Title of Invention

"A POTTING METHOD AND AN APPARATUS FOR POTTING HOLLOW FIBRE MEMBRANES"

Abstract

A method of forming a pot for an array of hollow fibre membranes (7) including the steps of placing the ends (6) of the fibre membranes (7) in a mould (5); forming a first layer (20) of curable resin material in a non-cured state around the fibre membrane ends (6), applying a second layer (21) of a second material to the first layer (20) prior to full curing of the first layer, the second material layer being chemically reactive with the first layer material to form an adhesive bond therebetween; at least partially curing both layers and removing the pot formed from the mould (5), wherein the second layer material is of higher flexibility than the first layer material when each layer is fully cured. Apparatus for performing the method is also disclosed(fig. 1)

Full Text

TECHNICAL FIELD The present invention relates to a potting method and an apparatus for potting hollow fibre membranes typically used in filtration systems. BACKGROUND ART The potting materials used to support and hold arrays of porous hollow fibre membranes are usually a compromise between materials which have sufficient rigidity to provide adequate support but sufficient softness and flexibility to avoid breakage of the fibres where they enter the pot. Too rigid a material produces rapid breakage of fibres adjacent the pot while too soft a material does not have sufficient mechanical strength to adequately support the fibres. The materials are also chosen to resist breakdown as a result of exposure to various types of feed as well as cleaning fluids used to maintain the fibres. Known systems employ single layers of epoxy, polyurethane or silicon materials, however, each suffer from the disadvantages outlined above. The present invention seeks to overcome or at least ameliorate one or more of the disadvantages of the prior art outlined above or at least provide a useful alternative. DISCLOSURE OF THE INVENTION According to one aspect, the present invention provides a method of forming a pot for an array of hollow fibre membranes including the steps of placing the ends of said fibre membranes in a mould; forming a first layer of curable resin material in a non-cured state around said fibre membrane ends, applying a second layer of polyurethane resin material to said first layer prior to While significant strides have been made toward achieving CRF regulation through administration of CRF receptor antagonists, there remains a need in the art for effective small molecule CRF receptor antagonists. There is also a need for pharmaceutical compositions containing such CRF receptor antagonists, as well as methods relating to the use thereof to treat, for example, stress-related disorders. The present invention fulfills these needs, and provides other related advantages. In particular the invention relates to novel compounds which are potent and specific antagonists of corticotropin-releasing factor (CRF) receptors. The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof (Formula Removed) wherein R R1 R4 YandX m and n PQ is aryl or heteroaryl, wherein each of the above groups R may be substituted by 1 to 4 substituents indendently selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 mono or dialkylamino, nitro, cyano and a group R4; is hydrogen, C1-C6 alky], C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, NH2, halogen or cyano; is hydrogen or C(H)n(R5)q(CH2)pZR6; is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl or [CH(Rs)(CH2)p]mZR6; is C3-C7 cycloalkyl, which may contain one or more double bonds; aryl; or a 5-6 membered heterocycle; wherein each of the above groups R4 may be substituted by one or more groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, Cl- C6 mon a or dialkylamino, nitro, and cyano; is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl or (CH2)pZR6; is C1-C6 alkyl, which may be substituted by one or more groups selected from halogen, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 mono or dialkylamino, nitro, cyano and a group R4; are independently carbon or nitrogen; are independently 0 or 1; is 0 or an integer from 1 to 4; is 1 or 2; Z is a bond, 0, NH or S. Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, malic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, p-toluensulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Thus, the term "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all acceptable salt forms. The solvates may, for example, be hydrates. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates. In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein'hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I). Further, in the case of a carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the like. With regard to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as recemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. The term C1-C6 alkyl as used herein as a group or a part of the group refers to a straight or branched alkyl group containing from 1 to 6 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl or hexyl. The term C3-C7 cycloalkyl group means a non aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atom such as, for example, cyclopropyl, cyciobutyl, cyclopentyl, cyclohexyl or cycloheptyl; while unsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and the like. The term halogen refers to a fluorine, chlorine, bromine or iodine atom. The term halo C1-C6 alkyl means an alkyl group having one or two carbon atoms and wherein at least one hydrogen atom is replaced with halogen such as for example a trifluoromethyl group and the like. The term C2-C6 alkenyl defines straight or branched chain hydrocarbon radicals containing one or more double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl and the like. The term C1-C6 alkoxy group may be a straight or a branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like. The term halo C1-C6 alkoxy group may be a C1-C6 alkoxy group as defined before substituted with at least one halogen, preferably fluorine, such as OCHF2, or OCF3. The term C2-C6 alkynyl defines straight or branched chain hydrocarbon radicals containing one or more triple bond and having from 2 to 6 carbon atoms including acetylenyl, propynyl, 1-butynyl, 1-peniynyl, 3-methyl-l-butynyl and the like. The term C1-C6 mono or dialkylamino represents an amino group independently substituted with one or two C1-C6 alkyl groups, as defined before. The term aryl means an aromatic carbocyclic moiety such as phenyl, biphenyl or naphthyl. The term heteroaryl means an aromatic heterocycle ring of 5-to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono-and bicyclic ring systems. Representative heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazdnyl, cinnolinyl, phthalazinyl, and quinazolinyl. The term heterocycle means a 5 to 7-membered monocyclic, or 7-to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quatemized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings. The heterocycle may be attached via any heteroatom or carbon atom, Heterocycjes include heteroaryls as defined above. Thus, in addition to the aromatic heteroaryls listed above, heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. The term 5-6 membered heterocycle means, according to the above definition, a monocyclic heterocyclic ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heterocycle may be attached via any heteroatom or carbon atom. Thus, the term includes (but is not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Representative compounds of this invention include the following structure (II) and (III) (Formula Removed) wherein, respectively, X corresponds to a carbon and a nitrogen atom. Thus, representative compounds of this invention include the following structures (IIa), (IIb), (IIc), (IId), when X corresponds to a carbon atom R, (Formula Removed) Depending upon the choice of X, the representative compounds of this invention include, but are not limited to, the following compounds (Ia-1), (Ib-1), (Ic-1). (Formula Removed) Depending upon the choice of X and Y the representative compounds of this invention include, but are not limited to, the following compounds (1-1), (1-2), (1-3) and (1-4). (Formula Removed) More specific embodiments of the invention include, but are not limited to, compounds of the formula (I); (II), (III), (IIa), (IIb), (IIe), (IId); (IIa-1), (Ib-1), (Ic-1); 0-1), (1-2), (1-3), (1-4): wherein: • R2 and R3 are not simultaneously hydrogen. Furtehr specific embodiments of the invention include, but are not limited to, compounds of the formula (I); (II), (III), (IIa), (IIb), (IIe), (IId); (Ia-1), (Ib-1), (Ic-1); (1-1), 0-2), (1-3), (1-4): wherein: • R) is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably methyl or trifluoromethyl. Preferred embodiments of the invention include, but are not limited to, compounds of the formula (I); (II), (III), (IIa), (IIb), (IIe), (IId); (Ia-1), (Ib-1), (Ic-1); (M), (1-2), 0-3), 0-4): wherein: • R2 and R3 are not simultaneously hydrogen; and • RI is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably methyl or trifluoromethyl; More preferred embodiments of the invention