Individual antipodes of a compound of formula VII can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of formula VII can be obtained, for example, by the use of corresponding individual endo or exo isomers of a compound of formula II or by separation of a resulting mixture by standard techniques.

Reaction scheme XII As described in Reaction Scheme III, a compound of formula IX can be easily made by the process described. As illustrated in Reaction Scheme XII, the treatment of a compound of formula IX, with an aldehyde reactant of the formula RCHO, which can be obtained from commercial sources or easily synthesized by one skilled in the art, produces an intermediate imine of formula XXXIII. The treatment of the intermediate of formula XXXIII, with a base such as DBU, results in a compound of formula XXXIV, which is a compound of formula I wherein M and M 'are each a bond and E is CHR7. Individual antipodes of a compound of formula XXXIV can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. The individual α, or β isomers of a compound of formula XXXIV can be obtained, for example, by separation of a resulting mixture by standard techniques.

Reaction scheme XIII As described in Reaction Scheme I, a compound of formula IV, wherein Z- = S, can be easily made by the process described. As illustrated in Reaction Scheme XIII, the treatment of a compound of formula IV, wherein Z2 = ?, with an agent capable of reductively removing the sulfur, such as Raney nickel, yields a compound of formula XXXV, which is a compound of formula I, where M and M 'are each a bond and E is CH2. Individual antipodes of a compound of formula XXXV can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of formula XXXV can be obtained by separation of a resulting mixture by standard techniques.

XIV Reaction Scheme Reaction Scheme xrv describes a method for the preparation of compounds of formula I, wherein an intermediate of formula II (where Z, is 0) is saponified to an acid of formula VIII by treatment with a base, such as sodium hydroxide. The acid can then be coupled to an amine of the formula H? NLG via a variety of coupling reagents, for example, as described in The Practice of Peptide? Ynthesis,? Pringer-Verlag, 2nd Ed., Bodanszy, Miklos, 1993 (incorporated herein by reference in its entirety), to produce an amide intermediate of formula IX. The intermediate of formula IX can be treated with a reagent of formula R7R7'-C-X1X2 (where X1 and X2 are independently F, Br, Cl, or i, or X1 and X2 are taken together with the carbon to which they are united to form C = 0), to produce a compound of formula XXXVI, which is a compound of formula I where Zi is O, M and M 'are bonds and E is CR7R7' (such as where one of R7 and R7 ' is H, C? -4 alkyl or C? -4 haloalkyl and the other is R1OC = 0). When the intermediate of formula R, R7'-C-X1X2 is a ketone (X1 and X2 are taken together with the bonded carbon to form C = 0), the amines of formula IX can be condensed with these intermediate carbonyl compounds, for example , in the presence of sodium hydroxide in water at a temperature between 0 ° C and 25 ° C using the procedures described by DA Johnson et al. , J. Org. Chem. 31, 897 (1966) and Uozu i et al. , Tetrahedron Letters, 4.2 407-410 (2001). (See Reaction Scheme III above for when the intermediate of formula R7R7'-C-X1X2 is an aldehyde). When the intermediate of formula RR7'-C-X1X2 is a dihalide (X1 and X2 are halogens), condensation can be conducted, for example, in the presence of a base by heating the mixture of IX and RR7'-C -X1X2 in an inert solvent. Preferred dihalides of formula R7R'-C-X1X2 are ethyl bromofluoroacetate and ethyl bromodi luoroacetate.

Examples of suitable bases include alkali carbonate salts, such as potassium, sodium and lithium, and hydride bases such as sodium hydride. Examples of inert solvents include ethers such as diethyl ether, tetrahydrofuran and dioxane; esters such as ethyl acetate; amides such as dimethylformamide; and acetonitrile. Although the cyclization of compounds of formula IX and R7R7'-C-X1X2 can proceed at room temperature, the reaction is preferably carried out by heating above room temperature. The dihalides, aldehydes and ketones of the formula R7R7'-C-X1X2 can be prepared by the known methods and many are commercially available. For example, see March, J. Advanced Organic Chemistry; 3rd Ed., John Wiley; New York, 1985. Other synthetic routes which can be employed for the conversion of compounds of formula IX to compounds of formula XXXVI are analogous to those found in WO-9414817, US-5, 643,855, O-0107440, WO-9910313, WO-9910312 and JP-46016990 and references therein. Individual optical isomers of a compound of formula XXXVI (also known as antipodes) can be obtained, for example, by the use of corresponding individual antipodes of a compound of formula II or by separation of the racemic mixture by standard techniques. The individual α or β isomers of a compound of formula XXXVI can be isolated from the resulting mixture, for example, by standard techniques.

XV Reaction Scheme As shown in Reaction Scheme XV, the compounds of formula I, where Z? is O, M and M 'are bonds and E is R7R7' can be prepared by transforming the imidazolinones of formula XXVII. The ester of formula XXXVII is hydrolysed, for example, with sodium hydroxide in a solvent such as methanol or ethanol at about 0 ° C to 50 ° C to provide the corresponding carboxylic acid. The acid can be converted to the corresponding ester (R7 '= COOR1) or amide (R7 '= CONR1R1') of formula XXXVIII by treatment with thionyl chloride or oxalyl chloride to form the acid chloride followed by treatment with the appropriate alcohol R -'-OH or amine H-NR'R1 ', respectively. Treatment of the acid chloride with ammonia yields the unsubstituted amide, R = 'CONH2, which can be dehydrated as by conventional methods to form the nitrile, R' = CN. Alternatively, esterification of the carboxylic acid can be achieved by reacting the acid with an appropriate alkyl halide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide, for example, at about 0 ° C to 60 ° C. C to produce an ester of formula XXXVIII (R7 = COOR1). The amide of compound XXXVIII (R ^ CONR'R1 ') can also be obtained by coupling 1,3-dicyclohexylcarbodiimide (DCC) between the carboxylic acid and the appropriate H-NR * -R1' amine. The DCC coupling procedure is described by Bodanszky, M. and Bodanszky, A; in Practice of Peptide Synthesis, Vol. 21; Springer-Verlag, New York: (1984). Reduction of the carboxylic acid or ester with a reducing agent such as aluminum hydride in solvent such as tetrahydrofuran, for example, from 0 ° C to 80 ° C produces the corresponding alcohol, a compound of formula XXXVIII wherein R7 '= CHOH. The treatment of alcohol with a R1J-halide (wherein R1J is alkyl (eg, C, -C6 alkyl) or substituted alkyl; alkenyl (eg, C-C6 alkenyl) or substituted alkenyl; cycloalkyl (e.g. C-Cβ cycloalkyl) or substituted cycloalkyl, substituted heterocycloalkyl or heterocycloalkyl, substituted aryl or aryl (for example, substituted by alkyl or additional substituents), substituted heterocycle or heterocycle (e.g., heteroaryl or substituted heteroaryl, such as heteroaryl substituted by alkyl) and further substituents), in the presence of a base such as potassium carbonate, in an inert solvent such as acetonitrile, yields the compounds of formula XXXVIII, wherein R7 '= CH2OR13 Further substitutions of R7' are also obtainable from the C02Et group of the compounds of formula XXXVII using transformations of the functional group, such as those known to one skilled in the art.

Reaction scheme XVI XXXIX XL Reaction Scheme XVI describes another method for incorporating the additional substitution on a compound of formula I. As illustrated in Reaction Scheme XVI, a compound of formula XXXIX, which can be prepared according to the above reaction schemes, it can be incubated in the presence of a suitable microorganism or enzyme resulting in the formation of a hydroxylated analog of formula XL. Such a process can be employed to produce the regiospecific as well as enantiospecific incorporation of a hydroxyl group in a molecule of formula XXXIX by a specific microorganism or by a series of different microorganisms. Such microorganisms can be, for example, bacterial, yeast or fungal in nature and can be obtained from distributors such as ATCC or identified for use in this method such as by methods known to one skilled in the art. Compound XL is a compound of formula I, wherein Y is as described above and At and A ^ are preferably CR.

Reaction scheme XVII XU xu Reaction Scheme XVII describes another method for incorporating the additional substitution on a compound of formula I. As illustrated in Reaction Scheme XVII, a compound of formula XLI, which can be prepared according to the reaction Schemes above, it can be incubated in the presence of a suitable microorganism or enzyme resulting in the formation of a diol analog of formula XLII. Such a process can be used to produce the regiospecific as well as enantiospecific transformation of a compound of formula XLI to a 1-2 diol of formula XLII by a specific microorganism or by a series of different microroganisms. Such microorganisms can be, for example, bacterial, yeast or fungal in nature and can be obtained from distributors such as ATCC or identified for use in this method such as by methods known to one skilled in the art. Compound XLII is a compound of formula I, where Y is as described above and Ai and A2 are preferably CR7. The present invention also provides the methods of Reaction Schemes XVI and XVII. Accordingly, in one embodiment, the present invention provides a method for the preparation of a compound of the following formula XL, or salt thereof: XL where the symbols are as defined in this one, comprising the steps of contacting a compound of the following formula XXXIX, or exit from it: XXXIX where the symbols are as defined later; with an enzyme or microorganism layer to catalyze the hydroxylation of compound XXXIX to form compound XL, and effect hydroxylation.

In another preferred embodiment, the present invention provides a method for the preparation of a compound of the following formula XLII, or a salt thereof: xm where the symbols are as defined in this, comprising the steps of contacting a compound of the following formula XLI, or salt thereof: XU where the symbols are as defined above; with an enzyme or microorganism capable of catalyzing the opening of the epoxide ring of the compound LXI to form the diol of the compound XLII, and effect the opening of the ring and the diol formation.

All the stereoconfigurations of the centers quirales of the compounds of the formulas XXXIX, XL, XLI, and XLII are contemplated in the methods of the present invention, since be alone (that is, substantially free of others stereoisomers) or in admixture with other stereoisomeric forms. The conversion of an isomer selectively (for example, hydroxylation of the exo isomer prefferentially to hydroxylation of the endo isomer) when put in contact with an isomeric mixture is a preferred embodiment of the invention. The conversion to an isomer selectively (by example, hydroxylation on the exo "exo isomer" front preferentially to the endo front "endo isomer" or regioselective opening of an epoxide to form one of two possible regioisomers of a trans diol) is a preferred embodiment of the invention. Hydroxylation of an achiral intermediate to form a simple optical isomer of the hydroxylated product is also a preferred embodiment of the invention. Resolution of a racemic mixture of an intermediate by selective hydroxylation, or opening of the epoxide ring and diol formation, to generate one of two possible optical isomers is also a preferred embodiment of the invention. The term "resolution" as used in this denotes partial resolution, as well as, preferably, complete. The terms "enzymatic process" or "enzymatic method", as used herein, denotes a process or method of the present invention that employs an enzyme or microorganism. The term "hydroxylation", as used herein, denotes the addition of a hydroxyl group to a methylene group as described above. Hydroxylation can be achieved, for example, by contact with molecular oxygen according to the methods of the present invention. The diol formation can be achieved, for example, by contact with water according to the methods of the present invention. The use of "an enzyme or microorganism" in the present methods includes the use of two or more, as well as an enzyme or microorganism. The enzyme or microorganism used in the present invention can be any enzyme or microorganism capable of catalyzing the enzymatic conversions described therein. Enzymatic or microbial materials, regardless of origin or purity, can be used in the free state or immobilized on a support such as by trapping or physical adsorption. The microorganisms or enzymes suitable for use in the present invention can be selected by examining the desired activity, for example, by contacting a candidate microorganism or enzyme with a starting compound XXXIX or XLI or salt thereof, and noting the conversion to the compound XL or XLII corresponding or salt thereof. The enzyme may be, for example, in the form of plant or animal enzymes or mixtures thereof, cells of microorganisms, crushed cells, cell extracts, or of synthetic origin. Exemplary microorganisms include those within the genera: Streptomyces or Amycolatopsis. Particularly preferred microorganisms are those within the species Streptomyces griseus, especially Streptomyces griseus ATCC 10137, and Amycolatopsis orientalis such as ATCC 14930, ATCC 21425, ATCC 35165, ATCC 39444, ATCC 43333, ATCC 43490, ATCC 53550, ATCC 53630, and especially ATCC 43491. The term "ATCC" as used herein refers to the access number of the American Type Culture Collection, 10801 University BIvd., Manassas Virginia 20110-2209, the deposit for the referred organism. It should be understood that the mutants of these organisms are also contemplated by the present invention, for use in the methods described herein, such as those modified by the use of chemical, physical (for example, X-rays) or biological means (by example, molecular biology techniques). Preferred enzymes include those derived from microorganisms, particularly those microorganisms described above. Enzymes can be isolated, for example, by extraction and purification methods such as by methods known to those of ordinary skill in the art. An enzyme can be used, for example, in its free state or in immobilized form. One embodiment of the invention is that where an enzyme is adsorbed to a suitable carrier, for example, diatomaceous earth (Celita Hyflo? Upercel porous), microporous polypropylene (Enka Accurel® polypropylene powder), or a non-ionic polymeric adsorbent such as Amberlite® XAD-2 (polystyrene) or XAD-7 (polyacrylate) from Rohm and Haas Co. When used to immobilize an enzyme, a carrier can control the particle size of the enzyme and prevent the aggregation of the enzyme particles when used in an organic solvent. The immobilization can be carried out, for example, by precipitating an aqueous solution of the enzyme with cold acetone in the presence of Celite Hyflo ™ upercel followed by vacuum drying, or in the case of a non-ionic polymeric adsorbent, incubating the enzyme solutions with adsorbent in a shaker, removing the excess solution and drying the enzyme adsorbent resins under vacuum. While it is desirable to use the smallest amount of enzyme possible, the amount of enzyme required will vary depending on the specific activity of the enzyme used. Hydroxylation as described above can take place in vivo. For example, the liver enzyme may selectively hydroxylate, relative to the endo isomer, the exo ixomer of a compound of the present invention. In conducting the methods of the present invention outside the body, the microsomal hydroxylase of the liver can be used as the enzyme for catalysis. These processes can also be performed using microbial cells that contain an enzyme that has the ability to catalyze the conversions. When a microorganism is used to perform the conversion, these procedures are conveniently carried out by adding the cells and the starting material to the desired reaction medium. Where the microorganisms are employed, the cells can be used in the form of dry cells or intact moist cells such as heat-dried or spray-dried cells, lyophilized, or in the form of treated cellular material such as cell extracts or broken cells. . Extracts of immobilized cells in polypropylene from Celite® or Accurel as described above can also be employed. The use of genetically manipulated organisms is also contemplated. The host cell can be any cell, for example Escherichia coli, modified to contain a gene or genes to express one or more enzymes capable of performing the catalysis as described above. Where one or more microorganisms are employed, the enzymatic methods of the present invention can be carried out subsequent to the fermentation of the microorganism (conversion and two-step fermentation), or concurrently with it, that is, in the latter case, by conversion and fermentation in itself (conversion and single stage fermentation).

The growth of microorganisms can be achieved by one of ordinary skill in the art by the use of an appropriate medium. Suitable means for the growth of microorganisms include those which provide nutrients necessary for the growth of microbial cells. A typical growth medium includes carbon sources, nitrogen sources, and necessary elements (for example, in trace amounts). You can also add inductors. The term "inducer", as used herein, includes any compound that enhances the formation of the desired enzymatic activity within the microbial cell. The carbon sources may include sugars such as maltose, lactose, glucose, fructose, glycerol, sorbitol, sucrose, starch, mannitol, propylene glycol, and the like; organic acids such as sodium acetate, sodium citrate, and the like; and alcohols such as ethanol propanol and the like. Nitrogen sources may include NZ amine A, corn infusion liquor, soybean meal, beef extracts, yeast extracts, molasses, psmnification yeast, tryptone, nutrisoya, peptone, yeast amine, amino acids such as glutamate sodium and the like, sodium nitrate, ammonium sulfate and the like.

The trace elements may include salts of magnesium, manganese, calcium, cobalt, nickel, iron, sodium and potassium. The phosphates can also be added in traces or, preferably, greater than trace amounts. The medium employed may include more than one carbon or nitrogen source or another nutrient. Preferred means for growth include aqueous media. Agitation and aeration of the reaction mixture affects the amount of oxygen available during the conversion process when conducted, for example, in fermenting tanks or shake flask cultures during the growth of microorganisms. The incubation of the reaction medium is preferably at a temperature between about 4 and about 60 ° C. The reaction time can be appropriately varied depending on the amount of enzyme used and its specific activity. The reaction times can be reduced by increasing the reaction temperature and / or increasing the amount of the enzyme added to the reaction solution. It is also preferred to use an aqueous liquid as the reaction medium, although a miscible or immiscible aqueous / organic (biphasic) liquid mixture or an organic liquid may also be employed. The amount of enzyme or microorganism employed in relation to the starting material is selected to allow the catalysis of the enzymatic conversions of the present invention. The solvents for the organic phase of a biphasic solvent system can be any water-immiscible organic solvent, such as toluene, cyclohexane, xylene, trichlorotrifluoroethane and the like. The aqueous phase is conveniently water, preferably deionized water, or a suitable aqueous buffer, especially a phosphate buffer. The biphasic solvent system preferably comprises between about 10 to 90 volume percent of organic phase and between about 90 to 10 volume percent of aqueous phase, and more preferably contains about or volume percent of organic phase and of or about 80 volume percent of the aqueous phase. An exemplary embodiment of the processes starts with the preparation of an aqueous solution of the enzyme (s) or microorganisms to be used. For example, the preferred enzyme (s) or microorganisms can be added to a suitable amount of an aqueous solvent, such as phosphate buffer or the like. The mixture is preferably adjusted to and maintained at a desired pH. Compounds XL and XLII produced by the processes of the present invention can be isolated and purified, for example, by methods such as extraction, distillation, crystallization, and column chromatography. Other compounds of the formula I, such as the compounds where M is CR7R7 'or the compounds where one of M or M 'is different than a bond and E is CHR7, can easily be prepared by one of ordinary skill in the art, for example, by methods analogous to those described herein. Exemplary methods for the preparation of the compounds of formula II (employed in the above reaction schemes) are illustrated in the following reaction schemes 1 to 3.

Reaction scheme 1 As shown in reaction scheme 1, an ethyl glyoxylate derivative can be treated with saturated aqueous NH 4 Cl and the appropriate diene of formula A to produce the compound of formula II, where Q = H. Such cyclization can be improved by the addition of metal salts, such as, but not limited to, ytterbium trifluoromethanesulfonate (III), as described in the documents cited previously. An intermediate of formula II can be elaborated where Q? H, by means of protecting the secondary nitrogen with a protecting group such as BOC, followed by treatment with reactive intermediates of formula QX, where X represents a leaving group or X is an electrophilic center which can react to finally complete the definition of Q as described above, in the presence of a base, such as LDA, or a coupling agent as is already known to one skilled in the art, followed by deprotection of the BOC group with an acid such as saturated ethanolic HCl. Reaction scheme 2 As shown in reaction scheme 2 (with preferred conditions indicated therein), the commercially available chiral intermediary (D or L pure) N- (tert-butoxycarbonyl) -L-4-hydroxyproline, B, can be treated with a reducing agent, such as BH3"THF, to produce a primary alcohol, which can then be selectively protected with an agent such as TBSOTf, in the presence of a base (e.g., 2,6-lutidine), to provide the alcohol intermediary C. The secondary C alcohol can then be differentially protected by treatment with an agent such as TsCl, in the presence of a base (eg, pyridine), followed by deprotection of the primary alcohol (which can be achieved by treatment with an acid, such as para-toluenesulfonic acid), to provide the intermediate alcohol D. The resulting alcohol D can be oxidized, such as under standard Swern conditions, to provide the corresponding aldehyde intermediate E. The aldehyde intermediate E can be treated directly with tencylamine and diethyl cyanophophonate to produce intermediate F. Treatment of intermediate F with a base, such as Huning base, with heating, provides the bicyclic intermediate G. The treatment of G with a base, such as sodium methoxide, converts the nitrile intermediate G directly to the ester intermediate H. The treatment of the intermediate H with an agent to remove the benzyl group, such as palladium on carbon with hydrogen gas, results in the formation of an intermediate of Formula bundle where Q = Hydrogen. Alternatively, the intermediate of formula H can be treated with reactive intermediates of formula QX, where X represents a leaving group or X is an electrophilic center which can react to finally complete the definition of Q as described above, in the presence of a base, such as LDA, or a coupling agent as is already known to one skilled in the art, which, after treatment with an agent such as palladium on carbon, produces an intermediate of formula Ia where Q? H. The various intermediates of the reaction scheme 2 can be purified, for example, by purification of silica, or simply, for example, they can be brought into the next stage (for example, conversion of D or F without isolation of E). . The method of reaction scheme 2 is new, as are the intermediates prepared therein, all of which form a part of the present invention. Accordingly, for example, the following method is new as are the intermediates and individual steps produced therein (e.g., E, F, G, H, J, and lia): a method for the preparation of a compound of the following formula lia: where BOC is t-butoxycarbonyl; and Q is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl, arylalkyl or substituted arylalkyl, alkynyl or substituted alkynyl, aryl or substituted aryl, heterocycle or substituted heterocycle, halo, CN, R: 0C = 0, RJ3 = 0, R5R6NC = 0, HOCR7R7 ', nitro, R] 0CH2, l, NH2, C ^ OSR1, S0: R1 O NR4Rb; comprising the steps of (i) treating a compound of the following formula B: with a reducing agent to reduce the carboxylic acid group to hydroxymethyl, followed by the protection of the hydroxy to provide a compound of the following formula C: where Prol is a hydroxyl protecting group; (11) protecting the unprotected hydroxyl group of the compound of formula C, followed by deprotection of Prol-0- to form the hydroxyl, yielding a compound of the following formula D: D 0-Pro2 where Pro2 is a protecting group; (in) oxidizing the hydroxymethyl group of D, yielding an aldehyde of the following formula E: (iv) treating E with benzylamine and diethyl cyanophosphonate, yielding a compound of the following formula F: (v) treating the compound of the formula F with a base with heating to produce a compound of the following formula G: (vi) treating the compound of the formula G with a base to convert the nitrile group to methoxycarbonyl, yielding a compound of the following formula H: and (vii) removing the benzyl group of the compound of the formula H to form the compound of the formula lia, wherein, optionally, the compound of the formula H is contacted with a compound QX, where X is a leaving group or X is an electrophilic center, which can react to form a group Q, prior to the removal to form the compounds of the formula lia, where Q is different from hydrogen.

The method of reaction scheme 2 is especially useful for the preparation of non-natural amino acids, which can be employed, by methods analogous to those using the compounds of formula II, in the preparation of the present compounds of formula I.

Reaction scheme 3 As shown in Reaction Scheme 3 (with preferred conditions indicated therein), the intermediate imine activated M can be generated by the reactions of an isocyanate of activated sulphonyl such as isocyanate, p-toluenesulfonyl, with ethyl glyoxylate and heating . The imine M can be cyclized with an appropriate diene intermediate of formula A to produce an intermediate of formula II '. Such cyclization can be improved by the addition of metal salts, such as, but not limited to, ytterbium trifluoromethanesulfonate (III), as described in the references cited previously. The tosyl protecting group can be removed from intermediate II 'by a number of reagents, such as those known to one skilled in the art, such as hydrogen bromide in acetic acid, to provide an intermediate of formula II. The intermediate of formula II 'can be treated with reactive intermediates of formula QX, wherein X represents a leaving group or X is an electrophilic center which can react to ultimately complete the definition of Q as described earlier, in the presence of a base , such as LDA, or a coupling agent as is already known to one skilled in the art, to provide the intermediate of formula T. The tosyl protecting group can be removed from the intermediate T by a number of reagents known to one skilled in the art. technique, such as hydrogen bromide in acetic acid, to provide an intermediate of formula II, wherein Q? H.

Preferred Compounds A preferred subgenre of the compounds of the present invention includes the compounds of the formula I or salts thereof, wherein one or more, preferably all, of the following substituents are as defined below: G is an aryl group ( especially, phenyl or naphthyl) or heterocycle (e.g., heteroaryl), wherein the group is mono- or polycyclic, and which is optionally substituted at one or more positions, preferably hydrogen, C? _6 alkyl, alkyl substituted with one or more halogens (for example, perfluoroalkyl), heterocycle, alkyl, hydroxy substituted alkyl, substituted alkyl or alkyl, alkynyl, Cl, F, Br, I, CN, RJXYO, R1C = 0, R1HNC = 0, R1RNC = 0, H0CR3R3 ' , nitro, R-OCH :, RJD, NH2, NR ** R5,? R1,? ^ OR1, S0R1,? 02OR1, S02NR-R- ', (R)) (R1'?) P = 0, (R1 ) (R1 ') P = 0, or (R1') (NHR1) P = 0;E is C = Z_ > , CHR7,? O ?, P = OR2, or P = 00R2; Zi is 0, S, or NR6; Z2 is 0, S, or NR6; Ai is CR '(especially, CH); A2 is CR7 (especially CH); And it is J-J'-J "where J is (CR; R7 ') n and n = 0-2, J' is a bond or NH, NR6, C = 0, cycloalkyl (especially cyclopropyl or cyclobutyl), or cycloalkenyl (especially cyclobutenyl or cyclopentenyl), and J "is (CR7R7 ') nyn = l-2, where Y is not a bond; CRR7'-CRR7 ', CRR = CRT #, CRV-C = 0, NR9-CR7R7', cycloalkyl (especially cyclopropyl or cyclobutyl) or cycloalkenyl (especially cyclobutenyl or cyclopentenyl); Q is H, C? -6 alkyl , alkyl substituted with one or more halogens (for example, perfluoroalkyl), alkyl C? -6 substituted with hydroxy, alkenyl (for example, aillo), alkynyl, Cl, F, Br, I, aplaxyl (for example, benzyl) or substituted arylalkyl, CN, R1OC = 0, RJ 0, R5RGNC = 0, H0CR7R7 ', R ^ CH;, Rx0, NH ?, or NR4R5; M is a link or NR10, and M 'is a bond or NR10, with the proviso that at least one of or M' must be a bond; L is a bond, (CR7R7 ') n, NH, or R5 where n = 0-l; R1 and R1 'are each independently H, alkyl, perfluoroalkyl, cycloalkyl, heterocycle, cycloalkylalkyl, or heterocycloalkyl; R 2 is alkyl, perfluoroalkyl, cycloalkyl, heterocycle, cycloalkylalkyl, or heterocycloalkyl; R3 and R3 'are each independently H, alkyl, perfluoroalkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocyclealkyl, Cl, F, Br, I, CN, alkoxy, amino, NRXRY thiol, or alkylthio; R is H, alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, R1C = 0, R1NHC = 0, or SOJSFR-V; R5 is alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, R1C = 0, R1NHC = 0, SOsOR1, or S02NR: R; R6 is alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, cycloalkylalkyl or substituted cycloalkylalkyl, heterocycloalkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, CN, OH, OR1, R1C = 0, R1NHC = 0 ,? O? OR1, or? OJft'JR1 '; R7 and R7 'are each independently H, alkyl, perfluoroalkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, aryl, arylalkyl, Cl, F, Br, I, CN, OR1, nitro, hydroxylamine, hydroxylamide, amino, NHR * 5, NR2R5, NOR1, thiol, alkylthio, R1C = 0, R1NHC = 0, O? 02NR1R1 '; R8 and Rfi 'are each independently H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, halo, CN, OR1 , amino, NHR4, NR2R5, ÑOR1, alkylthio or substituted alkylthio, R: C = 0, R1NHC = 0,? 02OR1, O? 02NR1R1 '; R9 and R9 'are each independently H, alkyl, alkenyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, aryl, arylalkyl, C ?, OH, OR1, R10 is H, alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, aryl, arylalkyl , C ?, OH, OR1, RxC = 0, RxOC = 0, R ^ '? C),? 02OR1, or S0? R1R1'. A more preferred subgenus of the compounds of the invention includes the compounds of formula I or salts thereof wherein one or more, preferably all, of the following substituents are as defined below: G is an aryl or heteroaryl group, wherein the group is mono- or polycyclic, and which is optionally substituted in one or more positions with hydrogen, C1-3 alkyl, allyl or substituted allyl, alkynyl, Cl, F, Br, I, C ?, R1C = 0, R ^? C ^ 0, R "" R2? C = 0, haloalkyl (especially, perfluoroalkyl), hydroxyalkyl of C1-C3, HOCR3R3 ', nitro, R ^ CH ?, R20,? R "R5, O? R1; is C = Z2, CHR7 or? 02; ZI is O,?, or? C ?; Z2 is O,?, or? C ?; Aj is CR7 (especially, CH); A2 is CR7 (especially CH); Y is J, cyclopropyl, or cyclobutyl, where J = (CR7R7 ') n and n = l-3; W is CR7R7'-CR7R7 ', CR8 = CR8', CR7R7'-C = 0, cyclopropyl, or cyclobutyl; Q is hydrogen, C? - alkyl, alkynyl, Cl, F, Br, I, CN, R0C = 0, R4C = 0, R5R6NC = 0, haloalkyl (especially, perfluoroalkyl), hydroxyalkyl of Ci-Ce, HOCR7R7 ', R-OCH, R-O, NH2, or NR4R5; M is a link and 'is a link; L is a bond, (CR7R7 ') n, NH, or NR5, where n = 0-l; R1 and R1 'are each independently H, alkyl, cycloalkyl, heterocycloalkyl, or perfluoroalkyl; R2 is alkyl, cycloalkyl, heterocycloalkyl, or perfluoroalkyl; R3 and R3 'are each independently H, alkyl, perfluoroalkyl, Cl, F, Br, I, CN, alkoxy, amino, NR1Ri, thiol, or alkylthio; Rq is H, alkyl, cycloalkyl, heterocycloalkyl, R1C = 0, R1NHC = 0, SO ^ OR1, or? O-NR ^ 1 '; R is alkyl, cycloalkyl, heterocycloalkyl, R1C = 0, R1NHC = 0,? OpOR1, or? 02NR-R1 '; R7 and R "are each independently H, alkyl, arylalkyl, heteroaryl, perfluoroalkyl, heteroarylalkyl, Cl, F, Br, I, CN, OR1, amino, NHR4, NR2R5, NOR1, thiol, alkylthio, R1C = 0, R ^ HC ^ O,? 02ORJ or S02NR1R1 '; and R10 is H, alkyl, cycloalkyl, heterocycloalkyl (especially, heteroarylalkyl), aryl, heteroaryl (such as heteroaryl), arylalkyl, CN, R1C = 0, Another most preferred subgenus of the compounds of the invention includes the compounds of the formula I or salts thereof, wherein one or more, preferably all, of the following substituents are as defined below: G is an aryl or heteroaryl group, where the group is mono- or polycyclic, and which is optionally substituted at one or more positions with hydrogen, C1-3 alkyl, allyl or substituted allyl, alkynyl, Cl, F, Br, I, CN, R ^ O, R'HNC = 0, haloalkyl (especially, perfluoroalkyl), hydroxyalkyl Ci-Cj, HOCR R, nitro, R ** OCH, -, R "" 0, NRV, O? R1; E is C = Z2; Zi is O; Z2 is O or NCN; Ai is CR7 (especially, CH); A2 is CR7 (especially CH); Y is J, where J = (CR7R7 ') n and n = l-3; W is CRR7'-CR7R7 ', CR8 = CR8', or CR7R7'-C = 0; Q is hydrogen, C? -4 alkyl, alkyl, Cl, F, Br, I, CN, R4C = 0, R5R6NC = 0, haloalkyl (especially, perfluoroalkyl), hydroxy alkyl of C? -C6, HOCR R, RkX? 2, R-O, NH2, or NR4R5; M is a link and M is a link; L is a link; R1 and R1 'are each independently H, alkyl, or perfluoroalkyl; R2 is alkyl, or perfluoroalkyl; R3 and R3 'are each independently H, alkyl, perfluoroalkyl, Cl, F, Br, I, CN, alkoxy, amino, NR "2R2, thiol, or alkalithium; R4 is H, alkyl, R ^ O, R1NHC = 0 , or S02NR1R1 '; R5 is alkyl, R1C = 0, R1NHC = 0, or SOJNRV; R' and R "" are each independently H, alkyl, aplakyl, heteroaryl, perfluoroalkyl, heteroarylalkyl, Cl, F, Br, I, CN, OR1, amino, NHR4, NR2R ÑOR1, R] C = 0, R1NHC = 0, or? 02NR1R1 '; and R10 is H, alkyl, aplo, heteropole, aplakyl, heteroarylalkyl, CN, R1C = 0, R1R1'NC = 0, O? 02NR1R1 '. A particularly preferred subgenus of the compounds of the invention includes the compounds of the formula I or salts thereof, wherein one or more, preferably all, of the substituents are as defined below. An aryl group (especially phenyl or naphthyl) or heterocycle (especially benzo-fused heterocycle groups such as indole, benzothiophene, benzothiazole, benzothiadiazole, benzisoxazole, benzoxadiazole, oxidobenzothiophene, benzofuran or benzopyran), where the group is mono- or polycyclic, and which is optionally substituted in one or more positions, such as 1 to 5 positions (preferably 1 to 2 positions), with substituents selected from one or more of hydrogen, NH 2, alkyl (especially having 1 to 4) carbons) or substituted alkyl (especially having 1 to 4 carbons and substituted with halo, such as the substituted alkyl group CF3), halo (especially F, Cl, Br or I), heterocycle (such as tetrazole or oxazole), CN, nitro,? R1 or RL0 (especially where R1 is alkyl); E is C = Z; or CHR7 (especially where R 'is hydrogen); Zi is O or S; Z2 is 0,?, Or NR6 (especially where R6 is CN or phenyl); i is CR7 (especially where R 'is hydrogen); A2 is CR7 (especially where R7 is hydrogen); Y is (CR7R7 ') n and n = l-2 (especially where R7 and R7' are hydrogen); W is CR7R7'-CR7R7 ', CR8 = CRB', or NR9-CR7R7 '(especially where R7, R7', R8 and Rn 'are hydrogen and R9 is as defined in this preferred subgenus); Q is H, alkyl (especially having 1 to 4 carbons), alkenyl (especially having 1 to 4 carbon atoms), arylalkyl (especially benzyl) or substituted arylalkyl (especially substituted benzyl, such as benzyl substituted with halo); M is a bond or NH (especially a bond), and M 'is a bond; L is a link; R1 and R1 'are each independently alkyl (especially having 1 to 4 carbons) or substituted alkyl (especially having 1 to 4 carbons and substituted with halo), heterocyclo (such as imidazole or isoxazole) or substituted heterocyclo (such as imidazole substituted with methyl), aryl (especially phenyl), or substituted aryl (especially phenyl substituted with one or more of halo, nitro, alkyl substituted with halo such as CF3, or alkyl having 1 to 4 carbons), arylalkyl (especially benzyl or phenethyl) or substituted arylalkyl (especially substituted benzyl such as benzyl substituted with nitro and / or halo); and R9 and R9 'are each independently H, alkyl (especially having 1 to 4 carbons), alkenyl (especially having 1 to 4 carbons), arylalkyl (especially benzyl), R1C = 0, R10C = 0, R1NHC = 0, or SO2OR1 (especially where each R1 is independently as defined in this preferred subgenre).