include, but are not limited to, compounds of_ the formula (I); (II), (III), (IIa), (IIb), (IIc), (IId); (a-1), (Ib-1), (Ic-1); 0-1), 0-2), (1-3), 0-4): wherein: • R2 and R3 are not simultaneously hydrogen; • R1 is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably methyl or trifluoromethyl; • R is an aryl group selected from: 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2- chloro-4-trifluoromethyl, 2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4- dimethyl-phenyl, 2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl, 2-methyl-4- trifluoromethyl, 2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, 2- methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-calorophenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl 2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl, 2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl, 2-bromo-4-isopropylphenyl, 4-methyl-6-dimethylarninopyridin-3-yl, 4-dimethylamino-6-methyl-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl and 4-dimethylamino-pyridin-3 -yl . Preferred compounds according to the invention are: 5-(2,4-dichlorophenyl)-l-(1-ethylpropyl)-7-methyl-l.2,2a.3,4,5-hexahydro-1,5,6,8-tetraaza- acenaphthylene (1-1-1); 5-(2,4-dichlorophenyl)-l-(2-ethylbutyl)-7-methyl-l,2,2a,3,4,5,5a)8b-octahydro-l,5,6,8- tetraazaacenaphthylene (1-1-2); 5-(2,4-dichlorophenyl)-l-(2-methoxy-l-methoxymethylethyl)-7-methyl-l,2,2a,3,4,5,5a,8b- octahydro-1 ,5,6,8-tetraazaacenaphthylene (1-1-3); 7-methyl-l-(l-propylbutyl)-5-[4-(l,l,2-trifluoroethyl)-2-trifluoromethy]phenyl]-l,2,2a,3,4,5- hexahydro-1 ,5,6,8-tetraazaacenaphthylene (1-1 -4); 7-methyl-l -(1 -propylbutyl)-5-[4-(l , 1 ,2-trifluoroethyl)-2-trifluorornethylphenyl]-l ,2,2a(S),- 3,4,5-hexahydro-l,5,6,8-tetraazaacenaphthylene; 7-methyl-l-(l-propylbutyl)-5-[4-(l,l,2-trifluoroethyl)-2-trifluoromethylphenyl]-l,2,2a- (R),3,4,5-hexahydro-l,5,6,8-tetraazaacenaphthylene; 5-(2,4-dichlorophenyl)-7-methyl- 1 -( 1 -propylbutyl)- 1 ,2,2a,3 ,4,5-hexahydro- 1 ,5 ,6,8-tetraaza- acenaphthylene (1-1-5); 5-(2,4-dichlorophenyl)-7-methyl-l-(l-propylburyl)-l,2,2a-(S),3,4,5,5a,8b-octahydro-l,5,6,8- tetraazaacenaphthylene ; 5-(2,4-dichlorophenyl)-7-rnethyl-l-(l-propylbutyl)-l,2,2a-(R)3,4,5,5a,8b-octahydro-l,5,6,8- tetraazaacenaphthylene; 9-(2,4-dichlorophenyl)-4-(l-ethylpropyl)-2-methyl-5,6,6a,7,8,9-hexahydro-4H-l,3,4- triazaphenalene (isomer 1) and 9-(2,4-dichlorophenyl)-4-(l-ethylpropyl)-2-methyl- 5,6,6a,7,8,9-hexahydro-4H-l,3,4-triazaphenalene (isomer 2) (2-1-1); 5-cyclopropylmethyl- 1 -(2,4-dichlorophenyl)-7-methyl-l ,2,2a,3 ,4,5-hexahydro- 1 ,5,6, 8- tetraazaacenaphthylene (3-1-1); l-{2,4-dichlorophenyl)-5-(2-methoxyethyl)-7-methyl-l,2,2a,3,4,5-hexahydro-l,5,6,8-tetraaza- acenaphthylene (3-1-2); l-(2,4-dichlorophenyl)-5-(l-ethylpropyl)-7-methyl-l,2,2a,3,4,5-hexahydro-l,5,6,8-terraaza- acenaphthylene (3-1-3); l-(2,4-dichlorophenyl)-5-(2-ethylbutyl)-7-methyl-l,2,2a,3,4,5-hexahydro-l,5,6,8-tetraaza- acenaphthylene (3-1-4); 1-{2,4-dichlorophenyl)-7-methyl-5-{l-propylbutyl)-l,2,2a3,4,5-hexahydro-l,5,6,8-tetraaza- acenaphthylene (3-1-5); 7-methyl-5-(l-propylburyI)-l-[4-(l,1,2-trifluoro-ethyl)-2-trifluoromethyiphenyI]-l,2,2a,3,4,5- hexahydro-1 ,5,6,8-tetraazaacenaphthylene (3-1-6); 5-cyclopropyhnethyl-l -(2,4-dichlorophenyl)-7-methyl-4-propyl- 1 ,2,2a,3 ,4,5-hexahydro- 1,5,6,8-tetraazaacenaphthylene (3-1-7); 4-butyl-5-cyclopropylmethyl-l-(2,4-dichlorophenyl)-7-methyl-l,2,2a,3,4,5-hexahydrol,5,6,8-tetraazaacenaphthylene (3-1-8); 5-cyclopropylmethyl-l-(2,4-dichlorophenyI)-7-methyl-4-propoxy-l,2,2a,3,4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene (3-1-9); 4,5-dibutyl-l-(2J4-dichlorophenyl)-7-methyl-l,2,2a,3,4,5-hexahydro-l,5,6,8-tetraaza-acenaphthylene (3-1-10); 5-(2,4-dichlorophenyl)-l-(l-ethylpropyl)-7-methyl-l,2,2a,3,4,5-hexahydro-l,6,8-triaza-acenaphthylene (4-1-1). Compounds of formula (I), and salts and solvates thereof, may be prepared by the general methods outlined hereinafter. In the following description, the groups R, R1, R2, R3, R4, R5, R6, X, Y, Z, m, n, p and q have the meaning as previously defined for compounds of formula (I) unless otherwise stated. Compounds of formula (I) when R3 is different from hydrogen and m is 1 are equivalent to compounds of formula (IV), in which G corresponds to the previous meanings of R3 other than hydrogen, may be prepared by reaction of a compound of formula (V), (Formula Removed) wherein R7 is a C1-C4 linear or branched alkyl group and m is 1, equivalent to compounds of formula (VI). Then compounds of formula (VT) may react with the organo-metallic compound GM, (Formula Removed) wherein M is a metal to give compounds of formula (IV), optionally in the presence of a Lewis acid such as borontrifluoride etherate. Suitable metals for this reaction include lithium, copper or magnesium. Compounds of formula (I) when R3 is hydrogen are equivalent to compounds of formula (la), may be prepared by reduction of a compound of formula (V) wherein R7 is hydrogen and equivalent to compounds of formula (Va), in the presence of an organic acid (e.g. trifluoroacetic). Convenient reducing agents for this reaction are trialkylsilanes (e.g. triethylsilane). The reaction is preferably carried out in an aprotic solvent such as dichloromethane. (Formula Removed) Compounds of formula (IIb), corresponding to compounds of formula (II) in which R3 is hydrogen, may be prepared from compounds of formula (VII) according to the following general Scheme: (Formula Removed) wherein L is a leaving group selected in a group consisted from halogens, preferably chlorine and reactive residue of sulphonic acid (such as mesylate, triflate) and La represents a suitable reactive group able to render OLa a good leaving group (such as mesylate, triflate). The reaction takes place by heating using the amine R2NH2 (IX) in excess, preferably as solvent. (Formula Removed) Compounds of formula (VI), may be prepared by oxidation of the allyl group of compounds of formula (VIII) to the corresponding aldehyde followed by in situ cyclisation and conversion of the hydroxy group into the alkoxy group which will be described in details later on. The oxidation is carried out with osmium tetroxide in the presence of N-methylmorpholine oxide (NMO), followed by treatment with sodium periodate. The reaction is conveniently carried out in a water miscible organic solvent such acetone, tetrahydrofuran optionally in the presence of water. The conversion of the hydroxy group into C1-C4 alkoxy may be carried out by treatment of the hydroxy group with C1-C4 alcohol in the presence of a suitable inorganic acid, e.g. hydrochloric acid. Compounds of formula (VIII) may be prepared by treatment of a compound of formula (X), with the amine R2NH2 (IX). In an alternative process, compounds of formula (IIa), may be prepared by reaction of a compound of formula (XI), (Formula Removed) and when m is 1 it is equivalent to a compound of formula (XIa) (Formula Removed) with the amine (IX) in the presence of a suitable reducing agent, followed by in situ cyclisation. Suitable reducing agents for this reaction include hydride, for example a borane hydride, or a metal hydride complex like lithium aluminum hydride, borohydride, or an organo-metallic complex such as borane methyl sulphide, 9-borabicyclononane (9-BBN), triethylsilane, sodium triacetoxyborohydride, sodium cyanoborohydride. Alternatively, boranes may be produced in situ by reacting Sodium Borohydride in the presence of Iodine, an inorganic acid (e.g. sulphoric acid) or an organic acid such as formic acid, trifluoroacetic, acetic acid or methansulphonic acid. Suitable solvents for this reaction are alcohol (e.g. methanol), ether (e.g. tetrahydrofuran), or halohydrocarbon (e.g. dichloromethane) or an amide (e.g. N,N-dimethylformamide) at a temperature within the range of room temperature to the reflux temperature of the reaction mixture. Compounds of formula (X) wherein Y is nitrogen and X is carbon arc equivalent to compounds of fomula (Xa), may be obtained from a compound of formula (XIIa), (Formula Removed) equivalent to compounds of formula (XII) (Formula Removed) in which X is carbon, La is a suitable reactive group able to render OLa a good leaving group, (such as mesylate) and Ra corresponds to hydrogen or a suitable nitrogen protecting group, if necessary. Compounds of formula (XIIa) may be subjected to the following reactions: i) optionally removal of the nitrogen protecting group Ra; and ii) cyclisation in the presence of organic base such as a tertiary amine e.g. triethylamine. These reactions are preferably carried out in an aprotic solvent such as ether (e.g. tetrahydrofuran), halohydrocarbon such as dichloromethane or amide such as N,N-dimethyIformamide. Compounds of formula (XII) in which X is carbon and n is 0 are equivalent to compounds of formula (XIIa), may be prepared by introduction of the suitable reactive group La on a compound of formula (XIII3) in which Hal, Ra, n, are defined as above. (Formula Removed) Compounds of formula (XIII) may be obtained by reaction of a compound of formula (XV), wherein Rb is a suitable hydroxy protecting group, with amine (XIV), followed by protection of the nitrogen group (if necessary) and removal of hydroxy protecting group. The reaction with the arnine is suitably carried out in an aprotic solvent such as DMF (dimethylforrnamide) in the presence of a strong base (e.g. sodium hydride). Compounds of formula (XV) may be prepared by reduction of an ester of formula (XVI) to the corresponding hydroxy with a suitable reducing agent, such as diisobutylaluminumhydride followed by protection of the hydoxy group with a hydroxy suitable protecting group. Compounds of formula (XVI) may be prepared by reaction of a compound of formula (XVII) with allyl halide (e.g. allyl iodide). The reaction is carried out in the presence of an organic base such as lithiumhexamethyldisilazane at low temperature and in an aprotic solvent (e.g. tetrahydrofuran). Compounds of formula (XII) wherein n is 1 and X is carbon are equivalent to compounds of formula (XIIb), may be prepared by reduction of a compound of formula (XVIII), with a suitable reducing agent, e.g. sodium borohydride in a solvent such as for example an alcohol (e.g. methanol). (Formula Removed) Compounds of formula (XVIII) may be prepared by Wittig reaction of a compound of formula (XX) with a phosphorus ylide (XIX), in which R8 is a phenyl derivative, followed by hydrolysis with an acid (e.g hydrochloric acid). The reaction is carried out in an aprotic solvent such as acctonitrile or an ether such as tetrahydrofuran. Compounds of formula (XX) may also be prepared by oxidation of a compound of formula (XIII). The oxidation may be carried out using the conventional methods known for converting a hydroxy group into an aldehyde group. Thus, for example, the reaction may be carried out using Swern conditions. Compounds of formula (X) when Y is carbon and X is carbon are equivalent to compounds of formula (Xb), may be prepared by halogenation of a compound of formula (XXI), in which, when X and Y are both carbon, is equivalent to a compound of formula (XXIb). (Formula Removed) The halogenation reaction may be carried out using conventional methods known in the art. Thus for example the reaction may be carried out by treatment with PO(Hal)3, wherein within the halogens, chlorine is preferred. Compounds of formula (XXIb) may be obtained by reaction of a cyclohexanone of formula (XXIII), in which R7 is defined as before, with a salt (e.g hydrochloride) of acetamidine (XXII). The reaction is carried out in the presence of a C1-C4 alkaline alkoxylate (e.g. sodium methoxylate), in a solvent such as methyl alcohol. Compounds of formula (XXIII) when n is 1 are equivalent to compounds of formula (XXIIIa), may be prepared by reaction of a compound of formula (XXIV) with a silane derivative (XXV), wherein R7 is as defined before. The reaction is carried out in the presence of Lewis acid and in an organic solvent (Formula Removed) Compounds of formula (XXIII) when n is 0 are equivalent to compounds of formula (XXIIIb), may be prepared by reaction of a compound of formula (XXVI), in which R7 is defined as before and R7' has the same meanings as R7 but not at the same time, (Formula Removed) with an organo metallic compound (R9)2M (XXVII), in which R9 is an allyl group and M is a metal, optionally in the presence of a Lewis acid such as boron trifluoride etherate. Suitable metals for this reaction include lithium, copper and magnesium. Compounds of formula (X) when X is nitrogen are equivalent to compound of formula (Xc), may be prepared by reaction of a compound of formula (XXVIII) with allyl halide (e.g. allyl bromide). The reaction is carried out in the presence of an inorganic base such as sodium hydride at low temperature and in aprotic solvent (e.g. tetrahydrofuran or NN-dimethylformamide). (Formula Removed) Compounds of formula (XXVIII) when n is 0 and Y is carbon are equivalent to compounds of formula (XXVIIIa), may be prepared by subjecting a compound of formula (XXIX), in which q is as previously defined, (Formula Removed) Compounds of formula (XXIXa), corresponding to compounds (XXIX) in which q is l and Y is carbon, may be subjected to the following reactions: (Formula Removed) i) conversion of the hydroxy group into a suitable leaving group such as mesylate, ii) conversion of the nitro group into the amine by reduction in the presence of Na2S2O4 and an inorganic base such as potassium carbonate and in situ cyclisation. Compounds of formula (XXIXa), may be prepared by reduction of an ester compound of formula (XXX). The reduction can be conveniently carried out with sodium borohydride in a protic solvent such alcohol (e.g. methanol or ethanol) and preferably heating e.g. 40-100°C. Compounds of formula (XXX) may be prepared by reaction of a compound of formula (XXXI), with an ester compound (XXXII). The reaction takes place in an aprotic solvent such as DMF and in the presence of an inorganic base (i.e. sodium hydride). Compounds of formula (XXIX) when n is 2 and Y is carbon are equivalent to compounds of formula (XXIXb), may be prepared by reduction of compounds of formula (XXXIII) using conventional reducing reagent to convert aldehyde into alcohol. Thus a suitable reducing agent for this reaction is sodium borohydride. (Formula Removed) Compounds of formula (XXXIII) may be obtained by hydrolysis of enolether of formula (XXXIV). The reaction is preferably carried out in the presence of an inorganic acid such as for example hydrogen chloride. Compounds of formula (XXXIV) may be obtained from (XXXV) by Wittig reaction with the ylide (XIX), in the presence of a suitable organic base like n-BuLi. The reaction is carried out in an aprotic solvent such as acetonitrile or an ether such as tetrahydrofuran. Compounds of formula (XXXV) may be prepared by oxidation of compounds (XXIXa) when Y corresponds to carbon, by using conventional methods known to convert alcohol to aldehyde. Compounds of formula (XI) when R3 is different from hydrogen are equivalent to compounds of formula (XIb), may be prepared by reaction of a compound of formula (XI) when R3 is hydrogen (equivalent to a compound of formula (XIc)), with the organo metallic compound GMgBr (XXXVI), to give the alcohol compound (XXXVII), which may be oxidised to the keto compound (Xlb) according to the following scheme (Formula Removed) Compounds of formula (XIc) when m is 1 are equivalent to compounds of formula (Xld), may be prepared by oxidation of a compound of formula (X). (Formula Removed) The oxidation reaction is conveniently carried out in the presence of ozone at low-temperature e.g. — 78°C in a solvent such as dicholoromethane. Alternatively, the oxidation takes place by reaction with with osmium tetraoxide in the presence of N-methyl morpholine oxide (NMO) followed by treatment with sodium periodate. The reaction is conveniently carried out in a water miscible organic solvent such as acetone or tetrahydrofuran optionally in the presence of water. Compounds of formula (XIc) when X and Y are carbon, m is 0 and n is 1 are equivalent to compounds of formula (Xle), may be prepared by treating compounds of formula (XXXVIII) with an inorganic base such as potassium hydroxide in a solvent such as alcohol, followed by reaction with potassium permanganate. The reaction is suitably carried out in water. (Formula Removed) Compounds of formula (XXXVII), may be prepared by halogenation of a compound of formula (XXXIX). The halogenation reaction may be carried as described above. Compounds of formula (XXXIX) may be prepared by reaction of a compound of formula (XL) with a salt (e.g hydrochloric acid) of acetamidine (XXII) using condition as described above. Compounds of formula (XL) may be prepared by reacting compounds of formula (XXIV), in which R7 is as defined before, with nitromethane. Compounds of formula (XIc) when X is carbon, m is 0, n is 1 and Y is nitrogen are equivalent to compounds of formula (Xlf), may be prepared by oxidation of a compound of formula (XLI), using conventional oxidation methods known to convert a hydroxy group into an aldehyde. (Formula Removed) Compounds of formula (XLI) may be prepared by subjecting a compound of formula (XLII), wherein La is a suitable leaving group, such as mesylate, Ra and Rb are as defined above, to the following reactions: i) optionally, removal of the nitrogen protecting group, ii) cyclisation and iii) removal of the hydroxy protecting group Rb. Compounds of formula (XLII) may be prepared as discussed before by oxidation of a compound of formula (XLIII), followed by reduction to hydroxy group and conversion in a leaving group. The oxidation reaction is conveniently carried out in the presence of ozone at low temperature e.g. —78°C in a solvent such as dichloromethane. The reduction is carried out using sodium borohydride as reducing agent. Compounds of formula (XLIII) may be obtained from a compound of formula (XV) with amine (XIV), followed by protection of the nitrogen group. Compounds of formula (XLI) may be converted to compounds of formula (VIIa), corresponding to compounds of formula (VII) in which X is carbon, Y is nitrogen m and n arel, according to known methods. (Formula Removed) According to a previous Scheme, compounds of formula (Vila) may be converted to compound of formula (I-la), corresponding to compound of formula (1-1) in which R3 is hydrogen. Compounds of formula (Xc) in