In this particularly preferred subgenus, GL-can be, for example, an optionally substituted bicyclic fused heterocyclic group or optionally substituted naphthyl such as an optionally substituted benzo-fused heterocyclic group (e.g., linked to the remainder of the molecule through the benzene), especially such a group wherein the heterocyclic ring linked to benzene has 5 elements and is employed by benzoxazole, benzothiazole, benzothiadiazole, benzoxadiazole or benzothiophene, for example: where X is halo (especially Cl), OH, CN, N02 or '(by «j U is O or? (where S can optionally be oxygenated, for example, to SO); U1 is CH3 O CF3; each U "is independently N, CH or CF; Uj is N, O or?; U4 and u'J together with the atoms to which they are linked, form an optionally substituted 5-membered heterocyclic ring, which may be aromatic or partially unsaturated and which contains 1 to 3 heteroatoms in the ring, each U6 is independently CH or N, and fP) denotes optional double bond (s) within the ring formed by UJ, U4 and U5 Especially preferred are compounds of formula I which have the following structure, or salts thereof: where R9 and U "are as defined above, such as optionally substituted arylcarbonyl or optionally substituted aryloxycarbonyl, and Xd is an aryl substituent, such as nitro. Also especially preferred are compounds of formula I having the following structure or salts of the same : where n e s 1 or 2; Q is H, methyl or ethyl; each Ga is independently CN, N0¿, CF3, Cl, Br, F, OCH3, SCH3, I, CH3, C (0) -CH3 or - ^ j¡. ' GD is CN, H, F, Br, N02 or ^; VN Gc is CH or N; Gd is it? u 0; Ge is H or F; Rices - (,? - F. "- í -F; and 1 ** -CHa, or * CF, Uses and Utility The compounds of the present invention modulate the function of nuclear hormone (RHN) receptors, and include compounds which are for example, agonists, partial agonists, antagonists or antagonists. partial effects of the androgen receptor (AR), the estrogen receptor (ER), the progesterone receptor (RP), the glucocorticoid receptor (GR), the mmeralocorticoid receptor (MRI), the steroid and xenobiotic receptor (REX) , another RHN binding to the steroid, Orfan receptors or other RHNs. The selective modulation of such RHN is preferred over others within the RHN family. "Modulation" includes for example, activation (e.g., agonist activity such as selective androgen receptor agonist activity) or inhibition (e.g., antagonistic activity). The present compounds are thus used in the treatment of conditions associated with the RHN. A "condition associated with the RHN" as used herein, denotes a condition or alteration which can be treated by modulating the function of an RHN in a subject, wherein the treatment comprises prevention (eg, prophylactic treatment), partial relief or cure of the condition or alteration. Modulation may occur locally, for example, within certain tissues of the subject, or more extensively through a subject being treated for such a disorder or condition. The compounds of the present invention are used for the treatment of a variety of conditions and alterations including, but not limited to, those described below: The compounds of formula I can be applied as agonists, partial agonists, antagonists, or partial antagonists of the estrogen receptor, preferably selectively to such a receptor, in an array of medical conditions which involve modulation of the estrogen receptor path. Applications of such compounds include but are not limited to: osteoporosis, hot flashes, vaginal dryings, prostate cancer, breast cancer, endometrial cancer, cancers that express the estrogen receptor such as the cancers mentioned above and others, contraception, pregnancy, menopause, amenorrhea, and dysmenorrhea. The compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the progesterone receptor, preferably selectively to such receptor, in an array of medical conditions which involve modulation of the path of the progesterone receptor. . Applications of such compounds include but are not limited to: breast cancer, other cancers that contain the progesterone receptor, endometriosis, cachexia, contraception, menopause, cycle synchrony, meniginoma, dysmenorrhea, fibroids, pregnancy termination, induction of childbirth and osteoporosis. The compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the glucocorticoid receptor, preferably selectively to such receptor, in an array of medical conditions, which involve the modulation of the path of the glucocorticoid receptor. . Applications of such compounds include but are not limited to: inflammatory diseases, autoimmune diseases, prostate cancer, breast cancer, Alzheimer's disease, psychotic disease, drug dependence, non-insulin-dependent Diabetes Mellitus, and co-agents blocking the dopamine receptor or otherwise as agents for the treatment of disorders mediated by the dopamine receptor. The compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the mineralocorticoid receptor, preferably selectively to such receptor, in an array of medical conditions which involve the modulation of the trajectory of the mmeralocorticoid receptor. Applications of such compounds include but are not limited to: drug withdrawal syndrome and inflammatory diseases. The compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the aldosterone receptor, preferably selectively to such a receptor, in an array of medical conditions which involve modulation of the aldosterone receptor path. An application of such compounds includes but is not limited to: congestive heart failure. The compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the androgen receptor, preferably selectively to such a receptor, in an array of medical conditions which involve modulation of the path of the androgen receptor. Applications of such compounds include but are not limited to: hirsutism, acne, seborrhea, Alzheimer's disease, androgenic alopecia, hypogonadism, hyperpilosity, benign prostate hypertrophy, prostate adenomas and neoplasms (such as advanced metastatic prostate cancer), treatment of benign or malignant tumor cells containing the androgen receptor, as is the case for cancers of the breast, brain, skin, ovary, bladder, lymphatic, liver and kidney, modulation of pancreatic cancers of the VACM expression and applications here for the treatment of heart diseases, modulations of inflammation and immune, modulation of VEGF expression and the applications here for use as antiangiogenic agents, osteoporosis, suppression of spermatogenesis, libido, cachexia, endometriosis, polycystic ovary syndrome, anorexia, androgen supplementation for decreased testosterone levels related to age in men, female menopause, male hormone replacement, male and female sexual dysfunction, and inhibition of muscle atrophy in ambulatory patients. For example, pan AD modulation, with modulation of prostate selective RA ("MRAS") is contemplated to be particularly preferred, such as for the treatment of early stage prostate cancers. The compounds of formula I can be applied as (preferably, selective) antagonists of the mutated androgen receptor found in many tumor lines. Examples of such mutants are those found in representative prostate tumor cell lines, such as LNCap, (mutation T877A, Biophys Act., 187, 1052 (1990)), PCa2b, (L701H & amp; amp;; T877A, J. Urol., 162, 2192 (1999)) and CWR22, (mutation H874Y, Mol.Endo., 11, 450 (1997)). Applications of such compounds include but are not limited to: adenomas and neoplasms of the prostate, breast cancer and endometrial cancer. The compounds of formula I can be applied as agonists, partial agonists, antagonists or partial antagonists of the steroid and xenobiotic receptor, preferably selectively to such a receptor, in an array of medical conditions which involve the modulation of the path of the receptor. steroid and xenobiotic. The applications of said compounds include but are not limited to: treatment of the deregulation of cholesterol homeostasis, attenuation of the metabolism of pharmaceutical agents by co-administration of an agent (compound of the present invention), which modulates the regulatory effects of SRX P450. Together with the RHNs mentioned above, there is also a number of RHNs for which the activation or deactivation of ligands can not be characterized. These proteins are classified as RHN due to the strong sequence homology to the other RHNs, and are known as the Orphan receptors. Because Orphan receptors demonstrate strong sequence homology to other RHNs, compounds of formula I include those which serve as modulators of the function of RHN Orfano. The Orfano receptors which are modulated by the RHN modulators such as compounds within the scope of formula I, are exemplified but not limited to those listed in Table I. The exemplary therapeutic applications of Modulars of said Orphan receptors are also listed in Table I, but are not limited to the examples in this document.

Table 1. Receptors of the exemplary Orfano nuclear hormone, form (M = monomeric, D = heterodimeric, H = homodimeric), tissue expression and target therapeutic applications. (CN? = Central nervous system).

Receptor Form Tissue Expression Therapeutic Application Objective NURRI M / D Parkinson's Neurons Dopaminergic RZRß M Brain (pitutapa), Lung Disorder muscle ZORa M Cerebellum, Arthritis Cells, Purkmje Ataxia Cerebellum NOR-1 M Brain, Muscle, CNS Disorder, Cancer Heart, adrenal, Thymus NGFI-Bß M / D Brain CN Disorder? COUP-Tfa H Brain Disorder CNS COUP-TFß H Brain Disorder CNS COUP-TF ?? H Brain Disorder CNS Nur77 H Brain, Thymus, Disorder CNS Adrenal Rev-ErbAa H Muscle, Brain Obesity (Ubicuitos) HNF4a H Liver, Kidney, Intestine Diabetes? F-1 M Gonada, Pituitaria Metabolic Disorder LXRa, ß D Kidney (Ubiquitous) Metabolic Disorder GNCF M / H Testa, Ovarian Infertility ERRa, ß M Placenta, Infertility Marrow, Osteoporosis FXR D Liver, Kidney Metabolic Disorder CARa H Liver, Kidney Metabolic disorder PXR H Liver, Bowel Metabolic disorder The present invention thus provides methods for the treatment of conditions associated with the RHN, which include the step of administering a subject in need thereof to minus a compound of the formula I in an effective amount of the same. Other therapeutic agents such as those described below can be used with the compounds inventive in the present methods (for example, separately, or formulated together as a fixed dose). In the methods of the present invention, some other therapeutic agent (s) can be administered before or simultaneously with or following the administration of the compounds of the present invention. The present invention also provides pharmaceutical compositions comprising at least one of the compounds of formula I capable of treating a condition associated with RHN in an amount associated therewith and a pharmaceutically acceptable carrier (vehicle or diluent). The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, using conventional diluents or liquid or solid carriers, as well as pharmaceutical additives of a type appropriate for the desired mode of administration (e.g. , excipients, binders, preservatives, stabilizers, flavoring, etc.) in accordance with techniques such as those known in the art of a pharmaceutical formulation. It should be noted that the compounds of the present invention are, without limitation to their mechanism of action, used in the treatment of any of the conditions or disorders listed or described herein such as inflammatory diseases or cancers, or other proliferative diseases, and in compositions for treating such conditions or disorders.

Such conditions or disorders include, without limitation, any of those previously described, as well as those described hereinafter as: maintenance of muscle tension and function (for example in advanced age); investment or prevention of age-related functional weakness or decline ("BFRA") in later life (eg, sarcopenia); treatment of catabolic side effects of glucocorticoids; prevention and / or treatment of reduced bone mass, density or growth (for example, osteoporosis and osteopenia); treatment of chronic fatigue syndrome (CFS); chronic malagia; treatment of acute fatigue syndrome and muscle loss after selective surgery (for example, post-surgical rehabilitation); acceleration of wound healing; acceleration of bone fracture repair (such as acceleration of recovery of patients with hip fracture); Acceleration of healing of complicated fractures, for example, distraction of osteogenesis; in replacement of joints; prevention of post-surgical adhesion formation; Acceleration of the repair or growth of teeth; maintenance of sensory function (for example, hearing, sight, smell and taste); treatment of periodontal diseases; treatment of secondary wear to fractures and wear in conjunction with chronic obstructive pulmonary disease (COPD), chronic liver diseases, AIDS, weight loss, cancer cachexia, recovery from burns and trauma, chronic catabolic state (eg, coma), eating disorders (eg, anorexia) and chemotherapy; cardiomyopathy treatment; treatment of thrombocytopenia; treatment of growth retardation in conjunction with Crohn's disease; treatment of short bowel syndrome; treatment of irritable bowel syndrome; treatment of inflammatory bowel disease; treatment of Crohn's disease and ulcerative colitis; treatment of complications associated with transplantation; treatment of short psychological stature including growth hormone deficiency in children and short stature associated with chronic diseases; treatment of obesity and growth retardation associated with obesity; treatment of anorexia (for example, associated with cachexia or aging); treatment of hypercortisolism and Cushing's syndrome; Paget's disease; osteoartptis treatment; induction of pulsatile growth hormone release; treatment of osteochondrodysplasias; treatment of depression, nervousness, irritability and tension; treatment of reduced mental energy and self-esteem ba (for example, motivation / assertiveness); improvement of cognitive function (for example, the treatment of dementia, which includes Alzheimer's disease and short-term memory loss); treatment of catabolism in conjunction with pulmonary dysfunction and respiratory dependence; treatment of cardiac dysfunction (eg, associated with valve disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); decrease in blood pressure; protection against ventricular dysfunction or prevention of reperfusion events; treatment of adults on chronic dialysis, reversal or decrease in the catabolic state of aging; attenuation or reversal of protein catabolic responses after trauma (eg, reversal of the catabolic state associated with surgery, congestive heart failure, cardiac myopathy, burns, cancer, COPD, etc.); reduction of cachexia and loss of protein due to chronic diseases such as cancer or AIDS; treatment of hyperinsulidemia that includes nesidioblastosis; treatment of immunosuppressed patients; wear treatment in conjunction with multiple sclerosis or other neurodegenerative diseases; promotion of the repair of myelin; maintenance of the thickness of the skin; treatment of metabolic homeostasis and renal homeostasis (for example, in the weak elderly); osteoblast stimulation, bone remodeling and cartilage growth; regulation of food absorption; insulin resistance treatment, including NIDDM, in mammals (e.g., humans); treatment of insulin resistance in the heart; improvement of sleep quality and correction of relative hyposomatotropism of senescence due to the high increase in REM sleep and a decrease in REM latency; hypothermia treatment; treatment of congestive heart failure; lipodystrophy treatment (for example, in patients taking HIV or AIDS therapies such as protease inhibitors); treatment of muscular atrophy (for example, due to physical inactivity, rest or reduced weight pressure conditions); treatment of musculoskeletal impairment (for example in advanced age); improvement of total lung function; treatment of sleep disorders; and the treatment of the catabolic state of prolonged critical illnesses; treatment of hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, benign prostate hypertrophy, adenomas and neoplasms of the prostate (for example, advanced metastatic prostate cancer) and malignant tumor cells containing the androgen receptor, such as it is the case for cancers of breast, brain, skin, ovary, bladder, lymphatic, liver and kidney; cancers of the skin, pancreas, endometrium, lung and colon; osteosarcoma; hypercalcemia of diseases; metastatic bone disease; treatment of spermatogenesis, endometriosis and polycystic ovarian syndrome; preeclampsia against acting, pregnancy eclampsia and preterm delivery; treatment of menstrual syndrome; vaginal dryness treatment; Decreased testosterone levels in men related to age, male menopause, hypogonadism, male hormone replacement, male and female sexual dysfunction (eg, erectile dysfunction, decreased sex drive, sexual well-being, decreased libido), male contraception and female, hair loss, Reaven syndrome, and the improvement of bone / muscle strength / resolution; and the conditions, conditions and diseases collectively referred to as "Syndrome X" or Metabolic Syndrome as detailed in Johannsson J. Clin. Endocpnol. Metab., 82, 727-34 (1997). The present compounds have therapeutic utility in the modulation of immune cell activation / proliferation for example, as competitive inhibitors of ligand / cell-receptor receptor reactions involving CAM? (Molecules of Cell Adhesion) and Leucointegpnas. For example, the present compounds modulate LFA-ICAM 1, and are particularly useful as LFA-ICAM 1 antagonists, and in the treatment of all conditions associated with LFA-ICAM 1 such as immunological disorders. Preferred utilities for the present compounds include but are not limited to: inflammatory conditions such as those resulting from a non-specific immune system response in a mammal (e.g., adult respiratory distress syndrome, stroke, oxygen toxicity, multiple organ injury, secondary to septicemia, organ multiple injury syndrome secondary to trauma, tissue reperfusion injury, due to bypass or cardiopulmonary bypass, myocardial infarction or use with thrombolysis agents, acute glomerulonephritis, vasculitis, reactive arthritis, dermatoses with acute inflammatory components, apoplexy, thermal lesion, hemodialysis, leukapheresis, ulcerative colitis, necrotizing enterocolitis and syndrome associated with granulocyte transfusion) and conditions that result from a specific immune system response in a mammal (eg, psoriasis, rejection of organ transplant / t ejido), graft-versus-host reactions and autoimmune diseases including Raynaud's syndrome, autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, uveitis, inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis , and systemic lupus erythematosus). The present compounds can be used in the treatment of asthma or as an adjunct to minimize toxicity with cytokine therapy in the treatment of cancers. The present compounds can be used in the treatment of all diseases currently treatable through spheroidal therapy. The present compounds can be used for the treatment of these and other diseases alone, or with other immunosuppressive or antiflamatory inflammatory agents. According to the invention, a compound of the formula I can be administered prior to the onset of inflammation (in order to suppress an anticipated inflammation) or after the onset of inflammation. When provided prophylactically, the immunosuppressive compound (s) are preferably provided in advance of any inflammatory response or symptom (e.g., prior to, or shortly after the time of an organ or tissue transplant, but in advance of any of the symptoms or organ rejection). Prophylactic administration of a compound of formula I prevents or attenuates any subsequent inflammatory response (such as, for example, rejection of transplanted organs or tissues, etc.). Administration of a compound of formula I attenuates any current state of inflammation (such as, for example, the rejection of a transplanted organ or tissue). The compounds of the formula I can be administered by any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders.; sublingually; buccally parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation atomization; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing pharmaceutically acceptable, non-toxic vehicles or diluents. The present compounds can, for example, be administered in a form suitable for immediate release or prolonged release. Immediate release or prolonged release can be achieved by the use of pharmaceutical compositions comprising the present compounds or, particularly in the case of prolonged release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomally. Exemplary compositions for oral administration include suspensions which may contain for example, microcpstamma cellulose for volume imparting, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity improver, and sweetening or sabotating agents such as those known in the art; and immediate release tablets which contain for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants, such as those known in the art. The compounds of formula I can also be delivered through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets or dehydrated tablets by freezing are exemplary forms which can be used. Exemplary conditions include those which formulate the present compounds with the rapidly dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion, such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (? CMC), maleic anhydride copolymers (eg Gantrez), and release controlling agents as a polyacrylic copolymer (for example, Carbopol 934). Lubricants, binders, flavorings, colorants and stabilizers can also be added for ease of manufacture and use. Exemplary compositions for administration by inhalation or nasal spray include solutions in saline, which may contain for example, benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, and / or other solubilizing or dispersing agents such as those known in the technique. Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butane, water, Ringer's solution, a chloride solution. isotonic sodium, or other suitable dispersing agents or humectants and suspension including synthetic mono- or di-glycends and fatty acids, including oleic acid or Cremafor. Exemplary compositions for rectal administration include suppositories which may contain for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene). The effective amount of a compound of the present invention can be determined by one of ordinary skill in the art., and includes exemplary dosage amounts for a human adult from about 1 to 100 (e.g., 15) mg / kg body weight of the active compound per day, which may be administered in a single dose or in the dosage form individual divided, such as 1 to 4 times per day. It will be understood that the specific dose level and dosage frequency of any particular subject can be varied, depending on a variety of factors including the activity of the specific compound employed, the metabolic stability and the length of action of such a compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, combination of drug and severity of the particular condition. Preferred subjects for treatment include animals, more preferably mammalian species such as humans and domestic animals such as dogs and cats, and the like, subject to conditions associated with RHN. As mentioned above, the compounds of the present invention can be used alone or in combination with each of the other and / or suitable therapeutic agents employed in the treatment of conditions associated with RHN, for example, an antibiotic or other pharmaceutically material active. For example, the compounds of the present invention can be combined with agents that promote development, such as but not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, prostaglandins, senes E, compounds described in U.S. Patent No. 3,239,345, for example. , zeranol, and compounds described in U.S. Patent No. 4,036,979, for example, sulbenox or peptides described in U.S. Patent No. 4,411,890. The compounds of the invention can also be used in combination with growth hormone secretagogues such as GHRP-6, GHRP-1 (as described in U.S. Patent No. 4,411,890 and publications WO 89/07110 and WO 89/07111 ), GHRP-2 (as described in WO 93/04081), NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck) CP424391 (Pfizer) and B-HT920, or with the release factor of the growth hormone and its analogs or growth hormone and its analogues or somatomedins including IGF-1 and IGF-2, or with alpha-adrenergic agonists, such as clonidine agonists or serotonin 5-HTD, such as sumatriptan, or agents which inhibit somatostatma or its release, such as physostigmine and pipdostigmin. A still further use of the disclosed compounds of the invention is in combination with the parathyroid hormone, PTH (1-34) or bisphosphonates, such as MK-217 (alendronate). A still further use of the compounds of the invention is in combination with estrogen, testosterone, a selective estrogen receptor modulator, such as tamoxifen or raloxifen, and other modulators of the androgen receptor, such as those described in Edwards. J. P. et al., Bio. Med. Chem. Let. , 1003-1008 (1999) and Hamann, L. G. et al., J. Med. Chem. , 42, 210-212 (1999). A further use of the compounds of this invention is in combination with progesterone receptor agonists ("ARP"), such as levonorgestrel, medroxyprogesterone acetate (AMP). The compounds of the present invention may be employed alone or in combination with each of the other and / or other modulators of nuclear hormone receptors or other suitable therapeutic agents used in the treatment of the aforementioned disorders including: anti-aging agents -diabetics; anti-osteoporosis agents; anti-obesity agents; anti-mflamatory agents; anti-anxiety agents; anti-depressants; anti-hypertensive agents; anti-platelet agents; anti-thrombotic and thrombolytic agents; cardiac glycosides; cholesterol / lipid lowering agents; mineralocorticoid receptor antagonists; Phosphodiesterase inhibitors; inhibitors of the protein tyrosine kinase; thyroid simulators (which include thyroid receptor agonists); anabolic agents; therapies for HIV or AIDS; therapies used in the treatment of Alzheimer's disease and other cognitive disorders; therapies used in the treatment of sleep disorders; anti-proliferative agents; and anti-tumor agents. Examples of suitable antidiabetic agents for use in combination with the compounds of the present invention include biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins (including insulin secretagogues or sensitizer), meglitinides ( for example, rapaglinide), sulfonylureas (eg, glimepipda, glibupda, and glipizide), biguanide / glyburide combinations (eg, Glucovance®), thiazolidinediones (eg, troglitazone, rosiglitazone, and pioglitazone), PPAR-alpha agonists, PPAR- agonists gamma, alpha dual agonists / PPAR range, SGLT2 inhibitors, glycogen phospho-plasase inhibitors, fatty acid binding protein (aP2) inhibitors, such as those described in US Patent No. 09 / 519,079 filed March 6 of 2000, glucagon-like peptide-1 (GLP-1), and inhibitors of dipeptidyl peptidase IV (DP4). Examples of anti-osteoporosis agents suitable for use in combination with the compounds of the present invention include alendronate, psedronate, PTH, PTH fragment, raloxifene, calcitonin, spheroidal or non-spheroidal progesterone receptor agonists, RANK ligand antagonists, antagonists of the calcium sensitization receptor, TRAP inhibitors, selective estrogen receptor modulators (MRES), estrogen and AP-1 inhibitors. Examples of anti-obesity agents suitable for use in combination with the compounds of the present invention include aP2 inhibitors, such as those described in U.S. Patent Serial No. 09 / 519,079 filed March 6, 2000, PPAR range antagonists, delta agonists PPAR, beta 3 adrenergic agonists, such as AJ9677 (Takeda / Dimppon), L750355 (Merck), or CP331648 (Pfizer) or other beta 3 agonists known as described in U.S. Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5 , 48,064, a lipase inhibitor, such as orlistat or ATL-962 (Alyzima), a reuptake inhibitor of serotonin (and dopamma), such as sibutramine, topiramate (Johnson &Johnson) or axocin (Regeneron), a beta-receptor drug of the thyroid, such as a thyroid receptor ligand, as described in WO 97/21993 (U. Cal SF), WO 99/00353 (KaroBio) and GB98 / 284425 (KaroBio), and / or anorectic agent, such as dexamfetamine, fentermma, f enilpropanolamma or mazindol. Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include prednisone, dexamethasone, Enbrel®, cyclooxygenase inhibitors (i.e., COX-1 and / or COX-2 inhibitors such as N? AID, aspirin, indomethacin, ibuprofen, piroxicam, NaproxenT, Celebrex®, Vioxx®), CTLA4-Ig agonists / antagonists, CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate integrin antagonists (CellCept®), alpha integrin antagonists -4 beta-7, inhibitors of cell adhesion, gamma-interferon antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists, (for example, mfliximab, OR1384), inhibitors of prostaglandin synthesis, dubesonide, clofazimma , CNI-1493, CD4 antagonists (eg, proliximab), inhibitors of mitogen-activated protein kinase? 38, protein tyrosine kinase (PTC) inhibitors, IKK inhibitors, and therapies for the treatment of irritable bowel syndrome (e.g., Zelmac® and Maxi-KT openers, such as those described in U.S. Patent No. 6,184,231 Bl) . Examples of anti-anxiety agents suitable for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam and hydroxymamo pamoate. Examples of suitable anti-depressants for use in combination with the compounds of the present invention include citalopram, fluoxetham, nefazodone, sertraline and paroxetine. Examples of antihypertensive agents suitable for use in combination with the compounds of the present invention include beta-adrenergic blockers, calcium channel blockers (Type L and T type).; for example, diltiazem, verapa ilo, nifedipmo, amlodinipo and mibefradilo), diuretics (for example, chlorothiazide, chlorhydrothiazide, flumetiazide, hydroflumetiazide, bendroflumetiazide, methylchlorothiazide, tpclorometiazide, politiazide, benzthiazide, etacpnico and tpcpnafeno, chlortalidone, furosemide, musolimine, bumetamdo, triamtrenene, amilopdo, spironolactone), renin inhibitors, ACE inhibitors (for example, captopplo, zofenoplo, fosmopplo, enalapplo, ceranopril, cilazoplo, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (for example , losartan, ibesartan, valsartan), ET receptor antagonists (eg, sitaxsentan, atraxsentan and compounds described in U.S. Patent Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds described in WO 00 / 01389), neutral endopeptidase (EPN) inhibitors, vasopeptidase inhibitors (dual EPN-ACE inhibitors) (eg, or mapatrilat and gemopatrilat), and nitrates. Examples of anti-platelet agents suitable for use in combination with the compounds of the invention include, GPIIb / IIIa blockers (eg, abciximab, eptifibatide, tirofiban), P2Y1 antagonists (eg, clopidogrel, ticlopidma, CS-747), antagonists of the thromboxane receptor (e.g., ifetroban), aspirin, and PDE-III inhibitors (e.g., dipyridamole) with or without aspirin. Examples of cardiac glycosides suitable for use in combination with the compounds of the present invention include digitalis and oubain. Examples of suitable cholesterol / lipid lowering agents for use in combination with the compounds of the present invention include, HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatma, atorvastatma, simvastatin, NK-104 (aka tavastatin, or nisvastatma or nisbastatin) and ZD-4522 (aka rosuvastatma, or atavastatma or visastatma)), squalene smtetase inhibitors, fibrates, bilear acid sequestrants, ACAT inhibitors, MTP inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors , and inhibitors of the cholesterol ester transfer protein (e.g., CP-529141). Examples of mineralocorticoid receptor antagonists suitable for use in combination with the compounds of the present invention include spironolactone and eplerinon. Examples of phosphodiesterase inhibitors suitable for use in combination with the compounds of the present invention include PDEIII inhibitors such as cilostazol, and PDE V inhibitors such as sildenafil. Examples of thyroid simulants suitable for use in combination with the compounds of the present invention include thyrotropin, polymyroids, KB-130015, and dronedaron. Examples of anabolic agents suitable for use in combination with the compounds of the present invention include testosterone, diethylstilbesterol TRH, estrogens, β-agonists, theophylline, anabolic steroids, dehydroepiandrosterone, encephalinas, E-series prostaglandins, retinoic acid and compounds as described in U.S. Patent No. 3,239,345 for example, Zeranol ©; U.S. Patent No. 4,036,979 for example, Sulbenox® or peptides as described in U.S. Patent No. 4,411,890.

Examples of suitable HIV or SID therapies for use in combination with the compounds of the present invention include indinavir sulfate, rhinovir, saquinavir mesylate, ptonavir, lamivudine, zidovudine, lamivudine / zidovudine, zalcitabine, didanosine, stavudine and megestrol acetate combinations. . Examples of suitable therapies for the treatment of Alzheimer's disease and cognitive disorders for use in combination with the compounds of the present invention include donepezil, tracino, revastigmine, 5TH6, gamma-secretase inhibitors, beta-secretase inhibitors, beta-blockers, channel? K, Maxi-K blockers and KCNQ blockers. Examples of suitable therapies for the treatment of sleep disorders for use in combination with the compounds of the present invention include, melatomine analogs, melatonin receptor antagonists, agonists ML1B and GABA / NMDA receptor antagonists. Examples of suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporin A, pacl taxel, FK 506 and adpamycin. Examples of suitable anti-tumor agents for use in combination with the compounds of the present invention include paclitaxel, adriamycin, epothilones, cisplatin and carboplatin. The compounds of the present invention may furthermore be used in combination with nutptional supplements such as those described in U. 5,179,080, especially in combination with whey protein or casin, amino acids (such as leucine, branched-chain amino acids and hydroxymethylbutyrate) , trigl-i-céridos, vitamins (for example, A, B6, B12, folate, C, D, and E), minerals (for example, selenium, magnesium, zinc, chromium, calcium and potassium), carnitine, lipoic acid , creatine and coenzyme Q-10. In addition, the compounds of the present invention can be used in combination with therapeutic agents used in the treatment of sexual dysfunction, including but not limited to, PDES inhibitors, such as sildenafil or IC-351; with an antiresorptive agent, hormone replacement therapies, vitamin D analogues, calcium and elemental calcium supplements, cathepsin K inhibitors, MMP inhibitors, vitronectome receptor antagonists, Src SH2 antagonists, ARPase inhibitors -vacular-H + , progesterone receptor agonists, ppplabella, fluoride, RANK antagonists, PTH and its analogues and fragments, Tibolone, HMG-CoA reductase inhibitors, MRE ?, p38 inhibitors, prostanoids, 17-beta hydroxysteroid dehydrogenase inhibitors and inhibitors of the cmasa Src. The compounds of the present invention can be used in combination with male contraceptives, such as nonoxynol 9 or therapeutic agents for the treatment of hair loss, such as minoxidil and finasteride or chemotherapeutic agents, such as with HLRH agonists. For their preferred anticancer or antiangiogenic use, the compounds of the present invention can be administered either alone or in combination with other anti-cancer and cytotoxic agents and treatments employed in the treatment of cancer and other proliferative diseases for example, wherein the second The drug has the same or different mechanism of action as the present compounds of formula I. Examples of classes of anti-carcinogenic and cytotoxic agents employed in combination with the present compounds include but are not limited to: alkylating agents such as nitrogen mustard, alkylsulfonates, nitrosoureas, ethyleneimamines, and triazenes; antimetabolites such as folate antagonists, pupil analogs and pipmidine analogues; antibiotics such as anthracyclines, belomicmas, mitomicmas, diactinomycins and plicamycin; enzymes such as L-asparaginase; famesyl protein transferase inhibitors; 5a reductase inhibitors; inhibitors of the dehydrogenase spheroid 17β-hydroxy type 3; hormonal agents such as glucocorticoids, estrogens / antiestrogens, androgens / antiandrogens, progestins, and luteinizing hormone releasing hormone antagonists, octreotide acetate, microtubule dissolving agents, such as ecteinascidins or their analogs and derivatives; microtubule stabilizing agents such as taxanes for example, paclitaxel (Taxol®), docetaxel (Taxotero®), and their analogues and epothilones, such as epothilones A-F and their analogues; plant derived products such as vinca alkaloids, epipodophyllotoxins, taxanes; and topoisomerase inhibitors; prenyl protein transferase inhibitors; and miscellaneous agents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, platinum coordination complexes such as cisplatin and carboplatma; and other agents used as anti-carcinogenic and cytotoxic agents such as biological response modifiers; growth factors; immune modulating and monoclonal antibodies. The compounds of the invention can also be used in conjunction with radiation therapy.

Representative examples of these classes of anti-cancer and cytotoxic agents include but are not limited to, mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, εphosphamide, bisulfan, carmustine, lomustma, semustma, streptozocin, thiotepa, dicarbazm, methotrexate, thioguanine, mercaptopurine, fludarabma, pentastatin, cladribine, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubicin, bleomicma sulfate, mitomicma C, actinomycin D, safracin, saframycin, quinocarcin, discodermolide, vincristine, vmblastin, vinorelbromide tartrate, etoposide, phosphate etoposide, teniposide, paclitaxel, tamoxifen, estramustine, estramustine sodium phosphate, flutamide, buserelin, leuprolide, pteridines, diyneses, levamisole, aflacon, inferione, interleukins, aldesleukas, phygrastpna, ptuximab, BCG, tretinoin, irinotecan hydrochloride, betamethasone, gemcitabma hydrochloride, altretamine, and a topote and any of the analogous or derivatives thereof. Preferred members of these classes include, but are not limited to, paclitaxel, cisplatma, carboplatin, doxorubicin, carminomycin, daunorubicin, aminoptepna, methotrexate, metopterin, mitomycin C, ecteinascidin 743, or porphyromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine , cytosma arabinoside, podophyllotoxin or popdophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesma and leurosma. Examples of anticancer agents and other cytotoxic agents include the following: epothilone derivatives as found in German Patent NO. 4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253 and WO 00/00485; inhibitors of the cyclin-dependent kinase as found in WO 99/24416 (see also US Patent No. 6,040,321); and prize protein transferase inhibitors as found in WO 97/30992 and WO 98/54966; and agents such as those described generically and specifically in U.S. Patent No. 6,011,029 (the compounds of which the U.S. Patent may be employed in conjunction with any of the RHN modulators (including but not limited to, those of the present invention ) such as RA modulators, ER modulators, with HLRH modulators or with surgical castration, especially in the treatment of cancer). The combinations of the present invention can also be formulated or co-administered with other therapeutic agents that are selected for their particular utility in administration therapies associated with the conditions mentioned above. For example, the compounds of the invention can be formulated with agents to prevent nausea, hypersensitivity and gastric irritation, such as antiemetics and antihistamines Hx and H2. As it pertains to cancer treatment, the compounds of this invention are more preferably used alone or in combination with anti-carcinogenic treatments such as radiation therapy and / or cytostatic and / or cytotoxic agents, such as but not limited to, interactive agents. of DNA, such as cisplatma or doxorubicma; Farnesyl protein transferase inhibitors, such as those described in U.S. Patent No. 6,011,029; inhibitors of topoisomerase II, such as etoposide; inhibitors of topoisomerase I, such as CPT-11 or topotecan; tubilin stabilizing agents such as paclitaxel, docetaxel, other taxanes or epothilones; hormonal agents, such as tamoxifen; inhibitors of the smtase thymidylate, such as 5-fluorouracil; antimetabolites, such as methotrexate; antiangiogenic agents such as angiostatin, ZD6474, ZD6126 and comberstatin A2; kinase inhibitors, such as her2-specific antibodies, Iressa and CDK inhibitors; inhibitors of histone deacetylase, such as CI-994 and MS-27-275. Such compounds can also be combined with agents which suppress the suppression of circulating testosterone, such as HLRH agonists or antagonists or with surgical castration. For example, known therapies for metastatic prostate cancer include "complete androgen excision therapy", where tumor growth is inhibited by controlling the androgen supply in the prostate tissue via chemical castration (castration serves to inhibit production of circulating testosterone (T), and dihydrotestosterone (DHT)), followed by administration of androgen receptor antagonists (AR), which inhibit T / DHT function derived from the conversion of androgen precursors circulation to T / DHT by the tissue of the prostate). The compounds of the present invention can be used as RA antagonists in complete excision therapy, alone or in combination with other RA antagonists such as Flutamide, Casodex, Nilutamide or Cyproterone acetate. Another application of the present compounds is a combination with antibody therapy such as, but not limited to, antibody therapy against PSCA. An additional application is concerted with vaccine / immune modulating agents for the treatment of cancer. The compounds of the present invention can be used in accordance with the methods described in U.S. Provisional Patent Application. Series No. 60 / 284,438, entitled "Selective Androgen Receptor Modulators and Methods for Their Identification, Design and Use", filed on April 18, 2001, by Mark E.? Alvati et al. (Attorney's Document No. LD0250 (PSP)), in which the Provisional Patent Application is incorporated herein by reference in its entirety (including but not limited to, reference to all specific compounds within formula I of the present invention) ), and US Patent Application Series No. (not assigned), entitled "? Elective Androgen Receptor Modulators and Methods for their Identification, Design and Use", presented on June 20, 2001, by Mark E. Salvati et al. (Attorney's Document No. LDL250 (NP)), wherein the Patent Application is incorporated herein by reference in its entirety (including but not limited to, reference to all specific compounds within formula I of the present invention) . The other therapeutic agents above, when used in combination with the compounds of the present invention, can be used for example, in those amounts indicated in the Physicians' Desk Reference (PDR), or otherwise as determined by one of ordinary skill. in the technique. The following assays can be used in the evaluation of the activity of a compound as an RHN modulator. Various compounds of the present invention are determined to have the activity of the RA modulator using the transactivation assay, and standard RA binding assays as described below. At the concentration tested, certain compounds within formula I show little or no active activity in the assay employed (e.g., compounds of Example 97).