which X and Y are nitrogen and n is 1 are equivalent to compounds of formula (Xc'), may be prepared by reaction of a compound of formula (XLIV) with dibromoethane, in the presence of an organic or inorganic base. The reaction is suitably carried out in an aprotic solvent such as NN-dimethylformamide or acetonitrile. (Formula Removed) Compounds of formula (XLIV) may be prepared by compounds of formula (XLV) by treatment with iron and an inorganic acid e.g. hydrochloric acid. Compounds of formula (XLV) may be prepared by reaction of compound (XXXI) and the amine (XIV). Compounds of formula (XVII), (XXIV), (XXVI) and (XXXI) are either known compounds or may be prepared by analogous method to those described for known compounds. In summary, compounds of formula (I-la), may be prepared according to the following Scheme 1: (Formula Removed) in which Hal, R, R1, R7, R2, La, Ra and Rb are defined as above and preferably R7 is a methyl group, Hal is chlorine, Ra is t-butylcarbonyl, Rb is t-BuPh2 Si derivative, OLa is a mesyl group and step a stands for allylation with allyl iodide at 0°C in basic conditions (e.g. LiHMDS); the starting material may be prepared in similar way to what described in Wayne G. C. et al., J. Prakt. Chem., (2000), 342(5), 504-7; step b stands for reduction of the ester group with a suitable reducing agent, e.g. DIBA1-H, in usual conditions (CH2C12, 0°C to r.t.); step c stands for protection of the hydroxy group, preferably with t-BuPh2SiCl, in DMF with DMAP as catalyst (0°C to r.t); step d stands for reaction with the amine RNH2 (XIV) as described above; step e stands for protection of the amino group with a suitale protecting group, for example by treatment with (BOC)2O in presence of DMAP; step f stands for, i) oxidation with OsO4 in acetone/water, then ii) treatment with NalO4 in THF/water, and finally iii) reduction with NaBH4 in a suitable solvent (e.g. EtOH); step g stands for deprotection of the arnino protecting group (e.g. CF3CO2H in CH2Cl2); step h stands for intramolecular cyclisation, for example by mesylation of the hydroxy group in basic conditions (i.e. Et3N), step i stands for deprotection of the hydroxy protecting group (e.g. Et3N - 3HF in DMF at 40°C); step j stands for transformation of the hydroxy group in a suitable leaving group (e.g. mesylation); step k stands for reaction with the amine (IX) as described above. Alternatively, the synthesis can be modified following the steps below (starting from an already described intermediate) according to Scheme 2 Scheme 2 (Scheme Removed) in which step 1 stands for the first two reactions of previous step f, and step m stands for treatment with Et3SiH in the presence of BF3-Et2O. The synthesis is then completed as described in Scheme 1. In another alternative, the protection of the amino group can be avoided through the following sequence of steps (starting from an already described intermediate) according to scheme 2a Scheme 2a (Scheme Removed) in wich step n corresponds to previous step f); step o corresponds to previous step j); step p stands for reaction with the amine KNH2 (XIV) as described above; The synthesis is then completed as described in Scheme 1. In another embodiment of the invention, compounds of formula (1-2), in which R3 is hydrogen are equivalent to compounds of formula (I-2a), may be prepared according to the following Scheme 3 Scheme 3 (Scheme Removed) in which Hal, R, R1 R2, R7, Rb are defined as above and preferably R7 is a methyl group, Hal is chlorine, Rb is t-BuPh2 Si derivative, OLa is a mesyl group and step a' stands for esterification in usual conditions (R7OH, acid catalyst, reflux); step b' stands for alkylation with the suitable alleviating agent (e.g. methyl 5-iodovalerate in the presence of LiHMDS); step c' stands for intramolecular cyclisation in basic conditions (i.e. MeONa, refluxing toluene); step d' stands for phenylselenylation followed by oxidation with H2O2 and subsequent elimination; step e' stands for 1,4-carbonyl addition with a suitable silane such as allyltrimethylsilane catalysed by TiCl4; step f stands for reaction with the amidine (XXII) as described above; step g' stands for halogenation of the hydroxy group (e.g. by treatment with POC13 at reflux); step h' stands for oxidative cleavage of the double bond by, for example, ozonization; step i' stands for reductive amination in the presence of NaBH3CN with the amine (IX) and subsequent intramolecular cyclisation. In a further embodiment of the invention, compounds of formula (1-3) in which R3 is hydrogen are equivalent to compounds of formula (I-3a) may be prepared according to— Scheme 4 Scheme 4 (Scheme Removed) stands for protection of the amino group with a suitale protecting group, for example by treatment with (BOC)2O in presence of DMAP; step b" corresponds to previous step i); step c" stands for mesylation of the hydroxy group in basic conditions (i.e. Et3N); step d" stands for deprotection of the protective group of the amino, e.g. by treatment with TFA and then subsequent cyclisation in basic conditions, e.g. Et3N; step e" corresponds to previous step h') or corresponds to previous step 1); step f" corresponds to previous step i'); In another alternative, the last stages of the synthesis could be done as follow and compounds of formula (1-3) in which R3 is different from hydrogen corresponding to compounds of formula (I-3b) according to Scheme 5 Scheme 5 (Scheme Removed) in which step a'" step b'" step e"f stepd'"corresponds to previous step k); corresponds to previous step 1); stands for reduction, e.g. by treatment with Et3SiH, TFA; stands for formation of the ether group, e.g. by treatment with methanol in presence of PTSA; step e'" stands for reaction with an organo-metallic compound, such as R3Cu in presence of BF3.Et2O. Alternatively compounds of formula (I-3a), when it is not necessary to protect the amino group, may be prepared as examplified below in Scheme 6, starting from an already known intermediate: Scheme 6 (Scheme Removed) wherein step a"" corresponds to previous step i); step b" " corresponds to previous step j), followed by in situ intramolecular cyclisation; step c" " corresponds to previous step f); step d" " corresponds to previous steps j) and k). In another embodiment of the invention, compounds of formula (1-4) when R3 is hydrogen corresponding to compounds of formula (I-4a) may be prepared according to Scheme 7 Scheme 7 (Scheme Removed) in which step a'"" stands for reaction with nitromethane in usual conditions; step b'"" stands for reaction with the amidine (XXII) as described above; step c'" " corresponds to previous step g'); step d"'" stands for formation of the aldehyde group, e.g. by treatment with KOH in methanol and subsequent oxidation by KMnO4; step e"'" corresponds to previous step i'). Examples of suitable nitrogen protecting group include alkoxycarbonyl, e.g. t-butoxycarbonyl and arylsulphonyl, e.g phenylsulphonyl. In any of the above reaction the nitrogen protecting group may be removed by conventional procedures known for removing such groups (such as those described in Protective Groups in Organic Chemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973)). Thus, when Ra is alkoxycarbonyl, the group may be removed by acid hydrolisis using for example trifluoro acetic acid. Examples of suitable hydroxy protecting group include trihydrocarbyl silyl ethers such as the trimethylsilyl or t-butyldimethylsilyl ether. The hydroxyl protectin groups may be removed by well-known standard procedures (such as those described in Protective Groups in Organic Chemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973)). For example when Rb is a t-butyldimethylsilyl group, this may be removed by treatment with triethylamine trihydrofluoride. Pharmaceutical acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (3) using conventional methods. The compounds of formula (I) may readily be isolated in association with solvent molecules by crystallisation or evaporation of an appropriate solvent to give the corresponding solvates. When a specific enantiomer of a compound of general formula (I) is required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Thus the required enantiomer may be obtained from the racemic compound of formula (I) by use of chiral HPLC procedure. The subject invention also includes isotopically-labeled compounds, which are identical to those recited in formulas I and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, 11C, I4C, 18F, 123I and 125I. Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically - labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., I4C, isotopes are particularly preferred for their ease of preparation and detectability. "C and *F isotopes are particularly useful in PET (positron emission tomography), and I25I arc particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagen. The CRF receptor antagonists of the present invention demonstrate activity at the CRF receptor site including CRF I and CRF 2 receptors and may be used in the treatment of conditions mediated by CRF or CRF receptors. The effectiveness of a compound as a CRF receptor antagonist may be determined by various assay methods. Suitable CRF antagonists of this invention are capable of inhibiting the specific binding of CRF to its receptor and antagonizing activities associated with CRF. A compound of structure (I) may be assessed for activity as a CRF antagonist by one or more generally accepted assays for this purpose, including (but not limited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7: 88,1987) and Battaglia et al. (Synapse 1: 572,1987). The CRF receptors-binding assay was performed by using the homogeneous technique of scintillation proximity (SPA). The ligand binds to recombinant membrane preparation expressing the CRF receptors which in turn bind to wheatgerm agglutinin coated SPA beads. In the Experimental Part will be disclosed the details of the experiments. With reference to CRF receptor binding affinities, CRF receptor antagonists of this invention have a Ki less than 10 μm. In a preferred embodiment of this invention, a CRF receptor antagonist has a Ki of less than 10 μm. In a more preferred embodiment the value of Ki is less than 1 um and more preferably less than 0.1 μm. As set forth in greater detail below, the Ki values of representative compounds of this invention were assayed by the methods set forth in Example 5. Preferred compounds having a Ki of less than 1 um are compound numbers 3-1-3 and 3-1-10. More preferred compounds having a Ki less than 0.1 um are compound numbers 1-1-1, 1-1-4, 1-1-5,1-2-1, 3-1-5, and 3-1-6. Compounds of the invention may be useful in the treatment of central nervous system disorders where CRF receptors are involved In particular in the treatment or prevention of major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, the treatment of anxiety and the treatment of panic disorders. Other mood disorders encompassed within the term major depressive disorders include dysthymic disorder with early or late onset and with or without atypical features, neurotic depression, post traumatic stress disorders and social phobia; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood. Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc. Compounds of the invention are useful as analgesics. In particular they are useful in the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment pain; sport's injury pain; dysmennorrhoea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; low back pain e.g. spinal stenosis; prolapsed disc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain; itch; and thalamic pain such as post stroke thalamic pain. Compounds of the invention are also useful for the treatment of dysfunction of appetite and food intake and in circumstances such as anorexia, anorexia nervosa and bulimia. Compounds of the invention are also useful in the treatment of sleep disorders including dysomnia, insomnia, sleep apnea, narcolepsy, and circadian ritmic disorders. Compounds of the invention are also useful in the treatment or prevention of cognitive disorders. Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified. Furthermore compounds of the invention are also useful as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit. Compounds of the invention are also useful in the treatment of tolerance to and dependence on a number of substances. For example, they are useful in the treatment of dependence on nicotine, alcohol, caffeine, phencyclidine (phencyclidine like compounds), or in the treatment of tolerance to and dependence on opiates (e.g. cannabis, heroin, morphine) or benzodiazepines; in the treatment of cocaine, sedative ipnotic, amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) addiction or a combination thereof. Compounds of the invention are also useful as anti-inflammatory agents. In particular they are useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD) and non-steroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation. Compounds of the invention are also useful in the treatment of allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis. Compounds of the invention are also useful in the treatment of emesis, i.e. nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis. The compounds of the invention are useful in the treatment of emesis however induced. For example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5- fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); opioid analgesics, such as morphine; and gastro-oesophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia. Compounds of the invention are of particular use in the treatment of gastrointestinal disorders such as irritable bowel syndrome (IBS); skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough. Compounds of the invention are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hetnorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, hypoxia, anoxia, perinatal asphyxia cardiac arrest. The invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine. There is also provided as a further aspect of the invention the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of conditions mediated by CRF. In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of condition mediated by CRF, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof. It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms. Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation. Accordingly, the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Thus compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration the composition may take the form of tablets or formulated in conventional manner. The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative. The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt For intranasal administration, the compounds of the invention may be formulated as solutions ~ for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. A proposed dose of the compounds of the invention is 1 to about l000mg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected. Thus for parenteral administration a daily dose will typically be in the range of 1 to about 100 mg, preferably 1 to 80 mg per day. For oral administration a daily dose will typically be within the range 1 to 300 mg e.g. 1 to 100 mg. EXAMPLES In the Intermediates and Examples unless otherwise stated: Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus and are uncorrected. All temperatures refers to °C. Infrared spectra were measured on a FT-IR instrument. Proton Magnetic Resonance (1H-NMR) spectra were recorded at 400 MHz, chemical shifts are reported in ppm downfield (d) from Me4Si, used as internal standard, and are assigned as singlets (s), doublets (d), doublets of doublets (dd), triplets (t), quartets (q) or multiplets (m). Column chromathography was carried out over silica gel (Merck AG Darmstaadt, Germany). The following abbreviations are used in text: EtOAc = ethyl acetate, cHex = cyclohexane, CH2C12 = dichloromethane, Et2O = dietyl ether, DMF = N,N-dimethylformamide, DIPEA=N,N-diisopropylethylamine, MeOH = methanol, Et3N = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, DIBAL-H=diisobutylaluminium hydride, DMAP = dimethylaminopyridine, LHMDS = lithium hexamethyldisilazane; Tic refers to thin layer chromatography on silica plates, and dried refers to a solution dried over anhydrous sodium sulphate; r.t. (RT) refers to room temperature. Intermediate 1 (4.6-Dichloro-2-methyl-pyrimidin-5-yl)-acetic acid methyl ester Sodium (1.74g) was added portionwise to anh. MeOH (60mL), at 0°C, under N2. After consumption of metallic sodium, acetamidine hydrochloride (7.06g) was added. After 20 min of stirring, the precipitated NaCl was filtered off. A solution of 2-ethoxycarbonyl-succinic acid diethyl ester (6.04g) in anh. MeOH (20mL) was added to the solution of free acetamidine and the mixture was stirred at r.t. for 2 days. The reaction mixture was concentrated to dryness in vacuo and the yellow foam (8.69g) obtained was then mixed with POC13 (70mL) and heated at reflux for 3.5 hr. The resulting solution was cooled to r.t. and poured slowly into ice/water (600mL) and NR4OH (50mL) with vigorous stirring. The product was extracted with EtOAc (3x50mL) and with Et2O (3x20mL). The combined organic extracts were washed with H2O (60mL) and brine (40mL), dried over Na2SO4, filtered and concentrated in vacua. The crude oil was purified by flash chromatography (silica gel, cHex/EtOAc 9:1) to give the title compound as a yellow solid (4.27g). NMR ('H, CDC13): δ 5.85 (m, 1H), 5.15 (dq, IH), 5.11 (dq, 1H), 3.61 (dt, 2H), 2.67 (s, 3H). MS (m/z): 202 [M]+.2C1; 167 [MH-Cl]+.lCl. Intermediate 2 2-(4.6-Dichloro-2-methvl-pvrimidin-5-yl)-pent-4-enoic acid methyl ester A solution of intermediate 1 (1.33g, 5.68mmol) in anh. THF (8mL), under N2, was treated with lithium bis(trimethylsilyl) amide (1M solution in hexane, 11.5mL, 2eq,) at 0°C for 15 min before allylbromide (0.99mL, 2eq) was added. The mixture was stirred for 4 hr at r.t and quenched with water (20mL). The product was extracted with EtOAc (2x15mL) and the organic phase was washed with H2O (2xl5mL) and with brine (Ixl5mL), dried over Na2SO4 and concentrated in vacua. The crude product was purified by flash chromatography (silica gel, EtOAc/cHex 1:9) to give the title compound (673.8mg) as a white solid. NMR ('H, CDC13): δ 5.77 (m, 1H), 5.03 (m, 2H), 4.43 (dd, 1H), 3.76 (s, 3H), 3.12 (m, 1H), 2.78 (m, 1H), 2.73 (s, 3H). MS (m/z): 374[M] +2C1. Intermediate 3 2-(4,6-Dichloro-2-methyl-pyrimidin-5-yl)-pent-4-en-l-ol To a solution of intermediate 2 (257mg) in anh. CH2Cl2 (9.3mL), at — 78°C, under N2, was added DIBA1-H (1M solution in hexane, 5.6mL, 6eq). After the addition was complete the reaction mixture was stirred at — 78°C for 1 hr and at 0°C for 2 hr. The reaction mixture was poured into a solution of HC1 0.5N in ice (20mL) and extracted with CH2C12 (3xl0mL). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo to give the title compound (200mg) as a colourless oil. NMR ('H, CDC13): δ 5.76 (m, 1H), 5.12 (m, 1H), 5.01 (m, 1H), 4.16 (m, 1H), 4.06 (m, 1H), 3.91 (m, 1H), 2.8-2.6 (m, 2H), 2.70 (s, 3H), 1.50 (t, 1H). MS (m/z): 247 [M]+, 2C1 Intermediate 4 5-[l-(tert-Butyl-dirnethyl-silanyloxymethyl)-but-3-enyl]-4,6-dichloro-2-rnethylpyrimidine To a solution of intermediate 3 (200mg) in anh. DMF (12mL), at 0°C, under N2, was added te/-/-butyl-dimethylsilylchloride (245mg, 2eq) and imidazole (553mg, lOeq). The reaction was stirred at r.t. for 2 hr and more tert-butyl-dimethylsilylchloride (61mg, 0.5eq) was added. After 1 hr, sataq. NH4C1 (15mL) and EtOAc (15mL) were added and the aqueos phase was extracted with additional EtOAc (2xl5mL). The combined extracts were washed with H2O (l0mL), dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 19:1) to give the title compound (237mg) as a colorless oil. NMR ('H, CDC13): δ 5.72 (m, 1H), 5.10 (d, 1H), 4.98 (d, 1H), 4.11 (m, 1H), 3.94 (m, 2H), 2.69 (s, 3H), 2.6-2.7 (m, 2H), 0.82 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H). MS (m/z): 361 [M]+, 2C1 Intermediate 5 (2.4-dichlorophenvI)amine A solution of 2,4-dichloro-aniline (192mg) in anh. THF (12mL), under N2, was treated with sodium hydride (80% in mineral oil, 393mg) at 0°C for 15 min and then intermediate 4 (434mg, 1.19mmol) in anh. THF (4mL) was added. The mixture was heated to reflux for 3 hr and quenched with water (20mL). The product was extracted with EtOAc (2x20mL), dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, EtOAc/cHex 9:1) to give the title compound (41°mg).as a yellow oil. NMR CH, CDClj), T=55SC: δ 8.35 (bs, 1H), 8.13 (bd, 2H), 7.42 .(d, 1H), 7.25 (dd, 1H), 5.73 (m, 1H), 5.03 (m, 2H), 4.10 (dd, 1H), 3.99 (dd, 1H), 3.65 (bm, 1H), 2.75 (m, 2H), 2.47 (s, 3H), 0.82 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H). MS (m/z): 486 [MH]+, 3C1. Intermediate 6 (5-[l-(tert-Butyl-dimethyl-silanyloxymethyl)-but-3-enyl]-6-chIoro-2-methyl-pyrimidin-4-yl)- (2,4-dichlorophenyl)-carbamic acid tert-butyl ester To a solution of intermediate 5 (419mg) in anh. CPI2C12 (17mL), under N2, was added (Boc)2O (376mg, 2eq) and DMAP (cat). The reaction mixture was stirred at r.t. for 18 hr. The solution was diluted with water (l0mL) and extracted with EtOAc (3xl5mL). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated to dryness in vacuo. Flash chromatography of the crude product (silica gel, cHex/EtOAc 9:1) gave the title compound (420mg) as a yellow solid. NMR ('H, CDC13, 40°C): δ 7.47 (d, 1H), 7.30 (d, 1H), 7.14 (dd, 1H), 5.66 (m, 1H), 5.03-4.89 (m, 2H), 3.98-3.8 (m, 2H), 3.43 (b, 1H), 2.8-2.6 (m, 2H), 2.56 (bs, 3H), 1.41 (s, 9H), 0.77 (s, 9H), -0.02 (s, 3H), -0.10 (s, 3H). IR (nujol, cm"1): 1716. MS (m/z): 588 [MH]+', 3C1 Intermediate 7 [6-Chloro-5-(l-hydroxymethyl-but-3-enyl)-2-methyl-pyrimidin-4-yl]-(2.4-dichlorophenyl)-carbamic acid tert-butyl ester To a solution of intermediate 6 (50mg) in anh. DMF (ImL), under N2, was added TEA-3HF (21ul, l.Seq). The reaction was stirred at r.t. for 18 hr. The solution was diluted with water (l0mL) and extracted with EtOAc (3xl5mL). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated to dryness in vacuo. Flash chromatography of the crude product (silica gel, cHex/EtOAc 8:2) gave the title compound (30mg) as colourless oil. NMR ('H, DMSO, T=70°C): δ 7.69 (d, 1H), 7.43-7.33 (m, 2H), 5.64 (m, 1H), 5.00-4.88 (m, 2H), 4.54 (1H, m), 3.71 (m, 2H), 3.29 (m, 1H), 2.66 (m, 2H), 2.5 (s, 3H), 1.31 (s, 9H). MS (m/z): 472 [MH]+, 3C1 Intermediate 8 Methanesulfonic acid 2- (4-[tert-butoxycarbonyl-(2.4-dichlorophenyl)-amino]-6-chloro-2- methyl-pyrimidin-5-yl) -pent-4-enyI ester To a solution of intermediate 7 (130mg) in anh. CH2C12 (5.52mL), at r.t, under N2, was added Et3N (192μ1, 5eq) and CH3SO2C1 (43 μl, 2eq). The reaction was stirred at r.t. for 18 hr. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (3x25mL). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 8:2) to give the title compound (148mg) as a colourless oil. NMR ('H, DMSO, T=70°C): 5 7.72 (d, δ1H), 7.36 (dd, 1H), 7.28 (d, 1H), 5.56 (m, 1H), 5.00 (d, 1H), 4.92 (d, 1H), 4.46 (m, 2H), 3.51 (m, 1H), 3.02 (s, 3H), 2.65 (m, 1H), 2.54 (s, 3H), 2.50(m,lH), 1.38(s,9H). IR (cm-1): 1725,1641,1362 MS (m/z): 550 [MH]+, 3C1 Intermediate 9 5-Allyl-4-chloro-7-(2,4-dichlorophenyl)-2'methyl-6.7-dihydro-5H-pyrrolor[2.3-d]pyrimidine A solution of intermediate 8 (120mg) in TFA 20%/CH2C12 (7mL) was stirred at r.t. for 2 hr. To remove TFA, the solvent of the reaction mixture was evaporated in vacua and repeated additions of CH2Cl2 and evaporation were made. The crude intermediate was then dissolved in anh. THF (5mL) and Et3N (284u.l, 5eq) was added. After 1 hr of stirring at r.t, H2O was added and the aqueous layer was extracted with EtOAc (Sxl0mL). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated to dryness in vacua to give the title compound (124mg) as a colourless oil. NMR ('H, CDC13): δ 7.49 (dd, 1H), 7.30 (d+s, 2H), 5.77 (m, 1H), 5.16-5.12 (m, 2H), 4.00 (t, 1H), 3.77 (m, 1H), 3.57 (m, 1H), 2.7 (m, 1H), 2.47 (m, 1H), 2.45 (s, 3H). MS (mlz): 354 [MH]+, 3C1 Intermediate 10 [4-Chloro-7-(2.4-dich1orophenyl)-2-methyl-6.7-dihydro-5H-pyrrolor[2.3d]pyrimidin-5-yl1- acetaldehyde A solution of intermediate 9 (30mg) in CH2C12 (4mL) was ozonized (5g.h"') at -78°C for 5 min. When all the starting material had disappeared (according to TLC in cHex/EtOAc 75/25), the reaction mixture was first flushed with oxygen and then with nitrogen for 20 min. To the cooled reaction mixture was added (CH3)2S (25u.l, 4eq) and the temperature was allowed to warm up to r.t.. The solution was stirred for 18 hr at that temperature. The solvent was removed in vacua and the crude product was purified by flash chromatography (silica gel, cHex/EtOAc 3:1) to give the title compound (8mg) as a colourless oil. NMR ('H, CDCl3): δ 9.87 (s, 1H), 7.48 (t, 1H), 7.30 (m, 2H), 4.23 (t, 1H), 3.90 (m, 1H), 3.60 (dd, 1H), 3.29 (dd, 1H), 2.90 (dd, 1H), 2.42 (s, 3H). MS (mlz): 356 [MH]+, 3C1. Intermediate 11 5-[1-(tert-Butyl-diphenyl-silanyloxymemyl)-but-3-enyl]-4,6-dichloro-2-methyl-pyrimidine To a solution of intermediate 3 (152mg) in anh. DMF (4mL), at 0°C, under N2, was added DMAP (3.8mg), imidazole (420mg) and Ph2/BuSiCl (0.32mL). The reaction mixture was stirred at r.t. for 2 hr. To this solution were added 5mL of sataq. NILtCl and the mixture was extracted with Et2O (2x1 5mL). The combined organic extracts were washed once with water, once with brine and dried over Na2SCV The solids were filtered, the solvent was evaporated and the crude yellow oil was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to give the title compound as a colourless oil (270mg). NMR ('H, CDCl3): δ 7.65 (dd, 2H), 7.56 (dd, 2H), 7.49-7.36 (m, 6H), 5.67 (m, 1H), 5.03 (dd, 1H), 4.94 (dd, 1H), 4.17 (m, 1H), 4.00 (m, 2H), 2.70 (s, 3H), 2.69 (m, 1H), 255 (m, 1H), 0.98 (s, 9H). MS (mlz): 485 [MH]+, 2C1. In3termediate 12 (5-[tert-Butyl-diphenyl-silanyloxymethyl)-but-3-enyl1-6-chloro-2-inethyl-pyrimidin-4-yl)- (2.4-dichlorophenyl)-amine To a solution of 2,4-dichloroaniIine (80mg) in anh. THF (ImL), at 0°C, under N2, was added NaH (80 % in mineral oil, 31mg) and left to react at r.t. for 30 min. To this mixture cooled back at 0°C was added a solution of intermediate 11 (227mg, 0.467mmol) in anh. THF (2mL). The reaction mixture was stirred at reflux for 5 hr. It was then quenched with water (20mL), and extracted with Et2O (4x20mL). The combined organic extracts were washed once with water, once with brine and dried over anh. Na2SO4. The solids were filtered, the solvent evaporated and the crude orange oil was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to give the title compound as yellow oil (131.6mg). NMR ('H, CDC13): δ 8.2-7.7 (broad d, 1H), 7.55 (d, 2H), 7.50 (d, 2H), 7.40-7.20 (m, 9H), 5.70 (m, 1H), 5.07 (dd, 1H), 4.94 (dd, 1H), 4.06 (m, 2H), 3.70 (m, 1H), 2.71 (m, 2H), 2.50 (m, 3H), 0.95 (s, 9H). MS(w/z):610[MH]+,3Cl. Intermediate 13 (5-[1-(tery-Butyl-diphenyl-silanyloxymethyl)-but-3-enyl]-6-chloro-2-methyl-pyrimidin-4-yl}- (2,4-dichlorophenyl)-carbamic acid tert-butyl ester To a solution of intermediate 12 (128mg) in anh. CH2C12 (2mL), at r.t., under N2, were added Boc2O (61mg) and DMAP (3mg). The reaction mixture was stirred at r.t. for 16 hr. The complete conversion of the starring material was obtained after 2 days by addition of fresh Boc2O (58mg + 46mg) and catalytic amounts of DMAP. The reaction mixture was then diluted with water and extracted with CH2C12 (2x5mL). The combined organic extracts were washed once with water and dried over anh. Na2SO4. The solids were filtered, the solvent evaporated and the crude yellow oil was purified by flash