D Transactivation Assays: Specific Assays RA: The compounds of the present invention were tested in transactivation assays of a transfected reporter construct and using the endogenous androgen receptor of the host cells. The transactivation assay provides a method for identifying functional agonists and partial agonists that mimic, or antagonists that inhibit the effects of the native hormones in this case, dishidrotestosterone (DHT). This assay can be used to predict in vivo activity as there is a good correlation in both data series. See, for example, T. Berger et al., J. Steroid Bi ochem. Mol ec. Bi ol. 773 (1992), the description of which is incorporated herein by reference. For the transactivation assay, a reporter plasmid is introduced by transfection (a method to induce cells to capture foreign genes), in the respective cells. This reporter plasmid, comprising the cDNA for a reporter protein, such as secreted alkaline phosphatase (PHASE), controlled by the upstream sequences of the prostate-specific antigen (PSA) contain the androgen response elements (ERA). This reporter plasmid functions as a reporter for the transcription and modulation of RA activity. In this way, the reporter acts as a surrogate for the products (protein mRNA), normally expressed by a gene under the control of RA and its native hormone. To detect antagonists, the transactivation assay is carried out in the presence of constant concentration of the natural RA hormone (DHT) known to induce a defined reporter signal. Increased concentrations of a suspected antagonist will decrease the reporter's signal (eg, PHASE production). On the other hand, exposure of the transfected cells to increased concentrations of a suspected agonist will increase the production of. Reporter's signal For this assay, LNCaP and MDA 453 cells were obtained from the American Type Culture Collection (Rockville, DM), and were maintained in RMPI 1640 or DMEM medium supplemented with 10% fetal bovine serum (FB ?; Gibco) respectively. The respective cells were temporarily transferred by electroporation in accordance with the optimized procedure described by Heiser, 130 Methods Mol. Biol., 117 (2000), with the reporter plasmid pSEAP2 / PSA540 / Mej orator. The reporter plasmid was constructed as follows: commercial human placental genomic DNA, was used to generate by Polymerase Chain Reaction (PCR), a fragment containing the Bglll site (position 5284) and the Hind III site at position 5831 of the human prostate-specific antigen promoter (Access # U37672), Schuur, et al., J. Biol. Chem., 271 (12): 7043-51 (1996). This fragment was subcloned into the pSEAP2 / basic (Clontech), previously digested with BglII and HindIII to generate the p? EAP2 / PSA540 construct. Then a fragment carrying the fragment of the human sequence upstream AEP between positions -5322 and -3873, was amplified by PCR from human placental genomic DNA. Xhol and BglII sites were introduced with the primers. The resulting fragment was subcloned into p? EAP2 / PSA540 digested with Xhol and BH1II respectively, to generate the construct pSEAP2 / P? A540 / Enhancer. The LNCaP and MDA 453 cells were collected in medium containing 1% FBS stripped of mineral carbon. Each cell suspension was distributed in two Gene Pulser laboratory beakers (Bio-Rad), which then received 8 μg of the reporter construct, and were electroporated using a Bio-Rad Gen Button at 210 volts and 960 μ Faraday. After transfections, the cells were washed and incubated with medium containing fetal bovine serum removed from the mineral carbon in the absence (white) or presence (control) of 1 nM dihydrotestosterone (DHT; Sigma Chemical) and in the presence or absence of the standard anti-androgen bicalutamide or compounds of the present invention in concentrations ranging from 10 ~ 10 to 10 M (sample). Duplicates were used for each sample. The dilutions of the compound were performed in a Biomek 2000 laboratory work station. After 48 hours, a fraction of the supernatant was assayed for PHASE activity, using the Fosfa-Light Chemiluminescent Reporter Gen System (Tropix, Inc.). Viability of the remaining cells was determined using the Cellular Non-Radioactive Aqueous Proliferation Assay Cell Titrant 96 (MTS Assay, Promega). Briefly, a mixture of a compound (inert salt of 3- (4,5-d? Meth? Lt? Azol-2-? L) -5- (3-carboxymethoxyphenyl) -2- (-sulfofeml) -2H-tetrazole ?or; MTS) and an electron coupling agent (phenazine methosulfate; PM?) Was added to the cells. The MTS (Owen reagent) is bioreduced by the cells in formazan which is soluble in tissue culture medium, and therefore, its absorbance at 490 nm can be measured directly from the 96-well assay plates without further processing. The amount of product formazan measured by the amount of absorbance 490nm, is directly proportional to the number of living cells in culture. For each replicate, the PHASE reading was normalized by the Abs490 value derived from the MTS assay. For the antagonist mode, the inhibition l was calculated as: % inhibition = lOOx (1- [average control - average target / average sample - average target]).

The data were plotted and the concentration of the compound that inhibits 50% of the normalized PHASE was quantified (IC50) • For the agonist mode, the% Control refers to the effect of the compound under test compared to the maximum effect observed with the natural hormone , in this case, DHT, and it was calculated as: Control% = 100 x sample average - average white / average control - average white The plotted data and the concentration of the compound that activates the 50. levels of the normalized PHASE for the control, was quantified (EC50).

RG Specificity Test The reporter plasmid used was committed to the cDNA for the reporter's PHASE protein, as described for the specific transactivation assay. The expression of the reporter PHASE protein was controlled by the long terminal repeat sequences of the mouse mammary tumor virus (RTL VTMR), which contain three hormone response elements (ERH), which can be regulated by both RG and RP, see for example, G. Chalepakis et al., Cell, 53 (3), 371 (1988). This plasmid was transfected into A549 cells, which express the endogenous RG, to obtain a specific transactivation assay of the RG. A549 cell was obtained from the American Type Culture Collection (Rockville, MD), and maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS, Gibco). The determination of the RG-specific antagonist activity of the compounds of the present invention was identical to that described for the specific transactivation assay of the RA, except that the DHT was replaced with 5 nm of dexamethasone (? Igma Chemicals); a specific agonist for the RG. The determination of the RG-specific agonist activity of the compounds of the present invention was performed as described for the RA transactivation assay, wherein one measures the activation of the RG-specific reporter system by the addition of a test compound, in the absence of a known RG-specific agonist ligand.

RP-Specific Assay The reporter plasmid used committed the cDNA to the reporter's PHASE protein, as described for the specific transactivation assay of the RA. The expression of the reporter PHASE protein was controlled by the long terminal repeat of the mouse mammary tumor virus (RTL VTMR), which contains three hormone response elements (ERH), which can be regulated by both the RG and the RP. This plasmid was transfected into T47D, which expresses the endogenous RP, to obtain a specific transactivation assay of RP. T74D cells were obtained from the American Type Culture Collection (Rockville, DM), and were maintained in DMEM medium supplemented with 10% fetal bovine serum (FBS, Gibco); the determination of the RP-specific antagonist activity of the compounds of the present invention was identical to that described for the specific transactivation assay of RA, except that DHT was replaced with 1 nM of Promeastone (NEN), a specific agonist for the RP. The determination of the specific agonist activity of the RP of the compounds of the present invention was performed as described for the RA transactivation assay, wherein one measures the activation of the RP specific reporter system by the addition of a test compound, in the absence of a specific agonist ligand of the known RP.

RA Assay Assay: For the whole cell binding assay, human LNCaP cells (mutant AR T877A) or MDA 453 (native AR) in 96-well microtiter plates containing RPMI 1640 or DMEM supplemented with 10% carbon removed of CA-FBS (Cocaleco Biologicals) respectively, were incubated at 37 ° C to remove any endogenous ligand that could be complex-forming with the receptor in the cells. After 48 hours, either a saturation analysis to determine the Kd for dihydrotestosterone titrated, [3H] -DHT, or a competitive binding assay was performed to evaluate the ability of the test compounds to compete as [H] -DHT. For saturation analysis, medium (RPMI 1640 or DMEM-0.2% CA-FBS) containing [3 H] -DHT (in concentrations ranging from 0.1 nM to 16 nM) in the absence (total binding) or presence (non-specific binding) of a 500-fold molar excess of unlabeled DHT. After 4 hours at 37 ° C, an aliquot of the total binding medium was removed at each concentration of [3 H] -DHT to estimate the amount of free [3H] DHT. The remaining medium was removed, the cells were washed three times with PBS and harvested on UniFilter GF / B plates (Packard), Microscint (Packard) was added to the plates counted in a Superior Counter (Packard) to evaluate the amount of binding [3 H] -DHT. For the saturation analysis, the difference between the total link and the non-specific link was defined as the specific link. The specific binding was evaluated by? Catchard analysis to determine the Kd for [3H] -DHT. See for example, D. Rodboard, Mathematics and statistics of ligand assays: an illustrated guide: In: J. Langon and J.J. Clapp, eds., Ligand Assay, Masson Publishing U.S.A, Inc., New York, pp. 45-99 (1981), the description of which is incorporated herein by reference. For competition studies, medium containing 1 nM [3 H] -DHT and compounds of the invention ("test compounds") in concentrations ranging from 10"10 to 10 ~ 2 M were added to the cells. Two replicates were used. for each sample.After 4 hours at 37 ° C, the cells were washed, harvested and counted as described above.The data were plotted as the amount of [H] -DHT (% control in the absence of the compound of test) that remains over the range of the dose response curve for a given compound.The concentration of the test compound that inhibits 50? of the amount of ['H] -DHT bound in the absence of the competent ligand was quantified (IC50 ) after the transformation with log-logit The Ki values were determined by applying the Cheng-Prusoff equation to the IC50 values, where: (1 + (3H-DHT) / Kd for 3H-DHT).

After correction for the non-specific link, IC50 values were determined. The IC50 is defined as the concentration of the competition ligand necessary to reduce the specific binding by 50%. The Kds for [3H] -DHT for MADA 453 and LNCaP was 0.7 and 0.2 nM respectively.

Human Prostate Cell Proliferation Assay: The compounds of the present invention were tested ("test compounds") on the proliferation of human prostate cancer cell lines. For such, MDA PCa2b cells, a cell line derived from the metastasis of a failed castration patient, Navone et al., Clin. Cancer Res., 3, 2493-500 (1997), were incubated with or without the test compounds for 72 hours and the amount of [3H] -thymidine incorporated into the DNA was quantified as a way to assess the number of cells and therefore, proliferation. The MDA PCa2b cell line was maintained in BRFF-HPCl medium (Biological Research Faculty & Facility Inc., MD), supplemented with 10% FB? . For the assay, the cells were plated in 96-well micro-coated microplates and incubated at 37CC in 10% FBS. (removed from coal) / BRFF-BMZERO (without androgens).

After 24 hours, the cells were treated in the absence (white) or presence of 1 nM DHT (control) or with the test compounds (sample) of the present invention in concentrations ranging from 10 ~ 10 to 10"5 M. Duplicates were used for each sample. compound were performed in a Biomek 2000 laboratory work station. Seventy-two hours later, 0.44 uCi of [3H] -thymidine (Amersham) was added per well and incubated for another 24 hours, followed by tppsinization, harvesting the cells in filters GF / B added Micro-scint P to the filters before counting them in a Beckman Superior Counter.The inhibition l was calculated as:% inhibition = lOOx (1- [average / average / average] ? omUestra -? romed? ob? dnco]) • The data were plotted and the concentration of the compound that inhibits SO1., from the incorporation of [3H] -thymidine was quantified (IC50).

Mouse Mioblast Transactivation Assay C2C12? E developed two functional transactivation assays to assess the efficacy of the androgen agonist in a background of muscle cells using a luciferase reporter. The first assay (ARTA Stable 1) uses a cell line, Stable 1 (clone # 72), which stably expresses the full length mouse androgen receptor, but requires the temporal transformation of an enhancer / reporter. This cell line was derived from mouse ioblast cells C2C12. The second trial (ARTA Stable 2) uses a cell line,? Table 2 (Clone # 133), derived from Stable 1, which stably expresses both rAR and the reporter enhancer / luciferase. The enhancer / reporter construct used in this system is pGL3 / 2XDR-1 / luciferase. The 2XDR-1 was reported to be a specific response element of RA in CV-1 cells, Brown et al. The Journal of Biological Chemistry 272, 8227-8235, (1997). It was developed by random mutagenesis of a consensus enhancer sequence RA / RG.

ARTA Stablß 1: 1. Stable 1 cells were plated in a 96-well format at 6,000 cells / well in high-glucose DMEM without phenol red (Gibco BRL, Cat. No .: 21063-029) containing mineralized carbon. 10% and dextran treated with FB? (HyClone Cat. No.: SH30068.02), 50 mM HEPES buffer (Gibco BRL, Cat. No .: 15630-080), IX MEM Na Piruvato (Gibco BRL, Cat. No.: 11360-070), 0.5X Antibiotic-Antimycotic, and 800 μg / ml Geneticin (Gibco BRL, Cat. No .: 10131-035). 48 hours later, cells were transfected with pGL3 / 2XDR-1 / luciferase using LipofectAMINE Plis ™ Reagent (Gibco BRL, Cat. No .: 10964-013). Specifically, 5 ng / well of pGL3 / 2XDR-l / luciferase DNA was diluted and 50 ng / well of Salmon Sperm DNA (as carrier) was diluted with 5 μl / well of Opti-MEM medium (Gibco BRL, Cat. No.: 31985-070). To this, Plus reagent 0.5 μl / well was added. This mixture was incubated for 15 minutes at room temperature. In a separate vessel, 0.385 μl / well of LipofectAMINE reagent was diluted with 5 μl / well of Opti-MEM. The DNA mixture was then combined with the LipofectAMINE mixture and incubated for an additional 15 minutes at room temperature. During this time, the medium was removed from the cells and replaced with 60 μl / well of Opti-MEM. To this was added 10 μl / well of the DNA / LipofectAMINE transfection mixture. The cells were incubated for 4 hours. 3. The transfection mixture is removed from the cells and plated again with 90 μl of medium as in # 1 above. 4. 10 μl / well of the appropriate drug dilution was placed in each well. 5. 24 hours later, the Luciferase Assay System-teady-Glo ™ was used to detect the activity in accordance with the manufacturer's instructions (Promega, Cat. No .: E2520).

ARTA Stablß 2: 1. Stable 2 cells were plated in a 96-well format at 6,000 cells / well in high-glucose DMEM without ro or phenol (Gibco BRL, Cat. No .: 21063-029) containing mineral carbon 10% and dextran treated with FBS (HyClone Cat. No.:? H30068.02), 50 mM HEPES buffer (Gibco BRL, Cat. No .: 15630-080), IX MEM Na Piruvate (Gibco BRL, Cat. No.: 11360-070), 0.5X Antibiotic-Antimycotic, 800 μg / ml Geneticma (Gibco BRL, Cat. No .: 10131-035) and 800 μg / ml Hygromycin β (Gibco BRL, Cat. No .: 10687-010). 2. 48 hours later, the cells were removed and replaced with fresh 90 μl. 10 μl / well of the appropriate drug dilution was placed in each well. 3. 24 hours later, the Luciferase Assay System-teady-Glo ™ was used to detect activity in accordance with the manufacturer's instructions (Promega, Cat. No.:E2520). See U.S. Patent Application No. (unassigned), entitled "Cell Lines and Cell-Based Assays for Identification of Androgen Receptor Modulators" filed on June 20, 2001 by Jacked Ostrowski et al. (Document of the Attorney No. D0177), in which the Patent Application is incorporated herein by reference in its entirety.

Proliferation Assays Murine Breast Cell Proliferation Assay The ability of the compounds of the present invention ("test compounds") to modulate the function of the RA was determined by subjecting compound assays in a proliferation assay using the breast cell line of murine responsible for the androgen derived from the tumor Shionogi, Hiraoka et al. , Cancer Res., 47, 6560-6564 (1987). The Stable RA dependent clones of the original hiono line were established by passing the tumor fragments under general procedures described in an original manner in Teuto, et al. , Cancer Research 25, 1168-1175 (1965). From the above procedure, a stable line? C114, was isolated, characterized and used to test the examples compounds. The? C114 cells were incubated with or without the test compounds for 72 hours and the amount of [JH] -thymidine incorporated into the DNA was quantified as a surrogate endpoint to assess the number of cells and therefore, the speed of proliferation as described in Suzuki et al. , J.? Teroid Biochem. Mol. Biol. 37, 559-567 (1990). Cell line? C114 was maintained in MEM containing 10"8 M testosterone and 2% FCS treated with DCC For the assays, the cells were placed in 96-well microplates in the maintenance medium and incubated at 37 ° C. The following day, the medium was changed to serum free medium [Hams F-12: MEM (1: 1), v / v) containing 0.1% B? A] with (antagonist mode) or without (antagonist mode) 10"M testosterone and the test compounds of the present invention in concentrations ranging from 10" 10 to 10"5 M. Duplicates were used for each sample. Dilutions of the compound were performed in a Biomek 2000 laboratory work station. Twenty-two hours later, 0.44uCi of [3H] -thymidine (Amersham) was added per well, and incubated for another two hours, followed by trypsinization, and harvested the cells in GF / B filters. Added Micro-scint P? to the filters before counting them in a Beckman Superior Counter. For the antagonist mode, the% inhibition was calculated as:% inhibition = lOOx (1- [averaged3tr-? - average? Average / averagecontrai - averagewhite]). The data were plotted and the concentration of the compound that inhibits 50% of the [3H] -thymidine incorporation was quantified (IC50). For the agonist mode, the% Control is referred to as the effect of the compound under test compared to the maximum effect observed with the natural hormone, in this case, DHT, and was calculated as:% inhibition = lOOx (average). ? anco / promediOeonioi - promed? ob? anco) • The data were plotted and the concentration of the compound that inhibits 50% of the [3H] -thymidine incorporation was quantified (IC50).

In vivo Assay for Measuring AP-1 Transrepression Induced by RG: The AP-1 Assay is a cell-based luciferase reporter assay. A549 cells, which contain the endogenous glucocorticoid receptor, are stably transfected with an AP-1 DNA binding site linked to the luciferase gene. The cells then grow in RPMI + fetal calf serum (treated with mineral charcoal) + Penicillin / Streptomycin with 0.5 mg / ml geneticma. The cells were planted the day before the assay in approximately 40,000 cells / wells. On the day of the assay, the medium was removed by aspiration and 20 μl of assay buffer (RPMI without red phenol + 10% FC? (Treated carbon) + Pen /? Trep) was added to each well. At this point, either 20 μl of assay buffer (control experiments), the compounds of the present invention ("test compounds") (dissolved in DM ?O and added at varying concentrations) or dexamethasone were added to each well. (100 nM in DMSO), positive control). The plates were then pre-incubated for 15 minutes at 37 ° C, followed by stimulation of the cells with 10 ng / ml of PMA. The plates were incubated for 7 hours at 37 ° C after which 40 μl of the luciferase substrate reagent was added to each well. The activity is measured by analysis in a luminometer that compares the control experiments treated with buffer or dexamethasone. The activity is designated as% inhibition of the reported system compared to the buffer control with 10 ng / ml of PMA alone. The control, dexamethasone, in concentration of < 10 μM activity typically repressed at 65%. The test compounds are actively considered which showed an inhibition of PMA induction of 50% or greater at a test compound concentration of 10 μM.

RA Antagonist Assay of the Wet Weight Test of the Prostate: The activity of compounds of the present invention as RA antagonists was investigated in an immature male rat model, a recognized, standard test of the androgen activity of a given compound , as described in LG Hershberger et al., Proc. Soc. Expt. Biol. . Med., 83, 175 (1953); P.C. Walsh and R.F. Gittes, "Inhibition of extratesticular stimuli to prostate growth in the castred rat by antiandrogens", Endocpnol ogy, 86, 624 (1970); and B.J. Furr et al., "ICI 176,334: A novel non-estepod, peppherally selective antiandrogen", J. Endocpnol., 133, R7-9 (1987) the descriptions of which are incorporated herein by reference. The basis of this trial is the fact that male secondary sex organs, such as the prostate and seminal vesicles, play an important role in reproductive function. These glands are stimulated with growth and are maintained in size and secondary function by the continuous presence of testosterone serum (T), which is the best androgen serum (> 95%) produced by Leydig cells in the testes ba or the control of the pituitary luteinizing hormone (HL) and the follicle stimulating hormone (FSH). Testosterone is converted to the most active form, dihydrotestosterone (DHT), within the prostate by 5a-reductase. Adrenal androgens also contribute to about 20% of the total DHT in the rat prostate, compared to 40% of those in men over 65 years of age. F. Labrie et al. Clin. Invest. Med., 16, 475-492 (1993). However, this is not the best route, although in both animals and humans, it leads to castration to almost complete the involution of the prostate and seminal vesicles without adrenalectomy accompaniment. Therefore, under normal conditions, adrenals do not support significant growth of prostate tissues. M.C. Luke and D? Coffey, "The Physiol ogy of Reproduction" ed. by E. Knobil and J.D. Neill, 1, 1435-1487 (1994). Although the male sex organs are the most responsible tissues for the modulation of androgen activity, this model is used to determine the androgen dependent growth of the secondary sex organs in immature castrated rats. The immature male rats (Sprague-Dawley, Harán? Prague-Dawely from 19-10 days of age) were castrated under anesthesia of methophane. Five days after surgery these castrated rats (60-70 g, 23-25 days of age) were dosed for 3 days. The animals were subcutaneously dosed (s) 1 mg / kg with Testosterone Propionate (TP) in peanut oil vehicle and the test compounds against androgen (compounds of the present invention) were orally dosed by priming (po) in suspensions dissolved in 80% PEG 400 and 20% Tween 80 (PEGTW). The animals were dosed (v / p) to 0.5 ml of the vehicle / 100 g of body weight. The experimental groups were the following: 1. Control vehicle 2. Testosterone propionate (TP) (3 mg / rat / day, subcutaneously) 3. Casodex plus TP (po administered in PEGTW, QD) a recognized androgen counter, as a compound reference. 4. To demonstrate antagonist activity, a compound of the present invention ("test compound") with TP (c.s as administered in group 2) was determined in a range of doses (p.o. in PEGTW, QD). 5. To demonstrate agonist activity, a compound of the present invention ("test compound") was administered alone (p.o. in PEGWT, QD) in a range of doses. At the end of the treatment on day 3, the animals were sacrificed, and the ventral prostate was weighed. To compare data from different experiments, the weight of the sexual organs was first standardized as mg per 100 g of body weight, and the increase in weight of the organ induced by TP was considered as the maximum increase (100%). An ANOVA test was used followed by a detailed study or Fischer for statistical analysis. The gain and loss of the weight of the sexual organ reflects changes in the number of cells (DNA content) and cell mass (protein content), depending on the concentration of serum androgen. See Y. Okuda et al., J. Urol., 145, 188-191 (1991), the description of which is incorporated herein by reference. Therefore, the measurement of the wet weight of the organ is sufficient to indicate the bioactivity of androgens and androgen antagonist. In immature castrated rats, replacement of seminal vesicle (VS) and ventral prostate (PV) increases the exogenous endogenous in a dose dependent manner. The maximum increase in organ weight was 4 to 5 times when the dose is 3 mg / rat / day of testosterone (T) or 1 mg / rat / day of testosterone propionate (PT) for 3 days. The EC5U of T and PT is about 1 mg and 0.03 mg, respectively. The increase in the weight of the PV and VS also correlates with the increase in the concentration of serum T and DHT. Although administration of T shows 5 times high serum concentrations of T and DHT at 2 hours after subcutaneous injection rather than PT, however, these high levels decline very rapidly. In contrast, serum concentrations of T and DHT in animals treated with PT are fully consistent during the 24 hours, and therefore, PT shows potential around 10-30 times higher than free T. In this immature castrated rat model, a known AR antagonist (Casodex) is also administered simultaneously with 0.1 mg PT (ED) which inhibits the increase in testosterone-mediated weight of the PV and VS in a dose dependent manner. Antagonistic effects are similar when dosed orally or subcutaneously The compounds of the invention also exhibit RA antagonist activity by suppressing the increase in testosterone-mediated weight of PV and VS.

RA agonist assay of the Dós Weight Test Prósta Húmeda & Ani Elevator: The activity of compounds of the present invention as an AR antagonist was investigated in an immature male rat model, a recognized test of the anabolic effect in muscle and sustained effects on sexual organs by a given compound, as described in LG Hershberger et al., Proc. Soc. Expt. Biol. Med. , 83, 175 (1953); B. L. Beyler et al, "Methods for evaluating anabolic and catabolic agents? N laboratory animáis"; J. Amer. Med. Women's Ass. 23, 708 (1968); H. Fukuda et al., "Investigations of the levator ani muscle as an anabolic steroid assay", Nago Dai, Yak, Ken, Nem. 14, 84 (1966), the descriptions of which are incorporated herein by reference. this assay is reliable in the well-defined action of androgenic agents in the maintenance and growth of muscle tissues and secondary sex organs in animals and men.The adrogenic spheroids, such as testosterone (T), have been well characterized by their ability to maintain Muscle mass Treatment of animals or humans after castration with an exogenous source of T results in a nullification of muscle atrophy The effects of T on muscle atrophy in the ani muscle have been well characterized M. Masuoka et al., "Constant cell population in normal, testosterone deprived and testosterone stimulated levator ani muscles" Am. J. Ana t 119, 263 (1966); Z. Gop et al., "Testosterone hypertrophy of levator a nor muscle of castrated rats. I. Quantitative data "Boil." Soc Ital. Biol. Sper. 42, 1596 (1966); Z. Gori et al., "Testosterone hypertrophy of levator ani muscle of castrated rats. II. Electronmicroscopic observations "Boil." Soc Ital. Biol. Sper. 42, 1600 (1966); A. Boris et al., Steroids 15, 61 (1970) .As described above, the effects of androgens in the maintenance of Secondary male sex organs, such as the prostate and seminal vesicles, are well described.Castration results in involution and atrophy of the prostate and seminal vesicles.This effect can be reversed by exogenous addition of androgens. ani elevator, as the sexual organs of the male are the tissues most responsible for the effects of androgenic agents, this model was used to determine the androgen turnover dependent on atrophy in the levator ani muscle and secondary sex organs in immature castrated rats. The sexually mature rats (? Prague-Dawley, Harian, 200-250 g, 6-8 weeks old) were acquired castrated from the seller (Taconic) .The rats were divided into groups and they were treated daily for 7 to 14 days with one of the following: 1. Control vehicle 2. Testosterone propionate (PT) (3 mg / rat / day, subcutaneously) 3. Casodex plus PT (administered p.o. in PEGTW, QD), a recognized androgen counter, as a reference compound. 4. To demonstrate antagonist activity, a compound of the present invention ("test compound") with PT (c.s as administered in group 2) was administered (p.o. in PEGTW, QD) in a range of doses. 5. To demonstrate agonist activity, a compound of the present invention ("test compound") was administered alone (p.o. in PEGTW) in a range of doses. At the end of the treatment of 7-14 days, the animals were sacrificed by carbon dioxide, and the ani elevator, seminal vesicle and ventral prostate were weighed. To compare data from different experiments, the levator ani muscle and the heavy sex organ were first standardized as mg per 100 g of body weight, and the increase in body weight induced by PT was considered as the maximum increase (100%). It was used for statistical analysis? Uper-anova (one factor). The gain and loss of weight in the sexual organ reflects the change in cell number (DNA content) and cell masses (protein content), depending on the androgen concentration of serum. See Y. Okuda et al., J. Urol., 145, 188-191 (1991), the description of which is incorporated herein by reference. Therefore, the measurement of the wet weight of the organ is sufficient to indicate the androgen bioactivity and androgen antagonist. In immature castrated rats, the replacement of exogenous androgens increases the ani elevator, seminal vesicle (VS) and prostate in a dose dependent manner. The maximum increase in organ weight was 4 to 5 times when the dose is 3 mg / rat / day of testosterone (T) or 1 mg / rat / day of testosterone propionate (PT) for 3 days. The EC5c of T and PT was around 1 mg and 0.03 mg, respectively. The increase in the weight of PV and V? it also correlates with the increase in the concentration of serum T and DHT. Although the administration of T shows 5 times higher the concentration of serum T and DHT in the 2 hours after the injection than PT, according to this the high levels decline very quickly. In contrast, serum concentrations of T and DHT in animals treated with PT where it is completely consistent during the 24 hours, and therefore, PT shows around 10-30 times high potential that free T.

MDA Pca2b Human Prostate Znnnograph Test M vivo anti-tumor tumors were tested: MDA-Pca-2b human prostate tumors were maintained in nude Balb / c un / a mice. The tumors were propagated in subcutaneous transplantation in nude male adult mice (4-6 weeks of age) using fragments of tumors obtained from the donor mouse. The passage of the tumor occurs every 5-6 weeks. For antitumor efficacy assays, the required number of animals needed to detect a significant response was discharged at the start of the experiment and each was provided with a subcutaneous implant of a tumor fragment (-50 mg) with a trocar of measurement 13. The tumors they were allowed to grow to approximately 100-200 mg (tumors outside the range were excluded) and the animals were evenly distributed to several treatment and control groups. The treatment of each animal was based on the individual body weight. The treated animals were checked every day for the related toxicity / mortality treatment. Each group of animals was weighed before the start of treatment (WT1) and then again following the last dose of treatment (Wt2). The difference in body weight (Wt2-Wtl), provides a measure of toxicity related to the treatment.

The tumor response was determined by measuring the tumors with a calibrator twice a week, until the tumors reached a predetermined "target" size of 0.5 gm. The tumor weights (mg) were estimated from the formula: Tumor Weight = (length per am? L? Tud2) - = - 2. The final point of response was expressed in terms of inhibition of tumor growth. { % T / C), defined as the ratio of the average tumor weights of the treated tumors (T) to those of the control group (C). To estimate tumor cell death, time doubling tumor volume was first calculated with the formula: TVDT = mean time (days) for control tumors to reach an objective size - Mean time (days) for tumors to control reach half of the target size and, Log of cell death = (TC) -H (3.32 x TVDT) Statistical evaluations of the data were performed the generalized Wilcoxon test of Gehan.

Prostate tumor Dunning: The tumor of prostate R3327H Dunning, is an adenocarcinoma of the prostate responsible for the androgen well differentiated, derived spontaneously, (? Molev JK, Heston WD,? Cott WW, and Coffey D ?, Cancer Trea t Rep. 61 , 273-287 (1977)). The growth of the R3327H subline has been selected for this highly androgen-dependent growth and reproducible in intact male rats. Therefore, this model and other sublines of this tumor have been widely used to evaluate the in vivo anti-tumor activities of antiandrogens, such as flutamide and bacilutamide / Casodex (Maucher A., and von Angerer, J. Cancer Res. Cl in. On col., 119, 669-674 (1993), Furr BJA Futo, URL 18 (suppl 3), 2-9 (1990),? Hain? A. and Huot Rl. J. Steriod Bi ochem. , 711-718 (1988)). At the beginning of the study, the Dunning tumor pieces (about 4 x 4 mm) were transplanted subcutaneously from the flank of mature, male Copenhagen rats (6-7 weeks old, Harlan-? Prague Dawley, Indianapolis, MD). About 6 weeks after the implant,. Animals with tumors of measurable size (around 80-120 mm2) were randomized into treatment groups (8-10 rats / group), and treatments were initiated. A group of rats was castrated to serve as the negative control of tumor growth. The animals were treated daily with compounds of the current invention, standard antiandrogens such as bacilutamide or vehicle (control) for an average of 10 to 14 weeks. The compounds were dissolved in a vehicle of (2.5 ml / kg body weight) 10% polyethylene glycol and 0.05% Tween-80 in 1% carboxymethylcellulose, PEG / CMC, (? Igma, St. Louis, MO). Therapeutic experiments could include three groups of gradual doses for each of the test compounds or standards (in a range of 300-3 mg / kg). Tumors in the vehicle group (control), each one reached a size of 1500 to 2500 mm3, while the castrated animal group typically showed tumor stasis during the 14 weeks of observation. Animals treated orally with 20 mg / kg bicalutamide or flutamide, could be expected to show a 40% reduction in tumor volumes, compared with control after 14 weeks of treatment. The size of the tumors was measured weekly by vernier caliper (Froboz, Switzerland), taking perpendicular measurements of length and amplitude. Tumor volumes are measured in mm3 using the formula: Length x Amplitude x Height = volume. Statistical differences between the treatment and control groups are evaluated using multiple ANOVA analysis followed by a Student's T-test not parametpca endpoint.

Mature Rat Prostate Weight Test: The activity of the compounds of the present invention was investigated in a mature male rat model, which is a variation of the ani and wet weight prostate weight test, described above. The above live m-tests are recognized assays for determining the anabolic effects on muscle and support effects in sexual organs by a given compound, as described in L. G Hershberger et al. , 83 Proc. Soc. Expt. Bi ol. Med. , 175 (1953); B. L. Beyler et al. , "Methods for evaluating anabolic an catabolic agents in laboratory chemistry" 23 J. Amer. Med. Women's Ass. 708 (1968); H. Fukuda et al., "Investigations to the levator ani muscle as anabolic steroid assay" J Nago Da i, Yak, Ken, Nem 84 (1966), descriptions of which are hereby incorporated by reference. These trials fall into the well-defined action of adrenergic agents in the maintenance and growth of muscle tissues and accessory sex organs in animals and man.The sexual accessory organs of the male, such as the prostate and seminal vesicle, play an important role in reproductive function These glands are stimulated to grow and maintain their size and secretory function by the continuous presence of serum testosterone (T), which is the androgen of the main serum (95%) produced by Leydig cells in the testes under Control of the pituitary luteinizing hormone (HL) and follicle stimulating hormone (HEF) Testosterone is converted to the most active form, dihydrotestosterone (DHT), within the pr stata by 5AR. Adrenal androgens also contribute about 20% of the total DHT in the rat prostate, compared with 40% of that in men 65 years of age. F. Labpe et al. 16 Clin. Invest. Med., 475-492 (1993). However, this is not a major trajectory, since in both animals and humans, castration leads to the almost complete involution of the prostate and seminal vesicles without concomitant adrenalectomy. Therefore, under normal conditions, adrenals do not support significant growth of prostate tissues, M.C. Luke and D.S. Coffey, "The Physiology of Reproduction" ed. By E. Knobil and J. D. Neill, 1, 1435-1487 (1994). Since the sexual organs of the male and the ani elevator are the tissues most responsible for the modulation of androgen activity, this model is used to determine the activity of compounds that modulate the trajectory of the androgen receptor in mature rats. Along with this mitogenic activity in tissues such as prostate, seminal vesicle and muscle, testosterone also serves as a negative regulator for its own biosynthesis. The production of testosterone in Leydig cells of the testis is controlled by the level of circulation of HL released from the pituitary gland. The HL levels are themselves, controlled by the level of HLRH produced in the hypothalamus region. The levels of testosterone in the blood serve to inhibit the secretion of HLRH and subsequently reduce levels of HL and finally the levels of circulating testosterone. By measuring HL blood levels as affected by the compounds of the present invention ("test compounds"), it is possible to determine the level of agonist or antagonist activity of said compound in the hypothalamic axis of this endocrine cycle. Equalized tests of Harran Sprague-Dawley rats (40-42 days of age, 180-220 g), were dosed daily by priming (po) with the test compounds in suspensions / dissolved of 80% PEG 400 and 20% of Tween 20 (PEGTW) for 14 days. Two control groups, one intact and one neutered, were dosed daily with the PEGTW vehicle. Animals were dosed (v / p) at 0.5 ml vehicle / 100g body weight. The experimental groups were as follows: 1. Intact vehicle (p.o., PEGTW, QD) 2. Control vehicle (p.o. PEGTW, QD) 3. Bicalutamide (Casodex, a recognized antiandrogen, as a reference compound) or a compound of the present invention, p.o in PEGTW QD (in a dose range). At the end of the 14 days of treatment, the animals were sacrificed, and the ventral prostate, the seminal vesicles and the ani elevator were surgically removed and weighed. To compare the data from different experiments, the heavy organs were first standardized as mg per lOOg of body weight, and expressed as a percentage of the value of the respective organ in the intact group. Rat luteinizing hormone (HLr) is quantitatively determined with the Biotrak team

[1251] (Amersham Pharmacia Biotek), following the manufacturer's instructions. The assay is based on competition for the HL present in the serum of the [125I] rHL binding in an Amerlex-M antibody / perlilla suspension. The radioactivity that remains after the incubation with the serum and subsequent washes is extrapolated in a standard curve to obtain a reading in ng / ml. The gain and loss of the sexual organ and weight of the ani elevator reflects the changes in cell number (DNA content) and cell mass (protein content), depending on the serum androgen concentration, see Y. Okuda et al. , J. Urol., 145, 188-191 (1991), the description of which is incorporated herein by reference. Therefore, the measurement of the wet weight of the organ is sufficient to indicate the bioactivity of androgens and androgen antagonists. In the mature rat assay, the agonist agents will have no effect or will increase the weight of one or more of the organs responsible for androgens (am elevator, prostate, seminal vesicle) and will have no effect or a suppressive effect on the secretion of HL. Compounds with antagonist activity will decrease the weight of one or more of the organs responsible for androgens (ani elevator, prostate, seminal vesicle) and will have no effect or a reduced surprise effect on the secretion of HL.

Human Prostate Zenograph MDA Trial Pca2b They tested anti-tumor in vivo: MDA-Pca-2b human prostate tumors were maintained in nude Balb / c un / un mice. The tumors were propagated in subcutaneous transplantation in nude adult male mice (4-6 weeks of age) using fragments of tumors obtained from the donor mouse. The passage of the tumor occurs every 5-6 weeks.

For antitumor efficacy assays, the required number of animals needed to detect a significant response was poured at the start of the experiment and each was provided with a subcutaneous implant of a tumor fragment (~ 50 mg) with a trocar of measurement 13. The tumors they were allowed to grow to approximately 100-200 mg (tumors outside the range were excluded) and the animals were evenly distributed to several treatment and control groups. The treatment of each animal was based on the individual body weight. The treated animals were checked every day for the related toxicity / mortality treatment. Each group of animals was weighed before the start of treatment (WTl) and then again following the last dose of treatment (Wt2). The difference in body weight (Wt2-Wtl), provides a measure of toxicity related to the treatment. The tumor response was determined by measuring the tumors with a calibrator twice a week, until the tumors reached a predetermined "target" size of 0.5 gm. The tumor weights (mg) were estimated from the formula: Tumor Weight = (length by amplitude2) -r-2. The endpoint of response was expressed in terms of inhibition of tumor growth (% T / C), defined as the ratio of the average tumor weights of the treated tumors (T) to those of the control group (C): estimate the tumor cell death, the double time of the tumor volume was first calculated with the formula: TVDT = mean time (days) for the control tumors to reach an objective size - Mean time (days) for the control tumors reach half of the target size and, Log of cell death = (TC) - * - (3.32 x TVDT) The statistical evaluations of the data were made the Wilcoxon generalized test of Gehan. The following Examples illustrate embodiments of the present invention, and are not proposed to limit the scope of the claims.

Abbreviations The following abbreviations are used here DBU = 1, 8-d? Azab? C? Clo [5.4.0] undec-7-ene 4-DMAP = 4-dimethylaminopyridine ee = enantiomeric excess DMF = dimethylformamide Et = ethyl EtOAc = ethyl acetate LDA = lithium dusopropylamide Base of Humg = N, N-dnsopropylethylamine Me = methyl TR = retention time TFA = tpfluoroacetic acid THF = tetrahydrofuran CCD = thin layer chromatography TM? = trimethylsilyl pT? A = para-toluenesulfonic acid? = heat t-Bu = tere-butyl Ph = Phenyl PhCY - toluene Pd / C = palladium on activated carbon TsCl = tosyl chloride TBSOTf = tpfluor ometan sulfonate tere-butldimethyl lsyl lyo TB? = tert-butyldimethylsilane Mel = methyl iodide (BOCYO = di-tert-butyl bicarbonate TEA = tpetilamma p-BuLi = n-butyllithium ta = room temperature CL = liquid chromatography EtOH = etariol DCE = dichloroethane DM? O = dimethylsulfoxide Ra-Ni = Raney nickel TM = molecular sieves EM (ER) = Electro-Dew mass spectrometry h = hours Ac-acetyl DEAD = a dietary Zodicarboxy lato DPPA = di f em l fos fop la zida Example 1 (5a, 8o., 8aa) -8, 8a-Dihydro-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1,5-a] pyridin-1, 3 (2H, 5H) -diona (IB) A. Ethyl ester of βndo / exo-2- [[[3- (Trifluoromethyl) phenyl] mino] carbonyl] -2-azabicyclo [2.2.1] hept-5-en-3-carboxylic acid (IA) 2-Azabicyclo [2.2.1] hept-5-en-3-carboxylic acid ethyl ester (0.253 g, 0.15 mmol) was dissolved in toluene and 3- (tpfluoromethylphenyl) isocyanate (0.311 g, 0.166 mmol) was added. . The reaction was heated to 70 ° C poi. h and then cooled to -20 ° C for 12 h. The compound IA precipitated on cooling, was filtered and rinsed with cold toluene. During the drying process, 0.097 g of IA was recovered and taken in the next step without further purification.

B. (5a, 8a, 8aa) -8, 8a-Dihydro-2- [3- (trifluoromethyl) phenyl] -5,8-m-tatanoimidazofl, 5-a] pyridin-1, 3 (2H, 5H) -dione (IB) Intermediate Compound IA (0.150 g, mmol) was dissolved in toluene (5 ml) and DBU (0.1 ml) was added. The reaction was heated at 80 ° C for 1.5 h and then the toluene m va cuo was removed. The resulting residue was purified by flash chromatography on S02 eluting with 10 ^ -30 acetone in hexanes to give 0.76 g of Compound IB as a white solid. HPLC: 92% at 2.93 min (retention time) (crmumnd YMC S5 OD? 4.6 x 50 mm eluting with methane] aqueous at 10-90% for 4 minutes containing 0.1% TFA, 4 ml / rnin, verifying 220 nm) MS (RE): m / z 309.09 [M + H] Y Example 2 (5o, 8a, 8ao.) -8, 8a-Dihydro-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1,5-a] pyridin-1, 3 (2H, 5H ) -dione (2C) (Alternative Procedure for the Preparation of IB) A. Ethyl ester of endo / exo-2- (chlorocarbonyl) -2-azabicyclo [2.2.1] hspt-5-en-3-carboalicylic acid, (2A) To a suspension of NaHCO 3 (2.5 g, 30 mmol) in CH 2 Cl at 25 ° C was added phosgene (20% solution, 5.9 g, 12 mmol). 2-Azabicyclo [2.2.1] hept-5-en-3-carboxylic acid ethyl ester (0.5 g, 3.0 mmol) was added and the reaction was stirred at 25oY 'for 2 h. Then, the bicarbonate was filtered and rinsed with CH-C1-. The product was purified by flash chromatography on Si02 eluting with 1% -2% MeOH in CH2C1 to provide 0.367 g of Intermediate Compound 2A as a yellow solid.

B. Ethyl ester of endo / exo-2- [[[3- (Trifluoromethyl) phenyl] amino] carbonyl] -2-azabicyclo [2.2. l] he? t-5-en-3-carboxylic, (2B) J- Intermediate Compound 2A (0.100 g, 0.44 mmol) and 3-tr? Fluoro-methylaniline (0.075 ml, 0.44 mmol) were dissolved in 5.0 ml of toluene. Then catalytic 4-DMAP and dusopr opylamine (0.3 ml, 2.1 mmol) were added. The reaction was heated to 50 ° C for 14 h. The volatile organic products were then removed and the residue was purified by flash chromatography on silica eluting with methanol / CH_C1. to 0.5, -1.0": to give 0.39 g of intermediate compound 2B as a pale yellow oil. 0 C. (5a, 8a, 8a) -8, 8a-dihydro-2- [3- (trifluoromethyl) phenyl] -5,8-m-tatanoimidazo [1,5-a] pyridin-1,3 (2H, 5H) -dione ( 2C) The title compound was prepared as described in Example 1, step B.

Example 3 (5ot, 8a, 8aa) -8, 8a-Di-idro-2- [1-naphthalythyl] -5,8-m-tatanoimidazo [1, 5-a] pyr? Din-l, 3 (2H, 5H) - diona (3B) A. ßndo / exo-2- [(1-naphthalenylamino) carbonyl] -2-azabicyclo [2.2.1] hspt-5-en-3-carboxylic acid ßstßr (3A) 1-naphthyl amine (0.20 g, 1.39 mmol) was dissolved in a solution of tpfosgen (0.136 g, 0.46 mmol in dichloroethane at 25 ° C. The solution was heated to 70 ° C. for 30 min and then turned to Z5. C. Then triethylamine (0.58 ml, 4.17 mmol) was added and the reaction was heated to 70 ° C. After 2 h, the reaction was cooled to 25 ° C. and di dc ethyl ester [? .2.1] was added. hep-5-en-3-carboxylic acid (0.2C9 g, 1.25 mmol) The reaction was stirred at 25 ° C for 14 h, the volatile organic products were then removed m vacuo and the resulting residue was purified by flash chromatography on S? O "eluting with (4: 1 - 1: 1) ethyl acetate / hexanes to give 0.190 g of Intermediate Compound 3A as a white solid.

B. (5", 8a, 8a") -8, 8a-Dihydro-2- [1-naphthalysyl] -5,8-methanoimidazo [1,5-a] pyridin-1,3 (2H, 5H) -dione (3B) e dissolved intermediate 3A (0.150 g) in toluene (5 ml) and DBU (0.1 ml) was added. The reaction was heated at 80 ° C for 1.5 h and then removed with toluene. The resulting residue was purified by flash chromatography on 0 0 eluting with 10% acetone -30 ° C in hexanes to give 0.76 g of Compound 3B as a white solid. HPLC: 95% at 3067 mm (retention time) (YMC SS OD column 4.6 x 50 mm eluting with 10-90q aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / ml, verifying at 220 nm) MS (RE): m / z 291.2 [M + H] Y Example 4 (5a, 8a, 8aa) -2, 3, 8, 8a-Tetrahydro-2- [3- (trifluoromethyl) phenyl] -3- t? Oxo-5,8-methanoim? Dazo [1, 5-a ] pir? din-l, 3 (2H, 5H) -one (4B) A. Endo / ßxo-2- [[[3- (trifluoromethyl) phenyl] amino] thioxomethyl] -2- azabicyclo [2.2. l] hept-5-en-3-carboxylic acid (4A) To a solution of 2-azabicyclo-2-ethyl ester. 2 .1] hept-5-en-3-carboxylic acid (0.253 g, 1.5 mmol) 10 in toluene (7.0 ml) was added 3- (trifluoromethylphenyl) -isothiocyanate (0.339 g, 1.66 mmol). After 14 h at 25 ° C, the reaction was diluted with EtOAc and washed with 1N NaOH (2 x 10 ml.) The organic layer was dried over anhydrous sodium sulfate and the crude material was purified by chromatography on silica gel using a gradient of 0 to 20 [deg.] of acetone in hexane to give 188 mg (34 Y of intermediate 4B.

B. (5a, 8a, 8aa) -2, 3, 8, 8a-Tetrahydro-2- [3- (trifluoromethyl) -phenyl] -3-thioxo-5,8-methoimidazo [1,5-a] pyridine- l (5H) -one (4B) - The intermediate compound 4A (180 mg, r mm -J) was dissolved in anhydrous toluene (5 ml) and DBU (0.042 ml) was added. The reaction was heated to 80 ° C for 1.5 h and then cooled to 25 ° C. The volatiles were removed m va cuo and the resulting residue was purified by flash chromatography on Si0 eluting with a gradient of 0-20% acetone / hexane to give pure compound 4B (67 mg) as a yellow oil. HPLC: 66.9% at 2980 min (retention time; 5 (column YMC S5 OD? 4.6 x 50 mm eluting with 10-90% aqueous methanol for 4 minutes containing 0.1% TFA, 4 ml / min, verifying 220 nm) MS (RE): m / z 343.07 [M + H] +.

Example 5 C (5a, 8a, 8aa) -8,8a-Dihydro-8a-methyl-2- [3- (trifluoromethyl) phenyl] -5,8-m-aminosimidazo [1, 5-a] pyridin-1, 3 ( 2H, 5H) -dione (5) / * & and X "1 5? e dissolved Intermediary Compound IB (0.020 g, 0. 06 mmol, from Example 1) in anhydrous THF (2.0 ml) and cooled to -78 ° C. Then LDA (soln 2.0 M in THF, 0.195 ml) was added slowly. After 1 h, Mel (0.008 ml, 0.12 mmol) was added and the reaction slowly warmed to 25 ° C. The reaction was then quenched with water and extracted with CHY1- (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the pure compound (0.008 g) as a white solid, CLAR: 100% at 3620 min (retention time) (column YMC? 5 ODS, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm) MS (RE): m / z 323.0 [M + H] Y Example 6 (5oc, 8a, 8ao) -2,3,8, 8a-Tetra idro-8a-methyl-3-thioxo-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1, 5 a] pyridin-l (5H) -one (6) To a solution of Compound 4B (0.056 g, 0.173 mmol, Example 4) in THF at -78 ° C, diisopropylamine was added.

And lithium (soln 2.0 M in THF, 0.173 ml). After 2 h, Mel (0.022 ml, 0.35 mmol) was added and the reaction was heated to 25Y; for 2 h. Then HY was added and the mixture was extracted with CH-.C1: (3 x 30 ml). The combined organic layers were dried over anhydrous sodium sulfate. The crude product was purified "And by flash chromatography on? I02 eluting with 10" acetone - in hexanes to give 0.034 g of Compound 6 as a white solid. HPLC: 90% at 4,023 min (retention time) (column YMC? 5 OD ?, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm) MS (RE): m / z 339.0 [M + H] Y Example 7 (5a, 8a, 8a) and (Sot, 8a, 8aβ) -2- (3,5-Dicopropyl) thiahydro-5,8-methanoimidazo [1,5-a] pyridin-1, 3 (2H, 5H) -dione (7Bi and 7Bii, respectively) Endo / ßxo-2- [[[3,5-dichlorophysnyl] amino] carbonyl] -2-azabicyclo [2.2.1] hept-5-en-3-carboxylic acid ßstβr (7a) To a solution of 3,5-dichlorophenylisocyanate (3.01 g, 16 mmol) in toluene (100 ml) was added 2-azabicyclo [2.2.1] heptan-3-carboxylic acid ethyl ester (2.70 g, 16.0 mmol) in toluene and the reaction was stirred at 25 ° C for 14 h. A white solid formed after 14 h and diethyl ether was added to precipitate more product. The reaction was then filtered and rinsed with cold diethyl ether. The crude urea intermediate, 2.81 g of a white solid, was isolated by filtration, dried and used directly in the next step.

B. (5a, 8a, 8aa) and (5a, 8a, 8aß) -2- (3,5-dichlorophrysil) tetrahydro-5,8-methanoimidazo [1,5-a] pyridin-1, 3 (2H, 5H ) -dione (7Bi and 7Bii) and added compound 7A (0.025 g, 0.070 mmol) to a suspension of TM (0.050 g) of recently activated 4Á in toluene (2.0 ml). DBU (0.42 ml, 2.96 mmol) was then added followed by heating at 80 ° C for 2 h. The mixture was then cooled to 25 ° C and filtered through cellta and extracted with methylene chloride. The organic products were washed with IN HCl and then dried over anhydrous sodium sulfate. Raw NMR showed a mixture of Compound 7Bi and Compound 7Bi ?, in a ratio of 2: 1.5, respectively. The diastereomers were separated by preparative CCD in O O "eluting with methylene chloride. This gave 0.006 g of Compound 17Bi as a white solid and 0.008 g of Compound 17Bii I blunt a white solid. 17Bi: CLAR: 100% at 3.383 min (retention time) (column YMC? 5 ODS, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm) MS (ER ): m / z 312.1 [M + H] 4. 17BÜ: CLAR: 99 '. to 3. ^ m :. (retention time) (column YMC? 5 OD? 4.6 x 50 mm eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm) EM (ER) : m / z 311.2 [M + H] +.

EXAMPLE 8 T-Hydro-2- [3- (trifluoromethyl) phenyl] -5,8-btanoimidazo [1,5- a] pyridin-1, 3 (2H, 5H) -dione (8B) 2 - [[[3- (trifluoromethyl) phenyl] amino] carbonyl] -2-azabicyclo [2.2.2.] octane-3-carboxylic acid ethyl ester (8A) To a solution of 2-azabicyclo-ethyl ester [2.2.2. ] octane-3-carboxylic acid (50 mg, 0.27 mmol) in anhydrous toluene (10 ml) was added 3- (tpfluoromethylphenyl) isocyanate (55.5 mg, 0.3 mmol). The reaction was stirred at 25 ° C overnight, then concentrated in vacuo and purified by preparative CCD on silica gel eluting with 30% acetone in hexanes to provide 37 mg (37%) of Intermediate Compound 8A .

B. T? Transhydro-2- [3- (tri luoromethyl) phenyl] -5,8-ethanoimidazo [l, 5-a] pyridin-l, 3 (2H, 5H) -dione (8B) To a solution of intermediate Compound 8A (37 mg, 0.1 mmol) in anhydrous toluene (10 ml) was added DBU (20 μL, 0.11 mmol). The solution was heated at 80 ° C for 2 hours. The solvent was removed by rotary evaporation and the crude material was purified by preparative HPLC on silica gel eluting with 30% acetone in hexanes to provide 16 mg (49 Y of Compound 8B as a white solid) HPLC: 99% at 3433 mm (retention time) (column YMC? 5 ODS 4.6 x 50 rr-m eluting with 10-90% aqueous methanol for 4 minutes containing 0.2V phosphoric acid, 4 ml / rnin, verifying at 220 nm) MS (ER ): m / z 325.2 [M + H] Y Example 9 (5 «, 8a, 8aa) and (Sot, 8, 8aß) -Tetrahydro-2- [3- (trifluoromethyl) -lysyl] -5,8-methanoimidazo [1,5-a]? Iridin-1, 3 (2H, 5H) -dione (9Fi and 9Fii, respectively) Path dβ Solid Support Synthesis A. Modified Mármifield Resin Formation (9A) Modified Marrifißld Resin To a suspension of NaH (60% in mineral oil, 0.353 g, 8.84 mmol) in DMF at 0 ° C was slowly added 3- (4-hydroxyphenyl) -1-proanol (1.3 g)., 8.55 mmol), and then warmed to 25 ° C and stirred for 1 h. The Merrifield resin (5 g, 0.57 mmol / g) was washed sequentially with methylene chloride, DMF and then suspended in 20 ml of DMF. The preformed alkoxide was added to the resin for a period of 5 minutes. The reaction was then heated to 80 ° C for 13 h. After cooling to 25 ° C, the reaction was filtered and sequentially rinsed with DMF (3 x 50 ml), hexanes (2 x 50 ml), methylene chloride (3 x 50 ml), methanol (2 x 50). ml), methylene chloride (3 x 50 ml) and dried under vacuum to give a white resin (4.6 g). NMR of solid-phase protons demonstrates the incorporation of the 3- (4-hydroxyphenyl) -1-propanol linker to form Resin 9A.

B. 2- (1, 1-dimethylethyl) ester of ßndo / exo-2-azabicyclo [2.2. l] heptan-2,3-dicarboxylic acid (9B) ? e dissolved 2-azabicyclocid ethyl ester [2.2.1. ] heptan-3-carboxylic acid (10.0 g, 59.0 mmol) in a mixture of dioxane (120 ml), water (60 ml) and IN NaOH (66 ml). Then (BOC) 0 (14.4 g, 218.25 mmol) was added and the mixture was stirred at rt for 14 h. The volatile organic products were removed in vacuo and then additional water (200 ml) was added and the mixture was extracted with CH2C1; (2 x 200 ml). The aqueous layer was then adjusted to pH = 4-5 with the addition of 5% KH? 04. The mixture was then extracted with CH2CY (3 x 100 ml). The combined organic layers were concentrated to give intermediate Compound 9B, crude, with a white solid (8.5 g). This material was recovered without further purification.

C. dés 2- (1,1-dimethylethyl) 3- (Modified Merrifield Resin) ester of endo / exo-2-azabicyclo [2.2. l] heptan-2, 3- dicarboxylic (9C) To Resin 9A was added DMF (15 ml) followed by shaking for 15 minutes. Compound 9B (0.275 g, 1.14 mmol) was then added in DMF followed by pyridine C (0.152 mL, 1.88 mmol). The addition of 2,6-dichlor obenzoyl chloride (0.163 ml, 1.14 mmol) was added and the reaction was shaken for 1 day. The identical amounts of acid, pipdin and chloride were then added followed by shaking for 2 days. Then, the reaction was filtered and rinsed in a And sequentially with DMF (3 x 20 ml), methanol (3 x 20 ml), methylene chloride (6 x 20 ml) and dried m va cuo to give Resin 9C as a white powder.

D. Modified Merrifield Resin ester of endo / exo-2- 0 azabicyclo [2.2.1. ] heptan-3-carboxylic acid (9D) The res at 9C (1 g) was suspended in TFA / DMF at 50- (30 ml) and sonicated at 60 ° C for 18 h. Then the reaction was filtered and washed with DMF (5 x 20 ml), methanol (2 x 20 ml), methylene chloride (2 x 20 ml) and dried ba or vacuum to give 0.7 g of Resma 9D as a white powder.

E. Be of modified Merrifiable Resin of endo / exo-2- [[[3- (trifluoromethyl) phenyl] mino] carbonyl] -2-azabicyclo [2.2, 1] h-ptan-3-carboxylic acid (9E) Resin 9D (0.50 g) was suspended in CHY1 (10 ml) and 3- (trifluoromethylphenyl) isocyanate (0.5 ml, 1.25 mmol) was added and the reaction shaken for 24 h. The ream was filtered and washed with CHYY (8 x 20 ml) and dried m va cuo to give Resma 9E as a yellow solid.

F. (5a, 8a, 8aa) and (5a, 8a, 8aβ) -Tβ-tetrahydro-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1,5-a] pyridine-1,3 (2H , 5H) -dione (9Fi and 9FÜ) To Dry 9E was added dry toluene (10 ml) and 0.25 g of activated 4A TM. Then DBU (0.25 ml) was added, and the reaction was heated at 80 ° C for 1.5 h.The reaction was filtered and rinsed with CH2C12 and the organic products were washed once with 1N HCl followed by drying over anhydrous sodium sulfate. The resulting process produced 24 mg (26% yield from the Merrifield resin charge) of a 4 to 1 mixture of 9Fi and 9Fii compounds, respectively Separation of 9Fi and 9Fii compounds was achieved by preparative HPLC (0% aqueous methanol - 100% for 20 minutes, 10 YMC ODSA reverse phase column, 20 x 100 mm) to give 0.005 g of Compound 9Fi as a white solid and 0.019 g of Compound 9Fii as a white solid. Example 11 and 12 for characterization Example 10 - "(5, 8a, 8aa) and (5, 8a, 8aß) -Tetrahydro-2- (2-naphthalenyl) -5,8-methanoimidazo [1,5-a] pyridine -l, 3 (2H, 5H) -dione (lOCi and lOCii, respectively) A. Modified M rrifield Resin ester of endo / exo-2- (chlorocarbonyl) -2-azabicyclo [2.2.1] heptan-3-carboxylic acid (10A) Ream 9D (0.50 g, synthesized as described in Example 9 ) was suspended in CH2C12 (10 ml) and phosgene (20% in toluene, 4.5 g) and NaHCO3 (1.5 g) were added. The resin was shaken for 22 h at 22 ° C and then filtered by rinsing with CHC1 (5 x 50 ml). The resin is then dried m va cuo to give Resma 10A as a yellow resin.

B. Be of Modified Merrifield Resin of ßndo / βxo-2- [(2-naphthalenylamino) carbonyl] -2-azabicyclo [2.2.1] eptan-3-carboxylic acid (10B) Res 10A (0.70 g) was suspended in CH2C12 (15 ml) and 2-naphthalamine (0.58 g, 4.0 mmol) was added. The base of Humg (0.88 ml) and 4-catalytic DMAP were added and the mixture was shaken at 70 ° C for 20 h. After cooling to 22 ° C, the ream was filtered and washed with CH-CY (8 x 20 ml) and dried m va cuo to give Resin 10B as a yellow solid.

C. (5a, 8, 8aa) and (5a, 8a, 8aß) -Tβ-tetrahydro-2- (2-naphthalenyl) -5,8-methanoimidazo [1, 5-a] pyridin-1, 3 (2H, 5H) -dione (lOCi and lOCii) To dry resin 10B (0.70 g) was added dry toluene (10 ml) and 0.25 g of activated 4A TM. Then DriC (0.65 ml, 4.0 mmol) was added and the reaction was heated to 80 ° C for 2.0 h. The reaction was filtered and rinsed with CH2C12 and the organic products were washed twice with IN HCl (30 ml) followed by drying over anhydrous sodium sulfate. The resulting process yielded 13 mg (11% yield) of a 1.5 to 1 mixture of Compound IOCi and IOCii, respectively. The separation of the mixture was achieved by flash chromatography on? IO. eluting with 1% MeOH in CH: CY to give 6 mg of IOCi as a white solid and 4 mg of Compound IOCii as a white solid. lOCi: CLAR: 99% at 2.94 minutes (YMC column? 5 OD ?, 4.6 x 50 mm; MeOH / H gradient: 0 to 10-90%, + 0.1% TFA, 4 ml / mm, detection at 220 nM) MS (RE): m / z 293.0 [M + H] +. lOCii: CLAR: 99% to 3.09 minutes (YMC column? 5 ODS, 4.6 x 50 mm; 10-90% MeOH / H0 gradient, 0.1% TFA, 4 ml / min, 220 nM detection) EM (ER ): m / z 293.0 [M + H] Y Example 11 (5a, 8o, 8aβ) -Tetrahydro-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1,5-a] pyridin-1,3 (2H, 5H) -dione (11 ) To a suspension of TM of recently activated 4Á 5 (1.5 g) in toluene (15 ml) was added ethyl ester of 2-azabicyclo [2.2.1. ] heptan-3-carboxylic acid (0.50 g, 2.96 mmol) in toluene. After 15 min, 3- (trifluoromethyl-femlisocyanate (0.41 ml, 2.96 mmol) was added and the reaction was stirred at 25 ° C for 14 h, then DBU (0.42 ml, 2.96 mmol) was added "> followed by heating at 80 ° C for 2 h The mixture was then cooled to 25 ° C and filtered through celite by rinsing with methylene chloride.The organic compounds were recovered to dryness and allowed to stand alone in the remaining DBU at 35 ° C. The crude mixture was purified by silica gel chromatography to give 735 mg (yield 80. Y.) of Compound 11 as a white solid, HPLC: 98% at 3.117 min (retention time) (YMC column). ? 5 OD ?, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / rnin, verifying 220 0 nm) MS (ER): m / z 311.1 [M + H] Y Example 12 (5a, 8a, 8aa) and (5a, 8ot, 8aß) -Tetrahydro-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1,5-a] pyridine-1,3 (2H , 5H) -dione (12i and 12ii, respectively) ? e prepared LDA by treating dusopropyl amine (0.091 ml, 0.650 mmol) in THF at -78 ° C with n-BuLi (1.6 M in hexanes, 0.304 ml). After 20 min, Compound 11 (0.100 g, 0.325 mmol) 0 was added slowly to LDA in THF. The reaction was slowly heated to -20 ° C and maintained for 15 min. The reaction was then cooled to -78 ° C and quenched by the addition of sat. NHjCl. Then the solution was extracted with CH, _C12 (3 x 30 ml) and the organics were dried under anhydrous sodium sulfate. The crude material was purified by preparative CCD on αO_ eluting with CHY12 to give a 1: 3 mixture of Compound 12i (Compound 11) and 12ii (0.091 g, 91%) as a white solid. 12ii: HPLC: 98% at 2987 m (retention time) (column YMC S5 ODS, 4.6 x 50 mm, eluting with 10-90 ° aqueous methanol for 4 minutes containing phosphoric acid at 0 JJ 4 ml / mm, verifying at 220 nm) MS (RE): m / 2 311.1 [M + H] J Example 13 (5 «, 8a, 8aa) and (5a, 8ot, 8aß) - [[2- (3,4-dichlorophenyl) Octahydro-1-oxo-5,8-methanoimidazo [1,5-a] pyridin-3-ylidene] amino] (13Bi and 13Bii, respectively) A. Ethyl esters of endo / exo-2- [(cyanoimino) [(3,4-dichlorophenyl) amino] methyl] -2-azabicyclo [2.2. l] β-ptan-3-carboxylic acid (13A) The 2-azabicyclo [2.2.1] heptan-3-carboxylic acid ethyl ester (169 mg, 1.0 mmol, 1 eq) in dimethylformamide was combined with N-cyano-N '- (3,4-dichlorophenyl) -thiourea ( 246 mg, 1.0 mmol, 1 eq) and l- [3- (dimethylamine) propyl] -3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol, 0.5 eq). The mixture was stirred at room temperature overnight. The reaction was quenched with IM citric citric acid and extracted with CH2C12. The combined organic extracts were dried and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with 30% acetone in hexanes to provide 192 mg (50.4%) of Compound 13A as a white semisolid. HPLC: 100% at 3260 minutes (column YMC 5 Combiscreen OD? -A? 5 eluting with aqueous methanol at 10-90, for a gradient of 4 minutes) MS (ER): m / z 381. [M + H] + .

B. (5a, 8, 8a) and (5a, 8a, 8aβ) - [[2- (3, -dichlorophenyl) octahydro-l-oxo-5, 8-methanoimidazo [1,5-a] pyridin-3- yliden] amino] (13Bi and 0 13Bii) Compound 13A (180 mg, 0.47 mmol, 1 eq) was combined in anhydrous toluene with DBU (72 mg, 0.47 mmol, 1 eq). The solution was heated at 60 ° C for 1 h. CCD (plate of Si0, CH- ^ OH to 1? In CH2C1) does not show remnants of materials of ! 5 game, although verification by CL indicated a peak with the same retention time as the starting material. The reaction was quenched with saturated aqueous NH4CI and extracted with CH2C12. The combined organic extracts were dried and concentrated in vacuo. The crude material was purified r "by flash chromatography on silica gel eluting with CH-, OH at 0.5 ^ in CH2C12 to provide two isomers. Compound 13Bi was obtained in 52% yield (82 mg) as a white semi-solid. HPLC: 100% at 3297 minutes (column YMC Combiscreen OD? -A S5 eluting with 10-90 aqueous methanol, po: a gradient of 4 minutes.) MS (RE): 335.08 [M + J. Compound 13BÜ was obtained in 25% yield (40 mg) as a white solid. HPLC: 100% at 3323 minutes (YMC Combiscreen ODS-A column 5 eluting with 10-90% aqueous methanol over a 4 minute gradient.) MS (ER): m / z 335.06 [M] + - and 337.07 [ M + 2H] Y Example 14 (5 «, 8a, 8a«) - 8a- [(4-Bromophenyl) methyl] -2- (3, 5-dichlorophenyl) tetrahydro-5,8-methanoimidazo [1,5-a] pyridin-1, 3 (2H, 5H) -dione (14) Compound 7Bi (0.217 g, 0.701 mmol, prepared as described in Example 7) was added to freshly prepared LDA (1.227 mmol n-BuLi, 1.402 mmol diisopropylamine) in THF at -78 ° C. After the addition, the reaction was slowly heated to -20 ° C and maintained at this temperature for 20 minutes. The mixture was then cooled to 78 ° C and 4-bromobenzyl bromide (0.175 g, 0.70 mmol) in THF was added.The reaction was then heated to 0 ° C and after 2 h, it was quickly cooled by the addition of Saturated NH4C1, then the solution was extracted with CH1Cl (2 x 30 ml) and dried by anhydrous sodium sulfate The resulting material was purified by preparative silica gel CCD eluting with CHC12 to give Compound 14 ( 0.083 g) as a clear oil CLAR: 98% at 4160 min (retention time) (column YMC S5 OD ?, 4.6 x 50 mm, eluting with 10-90"aqueous methanol? for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm) MS (RE): m / z 481.1 [M + H] +.