chromatography (silica gel, cHex/EtOAc 9:1) to give the title compound as pale yellow oil (138mg). NMR ('H, DMSO, 70 °C): δ 7.67 (d, 1H), 7.54-7.30 (m, 5H+5H), 7.19 (m, 2H), 5.51 (m, 1H), 4.87 (d, 1H), 4.82 (d, 1H), 3.94 (m, 1H), 3.84 (bm, 1H), 3.53 (m, 1H), 2.57 (s, 3H), 2.62 (m, 1H), 2.35 (m, 1H), 1.35 (s, 9H), 0.90 (s, 9H). IR(nujol,cm'1):1732. MS (777/2): 710 [MH]+, 3 Cl, 722 [M+Na]+, 610 [MH-Boc+H]+. Intermediate 14 (5-[1-tert-Butyl-diphenyl-silanyloxymethyl)-3-hydroxy-propyl1-6-chloro-2-methyl-pyrimidin-4-yl)-(2,4-dichlorophenyl)-carbamic acid tert-butyl ester A solution of intermediate 13 (108mg) in 3mL of CH2C12/CH3OH (9:1) was cooled at-78°C. 03 was bubbled in the solution for 30 min under magnetic stirring. NaBKU (23.1mg) was then added under N2 atmosphere at low temperature. The reaction mixture was stirred for 3 hr at r.L. It was then quenched with water and extracted with CH2C12 (2x5 mL). The combined organic extracts were washed once with sat.aq. NH4C1 and dried over anh. Na2SO4. The solids were filtered, the solvent was evaporated and the crude yellow oil was purified by flash chromatography (silica gel, cHex/EtOAc 9:1) to give the title compound as a colourless oil (59mg). NMR ('H, DMSO, 70 °Q: δ 7.65 (d, 1H), 7.48-7.34 (m, 5H+5H), 7.28 (d, 1H), 7.12 (bd, 1H), 5.51 (m, 1H), 4.18 (t, 1H), 4.02 (bt, 1H), 3.82 (bm, 1H), 3.51 (m, 1H), 3.29 (bm, 2H), 2.55 (s, 3H), 2.05 (m, 1H), 1.84 (bm, 1H), 1.35 (s, 9H), 0.89 (s, 9H). IR (film, cm'1): 1733. MS (m/z): 714 [MH]+, 3 Cl, 736 [M+Na]+, 3 Cl, 678 [MH-HClf , 2 Cl, 614 [MH-Boc+H]+. Intermediate 15 Methanesulfonic acid 3- f 4-[tert-butoxycarbonyl-(2,4-dichlorophenyl)-amino]-6-chloro-2- methyl-Pyrimidin-5-yl}-4-(tert-butyl-diphenyl-silanyloxy)-butyl ester To a solution of intermediate 14 (57mg) in anh. CH2C12 (ImL), were added Et3N (55μl) and MsCl (13μl) at r.t., under N2. The reaction mixture was stirred for 5 hr, diluted with water and extracted with CH2Cl2 (2x5mL). The combined organic extracts were washed once with water, once with brine, and dried over anh. Na2SO4. The solids were filtered, the solvent evaporated to obtain the crude colourless title compound (60mg). NMR ('H, DMSO, 70 °C): δ 7.65 (d, 1H), 7.50-7.34 (m, 5H+5H), 7.24 (bd, 1H), 7.15 (bd, 1H), 420^.00 (m, 3H), 3.80-3.60 (m, 2H), 3.02 (s, 3H), 2.56 (s, 3H), 2.30-2.10 (m, 2H), 1.35 (s, 9H), 0.89 (s, 9H). IR (nujol, cm'1): 1725. MS (m/z): 794 [MH]+, 3 Cl, 694 [MH-Boc+H]+. Intermediate 16 Methanesulfonic acid 4-(tert-butyl-diphenyl-silanyloxy)-3-4-chloro-6-(2,4-dichlorophenyl- amino)-2-methyl-pyrimidin-5-yl]-butyl ester To a solution of intermediate 1 5 (58mg) in anh. CH2C12 (1mL), at r.t., under N2, was added TFA (200μl, 35eq). The reaction mixture was stirred for 16 hr, then evaporated under reduced pressure, diluted several times with CH2Cl2 and evaporated again to obtain the crude title compound (64mg) as a yellow oil. MS (Wz): 694 [MH]+, 3 Cl. Intermediate 17 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-8-(2.4-dichlorophenyl)-2-methyl-5.6.718- tetrahydro-pyrido [2.3 -d] pyrimidine To a solution of intermediate 16 (64mg) in anh. THF (ImL), at 0°C, under N2, was added Et3N (l00μl). The reaction mixture was stirred for 16 hr at r.t, then diluted with water and extracted with Et2O (2x20mL). The combined organic extracts were washed once with water, once with brine and dried over anh. Na2SO4. The solids were filtered, the solvent was evaporated and the crude oil was purified by flash chromatography (silica gel, cHex/EtOAc 95:5). to obtain the title compound as a colourless oil (26.4mg). NMR ('H, CDCl3): δ 7.74-6.98 (m, 5H+5H+1H+2H), 4.10-3.90, 3.76-3.55, 3.48-3.28 (m, 5H), 258-2.38 (m, 1H), 2.24, 2.22 (s, 3H), 2.1-1.9 (m 1H), 1.07 (s, 9H). MS (m/z): 598 [MH]+, 3 Cl. Intermediate 18 [4-Chloro-8-(2,4-dichoropheny)-2-methyl]-5.6,7.8-tetrahydro-pyride[2,3-d]pyrimidin-5-yl]- methanol To a solution of intermediate 17 (22mg) in anh. DMF (2mL), at r.t, under N2, was added Et3N3HF (20μl). The reaction mixture was stirred for 4 hr at 40°C, then diluted with water and extracted with Et2O (3x20mL). The combined organic extracts were washed once with water, once with brine and dried over anh. Na2SO4. The solids were filtered, the solvent evaporated and the crude oil was purified by flash chromatography (silica gel, cHex/EtOAc 2:1) to give the title compound as colourless oil (13mg). NMR ('H, DMSO, 90 °C): δ 7.66 (bs, 1H), 7.50-7.42 (m, 2H), 4.66 (m, 1H), 3.82 (bt, 1H), 3.68 (m, 1H), 3.66-3.36 (m, 2H), 3.20 (m, 1H), 2.33 (m, 1H), 2.14 (s, 3H), 1.94 (m, 1H). MS (m/z): 358 [MH]+, 3 Cl, 360. Intermediate 19 Methanesulfonic acid 4-chloro-8-(2.4-dichlorophenyl)-2-methyl-5.6.7.8-tetrahydro- pyrido[2.3-d]pyrimidin-5-ylmethyl ester To a solution of intermediate 18 (13mg) in anh. CH2C12 (ImL), at 0 °C, under N2, were added EtjN (20.0μl) and MsCl (6.0μl). The reaction mixture was stirred for 16 hr at r.t., then diluted with water and extracted with CH2C12 (3x10mL). The combined organic extracts were washed once with water, once with brine and dried over anh. Na2SO4. The solids were filtered and the solvent was evaporated to give the crude title compound (14.7mg) as a colourless oil. NMR ('H, CDC13): δ 7.50 (dd, 1H), 7.40-7.15 (m, 2H), 4.50-4.15 (m, 2H), 3.90-3.70 (m, 1H), 3.65-3.30 (m, 2H), 3.05 (s, 3H), 2.45-2.2 (m, 1H), 2.25 (s, 3H), 2.2- 2.0 (m, 1H). MS (inlz): 438 [MHf, 3 Cl. Intermediate 20 5-Iodo-pentanoic acid methyl ester To a solution of methyl 4-bromovalerate (14g) in acetone (63mL), Nal (11.5g) was added and the mixture was refluxed for 2 hr. It was then cooled to r.t. and the precipitate was filtered. The filtrate was evaporated and ether was added to the residue. The resulting suspension was filtered and the ethereal phase washed with 5% aq NaHSO3 (3xl00mL) and with brine (Ixl00mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated to give the crude title compound as a yellow oil (15.85g). NMR ('H, CDC13): δ 3.68 (s, 3H), 3.19 (t, 2H), 2.34 (t, 2H), 1.86 (m, 2H), 1.74 (m, 2H). MS (m/z): 242 [M]+, 211 [M-OMef ,1 15 [M-I]+. Intermediate 21 2-(2.4-dichlorophenyl)-heptanedioic acid dimethyl ester To a solution of methyl 2,4-dichlorophenylacetate (2g) in anh. THF (27mL), at -78°C, under N2, a 1M solution of LHMDS in THF (10.04mL) was added dropwise and the mixture was stirred at -78°C for 30 min. Neat intermediate 20 (2.87g, 1.3eq) was then added dropwise at -78°C and the dropping funnel was washed with anh. THF (2mL). The cooling bath was then removed and the mixture was stirred at r.t for 3.5 hr. The solvents were evaporated under reduced pressure. The residue was dissolved in ether, washed with water (3x30mL) and brine (lx30mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 9:1) to give the title compound as a pale yellow oil (2.7g). NMR ('H, CDC13): δ 7.39 (d, 1H), 7.30 (d, 1H), 7.22 (dd, 1H), 4.10 (t, 1H), 3.67 (s, 3H), 3.65 (s, 3H), 2.29 (t, 2H), 2.05 (m, 1H), 1.74 (m, 1H), 1.64 (m, 2H), 1.40-1.20 (m, 2H). IR (film, cm'1): 1738. MS (in/z): 332 [M]+, 300 [M-CH3OH]+, 159. Intermediate 22 3-(2.4-Dichlorophenyl)-2-hydroxy-cyclohex-l-enecarboxylic acid methyl ester Sodium (0.7g) was added portionwise under vigorous stirring, at 0°C, under N2, to anh. MeOH (26mL). After consumption of metallic sodium, anh. toluene (l00mL) was added and a MeOH/toluene mixture (36mL) was distilled off by means of a Dean-Stark apparatus. The mixture was allowed to cool to r.t. before adding a solution of intermediate 21 (2.52g) in anh. toluene (15mL). The mixture was refluxed for 3.5 hr and then cooled to r.t. before acidifying with AcOH. The organic phase was washed with water. The aqueous phase was extracted with EtOAc (2x20mL) and the combined organic extracts were washed with water (2x20mL), brine (2x20mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to obtain the title compound (colourless oil: 1.8g) NMR ('H, CDC13): δ 12.19 (s, 1H), 7.40 (d, 1H), 7.19 (dd, 1H), 7.08 (d, 1H), 4.07 (t, 1H), 3.81 (s, 3H), 2.35 (m, 2H), 2.01 (m, 1H), 1.73 (m, 1H), 1.60 (m, 2H). MS (m/z): 300 [M]+, 265, 233. Intermediate 23 5-(2.4-Dichlorophenyl)-6-oxo-cyclohex-l-enecarboxylic acid methyl ester Phenylselenenylchloride (2.44g) was placed in a two-necked flask under nitrogen and dissolved in anh. CH2C12 (21mL). The brown solution was cooled to 0°C and anh. pyridine (0.9mL) was added resulting in a yellow solution which was stirred at 0°C for 30 min. A solution of intermediate 22 (1.5g) in anh. CH2C12 (12mL) was added dropwise at 0°C and the reaction mixture was stirred at r.t. for 4.5 hr. The reaction mixture was then transfered to a separatory funnel and washed with 1M HC1 (2xl0mL) and with water (3xl0mL). The CH2C12 layer was then transfered to a flask and cooled to 0°C. Aqueous H2O2 (30% w/w, 3mL) was added and the mixture was stirred for 10 min at 0°C followed by addition of a second aliquot of H2O2 (3mL). The reaction mixture turned colourless and a white solid formed. After 20 min at 0°C the mixture was washed with sataq. NaHCO3 (2x10mL) and brine (1x10mL) and dried over anh. Na2SO,4. The solids were filtered and the solvent evaporated to give the title compound (1.45g) as a pale yellow oil, which becomes solid by cooling. NMR ('H, CDC13): δ 7.77 (m, 1H), 7.43 (d, 1H), 7.24 (dd, 1H), 7.11 (d, 1H), 4.12 (dd, 1H), 