Example 15 (5a, 8a, 8ao) -H -xaxahydro-2- (2-naphthalenyl) -3- (phenylimino) -5,8-methanoimidazo [1, 5-a] pyridin-l (5H) -one (15B) A. N- (2-Naphthalenyl) -2-azabicyclo [2.2. l] h-ptan-3-carboxamide (15A) Compound intermediate 9B (1.00 g, 4.15 mmo--, as prepared in Example 9) was dissolved in CH.C1 Y. ml) and TEA (2.31 ml, 16.6 mmol) and 2,6-dichlorobenzoyl chloride (0.594 ml, 4.15 mmol) were added.The mixture was stirred for 14 h and 2-aminonaphtal (0.593 g, 4.15 mmol) was added. in CH2C1 followed by the addition of 4-DMAP (0.010 g) After 3 h, the reaction was diluted with CH2C12 and washed once with IN HCl (40 mL), once with sat. NaHCO3. ac. (40 ml) and dried over anhydrous sodium sulfate. The crude intermediate (1.00 g, 2.73 mmol) was dissolved in CH2C1 (2.0 mL) and treated with TFA (2.0 mL) at 20 ° C. After 3 h, the reaction was quenched with aqueous sat'd NaHC03, and extracted with CH2C12 (3 x 30 mL) and dried over anhydrous sodium sulfate. The crude reaction was purified by preparative reverse phase HPLC to give 0.770 g of Compound 15A as a white solid.

B. (5a, 8a, 8aa) -H -xahydro-2- (2-naphthaleni) -3- (phenylimino) -5,8-methanoimidazo [1,5-a] pyridin-1 (5H) -one (15B) Intermediate compound 15A (0.050 g, 0.188 mmol) was dissolved in dichloroethane (2.0 ml) and phenyl isocyanide dichloride (0.026 ml, 0.188 mmol), 4-DMAP (0.010 g) and DBU (0.084 ml, 0.564 mmol) were added. , and the reaction was heated to 90 ° C in a sealed tube. After 14 h, the reaction was cooled to room temperature and concentrated m va cuo. The residue was purified by preparative CCD in αO_ eluting with CH 2 Cl 2 / acetone (9: 1) to give 0.063 g of Compound 15B as a cinnamon oil. HPLC: 93% at 3590 m (retention time) (column YMC? 5 ODS, 4.6 x 50 mm eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / mm, verifying 220 nm) MS (RE): m / z 368.37 [M + H] +.

Example 16 Hexahydro-2- [3- (trifluoromethyl) ßnil] -5,8-methanoimidazo [1,5- a] pyridin-l (5H) -one (16) Compound 4B (0.020 g, 0.062 mmol, as described in Example 4) was dissolved in absolute EtOH (2.0 mL) and Ra-Ni (excess) was added. After 3 h at 25 ° C, the reaction was filtered through celite by rinsing with EtOH. The crude material was purified by preparative CCD eluting with 30- acetone in hexanes, yielding 0.6 mg of Compound 16 as a white solid. HPLC: 100% at 2437 min (retention time) (column YMC? 5 OD ?, 4.6 x 50 mm eluting with 10-90% aqueous methanol for 4 minutes containing phosphoric acid at 0.2> -, 4 ml / min ., verifying at 220 nm) MS (RE): m / z 297.3 [M + H] J Alternative Preparation of Compound 16: A. (5, 8a, 8aa) -Hexahidro-3-thioxo-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1, 5-a] pyridin-1 (5H -one (16A) 2-Dzabicyclo-ethyl ester [.2.1. ] hept-5-en-3-carboxylic acid (0.250 g, 0.15 mmol) in toluene and 3- (trifluoromethylphenyl) isothiocyanate (0.334 g, 0.166 mmol) was added. The reaction was stirred at 25 ° C for 14 h and then IN NaOH (4 ml) was added. After half an hour, the aqueous layer was extracted with dichloromethane (3 x 25 ml). The combined organic layers were washed with brine (50 ml) and dried over Na 2 SO 4 and then the solvent was removed m • sa cuo. The resulting residue was purified by flash chromatography on 022 eluting with 10L acetone > -30% in hexanes to give 0.378 g of compound 16A as a yellow solid.

B. Hexahydro-2- [3-trifluoromethyl) phenyl] -5,8-methanoimidazo- [1,5-a] pyridin-1 (5H) -one (16b or 16) Compound 16A (0.020 g, 0.062 mmol) was dissolved in ethanol (2 ml) and Ra-Ni (-0.020 g) was added. After 3 h, the reaction mixture was filtered through cellta, concentrated, and the resulting residue was purified by preparative CCD on silica eluting with acetone to 30 I in hexanes to give 0.8 mg of 16 B as a white solid. HPLC: 99% at 2437 min (retention time) (column YMC? 5 ODS, 4.6 x 50 mm eluting with 10-90% aqueous methanol for 4 minutes containing 0.1% TFA, 4 ml / min, verifying 220 nm) MS (ER): m / z 29Y3 [M + H] Y Example 17 [5R- (5o, 8, 8aa)] and [5R- (5ot, 8a, 8aß)] -Tetrahydro-2- (4-nitro-1-naphthalenyl) -5,8-methanoimidazo [1, 5 a] pyridin-1, 3 (2H, 5H) -dione (17i and 17ii, respectively) ? e dissolved ethyl ester of R-2-azabicyclo acid [2.2.1. ] he-tan-3-carboxylic acid (0.169 g, 1.0 mmol) in toluene (10 ml) with recently activated 4 A TM (0.200 g).

To this was added an isocyanate solution of 4-m-l-naphthyl (0.210 g, 1.0 mmol), prepared in analogy to the procedure described in Example 3, step A) in 5 ml of toluene. After 15 h, the reaction was complete by LC, and DBU (0.224 mL, 1.5 mmol) was added and the reaction was heated at 80 ° C for 1.5 h. After cooling to rt, the reaction was filtered and then poured into IN HCl and extracted with CH2CY (2 x 30 ml). The organic compounds were dried over anhydrous sodium sulfate and then concentrated. It was determined that the The crude mixture is a 1: 2 ratio of Compound 17i and 173.1, respectively. The reaction mixture was separated by flash chromatography on silica gel eluting with CH_CY / acetone (1% acetone) to give Compound 17: HPLC: 98- to 2923 min (retention time) (column YMC S5? 5 OD ?, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm) MS (RE): m / z 338.1 [M + H] + and Compound 17 ??: CLAR: 96o- to 2753 mm (retention time) (column YMC? 5 OD ?, 4.6 x 50 mm, eluting with 10-90% aqueous methanol) -0 4 minutes, containing 0.2% phosphoric acid, 4 ml / mm, verifying at 220 nm) MS (ER): m / z 338.1 [M + H] \? E determined that both were Q4 ee by CLAR analysis chiral Example 18 (6a, 9ot, 9aa) -Tetrahydro-2- [3- (trifluoromethyl) phenyl] -6, 9-methane-2H-pyrido [1,2-d] [1, 2, 4] riazin-1, 4 (3H, 9aH) -dione (18D) - * & < -, CF3 A. 3 - [[3- [Trifluoromethyl] fanyl] amino] carbonyl] -2-azabicyclo [2.2. l] heptan-2-carboxylic acid The intermediate Compound 9B (964 mg, 4 mmol, 1 eq, Example 9) was dissolved in 20 ml of tetrahydrofuran and 1-methyl-2-pyrrolidone (487 μl, 4 mmol, 1 eq) was added. Methyl chloroformate (309 μl, 4 mmol, 1 eq). The mixture was stirred at rt for 15 min. Then 3- (Tpfluoromethyl) aniline (499 μl, 4 mmol, 1 eq) was added, and the reaction was stirred at rt for 72 h. The reaction was quenched by the addition of water and 0.1M aqueous citric acid. The mixture was extracted with Cri2Cl2. The combined organic extracts were dried, concentrated m va cuo, and purified by flash chromatography on silica gel eluting with 0.3% methanol in CH2C12 to provide 640 mg (41.6%) of Intermediate 18A.

B. 3 - [[1- [3- (Trifluoromethyl) phenyl] hydrazino] carbonyl] -2-azabicyclo [2.2.1] heptan-2-carboxylic acid ßstßr dl 1,1-dimethyl-ethyl ester (18B) Compound 18A (308 mg, 0.8 mmol, 1 eq) was dissolved in 15 ml of tetrahydrofuran. Sodium hydride (60% in oil, 38 mg, 0.96 mmol, 1.2 eq) was added, and the mixture was stirred at rt for 15 min. Then 0-diphenylphosphinylhydroxylamine (224 mg, 0.96 mmol, 1.2 eq) was added, and the reaction was stirred at rt for 1 h. The CL analysis indicated that the starting material had been consumed. Water was added, and the reaction was extracted with CH2C12. The combined organic extracts were dried and concentrated in vacuo to provide Compound 18B as a semi-solid in quantitative yield. The compound was used without further purification. CL: T.R. = 3.39 min (retention time) (column YMC Combiscreen OD? -A S5, eluting with 10-90% aqueous methanol for a gradient of 4 minutes).

C. 1- [3- (trifluoromethyl) -nyl] hydrazide of 2-azabicyclo [2.2. l] hβptan-3-carboxylic acid Compound 18B (136 mg, 0.34 mmol, 1 eq) was dissolved in 5 ml of CH2Cl2. trifluoroacetic acid (2 ml) was added, and the mixture was stirred at rt for 1 h. The CL analysis showed complete conversion to Compound 18C. The crude material was concentrated in va cuo and recovered in the next step.

D. (6a, 9a, 9aa) -Tβ-tetrahydro-2- [3- (trifluoromethyl) phenyl] -6,9-methane-2H-pyrido [1,2-d] [1, 2, 4] triazin-1, 4 (3H, 9aH) -dione (18D) Compound 18C was dissolved in 10 ml of CH2Cl2, and Hunig's base (10 eq) was added to bring the pH to 10.

The mixture was cooled to 10 ° C. Trifosgen (ca 1.5 eq) was dissolved in CH 2 C 12 and added dropwise to the reaction mixture. The reaction was stirred at 0 ° C and then allowed to stir at rt overnight. The CL analysis indicated that the starting material had been consumed. The mixture was washed with saturated aqueous NH 4 Cl, followed by saturated aqueous NaCl.

The CH2C12 layer was dried, concentrated in vacuo and purified by flash chromatography on silica gel eluting with 2% methanol in CH2C12- The material was further purified by preparative CL to provide 15 mg (14%) of Compound 18D as a light yellow solid. CLAR: 100% at 2523 min (retention time) (column YMC Combiscreen ODS-A S5 eluting with 10-90% aqueous methanol for a 4 minute gradient). MS (APCl): m / z 326.2 [M + H] +.

Example 19 (5, 8a, 8aa) and (5ot, 8ot, 8aβ) -8, 8a-Dihydro-2- (1H-indol-3-yl) -5, 8-m-atanoimidazo [1, 5-a] ir iridin -l, 3 (2H, 5H) -dione (19Bi and 19Bii, respectively) A. 3-Isocyanatoindole (19A) To a solution of mdol-3-carboxylic acid (1 g, 6.20 mmol, 1 eq) in 30 ml of tetrahydrofuran, tetylamine (0.86 ml, 6.20 mmol, 1 eq) and diphenylphosphoryl azide (1.3 ml, 6.20 ml) were added. mmol, 1 eq). The reaction was stirred at rt overnight. The mixture was concentrated m va cuo and purified by flash chromatography on silica gel eluting with 25% ethyl acetate in hexanes to provide a quantitative yield of the intermediate azide. The azide was heated at 100 ° C in 60 ml of toluene for 5 h. The m concentration gave the complete conversion to Compound 19A which was used directly in the next step.

B. (5a, 8a, 8aa) and (5a, 8, 8aβ) -8, 8a-Dihydro-2- (1H-indol-3-yl) -5,8-m-atanoimidazo [1,5-a] pyridine- l, 3 (2H, 5H) -dione (19Bi and 19Bii) To Compound 19A (6.20 mmol, 1 eq) in 50 ml of toluene at low Ta, was added a solution of 2-azab? c-ethyl ester? clo [2.2.1] heptan-3-carboxylic acid (1.03 g, 6.20 mmol, 1 eq) in 10 ml of toluene with TM of 4Á. The CCD analysis after several hours indicated that the starting material had been consumed. DBU (0.93 ml, 6.20 mmol, 1 eq) was added and the reaction was heated at 80 ° C for 3 h. The mixture was cooled, filtered and purified by flash chromatography on silica gel eluting with 50% acetone in hexanes to provide 120 mg (7%) of Compound 19Bi as yellowish cinnamon crystals. An additional 495 mg (29%) of material was a 4: 1 mixture of 19Bi and 19Bii, respectively. HPLC: 94% at 2.17 min (retention time) (YMC column? 5 OD ?, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm). MS (APCl): m / z 279.8 [M + H] +.

Example 20 (5, 8a, 8aa) -2- (Benzo [b] thiophen-3-yl) -8,8a-dihydro-5,8-methanoimidazo [1, 5-a] pyridin-1, 3 (2H, 5H) -dione (20B) A. 3-Aminobenzothiophene (20A) To a solution of 3-amino-benzo [b] thiophene-2-carboxylic acid methyl ester, (1 g, 4.83 mmol, 1 eq) in 1-methyl-2-? -rollolidinone (8 ml) was added piperazine (2.08). g, 24.13 mmol, 5 eq). The reaction was stirred at 130 ° C overnight. Ice was added, and the mixture was extracted with ethyl acetate. The organic extracts were washed twice with water, dried and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in hexanes to provide 600 mg (83%) of Compound 20A as a yellow oil.

B. (5a, 8a, 8ao) -2- (Banzo [b] thiophen-3-yl) -8,8a-dihydro-5,8-methanoimidazo [1,5-a] pyridin-1, 3 (2H, 5H) -dione (20B) was added Compound 20A (480 mg, 3.22 mmol, 1 eq) to a mixture of phosgene (20% in toluene, 6.38 g, 12.88 mmol, 4 eq) and NaHCO 3 (2.7 g, 32.2). mmol, 10 eq) in CH2Cl2 (50 ml). The resulting mixture was stirred at low N 2 for 10 min, filtered to remove NaHCO 3, and concentrated by evaporation without heating. To the resulting isocyanate was added ethyl ester of 2-azab-cyclo [2.2.1. ] hept-5-en-3-carboxylic acid (599 mg, 3.54 mmol, 1.1 eq) in 25 ml of toluene with TM of 4Á. The reaction was stirred at rt overnight. DBU was added (0.48 ml, 3.22 mmol, 1 eq) and the reaction was heated to 76 ° C by 2 h. The mixture was cooled, filtered through celite, and poured into aqueous, saturated NH 4 Cl solution. The mixture was extracted with CH2C13. The organic extracts were concentrated in vacuo and purified by flash chromatography on silica gel eluting with 0.6% methanol in CH2C12 to provide 480 mg (50.4%) of Compound 20B as a light yellow solid. HPLC: 99% at 2.57 min (retention time) (column YMC S5 OD ?, 4.6 x 50 mm eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying 220 nm) MS (RE): m / z 297-1 [M + H] +.

Example 21 (5a, 8a, 8aa) and (5a, 8ot, 8aβ) -2- (1,2-benzisoxazol-3-yl) tetrahydro-5,8-methanoimidazo [1,5-a] pyridin-1, 3 (2H, 5H) -dione (21Bi and 21BÜ, respectively) A. be ethyl acid ando / exo-2- [(1,2-benzisoxazol-3-ylamino) -2-azabicyclo [2.2.2] octane-3-carboxylic acid (21A) 1,2-Benzisoxazol-3-amine (134 mg, 1 mmol, 1 eq) was added to phosgene (20% in toluene, 0.5 ml, 1 mmol, 1 eq) in 5 ml of ethyl acetate at -5 ° C. . The reaction was allowed to warm to rt and then heated to reflux for 40 min. The mixture was cooled to rt and 2-azabicyclo-ethyl ester [2.2.1. ] heptan-3-carboxylic acid (422 mg, 2.5 mmol, 2.5 eq). The reaction was stirred at reflux for 2 h. The mixture was poured into water and extracted with CH2C12. The organic extracts were concentrated in vacuo and purified by flash chromatography on silica gel eluting with CH2C12 to provide 148 mg (45.0%) of Compound 21A as a light yellow solid.

B. (5a, 8a, 8aa) and (5a, 8, 8aß) 2- (1, 2--3yl bßncisoxazol)-tetrahydro-methanoimidazo 5,8 [l, 5a] pyridin-l, 3 (2H, 5H) -dione (21Bi and 21BÜ) ? e dissolved Intermediary Compound 21A (140 mg, 0.42 mmol, 1 eq) in toluene with TM of 4Á. DBU (65 mg, 0.42 mmol, 1 eq) was added and the reaction was stirred at 80 ° C for 1 h. The mixture was quenched with 5% aqueous HCl and extracted with CHC12. The organic extracts were dried, concentrated in going cuo, and purified by flash chromatography on silica gel eluting with CH2C12 to afford 16 mg (13.4%) of Compound 21Bi and 47 mg (39.5%) of Compound 21Bii. Compound 21Bi: CLAR: 93% at 2.367 min (retention time) (column YMC S5 ODS, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying 220 nm) MS (RE): m / z 284.12 [M + H] +. Compound 21Bii: CLAR: 95% a 2. 517 min (retention time) (column YMC S5 ODS, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 ml / mm, verifying 220 nm) MS (RE): m / z 284.13 [M + H] +.

Examples 22 to 88 Using the procedures described herein or by modification of the procedures described herein readily available to a person of ordinary skill in the art, the following additional compounds of Table 2 were prepared. Those of the following compounds which were prepared in pure enantiomeric form, are indicated in the structure box by the nomenclature (R) or (S). Those compounds not indicated were racemic mixtures which can easily be separated by one of ordinary skill in the art or prepared enantiomerically pure by the procedures described herein.

Table 2 The chromatography techniques used to determine the retention times of the compound of Table 2, are as follows: LC = YMC column? 5 OD ?, 4.6 x 50 mm, eluting with 10-90% MeOH / H20 for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm CLEM = YMC column? 5 OD ?, 4.6 x 50 mm, eluting with 10-90% MeOH / H20 for 4 minutes containing 0.1% TFA , 4 ml / min, verification at 220 nm --or EXAMPLE 89 Be 2- (1,1-diptylethyl) 6-mitylic acid (lS-βxo) -2,5-diazabicyclo [2.2. l] heptan-2,6-dicarboxylic acid and 2- (1,1-di-ethyl-ethyl) -6-methyl ester acid (lS-endo) -2,5-diazabicyclo [2.2. l] he-tan-2, 6-dicarboxylic This example illustrates a preferred method for obtaining a compound of the formula lia, the compound is useful as an intermediate in the preparation of the compounds of formula I (see, for example, Figure 2 herein).

A. asters 1, 1-dimethylethyl (2S-trans) -4-hydroxy-2- [[t (1, l-dimßtiletil) dimethylsilyl] oxy] mßtil] -1-pyrrolidinecarboxylic (89A) acid The N (-terc-butoxicarboml) -L-4-h? Drox ?? rolma YO. Og, 43.1 mmol) was dissolved in THF and cooled to 0 ° C. Then Borane / THF (1.0 M solution, 86.6 mL) was added over a period of 15 minutes. The reaction was then heated to 25 ° C followed by heating at reflux for 16 hours. The reaction flask was then removed from the heat source and anhydrous methanol (35 mL) was slowly added. After cooling to 25 ° C, the solvent was removed in vacuo and the resulting crude diol intermediate was taken directly. The crude diol (1.81 g, 8.34 mmol) was dissolved in methylene chloride (50 mL), 2,6-lutidine (1.46 mL, 12.51 mmol) was added and the mixture was cooled to -78 ° C. Then, tert-butyl dimethylsilyltrifluoro-methanesulfonate (1.92 mL, 8.34 mmol) was added. After 2 hours, the mixture was poured into IN HCl (100 mL), extracted with methylene chloride (2 x 100 mL) and the organic products were dried over anhydrous sodium sulfate. The resulting crude alcohol was purified by flash chromatography on? IO eluting with acetone in chloroform (0-5-10% acetone) to yield 1011 g. { 31 for 2 steps) of compound 89A as a clear oil. B. (1S-trans) -2-hydroxymethyl-4- [[(4-methylphenyl) sulfonyl] oxy] -1-pyrrolidinecarboxylic acid ester 1 (1-dimethylethyl) (89B) Intermediate Compound 89A (3.41 g, 10.3 mmoY was dissolved in anhydrous pyridine (30.0 mL) and cooled to CY. P-Toluenesulfonyl chloride (5.89 g, 30.9 mmol) was then added in portions over a period of 10 minutes. The flask was then placed in a refrigerator at 4 ° C for 48 hours.5 The resulting solution was poured into IN HCl (300 L), extracted with methylene chloride (3 x 200 mL) and the organic products were dried over sodium sulfate. Anhydrous sodium The crude tosylate intermediate was dissolved in THF (50 mL), to which HO (0.5 mL) was added followed by pTSA-H0 (1.03). - 0 mmol). Once the reaction was complete as determined by CCD, the mixture was poured into saturated aqueous NaHCO3 (150 mL) and extracted with methylene chloride (3 x 50 mL). The organic products were dried over sodium sulfate. The crude al.ILY was purified by flash chromatography on 15 Si (Y eluting with acetone / chloroform (0-5-10 acetone) to yield 2.71 g (11% for 2 steps) of the compound - "teunediapo 89B as a clear oil. C. (2S-trans) -2- [cyano [(phenylmethyl) amino] methyl] -4- [[(-methylphenyl) -i-sulphonyl] oxy] -1-pyrrolidinecarboxylic acid 1,1-dimethyl-ethyl ester cr OTs To an oxalyl chloride solution (2.0 M solution in CH; C1:, 2.82 mL) in CHJC1 (40 mL) at -78 ° C was added anhydrous dimethylsulfoxide (0.462 mL, 6.51 mmol). The mixture was allowed to stand for 15 minutes, after which a solution of Compound 89B (1.61 g, 4.34 mmol) in CH2C12 (10 mL) was slowly added. After an additional 30 minutes, triethylamine (1.81 mL, 13.02 mmol) was added and the reaction slowly warmed to 0 ° C. The reaction was then quenched with H; 0 (25 mL) and diluted with CH? C1 > (100 mL). The mixture was then washed consecutively with IN HCl (1 x 100 mL), saturated aqueous NaHCO- (50 mL), and water (2 x 50 mL). The organic products were dried over anhydrous sodium sulfate and the volatile organic products were removed in vacuo. The crude aldehyde intermediate (1.60 g, 4.34 mmol) was dissolved in THF (25 mL) and diethyl cyanophosphonate (90%, 0.95 mL, 5.64 mmol) was added followed by benzyl amine (1.23 mL, 11.3 mmol) after 2 h , the reaction was completed, as was observed by CCD and the volatile organic products were removed intra-cuo. The crude reaction mixture was purified by flash chromatography on? IO: eluting with acetone / chloroform (0-2-31 acetone) to yield 1.48 g (70-? Of Intermediate 89C as a white solid. Compound 89C is a 1: 1 mixture of diastereomers by NMR spectroscopy.

D. (1- S-endo) -6-cyano-5- (phenylmethyl) -2,5-diazabicyclo [2.2.1] hsptan-2-carboxylic acid 1,1-dimethyl-ethyl ester (89 Di); 1- (1-Exo) -6-cyano-5- (phenylmethyl) -2,5-diazabicyclo [2.2.1] heptan-2-carboxylic acid ester (89 DÜ); Intermediate Compound 89C (1.48 g, 3.05 mmol) was dissolved in dichloroethane (25 mL) and dusopropyl (t) amine (1.45 mL) was added. The mixture was heated to 100 ° C in a sealed tube for 18 hours. The volatiles were then removed m va cuo and the resulting crude material was purified by flash chromatography on S0O_ eluting with acetone / chloroform (acetone at 0 -2-3 aJ to yield a mixture of Intermediate Compound 89Di (0.591 g, 62%). %) and Intermediate Compound 89Dii (0.370 g, 38%) as light oils The structural assignments for Compounds 89Di and 89Dii were made after the NMR experiments of NOE, COESi and DEPT.

E. (lS-endo) -S- (phenylmethyl) -2,5-diazabicyclo [2.2.1] heptan-2,6-dicarboxylic acid (89E) ester 2- (1,1-dimethylethyl) -6-methyl ester; Intermediate Compound 89Di (0.400 g, 1.28 mmol) was dissolved in NaOMe (0.5 M, 12.8 mL) and heated at 60 ° C for 5 hours. The reaction was cooled to 0 ° C and 3N HCl (4.0 mL) was slowly added. After 2 hours at 0 ° C the reaction was poured into saturated aqueous NaHCJ3 (50 mL). The mixture was extracted with CH C1; (3 x 50 mL) and the combined organic products were dried over anhydrous sodium sulfate. The crude ester was purified by flash chromatography on SÍO2 eluting with chloroform / acetone (0-2-4% acetone) to yield 0.320 g (0.92 mmol, 72%) of Intermediate 89E as a clear zeite. F. (13-Exo) -5- (phenylmethyl) -2,5-diazabicyclo 2- (1,1-dimethylethyl) -6-methyl ester [2.2. l] hβptan-2,6-dicarboxylic acid (89F); Intermediate Compound 89Dii (0.400 g, I.28 mmol) was dissolved in NaOMe (0.5 M, 12.8 mL) and heated at 60 ° C for 5 hours. The reaction was cooled to 0 ° C and 3N HCl (4.0 mL) was slowly added. After 2 hours at 0 ° C the reaction was poured into saturated aqueous NaHCO3 (50 mL). The mixture was extracted with CH ^ Cl ^ (3 x 50 mL) and the combined organic products were dried over anhydrous sodium sulfate. The crude ester was purified by flash chromatography on SiO2 eluting with chloroform / acetone (0-2-4% acetone) to yield 0.290 g (0.85 mmol, 66%) of Intermediate Compound 89F as a clear oil.

G. 2- (1,1-dimethylethyl) -6-methyl ester of (lS-βndo) -2,5-diazabicyclo [2.2. l] heptan-2,6-dicarboxylic acid (89G); Intermediate Compound 89E (0.280 g, 0.81 mmol) was dissolved in absolute EtOH (10.0 mL) and Pd / C (Pd al 101, 0.080 g) was added. ? and introduced an atmosphere of H2 via a flask and the reaction was stirred at 25 ° C for 20 hours. The Pd was removed by filtration through celite followed by rinsing with EtOAc. The volatiles were removed m va cuo to yield Compound 89G (0.205 g, 99%) as yellow viscous oil. Compound 89G was taken directly without purification. MS (RE) = m / z 257.18 [M + H] +. CLAR RT = 1.223 min (95%) (YMC S5 ODS column, 4.6 x 50 mm, 10-90% MeOH / H20 gradient, 0.1% TFA, 4 mL / min, 220 nM detection).

H. ßßter 2- (1, 1-dimethylethyl) 6-methyl ester of (lS-exo) -2,5-diazabicyclo [2.2.l] hβptan-2,6-dicarboxylic acid (89H) Intermediate Compound 89F (0.310 g, 0.89 mmol) was dissolved in absolute EtOH (10.0 mL) and Pd / C (10% Pd, 0.080 g) was added. An HJ atmosphere was introduced via a flask and the reaction was stirred at 25 ° C for 20 hours. The Pd was removed by filtration through celite, followed by rinsing with EtOAc. The volatiles were removed in vacuo to yield Compound 89H (0.210 g, 92%) as yellow viscous oil. Compound 89H was taken directly without purification. MS (RE) = m / z 257.16 [M + H] +. CLAR TR = 1293 min (90%) (YMC S5 OD column ?, 4.6 x 50 mm; MeOH / H20 gradient at 10-90%, + 0.1% TFA, 4 mL / min, detection at 220 nM).

EXAMPLE 90 [5S- (5a, 8a, Saa)] -2- [4-cyano-3- (trifluoromethyl) enyl] hexahydro-1,3-dioxo-5, 8-ethanoimidazo [1,1-dimethylethyl ester] 1, 5-a] pyrazin-7 (8H) -carboxylic (90i) 1,1-Dimethyl-ethyl ester of [5S- (5a, 8a, 8aß)] -2- [4-cyano-3- (trifluoromethyl) phenyl] hexahydro-1,3-dioxo-5,8-matanoimidazo [1, 5-a] pyrazin-7 (8H) -carboxylic (90ii) To a solution of 4-isocyanato-2- (trifluoromethyl) -benzonitrile (1.0 mol) in toluene (4 mL) with activated 4A TM (0.300 g) was added Compound 89G (0.220 g, 0.856 mmol) in toluene (6%). mL). After 10 hours at 25 ° C, DBU (0.166 mL, 1.11 mmol) was added and the reaction was heated at 81 ° C for 2 hours. The reaction was then cooled to 25 ° C and poured into IN HCl (50 mL). The solution was then extracted with methylene chloride (3 x 30 mL) and the combined organic products were dried over anhydrous sodium sulfate. The resulting crude material was purified by flash chromatography on Si02 eluting with acetone / chloroform (0-2-4-8% acetone) to yield Compound 90i (0.155 g, 42%): MS (RE): m / z 437.09 [M + H] +. CLAR TR = 3280 min (100%) (YMC S5 OD column ?, 4.6 X 50 mm; MeOH / H20 gradient at 10-90%, + 0.1% TFA, 4 mL / min, detection at 220 nM) and the Compound 90ii (0.061 g, 16%) MS (ER): m / z 437.09 [M + H] Y TR of CLAR = 3.133 min (100%) (column YMC S5 ODS, 4.6 X 50 mm; gradient MeOH / H20 al 10-90%, + 0.1% TFA, 4 mL / min, detection at 220 nM); both as white foams.

EXAMPLE 91 5S- (5a, 8a, 8aa)] -4- (hexahydro-1,3-dioxo-5,8-matanoimidazo [1,5-a] pyrazin-2 (3H-1) -2- (O-methyl rifluo Benzonitrile (91) Compound 90i (0.115 g, 0.264 mmol) was dissolved in anhydrous methylene chloride (3 mL) and anhydrous TFA (1.0 L) was added at 25 ° C. After 1 hour, the reaction was concentrated in vacuo and the resulting residue was dissolved in methylene chloride and poured into saturated aqueous NaHCO. This solution was then extracted with methylene chloride (3 x 10 mL) and the combined organic products were dried over anhydrous sodium sulfate. This produced 0.089 g (9Y) of the free Compound 91 as a yellow solid. MS (ER): m / z 359.09 [M + Na] Y TR of CLAR = 1477 min (100%) (column YMC S5 ODS, 5 4.6 X 50 mm; 10-90% MeOH / H20 gradient, + 0.1'- TFA; 4 mL / min, detection at 220 nM).

EXAMPLE 92 2- (1,1-Dimethylethyl) -6-methyl ester ester of (lR-endo) -2,5-diazabicyclo [.2. l] heptan-2,6-dicarboxylic acid (92H) and 2- (1,1-dimethylethyl) -6-ma-thyl ester of (lR-exo) -2,5-diazabicyclo [2.2. l] heptan-2,6-dicarboxylic (921) This example illustrates a preferred method for obtaining a compound of formula Ia, the compound is useful as an intermediate in the preparation of the compounds of formula I (see, for example, Figure 2 herein). ^ u A. To be ((2R-cis) -4- hydroxy-1,2-pyrrolidinedicarboxylic acid (1- (1, 1-dimethylethyl) -2-ethyl) (92A) The cis-4-hydroxy-D-proline (10.0 g, 131.1 mmol) was suspended in absolute EtOH (100 mL) and = e bubbled anhydrous HCl. (g) through the reaction until a homogeneous solution resulted. This was left at 25 ° C for 1 hour and then the volatile organic products were removed in va cuo. The resulting HCl salt was triturated with diethyl ether and filtered to yield the crude ethyl ester as a white powder. The salt of the ethyl ester was used directly in the next reaction. The salt (-12 g) was suspended in acetone and cooled to 0 ° C. Then 10% aqueous Na 2 CO 3 (6.0 mL) was added followed by BOC 20 (1.37 g, 6.29 mmol) and then the reaction was slowly heated to 25 ° C. After 12 hours, the reaction mixture was poured into water and extracted with methylene chloride (3 >: 100 mL). The organic products were then dried over anhydrous sodium sulfate and concentrated in vacuo to yield the crude compound 92A as a white powder. This material was taken without further purification.

B. Be ((2R-trans) -4 - [[(4-methyl-phenyl) sulfonyl] oxy] -1,2-pyrrolidine-dicarboxylic acid 1- (1,1-dimethyl-ethyl) -2-ethyl (92B) The crude compound 92A (1.41 g, 5.44 mmol) was dissolved in THF (50 mL) and Ph3P (1.86 g, 70.8 mmol) was added. The mixture was cooled to 0 ° C and DEAD (1.11 mL, 70.8 mmol) was added. After 15 minutes, then methyl paratoluensulfonate (1.32 g, 70.8 mmol) was added and the solution slowly warmed to 25 ° C. After 14 hours, the reaction was concentrated in vacuo and purified by flash chromatography on silica eluting with acetone in chloroform. (0-2-3% acetone) to yield 0.845 g of the desired compound 92B as a yellow oil. CLAR TR = 3,373 min (95%) (column YMC? 5 ODS, 4.6 X 50 mm; gradient MeOH / H-0 at 10-90., + 0.1% TFA, 4 mL / min, detection at 220 nM). This material was taken without further purification C. being 1, 1-dimethylic acid (2R-trans) -2- (hydroxymethyl) -4- [[(4-methyl-phenyl) sulfonyl] oxy-1-pyrrolidinecarboxylic acid (92C) The crude compound 92B (5.50 g) , 13.32 mmol) was dissolved in THF (150 mL) and cooled to 0 ° C. Then LiBH4 (2.0 M in THF, 16.7 mL, 33.3 mmol) was added slowly and the reaction was allowed to warm to 25 ° C slowly. After 12 hours, the mixture was cooled to 0 ° C and the reaction was quenched with water (10 mL) and then AcOH (2.0 mL). After 15 minutes, the solution was poured into saturated NaHCO = and extracted with methylene chloride (3 x 50 mL) and the combined organic products were dried over anhydrous sodium sulfate. This produced the crude compound 92C (3.91 g) as a yellow oil, which was taken without purification. HPLC TR = 3.043 min (100%) (YMC S5 ODS column, 4.6 X 50 mm; MeOH / H? 0 to 10-90% gradient, 0.1% TFA, 4 mL / min, 220 nM detection).

D. (2R-trans) -2- [cyano [(phenylmethyl) amino] methyl] -4- [[(4-methylphenyl) -sulfonyl] oxy] -1-pyrrolidinecarboxylic acid 1-dimethylethyl ester (92D) To a solution of oxalyl chloride (solution 2-2 in CH: C12, 2.82 mL) in CH2C1 (40 mL) at -78 ° C anhydrous dimethylsulfoxide acyclone (0.462 mL, 6.51 mmol). The mixture was left to stand for 15 minutes, after which a solution of compound 92C (1.61 g, 4.34 mmol in CH_C1 (10 mL) was slowly added, after about 30 additional minutes, tetylamine (1.81 mL, 13.02 mmol) and the reaction was slowly warmed to 0 ° C. The reaction was then quenched with H20 (25 mL) and diluted with CHY1 (100 mL).

The mixture was then washed consecutively with IN HCl (1 x 100 mL), saturated aqueous NaHCO (50 mL), and water (2 x 50 mL). The organic products were dried over anhydrous sodium sulfate and the organic volatile products were removed m u u u. The crude aldehyde ion (1.60 g, 4.34 mmol) was dissolved i- in THF (25 mL) and diethyl cyanophosphonate (90%, 0.95 mL, 5.64 mmol) was added followed by benzyl amine (1.23 mL, 11.3 mmol). After 2 hours, the reaction was complete, as observed by CCD and the volatile organic products were removed m va cuo. The crude reaction mixture was purified -0 by flash chromatography on S? 02 eluting with acetone / chloroform (0-2-3% acetone) to yield 1.48 g (70- of intermediate Compound 92D as a white solid.) I determine that compound 92D is a mixture -1: 1 of diastereomers by NMR spectroscopy.

E. 1, 1-dimethylethyl ester of (lR-endo) -6-cyano-5- (phenylmethyl) -2,5-diazabicyclo [2.2. l] h-ptancarboxylic acid (92Ei); 1, 1-dimethylethyl ester of (lR-exo) -6-cyano-5- (phenylmethyl) -2,5-diazabicyclo [2.2. l] heptan-2-carboxylic acid (92Eii); The intermediate compound 92D (1.48 g, 3.05 mmol) was dissolved in dichloroethane (25 mL) and dusopropyl ethylamma (1.45 L) was added. The mixture was heated to 100 ° C in a sealed tube for 18 hours. The volatiles were then removed m va cuo and the resulting crude material was purified by flash chromatography on S ?0 eluting with acetone / chloroform (0-2-3% acetone), to yield a mixture of intermediate compound 92Ei (0.591 g , 62%) and intermediate compound 92Eii (0.370 g, 38?) As light oils. The structural assignments for Compounds 92Ei and 92Eii were made after the NMR experiments of NOE, COE? Y and DEPT.

F. 2- (1,1-dimethylethyl) 6-methyl ester of (lR-endo) -5- (phenylmethyl) -2,5-d-azabicyclo [2.2. l] heptan-2,6-dicarboxyl? co (92F) Compound 92Ei intermediate (0.400 g, 1.28 mmol) was dissolved in NaOMe (0.5 M, 12.8 mL) and heated at 60 ° C for 5 hours. The reaction was cooled to 0 ° C and H21 3N (4.0 mL) was slowly added. After 2 hours at 0 ° C the reaction was poured into saturated aqueous HCCl 3 (50 mL). The mixture was extracted with CH2C1 (3 x 50 mL) and the combined organic products were dried over anhydrous sodium sulfate. The crude ester was filtered through flash chromatography on S0O_ eluting with chloroform / acetone (0-2-4% acetone) to yield 0.320 g (0.92 mmol, 72 Y of intermediate compound 92F as a 10%). ^ i ^ p clear G. G. 2- (1,1-d? methylethyl) 6-methyl (lR-exo) -S- (phenylmethyl) -2,5-d? azabicyclo [2.2. l] heptan -2, 6-dicarboxylic (92G) Compound 92Eii intermediate (0.400 g, 1.28 mmol) was dissolved in NaOMe (0.5 M, 12.8 L) and heated. at 60 ° C for 5 hours. The reaction was cooled to 0 ° C and 3N HCl (4.0 mL) was slowly added. After 2 hours at 0 ° C the reaction was poured into saturated aqueous NaHCO 3 (50 mL). The mixture was extracted with CH2C12 (3 x 50 mL) and the combined organic products were dried over anhydrous sodium sulfate. The crude ester was purified by flash chromatography on Si02 eluting with chloroform / acetone (0-2-4% acetone) to yield 0.290 g (0.85 mmol, 66.) of intermediate compound 92G as a clear oil.

H. 2- (1, 1-dimethylathyl) 6-methyl ester of (lR-endo) -2,5-diazabicyclo [2.2.1] heptan-2,6-dicarboxylic acid Compound 92F intermediate (0.280 g, 0.81 mmol) was dissolved in absolute EtOH (10.0 mL) and Pd / C (Pd ai 10%, 0.080 g) was added. An atmosphere of H2 was introduced via a flask and the reaction was stirred at 25 ° C for 20 hours. The Pd was removed by filtration through celite followed by rinsing with EtOAc. The volatiles were removed in vacuo to provide compound 92H (0.205 g, 99%) as yellow viscous oil. Compound 92H was taken directly without purification. EM (ER) = m / z 257.18 [M + H] Y TR of CLAR = 1.223 min (95%) (column YMC? 5 OD ?, 4.6 X 50 mm; gradient MeOH / H20 5 at 10-90%, + 0.1% TFA, 4 mL / min, 220 nM detection).

I. to be (lR-exo) -2,5-diazabicyclo [2.2.1] hßptan-2,6-dicarboxylic acid 2- (1,1-dimethylethyl) -6-methyl ester Compound 92G intermediate (0.310 g, 0.89 mmol) was dissolved in absolute EtOH (10.0 mL) and Pd / C (10-fold Pd, 0.080 g) was added. The reaction was stirred at 25 ° C for 20 hours, the Pd was removed by filtration through celite, followed by rinsing with EtOAc, the volatile products were removed m va. Compound 921 (0.210 g, 92%) as yellow viscous oil Compound 921 can be taken directly without purification EM (ER) = m / z 257.16 [M + HjY TR of CLAR = 1.293 min. %) (column YMC? 5 OD ?, 4.6 X 50 mm; gradient MeOH / H_0 at 10-90%, + 0.1% TFA, 4 mL / min, detection at 220 nM).

Example 93 [5R- (5a, 8a, 8aa)] -4- [Octahydro-7- [(1,1-dimatylethoxy) carbonyl] 1,3-dioxo-5,8-methanoimidazo [5-a] pyrazin-2-yl] -2- (trifluoromethyl) benzonitrile (93i) [5R- (5a, 8a, 8aß)] -4- [octahydro- 7- [(1, 1-dimatile oxy) carbonyl] 1,3-dioxo-5,8-methanoimidazo [5-a] pyrazin-2-yl] -2- (trifluoromethyl) banzonitrile (93ii) To a solution of 4-isocyanato-2- (trifluoromethyl) -benzonitrile (1.0 mmol) in toluene (4 mL) with activated 4 A TM (0.300 g) was added Compound 92H or 921 (0.220 g, 0.856 mmol) (the compounds are epimerized to form the 13 same product) in toluene (6 mL). After 10 hours at 25 ° C, DBU (0.166 L, 1.11 mmol) was added and the reaction was heated at 81 ° C for 2 hours. The reaction was then cooled to 25 ° C and poured into 1N HCl (50 mL). The solution was then extracted with methylene chloride (3 x 30 L) and the organic products The combined extracts were dried over anhydrous sodium sulfate. The resulting crude material was purified by flash chromatography on Si02 eluting with acetone / chloroform (acetone at 0-2-4-8%) to yield Compound 93i (0.155 g, 42%) MS (ER): m / z 437.09 [M + H] TR from CLAR = 3.280 min (100 *; YMC S5 OD ?, "4.6 X 50 mm, gradient MeOH / H: 0 at 12-90%, + 0.1% TFA, 4 mL / min, detection at 220 nM) and Compound 93ii (0.061 g, 16%) MS (ER): m / z 437.09 [M + H] Y TR of CLAR = 3.133 min (100%) (column YMC S5 ODS, 4.6 X 50 mm; gradient MeOH / H20 at 10-90%, + TFA at 0.1 %; 4 mL / min, detection at 220 nM), both as white foams.

EXAMPLE 94 [1S (5, 8, 8a)] hexahydro-2- (4-nitro-l-na-talenyl) -1,3-dioxo-5,8-methanoimidazo [1 S, 1-dimethylethyl] -acetic acid ester 5- a] pyrazin-7 (8H) -carboxylic acid (94) Compound 89G (0.220 g, 0.856 mmol) was added to a suspension of recently activated 4A molecular sieves (0.300 g) in dry toluene (10.0 mL). To this mixture was added 4-nitronaphtal-1-isocyanate (0.214 g, 1.0 mmol). After stirring at 25 ° C for 14 hours, DBU (0.166 mL, 1.11 mmol) was added and the reaction was heated to 8QDC for 2 hours. After 2 hours, the reaction was cooled to 25 ° C and then poured into IN HCl (50 mL). This solution was extracted with methylene chloride (3 x 30 mL) and the combined organics were dried over anhydrous sodium sulfate. The crude material was purified by flash chromatography on silica eluting with acetone in 0-2-6% chloroform to yield 0.211 g of compound 94 as a yellow foam. HPLC: 95% at 3,130 min (retention time) (column YMC S5 OD? 4.6 X 50 mm; aqueous methanol at 10-90% for 4 minutes containing 0.2% phosphoric acid, 4 mL / min, verification at 220 nM ). MS (ER): m / z 439.19 [M + H] Y Example 95 [5? - (5, 8a, 8aa)] -tetrahydro-2- (4-nitro-1-naphthalenyl) -5,8-methanoimidazo [1, 5-a] pyrazin-1, 3 (2H, 5H -diona (95) Compound 94 (0.160 g, 0.37 mmol) was dissolved in methylene chloride (5.0 L) and TFA (1.5 mL) was added at 25UC. After 1.5 hours, the reaction was concentrated in vacuo and re-dissolved in methylene chloride. This solution was washed with NaHCO. watery saturated. The aqueous layer was extracted with methylene chloride (3 x 25 mL). The combined organics were then dried over anhydrous sodium sulfate. Concentration m vacuo yielded 0.115 g of compound 95 as a yellow solid. CLAR: 93? at 1747 mm (retention time) (YMC column? 5 OD? 4.6 X 50 mm; 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid, 4 mL / rnin, 220 nM verification). MS (ER): m / z 3bY0 ^ JiYYCY.

Example 96 [5S- (5a, 8a, 8aa)] -7- [(4-fluorophenyl) sulfonyl] tetrahydro-2- (4-nitro-1-naphthalanyl) -5,8-methanoimidazo [1, 5-a] p? razin- 1.3 (2H, 5H) -dione (96) Compound 94 (0.025 g, 0.074 mmol) was dissolved in pni zima (0.5 mL) and then 4-Y chloride was added to the sulfonyl chloride (0.028 g, 0.148 mmol). After 16 hours at 25 ° C, the reaction was concentrated m vacuo. The crude product was purified by flash chromatography on silica eluting with acetone in 5% chloroform to yield 0.029 g of column 96 as a yellow solid JAR: 99 10 The retention time) column YMC S5 ODS 4.6 X 50 mm; 10-90% aqueous methanol for 4 minutes containing 0.2% phosphoric acid c2, 4 mL / min, 220 nM verification), MS (ER) m / z 497.2 [M + H] Y Example 97 (5, 8a, 8a) -2- (7-fluoro-3-banzofuranyl) tetrahydro-5,8-methanoimidazo [1,5-a]? Iridin-l, 3 (2H, 5H) -dione and (5a, 8, 8aβ ) -2- (7-fluoro-3-benzofuranyl) tetrahydro-5,8-m-ethanoimidazo [1,5- a] pyridin-1, 3 (2H, 5H) -dione (97Ei and 97Eii, respectively) A. 7-Fluoro-2-benzofurancarboxylic acid (97A) The 3-fluorosalicylaldehyde reagents (1,000 g, 7.14 tpm &l 'and ethyl bromonate-alonate (1,900 g, 7.29 mmol) were reacted according to the procedure reported per Tana ka (J. A /? Chem. Soc. 1951, 13, 872) to yield 562 mg (44 *) of compound 97 A. B. 3-bromo-7-fluorobenzofuran (97B) * compound Compound 97A (562 mg, 3.12 mmol) was subjected to decarboxylation under the conditions described by Tanaka? T. Am. Chem. Soc. 1951, 13, 872), followed by bromination and debromination in accordance with the procedures described by Mochida et al. (EP 355827 A2) to yield 186 mg (28 -.J of compound 97B.

C. 7-Fluoro-3-benzofurancarboxylic acid (97C) Compound 97B (186 mg, 0.87 mmol) was followed by lithiation followed by carboxylation, according to the procedures described by Cugnon de Sévricourt et al. , Bul! . Soc. Chim. 144 (1977), to give 36 mg (23%) of .orrii-Fi.i, 97C.

D. 7-Fluoro-3-benzofurancarboxylic acid azide (97D) To a solution of compound 97C (36 mg, 0.20 mmol) n THF (2 ml) was added, via a syringe at room temperature. z, z zenre, E f 33 μi, 0.24 mrnol) and DPPA (52 μl, 0.24 mr.

The resulting mixture was stirred by: at this time the reaction was quenched by the addition of H:: 0 (2 ml). The layers were separated and the aqueous layer was extracted with Et_0 (1 x 5 ml). The combined organic phases were dried over 1% and concentrated under reduced pressure to leave a colorless residue which was purified by flash chromatography. (silica gel, 0 to 5% EtOAc in hexanes) producing 36 mq (88; of compound 97D.

E. (5a, 8, 8aa) -2- (7-Fluoro-3-benzofuranyl) tetrahydro-5, 8-ethanoimidazo [1, 5-a] pyridine-1, 3 (2H, 5H) -dione and (5a , 8o, 8a (3) -2- (7-fluoro-3-benzofuranyl) tetrahydro-5,8-methanoimidazo [1,5-a] pyridin-1, 3 (2H, 5H) -dione (97Ei and 97Eii, respectively.) A solution of compound 97D (36 mg, 0.18 mmol) in toluene (1.5 ml) was heated at 95 ° C. for 2 h.The reaction was repeated until 50 mg of freshly activated molar sieves were added ( powder) and a solution of 2-azabicyclo [2.2.1] heptan-3-carboxylic acid ethyl ester (32 mq, 0.19 mmol) in toluene (1.5 ml) The resulting mixture was stirred overnight, treated with DBU (30 μl, 0.20 mol) and heated at 85 ° C for 2 h After cooling the material was filtered through Celite eluting with CHYi; (50 i), washed with 1N HCl solution (2 x 25 ml ) and concentrated or reduced pressure, The remaining residue was purified by flash chromatography (silica gel, 0 to 52 of hexar.cs in CH2C1) to give 23 mg (44%) of compound 97Ei together with 19 mg (36%) of compound 97Eii as white solids. Compound 97Ei: HPLC: 100% at 2.93 min (retention time '(column YMC S5 ODS, 4.6 x 50 mm, eluting with aqueous methanol at 10-90- ^ for 4 minutes containing phosphoric acid at 0.2 4 ml / mm, verifying at 220 nm), MS (ER): m / z 301 JY K J. Compound 97Eii: HPLC: 100% at 3.00 min (retention time) (column YMC S5 ODS, 4.6 x 50 mm, eluting with 10-90% aqueous methanol for 4 minutes containing phosphoric acid at 0.21, 4: tJ / rr. ? n, verifying at 220 nm), MS (ER): m / z 301 [M + H] Y The corresponding compounds were also prepared where the 7-fluoro-3-benzofuranyl group is replaced with each of the following groups: 2-methy1,4,5,6,6-7-tetrafluoro-3-benzofuranyl, 3-benzofuranyl, 2-benzofuranyl, and 2-methyl-3-benzofuranyl Example 98 1,1-dimethylethyl ester of [5S- (5a, 8a, 8a)] -2- [4- Cyano-3- (trifluoromethyl) phenyl] hexahydro-8a-methyl-1,3-dioxo-5,8-m-aminosimidazo [1,5-a] pyrazin-7 (8H) -carboxylic (98) Compound 90i (0.100 g, 0.229 mmol1 was added to freshly prepared LDA (0.048 ml of diisopropylamine, 0.186 ml, 1.6M of BuLi) in THF (3.0 ml) at -78 ° C. After 32 mm, iodide was added. Methyl (0.029 ml, 0.458 mmol) and the reaction was slowly warmed to -20 ° C for 1 h and then quenched with saturated aqueous ammonium chloride, then the mixture was extracted with methylene chloride (3 x 30 l ^). The organic products were dried over anhydrous sodium sulfate and concentrated m va cuo, to give 0.077 g of the crude compound 98 which was recovered without "iii" ional purification CLAR: 93- to 3,243 mm (retention time1 (cciu). na 2MC S5 ODS, 4.6 x 50 mm, aqueous methanol at 10-90 * for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying at 220 nm), MS (ER): m / z 473.12 [M + NaH] Y Example 99 [5S- (5ot, 8x, Saa)] -4- (Hexahydro-1,3-dioxo-8a-methyl-5,8-methanoimidazo [1,5-a] pyrazin-2 (3H) -il) -2- (trifluoromethyl) benzonitrile (99) Compound 98 (0.070 g, 0.156 mmol) was dissolved in methylene chloride (2.0 mL) and TFA (0.75 mY at 25 [deg.] C. After 30 min, the reaction was rapidly cooled to NaHCO, aqueous, saturated and then extracted with methylene chloride (3 x 30 ml) The organics were then dried over anhydrous sodium sulfate and concentrated in vacuo The crude material was purified by preparative CCD flowing with 25% acetone in chloroform to give 0.031 q of compound 99 as a white solid CLAR: 86% at 1817 min (retention time) (column YMC? 5 OD ?, 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing acid phosphoric at 0.21-, 4 ml / min, verifying at 220 nm), MS (ER): m / z 35 Y 15 [M + HJJ Example 100 [5S- (5, 8a, Saa)] -7-Benzoyl-2- [4-cyano-3- (trifluoromethyl) phenyl] tetrahydro-5,8-methanoimidazo [1,5- a] pyrazin-1, 3 (2H, 5H) -dione (100) Compound 99 (0.023 g, 0.066 mmol) was dissolved in methylene chloride (2.0 ml) and then TEA (0.018 ml, 0.132 oi) and -DMAP (cat) were added followed by benzoyl chloride (0.011 ml, 0.099 mmol) . After 3 h, the reaction; The mixture was concentrated and then purified by preparative HPLC on silica eluting with 7% acetone in chloroform to give 0.021 g of compound 100 as a white foam. CLAP: u 'r 2,927 mm (retention time) (column YMC S5 OD ?, 4.6 x 50 mm, 10-90% aqueous methanol for 4 minutes containing 0.2, 4 ml / min phosphoric acid, verifying at 220 nm; ,? M < Eh >: m / z 455.10 [M + H] Y Example 101 [5S- (5a, 8a, 8aa)] -7- (4-Fluorobenzoyl) tetrah.dro-2- (4-n-tro-l-naphthalenyl) -5,8-methane-midazo [l , 5-a] p? .razin-l, 3 (2H, 5H) -dione (101) Compound 95 (0.077 g, 0.228 mmol) was dissolved in methylene chloride (2.0 ml) and TEA (0.127 ml, J l mrrul) \, -DMAP 0.C01 gY The reaction > The reaction was slowly warmed to 25 ° C. After 3 h, rec-ccioi, it was diluted with methylene chloride (50 ml). ^ c were washed successively with IN HCl and saturated aqueous NaHCO, and dried over anhydrous sodium sulfate.J crude matepal was purified by preparative CCD on silica eluting with 5% acetone in chloroform to give 0.022 q of compound 101 as a yellow solid CLAR: 100 'to 2,962 mm (retention time) (column YMC S5 ODS, 4.6 x 50 m, 10-90% aqueous methanol for 4 minutes containing fo-YYpco acid at 0.2 ^ 4 ml / rnin , verifying at 220 nm), MS (ER ,: m 461YY [M + H] '.

Example 102 Library Synthesis of the Solution Phase of [5S- (5a, 8 «, 8aa)] -2- (4-cyano-l-naph-alenyl) -tetrahydro-7- (5-isoxazolylcarbonyl) -5,8-methanoimidazo [1, 5-a] pyrazin-1, 3 (2H, 5H) -dione (102A), 4-fluorophenyl ester of [55- (5a, 8a, 8 a)] -2- (4-cyano-1) acid naphne-alanyl) hexahydro-l, 3-dioxo-5, 8-methanoimidazo [1,5-a] pyrazin-7 (8H) -carboxylic acid (102B), [5S- (5 ', 8a, 8aa)] - 2 - (-cyano-1-naphthalenyl) etrahydro-7- [(1-methyl-lH-3m-dazol-4-yl) sulfonyl] -5,8-methanoimidazo [1, 5-a] pyrazinyl, 3 (2H, 5H) -dione (102C) and [5S- (5a, 8a, 8aa)] -2- (4-cyano-l-naphthalenyl) -N- (4- fluorophenyl) hexahydro-1,3-dioxo-5,8-methanoimidazo [1,5-a] pyrazin-7 (8H) -carboxamide (102D) The postepcjr procedure is a general approximation. the synthesis of the compounds of the formula I in a solution phase library format. A more detailed description of the individual compounds made via this combinatorial approach is given below. A series of amine starting materials 1, 2 analogous to the structure of [5S- (5, 8a, 8a)] -tetrah-dro-2- (4-nitro-1-naphthalenyl) -5, 8- metaimidazo [1, 5-a] pyrazin-1,3 (2H, 5H) -dione (0.05 mmol, prepared as described in Example 95) were dissolved in dichloromethane (1.5 ml) in a polystyrene tube with a frit The reaction vessel was then added to each reaction vessel followed by the addition of the desired acid chloride, isocyanate, chloroformate or sulfonyl chloride (0.10 mmol) in 0.5 ml of automated non-poratorized dieioroet. were shaken at 25 ° C for 24 h and then Tris- (2-Y-Aminoethyl) amine Poystyrene HL (200-400 mesh, 3.3 mmol / g, 75 mq) was added to each reaction vessel and the vessels were shaken again by stirring. at 25 ° C. The liquid in each tube was drained in pre-filled 2.5 ml TRI tubes and the resin was rinsed with dichloromethane (3 x 0.25 ml). on then and analyzed by analytical CLAR and CL-MS. HPLC: (Phenomenex-Prime 5μ column C-18 4.6 x 50 mm eluting with 10-90% aqueous methanol for 4 minutes containing 0.1% TFA;, 4 ml / min, verifying at 220 nm).

A. [5S- (5a, 8a, 8aa)] -2- (4-cyano-l-naphthalenyl) tetrahydro-7- (5-isoxazolylcarbonyl) -5,8-ethanoimidazo [1,5-a] pyrazin-1 , 3 (2H, 5H) -dione (102A) ? e dissolved [5? - (5a, 8a, 8aa)] -4- (Hexahydro-1, 3-d? exo-, H-methanoirnidazo [1, 5-a] pyrazin-2 (3H) -yl) - 1-naphthalene-earbonitplo (0.030 g, 0.094 mmol) in diechloromethane (2.0 ml) in a polystyrene tube with a coarse frit. Then, N, N-1 usopropyl) ammomethyl polystyrene (3.49 mmol / g, 65 mg) was added to each reaction vessel followed by the addition of isoxazole acid chloride (0.025 g, 0.19 mmol). The tube was shaken at 25 ° C for 24 h and then polystyrene HL of Tris- (2-Am? Noet? L) amine '200-400 esh, 3.2 mmol / q, was added. mg) to the reaction vessel and shaken again for 18 h at 25 ° C. The liquid was drained in a 2.5 ml STR tube, pretreated, and the resin was rinsed with dichloromethane x 0.25 ml). The concentration did not yield the crude or 102A (0.058 as a yellow solid) No purification required CLAR: 1002 to 2237 min (retention time) (column YMC S5 OD ?, 4.6 x 50 mm, aqueous methanol at 10-90 for 4 minutes containing phosphoric acid ai 0.2'-, 4 ml / min, verifying at 220 nm), MS (ER): m / z 414.11 [M-rH] ". [5S- (5a, 8a, 8aa)] -2- (4-cyano-1-naphthalenyl) hßxahydro-1,3-dioxo-5,8-methoimidazo [1, 5-a] pyrazin-7 acid lupo-phosphonic acid (8H) -carboxylic (102B) It was dissolved [5? - (5a, 8, 8aa)] -4- (Hexah? Dro-1, 3-dioxo-5, 8-methaimidazo [1,5-a] pyrazin-2 (3H) -yl) -1-naphthalenecarbonitrile (0.030 g, 0.094 mmol) in dichloromethane , 2.2 rrl; in a polystyrene tube with a thick frit.

The addition of N, N- (Diisopr opyl) amimethyl polystyrene was added. (3.49 mmol / g, 65 mg) was added to each reaction vessel followed by addition of α-fluorophenylchloroformate (0.033 g, 0.19 mmol). The tube was shaken at 25 Ye for 24 h and then Tris- (2-Aminoethyl) amine Polystyrene HL (200-400 mesh, 3.3 mmol / g, 75 mg) was added to the reaction vessel and shaken again for 18 h at 25J C. The liquid was drained in a 2.5 ml? TR tube. ? ? dc and the resin was rinsed with dichloromethane (3 x 0.25 ml.) The concentration, in va cuo gave the crude compound 102B. (0.25.3 g) as a yellow solid. No purification was necessary. HPLC: 93% at 2987 min (retention time), column YMC? 5 OD ?, 4.6 x 50 mm., Aqueous methanol at 10-90 pcr 4 minutes containing 0.2% phosphoric acid, 4 ml / rnin, verifying 220 nm), MS (RE): m / z 457.07 [M + H] Y C. [5S- (5a, 8a, 8aa)] -2- (4-cyano-l-naphthalenyl) tetrahydro-7- [(1 ~ methyl-lH-imidazol-4-yl) sulfonyl] -5,8-methanoimidazo [1,5-a] pyrazin-1,3 (2H, 5H) -dione (102C) It was dissolved [5? - (5a, 8a, Saa)] -4- (Hexahydro-1,3-dioxo-5,6-methane-mJda zo [1, 5-a] pyrazin-2 (3H) -i Y -1-na alencarbonitrile (0.030 g, 0.094 mmol, in dichloromethane , -_. 0 ml) in a polystyrene tube with a thick frit. Then N, N '- (diisopropyl) aminomethyl polystyrene was added (3.49 mmol / g, 65 mg) was added to each reaction vessel followed by the editing of the bovine rust-sulfur oil (0.034 g, 2.19 mmol, Fi tube was shaken at 25 JC for 24 h and then added to the Tris reaction vessel. - (2-Aminoethyl) amine Polystyrene HL YY0-400 mesh, 3.3 mmol / g, 75 mg) and shaken again by lb at 25 ° C. The liquid was drained in a 2.5 ml preradio STR tube and the resin was rinsed with dichloromethane (3 x 0.25 ml I. The in va concentration gave the crude compound 102C. (0.04.3 g) as a yellow solid. No purification was necessary. HPLC: 70 ^ to 1.603 min (retention time (column YMC? 5 OD ?, 4.6 x 50 mm, aqueous methanol at 10-90.- for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verifying 220 nm), MS (RE): m / z 463.07 [M + H] J D. [5S- (5a, 8a, 8aa)] -2- (4-cyano-l-naphthalenyl) -N- (4-fluorophenyl) ) hexahydro-1,3-dioxo-5,8-methanoimidazo [1,5-a] pyrazin-7 (8H) -carboxamide (102D) It was dissolved [5? - (5a, 8a, Saa)] -4- (Hexah? Dro-1, 3-dioxo-2, ^ -met anaimid zo [1, 5-a] pyrazin-2 (3H) -il )Y- . phthanecarbonitrile (0.030 g, 0.094 mmol) in dichloromethane Y.O rnl) in a polystyrene tube with a coarse frit. Then N, N '- (diisopropyl) minomethyl polystyrene JY J2 mmoi / g, 65 mg) was added to each reaction vessel followed by the addition of 4-pyrrolidine (0.026 g, 0.19 mmol). The tube was shaken at 25 ° C for 24 h and then added to the reaction reagent Tris- (2-Ami noethyl) mine Poliestir no HL - -i u mesh mmol / g, 75 mg) and shaken again by 1! r. - f- The liquid was drained in a tube? TR of ml pretal ad? and the resin was rinsed with dichloromethane (3 x 0.25 rlY The concentration m v - c ^ o di "the compound - 102D (0.058 q) as a yellow solid, purification was not necessary. 2890 min (retention time '' (column YMC? 5 ODS, 4.6 x 50 mm, aqueous methanol at 10-90 for 4 minutes containing 0.2, 4 m? / Mr, phosphoric acid, verifying at 220 nm). ): m / z 456.4 [M + H] J Example 103 [5? - (5a, 8a, 8aß)] -Tetrah? dro-2- (4-n? tro-l-naphthalenyl) -7- (phenylmethyl) -5, 8-methane? M? Dazo [1, 5-a] p? Ratio-1, 3 (2H, 5H) -dione (103) The TFA salt of compound 95 (0.010 g, 0.022 mmol) s. The solution was DMF (0.5 ml) followed by the addition of KYO, Y r 2 g, 0.088 mmol) and benoyl bromide (0.005 ml, 0.044 ml, and 1-hr. PS, was removed from the DMF). and the priodium was purified by chromat "instantaneous imaging on eluyenao with acetone at 5. in chloroform.This yielded 2. YY of compound 103 as a yellow solid. -It has an intact hydantoin anille system. CLAn: I at 2280 min (retention time) (column YMC S5 OLY, 4.6 x 50 mm, aqueous methanol at 10-90 ° C for 4 minutes containing 0.2% phosphoric acid, 4 ml / min, verify.!, C -, 220 nm), MS (RE): m / z 461.12 [M + H + MeOH] Y Examples 104 to 199 The additional compounds of the present invention were prepared by procedures analogous to those of disbelief; -z previously. The compounds of Examples 104 to 199 have the following structure (L is a bond): where G, X, the same compound, retention time, molecular mass, and the procedure employed, are described in Table 3. The chromatography techniques used to determine -1 t.ernpe retention of the compound of Table 3 are as follow: C -EM - column YMC S5 OD ?, 4.6 x 50 mm eluting with MeOH / H: 0 to 10-90- for 4 minutes, containing 0.1% TFA; 4 rrJ / n m, checking at 220 nm. CLEM * = column YMC 55 OD ?, 4.6 x? O mm eluting with 10-90% MeOH / H-0 for 2 minutes, containing 0.1% TFA; 4 ml / mm, checking at 220 nm. LC = column YMC S5 ODS, 4.6 x 50 mm, eluting with MeOH / H0 at 10 - '0 for 4 minutes, containing 0.2% phosphoric acid, 4 Y J? R, verifying at 220 nm. The molecular mass of the Yompees.ee Ystaclos in Table 3 was determined by EM (ER) per. the formula m / z.

Table 3 Examples 200 to 217 Additional compounds of the present invention were prepared by methods analogous to those described above. The compounds of Examples 200 to 217 have the following structure (L is a bond): T Ht O where G, X, the name of the compound, retention time, molecular mass, and the procedure used, are described in Table 4. The chromatography techniques used to determine the retention times of the compound of Table 4 are as follows: LCMS = column YMC S5 OD ?, 4.6 X 50 mm eluting with MeOH / H20 at 10-90"-, for 4 minutes containing 0.1% TFA, 4 mL / mm, verification at 220 nm, CLEM * = column YMC S5 ODS, 4. 6 X 50 mm eluting with 10-90% MeOH / H20 for 2 minutes containing 0.1% TFA; 4 mL / min, verification at 220 nm. CL = column YMC S5 ODS, 4.6 X 50 mm eluting with 10-90% MeOH / H20 for 4 minutes containing 0.2% phosphoric acid, 4 mL / min, verification at 220 nm. The molecular masses of the compounds listed in Table 4 were determined by MS (E) by the formula m / z.

Table 4 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Compound of the following formula: (I) or a salt thereof, characterized in that the symbols have the following meanings and are selected, for each case, independently: G is an aryl or heterocycle group, where the group is mono- or polycyclic, and which is optionally substituted in one or more positions; E is C = Z2, CR7CPJ ', SCJ, P = OR, or P = OORY Z2 is O, S, NH, or NR6; A- is CR "'or N; Y is J-j'-j" where j is (CR7R7') nyn = 0-3, J 'is a bond or O, S,? = 0, S02, NH, NR6 , C = 0, OOO, NR1C = 0, CR7R7 ', C = CR8R8', R2P = 0, OPOOR2, OP02, OS02, ON, NHNH, NHNR6, NR6NH, NN, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, heterocycle or substituted heterocycle or aryl or substituted aplo, and J "is (CR7R7 ') nyn = 0-3, where Y is not a bond, W is CR7R7'-CRR7', CR8 = CR8 ', CRV-OO, NR9-CR7R7 ', N = CRT, N = N, NR9-NR9', substituted cycloalkyl or cycloalkyl, substituted cycloalkyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or substituted aryl or aplo; Q is H, substituted alkyl or alkyl, alkenyl or substituted alkene, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl, substituted arylalkyl, substituted alkynyl or alkylamino, substituted or substituted aryl, heterocycle or substituted heterocycle, halo, CN, R00, R4C = 0, RRbNC = 0 , HOCR7R7 ', nitro, RxOCH7, RxO, NH2, OOSR1, SO ^ R1 or NRV; M is a bond, O, CR7R7 'or NR10, and M' is a bond or NR10, with the proviso that at least one of M or M 'must be a bond; L is a bond, (CR'R ~ ") n, NH, NR5 or N (CR7R ') n, where n = 0-3; R1 and R1 'are each independently H, alkyl or substituted alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkyl, heterocycle or substituted heterocycle, cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aryl , arylalkyl or substituted arylalkyl; R 2 is alkyl or substituted alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted or substituted aployl, arylalkyl or substituted arylalkyl; R and R3 'are each independently H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted or substituted aryl, arylalkyl or substituted aryl-alkyl, halo, CN, hydroxylamine, hydroxamide, alkoxy or substituted alkoxy, amino, NR R, thiol, alkylthio or substituted alkylthio; Ra is H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, R "" C = 0, R ^ HOO,? O-OR1, or SO? NR ^ 1 '; R "is alkyl or substituted alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or substituted phenyl, arylalkyl or substituted arylalkyl, R- 'OO, R-NHOO, SO2R1,? O2OR1, or S02? R1R1'; R is substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, CN, OH, OR1, R1C = 0, RxNHC = 0, SO2R1, SO2OR1, or S02NR1R1 '; R7 and R7 'are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halo, CN, OR1, nitro, hydroxylamine, hydroxylamide, arrimo, NHR4, NRZR5, ÑOR1, thiol, alkylthio or substituted alkylthio, R1C = 0, R1OC = 0, R1NHC = 0, SO2R1, SOR1, PO ^ R1 ', RVN O, OOSR1, SO ^ R1, SO-.OR1, or? ONR1R1 '; RB and R8 'are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted or substituted aple, substituted arylalkyl or arylalkyl, nitro, halo, CN, OR1, amino, NHR * 1, NR2R5, ÑOR1, alkylthio or substituted alkylthio, SO2R1, P03R1R1 ', or S02NR1R1'; R9 and R9 'are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenlalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aplo, substituted alkyl or arylalkyl, CN, OH, OR1, R "" C = 0, R1OC = Ot R1NHC = 0, SO2R1, SO2OR1, or S02NR1R1 '; and R 10 is H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkemyl or cycloalkemyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted substituted alkyl, CN, OH, OR1, RJOO, R1OC = 0, R1R NC = 0, SO2R1, S02OR], or S02NR1R1 '; with the proviso that: where E is OO, M and M 'are both a bond, Zi is 0, Q is H and Ai and A are CH: (1) GL- is not phenyl, 4-chlorophenyl or benzyl when W is -CH = CH- and Y is -CH-CH2-; (11) G-L- is not phenyl when it is -CH = CH- or -CH2-CH2- and Y is -CH2-; (? i?) G-L- is not phenyl, -methoxyphenyl, 4-chlorophenyl, or (optionally substituted aplo) - (C! -C3) - alkyl-, when and Y are -CH2-CH2-; and (iv) G-L- is not 4- chlorofemlo or benzyl when and Y are phenylene; where E is OO, and M 'are a bond, Zi is O, and i and A2 are CH: (1) G-L- is not benzyl when Q is -C02CH3, W is -CH = CH- and Y is -CH- or -CH2-CH2-; and (11) G-L- is not phenyl when Q is methyl, W is -CH = CH- and Y is -CH2-; where E is C = S, M and M 'are both a bond, Zx is 0, Q is H, Ai and A., are CH, W is -CH = CH- and Y is -CH2- or -CH2-CH2 -, GL- is not phenyl; and where E is OO, M and M 'are both a bond, Zi is 0, Q is H, Y is -CH2-CH2-, and W is -CH = CH- or -CH2-CH2-, GL- is not 4- chlorophenyl (1) when Ai and A2 are C-CH3; and (ii) when Ai is C-isopropyl and A- is C-CH- (

2. Compound according to claim 1, characterized in that G is an aryl group or heterocycle, where the group is mono- or polycyclic, and which is optionally substituted in one or more positions, E is OZ2, CHR7,? 02, P = OR2, or P = OOR2, Zi is 0, S, or NR6, Z2 is 0, S, or NR6; A, is CR7; A2 is CR7; Y is J-J'-J "where J is (CR, -í'nR *") nyn = 0-2, J 'is a bond or NH, NRb, C = 0, cycloalkyl, or cycloalkenyl, and J "is (CR'R'Jn and n = 1-2, where Y is not a bond; W is CR7R7 ': P7R7' CR8 = CR8 'CR7R7 = 0, NR9 - CR7R7' cycloalkyl or cycloalkyl; Q is H, C? _b alkyl, alkyl substituted with one or more halogen, C? _f alkyl substituted with hydroxy, alkenyl, alkynyl, Cl, F, Br, I, substituted alkyl or substituted alkyl, CN, R10C = 0, R4O0, RbR6N 0, H0CR7R7 ', R10CH2, R'O, NH2, or NR4R5, M is a bond or NR10, and M' is a bond or NR10, with the proviso that at least one of M or M 'must be a bond; L is a link, (CR? 'Rr, 7 'Jn, NH, or NR "where n = 0-1; R1 and R1 'are each independently H, alkyl, perfluoroalkyl, cycloalkyl, heterocycle, cycloalkylalkyl, or heterocycloalkyl; R "" is alkyl, perfluoroalkyl, cycloalkyl, heterocycle, cycloalkylalkyl, or heterocycloalkyl; R3 and R3 'are each independently H, alkyl, perfluoroalkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, Cl, F, Br, I, CN, alkoxy, amino, NR "* R2, thiol, or alkylthio; R4 is H, alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, R1C = 0, R "" NHO, SO2OR1, or S02NR1R1 '; R5 is alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, R1C = 0, R ^ HOO,? O2R1, or S02NR1R1 '; R6 is alkyl or substituted alkyl, substituted cycloalkyl or cycloalkyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or substituted plodal, substituted alkyl or substituted alkyl, CN, OH, OR1, R- "O0, R ^ HC ^ O, SO2R1, or SO ^ NRV; R 'and R are each independently H, alkyl, perfluoroalkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, aplo, aplaxyl, Cl, F, Br, I, CN, OR1, nitro , hydroxylamma, hydroxylamide, amino, NHR4, NR2R5, ÑOR1, thiol, alkylthio, R- "O0, R1NHC = 0, S02OR1, or S02NR1R1 '; R8 and R are each independently H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or substituted phenyl, arylalkyl or substituted arylalkyl, halo, CN, OR1 , amino, NHR "1, NR2R5, ÑOR1, alkylthio or substituted alkylthio, R1C = 0, R1NHC = 0, SOzOR1, or S02NR1R1 '; RQ and R9 are each independently H, alkyl, alkenyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl , aplo, aplalkyl, CN, OH, OR1, R] OO, R'OOO, R ^ HOO,? OjR1, S020R1, or S02NR1R1 ', and R is H, alkyl, cycloalkyl, heterocycle, cycloalkylalkyl, heterocycloalkyl, aplo, aplaxyl , CN, OH, OR1, R ^ -O, Rx0C = O, RVNOO, SO2OR1, or? O: NR1Rr

3. Compound according to claim 1, characterized in that G is an aryl or heteroaryl group, where the group is mono- or polycyclic, and which is optionally substituted in a or more positions with hydrogen, C? -C3 alkyl, substituted aillo or aillo, alquililo, Cl, F, Br, I, CN, R1C = 0, R ^ NOO, R ^ NOO, haloalkyl, hydroxyalkyl of i-C3, HOCR3R3 ', nitro, RIOCH2, R ^,? RR5, or SR1; E is Z2, CHR7 or? 0; Zi is 0, S, or? C ?; Z2 is 0, S, or? C ?; Ai is CR7; A2 is CR7; Y is J, cyclopropyl, or cyclobutyl, where J = (CR7R7 ') n and n = l- 3; W is CR7R7'-CR7R7 ', CR8 = CR8', CR7R7'-OO, cyclopropyl, or cyclobutyl; Q is hydrogen, C] -C4 alkyl, alkyl, Cl, F, Br, I, C ?, R-OO, R4O0, R5Re? C = 0, haloalkyl, hydroxyalkyl C? -C6, HOCRV, R10CH2, R- * 0,? H2 or? RV; M is a link and M 'is a link; L is a bond, (CR7R7 ') n,? H, or? RC, where n = 0-1; R and R1 are each independently H, alkyl, cycloalkyl, heterocycloalkyl, or perfluoroalkyl; R 'is alkyl, cycloalkyl, heterocycloalkyl, or perfluoroalkyl; R and R3 are each independently H, alkyl, perfluoroalkyl, Cl, F, Br, I, CN, alkoxy, amino, NR "" R2, thiol, or alkylthio; R4 is H, alkyl, cycloalkyl, heterocycloalkyl, R1C = 0, R * "NHO0, SOsOR1, or? OsNR-'R1 ', R is alkyl, cycloalkyl, heterocycloalkyl, R1C = 0, R1NHC = 0, SO2OR1, or S02NR1R1 '; R7 and R7 'are each independently H, alkyl, arylalkyl, heteroaryl, perfluoroalkyl, heteroarylalkyl, Cl, F, Br, I, CN, OR1, amino, NHR4, NR2R5, NOR1, thiol, alkylthio, R1C = 0, R1NHC = 0, SO2OR1, or 1 or R is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, CN, R1C = 0, R1R1'NC = 0,? 020R1, or S02NR1R1 '.

4. Compound according to claim 1, characterized in that G is an aplo or hetero-group, where the group is mono- or polycyclic, and which is optionally substituted at one or more positions with hydrogen, C1-C3 alkyl, allyl or substituted allyl, alkynyl, Cl, F, Br, I, CN, R-O0, RYNOO, R] R2NC = 0, haloalkyl, hydroxyalkyl of C1-C3, H0CR3R3 ', nitro, R1OCH2, R: 0, NRR5, or SR1; E is OZ2; Zi is O; Z2 is O or NCN; Ai is CR7; A2 is CR7; Y is J, where J = (CR7R7 ') n and n = l-3; W is CR7R7'- CRV, CR & = CR8 ', or CR7R7'- OO; Q is hydrogen, C1-C4 alkyl, alkynyl, Cl, F, Br, I, CN, R4 0, Rr) R6NO0, haloalkyl, hydroxyalkyl of C? -C6, HOCR? R7 ', R1OCH2, R O, NH2 or NR4R5; M is a link and M 'is a link; L is a link; R1 and R are each independently H, alkyl, or perfluoroalkyl; R "is alkyl, or perfluoroalkyl, R and R are each independently H, alkyl, perfluoroalkyl, Cl, F, Br, I, CN, alkoxy, amino, NR'-R2, thiol, or alkylthio; R4 is H, alkyl , R1C = 0, R'NHOO, or SO-.NR ^ 1 '; Rb is alkyl, R ^ O, R- * NHO, or SOiNR1R1'; R 'and R are each independently H, alkyl, aplaikyl, heteropole, perfluoroalkyl, heteroaplalkyl, Cl, F, Br, I, CN, OR1, amino, NHR4, NR2R5, ÑOR1, R1C = 0, RxNHO0, or S02NR1R1 ', and R is H, alkyl, aplo, heteroample, arylalkyl, heteroarylalkyl , CN, R1C = 0, R1R1'NC = 0, OR S02NR1R1 '

5. Compound according to claim 1, characterized in that G is an aplo or heterocycle group, where the group is mono- or polycyclic, and which is optionally substituted at one or more positions with substituents selected from one or more of hydrogen, alkyl or substituted alkyl, halo, heterocycle, CN, nitro, or R "* 0; E is C = Z2 or CHR7 where R7 is hydrogen; Zi is O or S; Z2 is O,?, Or NR6 where R6 is CN or femlo; Ai is CR where R is hydrogen; A2 is CRp where R7 is hydrogen; Y is (CR7R7 ') n and n = 1-2 where R7 and R7' are hydrogen; W is CRV-CR7R7 ', CR8 = CR8', or NR9-CR7R7 'where R7, R7', R8 and R8 'are hydrogen; Q is H, alkyl, alkenyl, aplaxyl or substituted -lapplykyl; M is a bond or NH and M 'is a bond; L is an elation; R and R1 'are each independently alkyl or substituted alkyl, heterocycle or substituted heterocycle, aplo or substituted aryl, arylalkyl or substituted arylalkyl; and R9 is H, alkyl, alkenyl, aplaxyl, R1C = 0, R1OC = 0, R ^ HOO, or? O2R1.

6. Compound according to claim 1, characterized in that it is selected from the group consisting of: (5, 8, 8a) -8,8-dihydro-2- [3- (trifluoromethyl) phenyl] -5,8-methoimidazo [1, 5-a] p? ridin-l, 3 (2h, 5h) -dione; (5a, 8, 8aa) -2,3,8, 8a-tetrahydro-2- [3- (tpfluoromet ll) phenyl] -3-t-oxo-5,8-methynimidazo [l, 5-a ] p? r? dm-l (5h) -one; (5a, 8a, 8a) -8,8a-d? H? Dro-8a-met? L-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1, 5-a] p? R ? d? n-1, 3 (2h, 5h) -dione; (5a, 8, 8 a) -2,3,8, 8a-tetrahydro-8a-met? L-3-thioxo-2- [3- (trifluoromethyl) phenyl] -5,8-methane? M? dazo [1, 5-a] p? ridin-1 (5h) -one; (5a, 8a, 8a) -2, 3, 8, 8a-tetrahydro-2- (1-naphthalenyl) -3-110x0-5, 8-methane? M? Dazo [1, 5-a] p? r? dm-l (5h) -one; (5, 8a, 8a) -hexah? Dro-2- [3- (trifluoromethyl) phenyl] -5,8-methanoimidazo [1,5-a] p? Pd? N-l (5h) -one; (5a, 8a, 8a) -2- [3,5-bis (tpfluorometl] phenyl] -8,8a-d? H? Dro-5, 8-met no? M? Dazo [1,5-a] p? pdm-1, 3 (2h, 5h) -one; (5a, 8a, 8aa) -8, 8a-d? H? Dro-2- (2-naphthalenyl) -5, 8-methane? M? Dazo [1, 5-a] p? Rid? Nl, 3 ( 2h, 5h) -diona; (5a, 8, 8aa) -8, 8a-d? H? Dro-2- (1-naphthalenyl) -5,8-methanoimidazo [l, 5-a] p? R? Dm-l, 3 (2h, 5h) -diona; (5a, 8a, 8aa) -2- (3, 4-d? Chlorophen? L) -8, 8a-d? H? Dro-5, 8-methanoim? Dazo [1,5-a] pipdm-l, 3 (2h, 5h) -dione; [5s- (5a, 8a, 8aß)] -tetrah? Dro-2- [3- (trifluoromethyl) feml] -5,8-methoxy-azo [1,5-a] pyridm-1, 3 (2h, 5h) -diona; [5r- (5c., 8a, 8aß)] -tetrahydro-2- [3- (trifluoromethyl) feml] -5,8-methane? M? Dazo [1, 5-a] pipd? N- 1, 3 ( 2h, 5h) -diona; tetrahydro-2- (1-naphthalenyl) -5,8-ethanoimidazo [1,5-a] r? d? n-1, 3 (2h, 5h) -dione; tetrahydro-2- [3- (tpfluoromethyl) phenyl] -5,8-ethano-midazo [l, 5-a] p? r? d? n-1, 3 (2h, 5h) -dione; (5a, 8, 8a) -2- (4-bromo-l-naphthalenyl) -8,8a-d? -hydro-5,8-methane? M? Dazo [1, 5-a] pindin-1, 3 (2h, 5h) -dione; [5s - (5a, 8a, 8aß)] -2- (3, 5-d? Chlorophemol) tetrahydro-5,8-methanoimidazo [1,5-a] p? R? Dm-1, 3 (2h , 5h) -diona; [5s - (5, 8a, 8aß)] -2- (4-bromo-l-naphthalene? L) tetrahydro-5,8-methanoimidazo [1,5-a] p? R? Dm-l, 3 (2h, 5h) -diona; [5r- (5a, 8a, 8aß)] -2- (4-bromo-l-naphthalenyl) tetrahydro-5,8-methane-m? Dazo [1,5-a] pyridine-1, 3 (2h , 5h) -diona; [5r- (5a, 8a, 8aß)] - 2- (3,5-dichlorophenyl) tetrahydro-5,8-methane-m? Dazo [1,5-a] pyridine-1, 3 (2h, 5h ) -diona; (5, 8a, 8aß) -tetrah? Dro-2- (4-n? Tro-l-naphthalenyl j -5, 8-methane? M? Dazo [l, 5-a] p? R? Dm-l, 3 (2h, 5h) -dione; (5a, 8Oi, 8a) -hexah? Dro-2- (1-naphthalenyl) -3-t? Oxo-5, 8-methanoimidazo [1, 5-a] p? pd? nl (5h) -one; (5, 8, 8aß) -hexa-idro-3-t? oxo-2- [3- (tpfluorometyl) phenyl] -5, 8-methynim? dazo [1,5- a] r? din-l (5h) -one; (5a, 8a, 8aa) - (2- (3,5-dichlorophenyl) tetrahydro-5,8-methanoimidazo [1,5-a] pipd n-1, 3 (2h, 5h) -dione; (5, 8, 8aß) -tetrahydro-2- [3- (tpfluoromethyl) phenyl] -5,8-methane? m? dazo [1,5-a ] pindin-1, 3 (2h, 5h) -dione; (5a, 8, 8a) -tetrah? dro-2- [3- (tpfluoromethyl) phenyl] -5,8-methanoimidazo [1, 5-a] pi idin-1, 3 (2h, 5h) -dione; (5, 8a, 8a) -tetrahydro-2- (4-nitro-l-naphthalemyl) -5,8-methanoim? dazo [1, 5-a] pipdm -1.3 (2h, 5h) -dione; (5OÍ, 8a, 8a) -hexah? Dro-3-t? Oxo-2- [3- (tpfluoromethyl) phenyl] -5,8-methanoimidazo [1, 5 -a] p? r? d? n-1 (5h) -one; [5s- (5, 8a, 8a) -tetrah? dro-2- [3- (trifluoromethyl-1) fe-1] -5, 8-methane m? dazo [1, 5-a] p? r? dm-l, 3 (2h, 5h) -diona; (5, 8a, 8aß) -tetrah? Dro-2- (2-naphthalenyl) -5, 8-methane? M? Dazo [1, 5-a] p? R? Din-l, 3 (2h, 5h) -diona; (5a, 8a, 8ao;) -tetrah? Dro-2- (2-naphthalene? L) -5, 8-meta or? M? Dazo [1,5-a] p? R? Dm-l, 3 ( 2h, 5h) -diona; (5a, 8, 8aa) -tetrah? Dro-8a-met? L-2- (4-mtro-l-naphthalene? L) -5, 8-met no? M? Dazo [l, 5-a] pyridm -1, 3 (2h, 5h) -diona; (5a, 8a, 8aa) -8,8-d? Hydro-2- (-nitro-1-naphthalenyl) -5,8-methane? M? Dazo [1, 5-a] p? Pdm-l, 3 (2h, 5h) -diona; (5o¡, 8c., 8aß) -8, 8a-d? H? Dro-2- (4-nitro-1-naphthalenyl) -5,8-methanoimidazo [1, 5-a] p? R? Dm- 1, 3 (2h, 5h) -dione; (5a, 8a, 8aa) -tetrah? Dro-8a- (2-propen? L) -2- [3- (tpf luoromethyl) phenyl] -5,8-methanoimidazo [l, 5-a] p? Pd? nl, 3 (2h, 5h) -d? ona; (5a, 8a, 8aa) -tetrah? Dro-8a- (phenylmethyl) -2- [3- (tpfluoromethyl) phen? L] -5,8-methanoimidazo [1,5-a] pyridine-1,3 (2h) , 5h) -diona; [(octahydro-1-oxo-2-phenol-5,8-metanoimid zo [1,5-a] pyridin-3-ylidene) amino] carbonitrile; (5, 8, 8aß) - [[2- (3-chloro-4-fluorophenyl) octahydro-1-oxo-5,8-methane? M? Dazo [1, 5-a] p? Pd? N-3 -iliden] amino] carbomtplo; (5a, 8a, 8a) - [[2- (3-chloro-4-fluorophenyl) octahydro-l-oxo-5,8-methane? M? azo [1, 5-a] p? r? dm-3-uden] amino] carbonityl; (5a, 8a, 8aß) -2- (3-chlorophenyl) tetrahydro-5,8-metanoimid zo [1, 5-a] p? R? Dm- 1, 3 (2h, 5h) -dione; (5a, 8a, 8aa) -2- (3-chlorophenyl) tetrahydro-5,8-methanoimidazo [1, 5-a] p? Pd? N-1, 3 (2h, 5h) -dione; (5a, 8a, 8aß) - [[2- (3-chlorophen? L) octahydro-l-oxo-5,8-methane? M? Dazo [1,5-a] pindin-3? Lide] ammo] carbonitplo; (5a, 8a, 8aa) - [[2- (3-chlorophenyl) octahydro-l-oxo-5,8-methane? M? Dazo [1, 5-a] p? R? Din-3-lide ammo] carbomtplo; (5c., 8a, 8aß) - [[2- (3,5-dichlorophenyl) octahydro-l-oxo-5,8-methane? M? D zo [1, 5-a] p? Ridin-3 -? l? den] amino] carboni tplo; (5a, 8a, 8aa) - [[2- (3,5-dichlorophenyl) octahydro-l-oxo-5,8-methanoimidazo [1,5-a] p? Ridin-3? L? Den] amino] carbonitrile; (5a, 8a, Saa) -2- (3-chloro-4-fluorofeml) tetrahydro-5,8-methane? M? Dazo [1, 5-a] p? R? Dm-1.3 (2h , 5h) -diona; (5a, 8a, 8aß) -2- (3-chloro-4-fluorophen? L) tetrahydro-5,8-methane? M? Dazo [1, 5-a] pipdm- 1, 3 (2h, 5h ) -diona; (5a, 8, 8aß) - [[2- (3,4-d? Chlorophenyl) octahydro-l-oxo-5,8-methane? M? Dazo [1, 5-a] p? R? Dm-3 - iliden] amino] carbonitplo; (5a, 8c., 8aa) - [[2- (3,4-dichlorophenyl) octahydro-l-oxo-5,8-methane? M? Dazo [l, 5-a] p? Pd? N- 3-? L? Den] amino] carbonitplo; (5a, 8a, 8aß) -tefrah? Dro-2- [4-n? Tro-3- (tpfluoromethyl) phenyl] -5,8-methane? M? Dazo [1,5-a] pyridm-l, 3 (2h, 5h) -diona; (5a, 8a, 8aa) -tetrah? Dro-2- [4-nitro-3- (tpfluorornethyl) phenyl] -5,8-methane-m? Dazo [1, 5-a] pyrid? N-1, 3 (2h, 5h) -diona; (5a, 8a, 8aß) -2- (3-chloro-4-fluorophenyl) -8,8a-dihydro-5,8-methanoim-dazo [1, 5-a] p? Ridm-1, 3 ( 2h, 5h) -diona; (5a, 8a, 8aa) -2- (3-chloro-4-fluorofeml) -8,8a-dihydro-5,8-methanoimidazo [1, 5-a] pipd? N-1, 3 (2h, 5h) -diona; (5a, 8a, 8aa) - 8, 8a-d? H? Dro-8a-met? L-2- [4-nitro-3- (tpfluoromethyl) phenyl] -5,8-methanoimidazo [1, 5-a ] p? pdm-1, 3 (2h, 5h) -dione; (5a, 8a, 8aß) -4- (octahydro-1, 3-d? Oxo-5, 8-methane? M? Dazo [l, 5-a] p? Ridm-2-il) -2- (tpfluorometll) benzonitrile; (5a, 8c., 8aa) -4- (octah? Dro-1, 3-d? Oxo-5, 8-methane? M? Dazo [1, 5-a] p? R? Dm-2-? ) -2- (trifluoromethyl) benzomethyl; (5a, 8, 8aß) -4- (1,2, 3, 5, 8, 8a-hexahydro-1,3-d? Oxo-5,8-methane? M? Dazo [1, 5-a ] p? pdin-2-? l) -2- (tpfluorometll) benzon? tplo; (5a, 8a, 8aOÍ) -hexah? Dro-2- (2-naphthalenyl) -3- (phenylimmo) -5, 8-methane? M? Dazo [1, 5-a] p? Ridin-l- (5h ) -one; (5a, 8a, 8aß) -2-methox? -4- (octahydro-1, 3-d? Oxo-5,8-methanoimidazo [1,5-a] p? Pdm-2-? L) - 1-naphthalenecarbon trile; (5a, 8Oi, Saa) -2-methox? -4- (octahydro-1, 3-d? Oxo-5, 8-methanoimidazo [1, 5-a] p? R? Dm-2-? ) -1-naphthalenecarbon trile; (5a, 8a, 8aa) -8a- [(4-bromophenyl) methyl] -2- (3,5-dichlorophenyl) tetrahydro-5,8-methanoim? Dazo [1, 5-a] p? Ridin-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aß) -tetrahydro-2- (4-nitro-1-naphthalenyl) -5,8-methane? M? azo [1, 5-a] pipdm-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -tetrah-dro-2- (-nitro-l-naphthalemyl) -5,8-methoimidazo [l, 5-a] pyridin-l, 3 (2H, 5H) - diona; [5R- (5a, 8Oi, 8aa)] -tetrah? Dro-2- (4-n? Tro-l-naphthalene? L) -5,8-methanoimidazo [1, 5-a] p? Pdm-l, 3 (2H, 5H) -dione; [5R- (5a, 8a, 8aa)] -4- (octahydro-1,3-dioxo-5,8-methanoim? Dazo [1,5-a] p? Pdm-2-? L) -2- ( tpfluoromethyl) benzomtplo; [5S- (5a, 8a, 8aß)] - tetrahydro-2- [4-n? Tro-3- (tpfluoromethyl) phenyl] -5,8-methane? M? Dazo [1, 5-a] p ? r? d? n-1, 3 (2H, 5H) -dione; [5S- (5a, 8Oi, 8aa)] -tetrahydro-2- [4-nitro-3- (trifluoromethyl) phenyl] -5,8-methane? M? Dazo [1,5-a] p? R ? d? nl, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aß)] - 4- (octahydro-1, 3-d? Oxo-5,8-methane? M? Dazo [1,5-a] p? Pdm-2-? l) -2- (tpfluorornethyl) benzonitrile; [5? - (5a, 8Oi, 8aa)] -4- (octah? Dro-1, 3-d? Oxo-5, 8-methane? M? Dazo [1,5-a] p? Pdm-2- ?) -2- (trifluoromethyl) benzon? tplo; (5a, 8a, 8aa) -2- (benzo [b] t? Ofen-3-? L) -8, 8a-d? H? Dro-5, 8-methane? M? Dazo [1,5-a ] p? pd? nl, 3 (2H, 5H) -dione; [5R- (5a, 8a, 8aß)] -4- (octahydro-1,3-d? Oxo-5,8-methane? M? Dazo [1, 5-a] p? Pd? N-2-? l) -2- (tpfluoromethyl) benzonitrile; [5R- (5a, 8, aa)] -tetrahydro-2- [4-n? Tro-3- (tpfluoromethyl) phenyl] -5,8-methane? M? Dazo [1,5-a] p? Rid ? nl, 3 (2H, 5H) -dione; [5R- (5a, 8a, 8aß)] -tetrah? Dro-2- [4- n? Tro-3- (tpfluorometll) phenyl] -5,8-methane? M? Dazo [1,5-a] p ? pdm-l, 3 (2H, 5H) -dione; [5R- (5a, 8a, 8aß)] -tetrah? Dro-2- (4-nitro-l-naphthalenyl) -5,8-methane? M? Dazo [1, 5-a] p? Pdm-l, 3 (2H, 5H) -d? Ona; (6a, 9a, 9aa)] -tetrah? Dro-2- [3- (tpfluoromethyl) -feml] -6, 9-methane-2H-pyrid [1,2-d] [1,2,4] tpazin-1, 4 (3H, 9aH) -dione; (5a, 8a, 8aa) -8, 8a-dihydro-2- (lH-mdol-3? L) -5,8-methanoimidazo [1, 5-a] p? R? Din-1, 3 (2H, 5H) -dione; (5a, 8a, 8aa) -2- (3-chlorophenyl) -8,8a-d? -hydro-5,8-methanoimidazo [1, 5-a] p? Ridm-1, 3 (2H, 5H) -diona; (5a, 8a, 8aß) -8, 8a-d? H? Dro-2- (lH-mdol-3? L) -5, 8-met no? M? Dazo [1,5-a] p? r? dm-1, 3 (2H, 5H) -dione; (5a, 8a, 8aa) -2- (benzo [b] thiophen-3? L) -8,8a-d? Hdro-5,8-methane? M? Dazo [l, 5-a] p? pdm-1, 3 (2H, 5H) -dione; (5a, 8a, 8aa) and (5a, 8a, 8aß) -2- (1,2-benzisoxazole-3? L) tetrahydro-5,8-methanoimidazo [1,5-a] pipdm- 1, 3 (2H, 5H) -dione; (5a, 8a, 8aa) -4- (octah? Dro-1, 3-d? Oxo-5,8-methanoimidazo [l, 5-a] p? Pdm-2-? L) -1-naphthalenecarbonitp; (5a, 8a, 8aß) -4- (octahydro-1, 3-d? Oxo-5, 8-methane? M? Dazo [1,5-a] p? Pd? N-2-? L) -1-naphthalenecarbonitrile; (5a, 8a, 8aß) -tetrah? Dro-2- (1-naphthalenyl) -5,8-methane-m? Dazo [1,5-a] pyridin-1,3 (2H, 5H) -dione; (5a, 8a, 8aa) -tetrahydro-2- (1-naphthalenyl) -5,8-methanoimidazo [1, 5-a] pipd? N-l, 3 (2H, 5H) -dione; (5a, 8a, 8aa) -2- (4-fluoro-l-naphthalene? L) tetrahydro-5,8-methane? M? Dazo [1,5-a] p? Ridin-l, 3 (2H , 5H) -dione; (5a, 8a, 8aß) -2- (4-fluoro-1-naphthalene I) tetrahydro-5, 8-methane-m? Dazo [1, 5-a] pindm-1, 3 (2H, 5H) -dione; (5a, 8a, 8aβ) -2- (4-chloro-1-naphthalenyl) tetrahydro-5,8-methanoimidazo [1,5-a] pindm-1,3 (2H, 5H) -dione; (5a, 8a, 8aa) -2- (4-chloro-l-naphthalenyl) tetrahydro-5,8-methane-m? Dazo [1, 5-a] p? Ridm-1, 3 (2H, 5H ) -diona; (5a, 8a, 8aa) -8, 8a-d? H? Dro-2- (1-oxidebenzo [b] t? Ofen-3? L) -5,8-methane? M? Dazo [l, 5 -a] p? r? dm-1, 3 (2H, 5H) -dione; (5a, 8a, 8aa) -4- (1, 2,3,5,8, 8a-hexahydr-1, 3-d? Oxo-5, 8-meta or? M? Dazo [1, 5 a] p? pd? n-2-yl) -1-naphthalenecarbonitpyl; (5a, 8a, 8aa) -tetrah? Dro-2- [4- (1H-tetrazol-5? L) -1-naphthalenyl] -5,8-methane? M? Dazo [1, 5-a] p ? r? din-1, 3 (2H, 5H) -dione; (5S, 8S, 8aR) -4- [Octah? Dro-7- [(1,1-dimethylethoxy) -carbonyl] -1,3-d? Oxo-5,8-methane? M? Dazo [1.5 -a] p? razm-2-? l] -2- (tpfluoromethyl) -benzonitp; (5R, 8R, 8aR) -4- [Octah? Dro-7- [(1, 1-d? Methyletox?) Carbonyl] -1, 3-dioxo-5, 8-methane? M? Dazo [1.5 -a] p? razm-2-? l] -2- (trifluoromethyl) benzonit yl; [5S- (5a, 8a, 8aa)] -4- [Hexahydro-1, 3-d? Oxo-5, 8-meta or? M? Dazo [1, 5-a] p? Razm-2 (3H) -yl) -2- (tpfluoromethyl) benzomtplo; (5R, 8R, 8aR) -4- [Octah? Dro-7- [(1,1-d? Methyletox?) -carbonyl] -1,3-d? Oxo-5,8-metaimidazo [1.5 -a] p? razm-2-? l] -2- (tpfluoromethyl) -benzonitrile; (5S, 8S, 8aR) -4- [Octah? Dro-7- [(1, 1-d? Met? Letox?) Carbonyl] -1, 3-d? Oxo-5, 8-methynimidazo [l, 5-a] p-razin-2-yl] -2- (trifluoromethyl) -benzonitrile; 1-d-methylethyl ester of [5S- (5a, 8a, 8aa) Hexahydro-2- (-nitro-1-naphthalenyl) -1, 3-dioxo-5,8-methane? m? dazo [l , 5-a] pyrazm-7 (8H) -carboxylic acid; [5S- (5a, 8a, 8aa)] -Tetrahydro-2- (4-m-l-naphthalenyl) -5,8-methanoimid zo [1,5-a] pyraz-n-1,3 (2H, 5H ) -diona; [5S- (5a, 8a, 8aa)] -7- [(-Fluorophenyl) sulfonyl] -tetrahydro-2- (4-mtro-1-naphthalene?) -5,8-methane? M? Dazo [ 1, 5-to pyrazin-1,3 (2H, 5H) -dione; (5a, 8a, 8aa) -2- (7-Fluoro-3-benzofuranyl) tetrahydro-5,8-methanoim? Dazo [1,5-a] pipdm-l, 3- (2H, 5H) -dione; (5a, 8a, 8aß) -2- (7-Fluoro-3-benzofuranyl) tetrahydro-5,8-methane-m? Dazo [1, 5-a] pipdm-l, 3- (2H, 5H) -diona; 1, 1-d? meth? lethyl acid ester [5? - (5a, 8a, 8aa)] -2- [4-C? ano-3- (trifluoromethyl) phenyl] hexahydro-8a-met? ll, 3-d? oxo-5,8-methane? m? dazo [1,5-a] pyrazin-7 (8H) -carboxylic acid; [5? - (5a, 8a, 8aa)] -4- (Hexah? Dro-1, 4-d? Oxo-8a-met? L-5, 8-methane? M? Dazo [1, 5-a] pyrazn-2 (3H) -? l) -2- (tpfluoromethyl) benzonityl; [5S- (5a, 8a, 8aa)] -4- (7-Benzo? Lhexah? Dro-8a-met? -1, 3-dioxo-5,8-methane? M? Dazo [1,5-a] p? raz? n-2 (3H) -yl) -2- (tpfluoromethyl) benzonitrile; [5S- (5a, 8a, 8aa)] -7- (4-Fluorobenzoyl) tetrahydro-2- (4-nitro-1-naphthalenyl) -5,8-methane midazo [1,5-a] p? razin-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] - 2- (4-C? Ano-l-naphthalenyl) tetrahydro-7- (5-isoxazolylcarbonyl) -5,8-methane? M? Dazo [l, 5-a] ] pyrazm-1, 3 (2H, 5H) -dione (102A), 4-fluorophenyl ester of [5S- (5a, 8a, 8aa)] -2- (4-cyano-1-naphthalenyl) hexahydride 1,3-dioxo-5,8-methanoimidazo [1,5-a] p? Raz? N-7 (8H) -carboxylic (102B), [5S- (5a, 8a, 8aa)] -2- (4 -c? an-l-naphthalenyl) tetrahydro-7- [(1-methyl-lH-? mid zol-4-yl) sulfon? l] -5,8-methane? m? dazo [l, 5-a] p? razm-1, 3 (2H, 5H) -dione (102C); [5? - (5a, 8a, 8aa)] -2- (4-c? Ano-l-naphthalenyl) -N- (4-fluorophenyl) hexahydro-l, 3-dioxo-5,8-methanoimidazo [ 1,5-a] pyrazin-7 (8H) -carboxamide; [5S- (5a, 8a, 8aß)] -Tetrah? Dro-2- (-n? Tro-l-naphthalenyl) -7- (phenylmethyl) -5,8-methane? M? D zo [1, 5- a] p? razm-l, 3 (2H, 5H) -dione; 1, 1-d? meth? lethyl acid ester [5R- (5a, 8a, 8aa)] -2- [4-C? ano-3- (tpfluoromethyl) phenyl] hexahydro-1, 2- d? oxo-5,8-methanoimidazo [1,5-a] p? razm-7 (8H) -carboxylic acid; 1,1-dimethylethyl ester of [5R- (5a, 8a, 8aa)] -Hexahidro-2- (4-n? tro-1-naphthalene? -1) -1, 3-d? oxo-5, 8- methane? m? dazo [1, 5-a] p? ratio? 7 (8H) -carboxylic; [5R- (5a, 8a, 8aa)] -Tetrahydro-2- (-nitro-1-naphthale-yl) -5,8-methanoimidazo [1,5-a] pyraz-n-1,3 (2H, 5H) -diona; [5R- (5a, 8Oi, 8aa)] -4- (Hexah? Dro-1, 3-d? Oxo-5,8-methanoimidazo [1,5-a] pyraz-2 (3H) -yl) -2 - (tnfluoromethyl) benzomtplo; [5S- (5a, 8a, 8aa)] -4- (7-Benzo-lhexahydro-l, 3-d? Oxo-5, 8-methane? M? Dazo [l, 5-a] p? Razm-2 (3 H) -? L) -2- (trifluoromethyl) benzonityl; phenylmethyl ester of [5S- (5a, 8a, 8aa)] -2- [4-c? ano-3- (tpfluoromethyl) phenyl] hexahydro-1,3-d? oxo-5,8-methane? m? dazo [1, 5-a] p? razm-7 (8H) -carboxylic; [5S- (5a, 8a, 8aa)] -Tet ahydro-2- (2-met11-4-mtrofeml) -5,8-methanoimidazo [1, 5-a] p? R? Dm-l, 3 (2H , 5H) -dione; [5? - (5a, 8a, 8aa)] - 4- (Hexah? Dro-7-methy1-1, 3-d? Oxo-5, 8-methanoimidazo [1,5-a] pyrazin-2 (3H) -? l) -2- (trifluoromethyl) -benzomtplo; [5S- (5a, 8a, 8aa)] -7-Benzo-ltetrahydro-2- (4-n-tro-l-naphthalene?) -5,8-methane? M? Dazo [l, 5-a] p? raz? nl, 3 (2H, 5H) -dione; Phenylmethyl ester of [5S- (5a, 8a, 8aa)] -Hexahidro-2- (4-n-tro-l-naphthalenyl) -1, 3-d? oxo-5,8-methanoimidazo [1,5 -a] pyraz-7 (8H) -carboxylic acid; [5S- (5a, 8a, 8aa)] -Tetrah? Dro-2- (3-meth i 1-4 -nitrophenyl) -5,8-methane midazo [1, 5-a] p? R? D? Nl , 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -Tetrah? Dro-7-met? L-2- (4-n? Tro-l-naphthalenyl) -5,8-methanoimidazo [1, 5-a] p? r? dm-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -Tetrah? Dro-2- (4-n? Tro-l-naphthalene? L) -7- (2-propenyl) -5, 8-methane? M? Dazo [1, 5-a] p? razin-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -4- [Hexah? Dro-1, 3-d? Oxo-7- (phenylmethyl) -5,8-methanoimidazo [1, 5-a] p? -2 (3H) -yl] -2- (trifluoromethyl) benzomtplo; [5R- (5a, 8a, 8aa)] -Tetrah? Dro-2- (4-n? Tro-l-naphthalene?) -7- (2-pro? In? L) -5,8-methanoim? dazo [1,5-a] p? raz? nl, 3 (2H, 5H) -dione; [5R- (5a, 8a, 8aa)] - 7 - [(4-Fluorophenyl) sulfonyl] tetrahydro-2- (4-nitro-1-naphthalenyl) -5,8-methanoimidazo [1, 5-a] p? raz? nl, 3 (2H, 5H) -dione; [5R- (5a, 8a, 8aa)] -7-Benzoyltetrahydro-2- (4-n? Tro-l-naphthalene? L) -5,8-methanoimidazo [1, 5-a] p? 1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -Tetrahydro-2- (4-n-tro-l-naphthalenyl) -7- [(phenylmethyl) sulfonyl] -5,8-methanoim? Dazo [1, 5 -a] pyrazm-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -Tetrahydro-2- (4-nitro-l-naphthalenyl) -7- (phenylacetyl) -5,8-methanoimidazo [1, 5-a] p? Razm-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -Tetrah dro-2- (4-n? Tro-l-naphthalene? L) -7- (3-phen? L-1-oxoprop? L) -5, 8-methanoimidazo [1,5-a] p? Razm-l, 3 (2H, 5H) -dione; (5a, 8a, 8aa) -2- (2-Benzofuranyl) tetrahydro-5,8-methanoim? Dazo [1, 5-a] p? Pd? N-1, 3 (2H, 5H) -dione; (5a, 8a, 8aa) -Tetrah? Dro-2- [3-methox? -4- (4-oxazolyl) phenyl] -5, 8-met no? M? Dazo [l, 5-a] p? Pdm -l, 3 (2H, 5H) -dione; 1-d-methylethyl ester of [5S- (5a, 8a, 8aa) -2- (4-C? ano-l-naphthalene?) hexahydro-l, 3-d? oxo-5, 8-methanoimid zo [1, 5-a] p? raz? n-7 (8H) -carboxyl ico; [5? - (5a, 8a, 8aa)] -4- (Hexah? Dro-1, 3-dioxo-5, 8-methane? M? Dazo [1,5-a] p? Raz? N-2 ( 3H) -yl) -1-naphthalenecarbomtplo; [5S- (5a, 8a, 8aa)] - 4- [Hexah? Dro-7- (2-methyl-1-oxopropyl) -1,3-dioxo-5,8-methanoimidazo [1,5-a] ] p? razm-2 (3H) -? l] -1-naphthalenecarbonitrile; 1, 1-d? meth? lethyl acid ester [5S- (5a, 8a, 8aa)] -2- (4-C? ano-3-iodophene?) hexahydro-1,3-dioxo -5,8-methane? M? Dazo [1,5-a] p? Razm-7 (8H) -carboxylic; [5S- (5a, 8a, 8aa)] -4- (Hexahydro-1,3-d? Oxo-5,8-methanoim? Dazo [1,5-a] pyraz? N-2 (3H) -yl) -2-iodobenzonitplo; (5c., 8a, 8aa) -Tetrah? Dro-2- (2-met? L-3-benzofuranyl) -5, 8-methane? M? Dazo [1, 5-a] p? Ridm-l, 3 (2H, 5H) -dione; (5a, 8a, 8aa) -2- (2, 2-D? Met? L-2H-l-benzop? Ran-4-yl) tetrahydro-5,8-methanoimidazo [l, 5-a] p ? r? dm-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -7-Acet? Ltetrah? Dro-2- (4-nitro-1-naphthalenyl) -5,8-methane? M? Dazo [1, 5-a] pyraz -1, 3 (2H, 5H) -dione; [5S- (5a, 8a, Saa)] -Tetrah? Dro-7- (2-met? Ll-oxoprop? L) -2- (4-n? Tro-1-naphthalem) -5,8-methane? m? dazo [1, 5-a] pyraz-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -7- [4-Fluoro-3- (trifluoromethyl) -benzoyl] tetrahydro-2- (4-n-tro-l-naphthalenyl) -5,8-methane? M ? dazo [1, 5-a] p? razin-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, Saa)] -7- (4-chloro-3-n? Trobenzo? L) tetrahydro-2- (4-n? Tro-l-naphthalene?) -5, 8 -methanoim? dazo [1, 5-a] p? razm-l, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -Tetrahydro-7- (5-? Soxazole? Lcarbon? L) -2- (4-mtro-l-naphthalene? L) -5,8-methane? M? Dazo [1, 5-a] p? Razin-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -7- (4-Butylbenzoyl) tetrahydro-2- (4-n-tro-l-naphthalenyl) -5,8-methanoimidazo [1, 5-a] pyrazin-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa); -N- (3-Chloro-4-fluorophenyl) -hexah? Dro-2- (4-n-t-ol-naphthalemyl) -1,3-d? Oxo-5,8-methane? M? Dazo [l, 5-a] p? Razm-7 (8H) -carboxamide; [5? - (5a, 8a, 8aa)] -Tetrahydro-2- (-n? Ro-l-naphthalenyl) -1 - [4- (tpfluoromethyl) benzoyl] -5,8-methane m? Dazo [l, 5-a] pyrazin-1,3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -Hexahidro-N- (1-methylethyl) -2- (4-n? Tro-l-naphthalene? -1) -1,3-dioxo-5,8-methane? m? dazo [1,5-a] p? razin-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] -N- (4-Fluorofeml) hexahydro-2- (4-n-tro-l-naphthalenyl) -1, 3-dioxo-5,8-methanoimidazo [1 , 5-a] pyrazin-7 (8H) -carboxamide; [5S- (5a, 8Oi, 8aa)] - N - [(4-fluorophenyl) methyl] hexahydro-2- (4-n-tro-l-naphthalenyl) -1, 3-dioxo-5,8-methane? m? dazo [1,5-a] pyraz? n-7 (8H) -carboxa ida; 4-nitrophenyl ester of [5S- (5a, 8a, 8aa)] -Hexah? dro-2- (4-n? tro-l-naphthalemyl) -1, 3-d? oxo-5,8-methanoimidazo [ 1, 5-a] pyrazin-7- (8H) -carboxylic acid; 4-fluorophenyl ester of [5? - (5a, 8a, 8aa)] -Hexahidro-2- (4-nitro-1-naphthalene? -1) -1,3-d? oxo-5,8-methane? ? dazo [1, 5-a] pyraz? n-7 (8H) -carboxylic; 4- (Nitrophenyl) -methyl ester of [5S- (5a, 8a, 8aa)] -Hexah? dro-2- (4-n? tro-l-naphthalenyl) -!, 3-d? oxo-5, 8-methane? M? Dazo [1, 5-a] p? Raz? N-7 (8H) -carboxylic; butyl ester of [5S- (5a, 8a, 8aa)] -Hexah? dro-2- (4-n? tro-l-naphthalenyl) -1, 3-d? oxo-5,8-methane? m? dazo [1, 5-a] p? razm-7 (8H) -carboxylic; [5? - (5a, 8a, 8aa)] -Tetrah? Dro-7- [(1-met? L-lH-? M? D zol-4-? L) sulfonyl] -2- (4-n? tro-l-naphthalene? l) -5,8-methanoimidazo [1, 5-a] p? ratio-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8 a)] -7- [(4-chloro-3-n? Trofen? L) sulfoml] tetrahydro-2- (4-n? Tro-l-naphthalene? L) - 5, 8-methane-m? Dazo [1, 5-a] p? Razin-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -Tetrahydro-2- (4-n-tro-l-naphthalenyl) -7- [(2, 2, 2-trifluoroethyl) sulfonyl] -5,8-methanoim dazo [ 1, 5-a] p? Razin-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -7-Acetyl-2- (4-c-ano-l-naphthalenyl) tetrahydro-5,8-methanoimidazo [1, 5-a] pyraz? N-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] - 2- (4-cyano-l-naphthalenyl) tetrahydro-7- (2-methyl-l-oxopropyl) -5,8-methane? M? dazo [1, 5-a] p? razm-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -2- (4-cyano-l-naphthalenyl) -7- [4-fluoro-3- (trifluoromethyl) benzoyl] tetrahydro-5,8-methane? m? dazo [1,5-a] p? razm-l, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] - 7- (4-chloro-3-nitrobenzoyl) -2- (4-c-ano-l-naphthalenyl) tetrahydro-5,8-methanoimidazo [1,5-a] ] p? razm-l, 3 (2H, 5H) -d? ona; [5S- (5a, 8a, 8aa)] -7- (-But? Lbenzo? L) -2 - (4-c? Ano-l-naphthalene? L) tetrahydro-5,8-methane? M? Dazo [1,5-a] pyraz-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -N- (3-chloro-4-fluorophenyl) -2- (4-c? Ano-l-naphthalene?) Hexahydro-1,3-d? Oxo -5,8-methanoimidazo [1,5-a] pyrazn-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] - 2- (4-c? Ano-l-naphthalene? L) hexahydro-l, 3-d? Oxo-N- [4- (tnfluoromethyl) phenyl] - 5, 8-methane? M? Dazo [l, 5-a] p? Raz? N-7 (8H) -carboxamide; [5? - (5a, 8a, 8aa)] -2- (4-c? Ano-l-naphthale il) hexahydro-N- (1-melethyl) -1, 3-d? Oxo-5, 8- methanoimidazo [1,5-a] p? raz? n-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] -2- (4-cyano-l-naphthalenyl) -N- [(4-fluorofeml) methyl] hexahydro-1,3-dioxo-5, 8- methanoimidazo [1,5-a] pyrazin-7 (8H) -carboxamide; 4- (Methylphenyl) -methyl ester of [5? - (5a, 8a, 8aa)] -2- (4-c? ano-l-naphthalemyl) hexahydro-l, 3-d? oxo-5, 8- methane? m? dazo [l, 5-a] p? razm-7 (8H) -carboxylic; butyl ester of [5? - (5a, 8a, 8aa)] -2- (4-c? ano-l-naphthalenyl) hexahydr-1,3-d? oxo-5,8-methane? m? dazo [1,5-a] p? razm-7 (8H) -carboxylic; [5? - (5a, 8a, 8aa)] -7- [(4-chloro-3-nitrophenyl) sulfonyl] -2- (4-c-ano-l-naphthalenyl) tetrahydro-5, 8-ethanoimidazo [1, 5-a] p? razm-l, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -2- (4-cyano-1-naphthalenyl) tetrahydro-7- [(2,2,2-trifluoroethyl) sulfonyl] -5,8-methane? m? dazo [1, 5-a] p? ra? n-1, 3 (2H, 5H) -dione; t 5S- (5a, 8a, 8aa)] -7-Acet? l-2- [4-c? ano-3- (tpfluoromethyl) phen? l] tetrahydro-5,8-methanoim? dazo [1, 5-a] p? Razm-l, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -2- [4-c? Ano-3- (tpfluorornethyl) phen? L] tetrahydro-7- (2-met? Ll-oxoprop? L) -5, 8-methanoimidazo [1, 5-a] p? Ratio-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -2- [4-c? Ano-3- (tpfluoromethyl) phenyl] -7- [4-fluoro-3- (tpfluoromethyl) benzoyl] -tetrah? Dro-5 , 8-methane? M? Dazo [1,5-a] p? Razm-l, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -7- (-chloro-3-nitrobenzoyl) -2- [4-c? Ano-3- (tpfluoromethyl) fem] tetrahydro-5,8-methane? M? Dazo [1, 5-a] p? Razm-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -2- [4-c? Ano-3- (tpfluoromethyl) feml] tetrahydro-7- (5-? Soxazole? Lcarbon? L) -5,8-methane? m? dazo [1, 5-a] p? ratio? 1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -7- (4-butylbenzoyl) -2- [4-cyano-3- (tpfluoromethyl) phenyl] tetrahydro-5,8-methanoimidazo [1, 5-a] pyrazin-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] - - (3-chloro-4-fluoro-phenyl) -2- [4-c? Ano-3- (tpfluoromethyl) phenyl] hexahydro-1,3-d? oxo-5, 8-methanoim? dazo [1, 5-a] pyrazin-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] -2- [4-c? Ano-3- (tpfluoromethyl) phenyl] -hexah? Dro-1, 3-d? Oxo-N- [4- (tpfluoromethyl) phenyl ] -5,8-methanoimidazo [1,5-a] pyraz? N-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] -2- [4-cyano-3- (tpfluoromethyl) -feml] hexahydro-N- (1-methyl-ethyl) -1,3-dioxo-5,8-methanoim? azo [1,5-a] pyraz? n-7 (8H) carboxamide; [5? - (5a, 8a, 8aa)] -2- [4-c? Ano-3- (tpfluoromethyl) phen? L] -N- (4-fluorophen? L) exah? Dro-1, 3-d ? oxo-5, 8-methane? m? azo [1, 5-a] p? raz? n-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] -2- [4-c? Ano-3-tpfluoromethyl) feml] -N- [(4-fluorophenyl) methyl] hexahydro-1,3-d? Oxo- 5,8-methanoimidazo [1,5-a] ?? razm-7 (8H) -carboxamide; 4-N-Trophenyl acid ester [5? - (5a, 8a, 8aa)] -2- [4-c? ano-3- (tpfluoromethyl) fem] -hexah? dro-1, 3-dioxo-5, 8-methane? M? Dazo [1,5-a] pyraz? N-7 (8H) -carboxylic; 4-fluorophenyl ester of [5S- (5a, 8a, 8aa)] - 2- [4-c? ano-3- (tpfluoromet l) phenyl] -hexahydro-1,3-d? oxo-5, 8- methane? m? dazo [1, 5-a] p? raz? n-7 (8H) -carboxylic; 4- (Nitrophenyl) methyl ester of [5? - (5a, 8a, 8aa)] -2- [4-c? ano-3- (tpfluoromethyl) phenyl] -hexah? dro-1, 3-d? oxo -5,8-methanoimidazo [1,5-a] pyrazin-7 (8H) -carboxylic acid; butyl ester of the acid [5? - (5a, 8a, 8aa)] -2- [4-c? ano-3- (trifluoromethyl) phenyl] -hexah? dro-1, 3-d? oxo-5, 8- ethanoimidazo [1,5-a] pyrazm-7 (8H) -carboxylic acid; [5S- (5OÍ, 8a, 8aa)] -2- [4-c? Ano-3- (tpfluoromethyl) phenyl] tetrahydro-7- [(1-methyl-1H-imidazol-4? L) sulfonyl] - 5, 8-methanoimidazo [1,5-a] p? Razm-l, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -7- [(4-chloro-3-nitrophenyl) sulfonyl] -2- [4-c? Ano-3- (tnfluoromethyl) phenyl] tetrahydro-5, 8 -metanoim? dazo [1, 5-a] p? razm-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -2- [4-c? Ano-3- (tpfluoromethyl) -phenyl] tetrahydro-7- [(2,2, 2-tpfluoroethyl) sulfonyl] -5,8 -methanoimidazo [1, 5-a] p? razm-l, 3 (2H, 5H) -d? ona; [5S- (5a, 8a, 8aa)] -7-acetyl-2- (4-cyano-3-iodophenyl) tet ahydro-5,8-methanoimidazo [1, 5-a] p? Raz? Nl, 3 ( 2H, 5H) -dione; [5S- (5a, 8a, 8aa)] - 2- (4-cient-3-yodofeml) tetrahydro-7- (2-met? Ll-oxopropyl) -5,8-methane? M? Dazo [l , 5-a] p? Razin-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -2- (4-c? Ano-3-iodophenyl) -7- [4-fluoro-3- (trifluoromethyl) benzoyl] tetrahydro-5,8-methane? m? dazo [1,5-a] ?? razin-l, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -7- (4-chloro-3-m-benzoyl) -2- (4-c-ano-3-iodophenyl) tetrahydro-5,8-methanoimidazo [l, 5] -a] p? razm-l, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -2- (4-cyano-3-yodofeml) tetrah? ro-7- (5-issoxazolylcarboml) -5,8-methane? m? dazo [1, 5-a] p? ratio- 1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -7- (4-butylbenzoyl) -2- (4-cyano-3-iodophenyl) tetrahydro-5,8-methoimidazo [1,5-a] pyrazin - 1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] -N- (3-chloro-4-fluorofeml) -2- (4-c? Ano-3-yodofeml) hexahydro-1,3-d? Oxo-5 , 8-methanoimidazo [1,5-a] pyraz? N-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] -2- (4-cyano-3-iodophenyl) hexahydro-1,3-d? Oxo-N- [4- (trifluoromethyl) phenyl] -5,8-methanoim? dazo [1, 5-a] pyraz? n-7 (8H) -carboxamide; [5S- (Sor, 8a, 8aa)] -2- (4-c? Ano-3-iodophenyl) hexahydro-N- (1-met? Let? L) -1, 3-dioxo-5, 8-methanoimidazo [1, 5-a] pyrazm-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] -2- (4-c? Ano-3-yodofeml) -N- (4-fluorophen? L) hexahydro-l, 3-d? Oxo-5,8-methane ? m? dazo [1,5-a] p? raz? n-7 (8H) -carboxamide; [5S- (5a, 8a, 8aa)] -2- (4-c? Ano-3-iodophenyl) -N- [(4-fluorophenyl) -methyl] exahydro-1,3-d? Oxo-5 , 8-methanoimidazo [1,5-a] p? Razin-7 (8H) -carboxamide; 4-nitrophenyl ester of [5? - (5a, 8a, 8aa)] -2- (4-c? ano-3-iodophenyl) hexahydro-l, 3-dioxo-5,8-methanoimidazo [1, 5] a] pyrazin-7 (8H) -carboxylic; 4-fluorophenyl acid ester [5S- (5a, 8Oi, 8aa)] -2- (4-c? ano-3-iodophenyl) hexah d.ro-1,3-d? oxo-5,8-methanoimidazo [ 1, 5-a] p? Razin-7 (8H) -carboxylic; (4-n? trofeml) methyl ester of acid [5? - (5a, 8a, 8aa)] -2- (4-c? ano-3-iodophenyl) hexahydr-1,3-d? oxo -5,8-methane-m? Dazo [1,5-a] pyrazin-7 (8H) -carboxylic acid; butyl ester of acid [SS- (5a, 8a, 8aa)] - 2- (4-cyano-3-iodophenyl) hexahydr-1,3-d-oxo-5,8-methoimidazo [1,5-a] ] pyraz? n-7 (8H) -carboxylic; [5S- (5a, 8a, 8aa)] -2- (4-cyano-3-iodophenyl) tetrahydro-7- [(1-methyl-lH-? M? Dazol-4-yl) sulfonyl] -5 , 8-methanoim? Dazo [1, 5-a] pyrazm-1, 3 (2H, 5H) -dione; [SS- (5a, 8a, 8aa)] -7- ((4-chloro-3-nitrofeml) sulfonyl] -2- (4-c-ano-3-iodophenyl) tetrahydro-5,8-methanoimidazo [ 1, 5-a] p? r zm-1, 3 (2H, 5H) -dione; [5S- (5a, 8a, 8aa)] - 2- (4-c? ano-3-iodophenyl) tetrahydro -7- (methylsulfonyl) -5,8-methane-m? Dazo [1, 5-a] pyraz? N-1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aa)] -4- (hexahydro-1, 3-dioxo-5, 8-methanoimidazo [1,5-a] pyrazn-2 (3H) -yl) -2- (tpfluoromethyl) benzomethyl, ester 1, 1- d? met? letil? co of acid [5R- (5a, 8a, 8aß)] -hexah? dro-2- (4-n? tro-l-naphthalenyl) -1,3-dioxo-5, 8-methanoimidazo [1, 5-a] p? razm-7 (8H) -carboxylic acid, 1,1-d? -methyl-lethyl acid ester [5S- (5a, 8a, 8aß)] -2- [4-cyano] -3- (tpfluorometll) phen? L] -hexah? Dro-l, 3-d? Oxo-5,8-methanoimidazo [1, 5-a] pyrazm-7 (8H) -carboxylic; [5S- ( 5a, 8a, 8aß)] -tetrah? Dro-2- (4-n? Tro-l-naphthalenyl) -5, 8-met noim? Dazo [l, 5-a] p? Razm-l, 3 (2H , 5H) -dione, acidic ester 1, 1-d? Met? Let? L acid [5R- (5a, 8a, 8aß)] -2- [4-c? Ano-3- (trifluoromethyl) pheny] l] hexahydro-1,3-dioxo-5,8-methanoimidazo [1,5-a] p? razm-7 (8H) -carboxylic acid; [5? - (5a, 8a, 8aß)] -hexah? dro-2- (4-n? tro-l-naphthalene? l) -l, 3-dioxo-5, 8-1,1-dimethylethyl ester -met noim? d zo [1,5-a] pyrazin-7 (8H) -carboxylic acid; [5R- (Sa, 8a, 8aß)] -4- (hexahydro-1,3-d-oxo-5,8-methanoimidazo [1,5-a] pyraz-2 (lH) -yl) -2 - (trifluoromethyl) benzonitop; [5S- (5a, 8a, 8aß)] -4- (7-benzohexahexah? Dro-l, 3-dioxo-5, 8-methanoim? Dazo [1, 5-a] pyraz? N-2 (3H ) -yl) -2- (trifluoromethyl) enzonitrile; (Sa, 8a, 8aß) -tetrah? Dro-2- (2-met? L-4-n? Trofeml) -5, 8-methane? M? Dazo [l, 5-a] pir? D? N- 1, 3 (2H, 5H) -dione; [5? - (5a, 8a, 8aß)] -7-benzoyltetrahydro-2- (4-nitro-1-naphthalene? -5, 8-methane? M? Dazo [l, 5-a ] pyraz? n-1, 3 (2H, SH) -dione; (5a, 8a, 8aß) -2- (2-benzofuranyl) tetrahydro-5,8-methanoim? Dazo [1, 5-a] p? Pd? N-1, 3 (2H, 5H) -dione; (Sa, 8a, 8aß) -tetrah? Dro-2- (4, 5, 6, 7 -tetra fluoro-2-met? L-3-benzofuranyl) -5, 8-methane? M? Dazo [l, 5 -a] p? ridm-l, 3 (2H, 5H) -dione; (5a, 8a, 8aß) -tetrah? Dro-2- [3-methox? -4- (4-oxazole? L) phenyl] -5,8-methanoimidazo [1, 5-a] p? R? Dm- 1, 3 (2H, 5H) -dione; 1,1-dimethylethyl ester of [5S- (5a, 8a, Saß)] -2- (4-c? an-l-naphthalenyl) exah? drs-1,3-d? oxo-5,8-methane ? m? dazo [1,5-a] p? raz? n-7 (8H) -carboxylic; 1-d-methyl-methyl ester of the acid [5S- (5a, 8a, 8aß)] 2- (4-c? ano-3-yodofeml) hexahydr-1,3-d? oxo-5 , 8-met no? M? Dazo [1,5-a] pirazm-7 (8H) -carboxíllco; (Sa, 8a, 8aß) -tetrah? Dro-2- (2-met? L-3-benzofuranyl) -5,8-methanoimidazo [1, 5-a] p? Pdm-1, 3 (2H, SH) -diona; [5S- (5a, 8a, 8aß)] -2- (3, 5-dichlorophenyl) hexahydro-1,3-dioxo-5,8-methane-m? dazo [1,1-dimethylethyl] ester [1] , 5-a] p? Razin-7 (8H) -carboxylic; and (5a, 8a, 8aß) -2- (2, 2-dimet? l-2H-l-benzop? ran-4? l) tetrahydro-5,8-methane? m? dazo [1.5 -a] pyridm-1,3 (2H, 5H) -d? ona.

7. Pharmaceutical composition characterized in that it comprises the following formula: CO or a salt thereof, wherein the symbols have the following meanings and are selected, for each case, independently: G is an aryl or heterocycle group, where the group is mono- or polycyclic, and which is optionally substituted in one or more positions; E is OZj, CR'CR '', SO :, P = OR2, or P = OOR2; Zi is O, S, NH, or NRÉ; Z .. is O, S, NH, or NR6; Ai is CR7 or N; A2 is CR or N; And it is J-J'-J "where J is (CR ^ R7 ') nyn = 0-3, J' is a bond or O, S, S = 0,? 02, NH, NR6, OO, OOO, NR1C = 0, CR7R7 ', C = CR8R9', R2P = 0, OPOOR2, 0P02, 0? 02, ON, NHNH, NHNR6, NR6NH, N = N, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, heterocycle or substituted heterocycle or aplo or substituted aryl, and J "is (CR R") nyn = 0-3, where Y is not a bond, W is CR7R7'-CR7R7 ', CR8 = CR8', CR7R ~ "-C-0, NR9- CRR7 ', N = CR8, N = N, NR-NR, substituted cycloalkyl or cycloalkyl, cycloalkyl ilo or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aplo or substituted aryl; Q is H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, heterocycloalkyl or substituted heterocycloalkyl, substituted arylalkyl or substituted alkylalkyl, alkynyl or substituted alkyl, substituted or substituted halogen, heterocycle or substituted heterocycle, halo , CN, R1OC = 0, R4O0, R5R "NC = 0, HOCR7R7 ', nitro, R1OCH2, R * O, NH2, OOSR1,? O ^ 1 or NR4R'; M is a bond, 0, CR R" 'oy M is a link or NR10, with the proviso that at least one of M or M 'must be a link; L is a bond, (CR7R7 ') n, NH, NRD or N (CR7R') n, where n = 0-3; R1 and R1 are each independently H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, substituted heterocycloalkyl or heterocycloalkyl, substituted or substituted aryl, arylalkyl or substituted substituted alkyl; R "is alkyl or substituted alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkylmethyl, heterocycloalkyl or substituted heterocyclealkyl, substituted aryl or substituted aployl, substituted or substituted alkylalkyl; R3 are each independently H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkyl or substituted cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, substituted heterocycloalkyl or heterocycloalkyl, substituted or substituted aploid, aplakyl or substituted arylalkyl, halo, CN, hydroxylamine, hydroxamide, substituted alkoxy or alkoxy, amino, NR-R2, thiol, alkylthio or substituted alkylthio, R is H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, cycloa substituted lkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, substituted heterocycloalkyl or heterocycloalkyl, substituted or substituted aryl, arylalkyl or substituted arylalkyl, R 1 C = 0, R-NHOO, SO 2 OR 1; R is substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, substituted aryl or anole, substituted or substituted alkylalkyl, ROO, R ^ HOO, SO2R1,? O2OR1, or S02NR1R1 '; R is alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, substituted cycloalkenyl or cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or substituted heterocycloalkyl, substituted or substituted aryl, aplaxyl or substituted substituted alkyl, CN, OH , OR1, R: 0, R ^ HOO, S02R !, SO2OR1, or S02NR1R1 '; R and R7 are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkyl or substituted cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aplo, substituted alkyl or substituted phenyl, halo, CN, OR1, nitro, hydroxylamine, hydroxylamide, amino, NHR4, NR2R5, ÑOR1, thiol, alkylthio or substituted alkylthio, R "" 0, R "OO, R1NHC = 0, SO2R1, SOR1, RVNOO, OOSR1, SO2R1, SO2OR1, or S02NR1R1 '; R and R are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, or substituted aryl, substituted aryl or substituted aryl, nitro, halo, CN, OR 1, amino, NHR 4, NR 2 R 5, ÑOR 1, alkylthio or substituted alkylthio, OO R 1, R * OO 0, R- "O 0, O 2 R 1, PO s R 1 ' , OR S02NR1R1 '; R9 and R9' are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl , heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aplo, ap substituted alkyl or alkylalkyl, CN, OH, OR1, R1C = 0, R ^ OO, R - NHO0,? O.R1, S02OR1, O S02NR1R1 '; and R is H, substituted alkyl or alkyl, substituted cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted c-chloralkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or arylalkyl substituted, CN, OH, OR1, R1C = 0, R1OC = 0, R1R1'NC = 0,? O2R1, ? O2OR1, or S02NR1R1 '; and a pharmaceutically carrier acceptable

8. Pharmaceutical composition in accordance with claim 7, characterized in that it also comprises another anticancer agent.

9. The use of a compound of the following formula I: 0) or a salt thereof, where the symbols have the following meanings and are independently selected, for each case: G is an aryl or heterocycle group, where the group is mono- or polycyclic, and which is optionally substituted in one or more positions; E is C = Z2, CR7CR7 ',? 02, P = OR2, or P = OOR2; Zi is 0,?, NH, or NR6; Z2 is O, S, NH, or NR6; Ai is CR7 or N; A2 is CR7 or N; And it is J-J'-J "where J is (CR7R7 ') nyn = 0-3, J' is a bond u 0,?, S = 0, S02, NH, NR6, OO, OOO, NR1C = 0, CR7R7 ', C = CR8R8', R2P = 0, 0P00R2, 0P02, 0S02, C = N, NHNH, NHNR6, NR6NH, N = N, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, heterocycle or substituted heterocycle or aryl or aryl substituted, and J "is (CR7R7 ') nyn = 0-3, where Y is not a link; W is CRR7'-CR7R7 ', CR8 = CR8', CR7R7'-C = 0, NR9-CR7R7 ', N = CR8, N = N, NR9-R9', cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; Q is H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, heterocycloalkyl or substituted heterocyclealkyl, arylalkyl or substituted or substituted heterocycle, halo, CN, R: 0C = 0, R4C = 0, R5R6NC = 0, H0CR7R7 ', nitro, R-'OCH; ,, R1 ^ NH2, OO? R1, S02R1 or NRR5; M is a bond, 0, CR7R7 'or NR10, and M' is a bond or NR10, with the proviso that at least one of M or Mr must be a bond; L is a bond, (CRR ') n, NH, NR5 or N (CR7R7') n, where n = 0-3; R1 and R1 'are each independently H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl; R 2 is substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl; R3 and R3 'are each independently H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halo, CN, hydroxylamine, hydroxamide, alkoxy or substituted alkoxy, amino, NR1R2, thiol, alkylthio or substituted alkylthio; R 4 is H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, R - 0, R1NHC = 0,? 02OR1, or S02NR1R1 '; R5 is substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, substituted heterocyclealkyl or heterocycloalkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, R1C = 0 , or SOzNRV; R6 is substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, substituted heterocyclealkyl or heterocycloalkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, CN, OH , OR1, R1C = 0, R ** NH 0, S020R1, or S02NR1R1 '; R7 and R7 'are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halo, CN, OR1, nitro, hydroxylamine, hydroxylamide, amino, NHR4, NR2R5, OR1, thiol, alkylthio or substituted alkylthio, R1C = 0, R1OC = 0, R1NHC = 0, SOR1, P03R1R1 ', RVN O, C = O? R1,? O2R1, SO2OR1, or SO2NR-R1 '; R8 and R8 'are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, aryl or substituted aryl, arylalkyl or substituted arylalkyl, nitro, halo, CN, OR 1, amino, NHR 4, NR 2 R 5, OR 1, alkylthio or substituted alkylthio, OOSR 1, RO O, R ** C = 0, R * "NH 0, R 1 R 1 'NC = 0, SOjOR1, S = OR1,? O2R1, POaR'-R1', or? 02NR1R1 ', R9 and R9' are each independently H, substituted alkyl or alkyl, substituted alkenyl or alkenyl, cycloalkyl or substituted cycloalkyl, substituted cycloalkenyl or cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylalkyl or substituted cycloalkylalkyl, cycloalkenylalkyl or substituted cycloalkenylalkyl, heterocycloalkyl or heterocyclealkyl the substituted, aryl or substituted aryl, arylalkyl or substituted arylalkyl, CN, OH, OR1, R * "O0, R10C = 0, R1NHC = 0,? O2R1, SO2OR1, or S0NR1R1 '; and R 10 is H, substituted alkyl or alkyl, substituted cycloalkyl or cycloalkyl, substituted cycloalkenyl or cycloalkenyl, substituted heterocycle or heterocycle, substituted cycloalkylalkyl or substituted cycloalkylalkyl, substituted cycloalkenylalkyl or cycloalkenylalkyl, heterocyclealkyl or substituted heterocyclealkyl, substituted aryl or aryl, arylalkyl or substituted arylalkyl, CN, OH, OR1, R * "C = 0, R1OC = 0 R ^ 'NO, SO2R1,? O2OR1, or? 02NR1R1'. For the manufacture of a drug to modulate the function of a nuclear hormone receptor. Use according to claim 9, wherein the nuclear hormone receptor is a nuclear hormone receptor that binds the spheroid 11. Use according to claim 9, wherein the nuclear hormone receptor is the androgen receptor. Use according to claim 9, wherein the nuclear hormone receptor is the estrogen receptor 13. Use according to claim 9, wherein The nuclear hormone receptor is the progesterone receptor. 14. Use according to claim 9, wherein the nuclear hormone receptor is the glucocorticoid receptor. 15. Use according to claim 9, wherein the nuclear hormone receptor is the mineralocorticoid receptor. 16. Use according to claim 9, in