3.83 (s, 3H), 2.70 (m, 2H), 2.40-2.20 (m, 2H). IR (film, cm'1): 1737, 1673. MS (m/z): 298 [M]+, 263 [M -Cl]*, 126. Intermediate 24 5-Allyl-8-(2,4-dichlorophenyl)-2-methyl-5.6.7.8-tetrahydroquinazolin-4-ol To a solution of intermediate 23 (690mg) in anh. CH2C12 (6.5mL), at -78°C, TiCL, (0.255mL) was added. The resulting brown solution was stirred at -78°C for 5 min, after which a solution of allyltrimethylsilane (0.440mL) in anh. CH2C12 (6.5mL) was added. After stirring for 1.5 hr at -78°C, the reaction was quenched with water, diluted with CH2Cl2 and the mixture was allowed to warm to r.t.. The aqueous layer was extracted with CH2C12 and the organic phase was washed with brine (Ixl0mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated to obtain the allylated compound (676mg) as pale yellow oil and as a mixture of diastereoisomeric enolesters and ketoesters. Sodium (140mg, 3eq) was added portionwise to anh. MeOH (6mL) under N2. After consumption of metallic sodium, acetamidine hydrochloride (600mg) was added. After 10 min of stirring, the precipitated NaCl was filtered off and washed with anh. MeOH (2mL). The solution of free acetamidine was added to the crude allylated product (676g) and the mixture was stirred at r.t. for 18 hr. The solvent was evaporated and the crude product was purified by flash chromatography (silica gel, CH2Cl2/MeOH 98:2-------> 97:3) to give the title compound as a 3:1 mixture of two diastereoisomers (538mg). NMR ('H, CDCl3)(anti isomer): δ 11.82 (bs, 1H), 7.42 (d, 1H), 7.10 (dd, 1H), 6.58 (d, 1H), 5.87 (m, 1H), 5.06 (m, 2H), 4.34 (d, 1H), 3.01 (m, 1H), 2.68 (m, 1H), 2.37 (s, 3H), 2.20 (m, 1H), 2.07 (m, 1H), 1.80 (m, 1H), 1.70 (m, 1H), 1.49 (m, 1H). NMR ('H, CDCl3)(syn isomer): 6 11.70 (bs, 1H), 7.36 (d, 1H), 7.12 (dd, 1H), 6.81 (d, 1H), 5.83 (m, 1H), 5.02 (m, 2H), 4.23 (bt, 1H), 2.98 (m, 1H), 2.66 (m, 1H), 2.28 (s, 3H), 2.20 (m, 1H), 2.02-1.80 (m, 2H), 1.62-1.47 (m, 2H). MS (m/z): 348 [M]+, 307 [M -allyl]+. Intermediate 25 Anti-5-Allyl-4-chloro-8-(2.4-dichlorophenyl)-2-methyl-5.6.7.8-tetrahydroqunazoline (isomer 1) and Syn -5-Allyl-4-chloro-8-(2,4-dichlorophenyl)-2-methyl-5,6,7.8-tetrahydroquinazoline (isomer 2) Intermediate 24 (538mg) was dissolved in POC13 (5mL) and the mixture was refluxed for 2 hr. The POC13 was evaporated, the residue was dissolved in CH2C12 and treated with cone. NH4OH. The two phases were separated and the aqueous layer was extracted with CH2C12 (3xl0mL). The combined organic extracts were washed with brine (2xl0mL) and dried over Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 95:5)to give the title compound isomer 1 (262mg) and the title compound isomer 2 (94mg) as colourless oils. isomer 1 :NMR ('H, CDC13): δ 7.44 (d, 1H), 7.06 (dd, 1H), 620 (d, 1H), 5.86 (m, 1H), 5.14 (m, 2H), 4.63 (d, 1H), 3.16 (m, 1H), 2.60 (m, 1H), 2.59 (s, 3H), 2.30 (m, 1H), 2.16 (m, 1H), 1.89 (m, 1H), 1.80 (m, 1H), 1.64 (m, 1H). MS (m/z): 367 [M+H]*. isomer 2 :NMR ('H, CDC13): δ 736 (d, 1H), 7.15 (dd, 1H), 6.83 (bd, 1H), 5.82 (m, 1H), 5.10- 5.06 (m, 2H), 4J5 (m, 1H), 3.12 (m, 1H), 2.62 (m, 1H), 2.48 (s, 3H), 225 (m, 1H), 2.22-2.00 (m,2H), 1.90-1.78 (m,2H). MS (m/z): 367 [M+H]4. Intermediate 26 [5-Allyl-7-(2.4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2.3-d]pyrimidin-4-yl]- cycl opropylmethyl-amine A solution of intermediate 9 (160mg, 0.451mmol) in cyclopropylmethylamine (0.5mL) was heated at 130°C (screw cap vial) for 4 hr. The amine was then evaporated and the residue was purified by flash chromatography (silica gel, gradient: CH2Cl2/EtOAc 9:1 to 7:3) to give the title compound (162mg, 0.416mmol, 92%) as a colourless oil. NMR ('H, CDC13): δ 7.43 (d, 1H), 7.36 (d, 1H), 7.24 (dd, 1H), 5.86 (m, 1H), 5.20-5.13 (m, 2H), 4.39 (bt, 1H), 3.88 (dd, 1H), 3.71 (dd, 1H), 3.40-3.30 (m, 3H), 2.46 (m, 1H), 2.35 (m, 1H), 2.36 (s, 3H), 1.08 (m, 1H), 0.60-0.27 (m, 4H). MS (mlz): 389 [M+H]+(2 Cl). Intermediate, 27 5-Cyclopropvlmethyl -l-(2,4-dichlorophenyl)- 7-methyl-l,2.2a,3,4,5-hexahydro-1.5.6.8r tetraaza-acenaphthylen-4-ol To a solution of intermediate 26 (160mg, 0.411mmol) in a 8:1 mixture of acetone and water (8mL) was added N-methylmorpholine-N-oxide (l00mg, 2eq), followed by a 4% aqueous solution of OsO4 (0.260mL, 0.1 eq) and the reaction mixture was stirred at r.t. for 3.5 hr. The solution was then concentrated under reduced pressure, and sat.aq. Na2SO3 (50mL) was added. The aqueous phase was extracted with EtOAc (3x10mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude diol was dissolved in a 1:1 mixture of THF and water (8mL) and NaIO4 (132mg, 1.5eq) was added. The reaction mixture was stirred at r.t. for 45 min. It was then diluted with water and extracted with EtOAc (3xl0mL). The combined organic extracts were washed once with brine and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 1:1). The title compound was obtained as a colourless oil (11 Img, 0.284mmol, 69%). NMR ('H, DMSO-d6): δ 7.68 (d, 1H), 7.44 (m, 2H), 5.92 (d, 1H), 5.17 (m, 1H), 4.13 (t, 1H), 3.79 (m, 1H), 3.76 (dd, 1H), 3.50 (m, 1H), 3.15 (dd, 1H), 2.24 (m, 1H), 2.21 (s, 3H), 1.43 (dt, 1H), 1.06 (m, 1H), 0.50-0.20 (m, 4H). MS (mlz): 391 [M+H]+(2 Cl). Intermediate 28 5-Cyclopropylmethyl-l-(2.4-dichlorophenyl)-4-methoxy-7-methyl-1.2.2a,3.4.5-hexahydro-1.5.6.8-tetraaza-acenaphthylene A solution of PTSA (1.5mg, 0.042eq) in anh. MeOH (1.5mL) was added to the neat intermediate 27 (73mg, 0.187mmol) and the resulting solution was stirred at r.t for 18 hr. The solvent was then evaporated and the residue was dissolved in CH2C12 (l0mL). A solution prepared by diluting sataq. NaHCO3 with water (1:1, l0mL) was then added and the aqueous phase was extracted with CH2C12 (2x1 OmL). The combined organic extracts were washed with water (Ixl0mL), sat.aq. NaCl (Ixl0mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The title compound was obtained as a yellow oil and was used in the subsequent step without further purification (68mg, 0.168mmol, 90%). NMR ('H, acetone-d6): δ 7.53 (d, 1H), 7.47 (d, 1H), 7.35 (dd, 1H), 4.93 (t, 1H), 4.23 (t, 1H), 4.05 (dd, 1H), 3.78 (dd, 1H), 3.51 (m, 1H), 3.39 (s, 3H), 3.13 (dd, 1H), 2.53 (dddd, 1H), 2.25 (s, 3H), 1.40 (dt, 1H), 1.09 (m, 1H), 0.50-0.20 (m, 4H). MS(m/z):405[MH]+2Cl). Intermediate 29 Alternative preparation of intermediate 2: 2-[4-Chloro-7-(2>4-dichlorophenyl)-2-methyl-6.7- dihydro-5H-pyrrlo[2.3-d]pyrimidin-5-yl]-ethanol To a solution of intermediate 10 (93mg, 0.261mmol) in a 2:1 mixture of anh. CH2Cl2/MeOH (3mL), at 0°C, under N2, was added NaBH4 (20mg, 2eq). The reaction mixture was stirred at r.t. for 1 hr. The reaction was then quenched with water (l0mL) and concentrated under reduced pressure. The aqueous phase was extracted with EtOAc (3x10mL) and the combined organic extracts were dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The title compound was obtained as a white solid (80mg, 0.223mmol, 85%) and was used without further purification in the subsequent step. NMR ('H, CDC13): δ 7.54 (d, 1H), 7.40-7.30 (m, 2H), 4.20 (t, 1H), 3.93 (dd, 1H), 3.87 (m, 2H), 3.75 (m, 1H), 2.57 (s, 3H), 2.27 (m, 1H), 1.99 (m, 1H). MS (m/z): 358 [MH]+ (3C1). Intermediate 30 Methanesulfonic acid 2-[4-chloro-7-(2,4-dichlorophenyl)-2-methyl-6.7-dihydro-5H- pyrrolo[2.3-d]pyrimidin-5-yl]-ethyl ester To a solution of intermediate 29 (80mg, 0.223mmol) in anh. CH2C12 (2mL), at r.t., under N2, was added triethylamine (155μL, 5eq) followed by mesyl chloride (35μL, 2eq). The reaction mixture was stirred at r.t. for 1 hr. It was then quenched with water (l0mL) and extracted with CH2C12 (3xl0mL). The combined organic extracts were washed once with brine and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude compound was purified by flash chromatography (silica gel, cHex/EtOAc 1:1). The title compound was obtained as a pale yellow oil (71mg, 0.163mmol, 73%). NMR ('H, CDC13): δ 7.48 (m, 1H), 7.32 (m, 2H), 4.38 (m, 2H), 4.09 (t, 1H), 3.82 (dd, 1H), 3.66 (m, 1H), 3.00 (s, 3H), 2.46 (m, 1H), 2.42 (s, 3H), 2.14 (m, 1H). MS (/n/z): 436 [MH]+ (3C1). Intermediate 31 (5-[l-(tert- Butvl-diphenyl-silany1oxxymethyl)-but-3-enyl]-6-chloro-2-methyl-pyrimidin-4- vl} -( 2.4-bis-trifluoromethyl-phenyl)-amine To a solution of 2,4-bis(trifluoromethyl)aniline (2.11g, 9.21mmol) in anh. DMF (45mL), at 0°C, under N2, was added NaH 80%/oil (608mg, 22eq). After 30 min the reaction mixture was wanned to r.t After 30 min a solution of intermediate 11 (4.46g, 9-21mmol.) in anh. DMF (30mL) was added. The reaction mixture was left at r.L for 15 min, then cooled down at 0°C and diluted with water. The aqueous phase was extracted with EtOAc (3x50mL) and the combined organic extracts were washed with water (5 0mL), brine (50mL) and then dried over anh. Na2SO4 The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 97:3) to give the title compound (4.546g, 6.71minol, 73%) as a clear oil. NMR ('H, DMSO): δ 8.34 (s, 1H), 7.97 (s, 1H), 7.53 (d, 1H), 7.48 (d, 1H), 7.54-7.31 (m, 10H), 5.7 (m, 1H), 4.97 (d, 1H), 4.90 (d, 1H), 4.11 (m, 1H), 3.99 (m, 1H), 3.72 (m, 1H), 2.56 (m, 2H), 2.18 (s, 3H), 0.91 (s, 9H). MS (m/z): 678 [MH]+. Intermediate 32 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-2-methvl-8-f2.4-bis-trifluoromethyl-phenyl)-5,6.7.8-tetrahvdro-pvrido[2,3-tf]pyrimidin-7-ol To a solution of intermediate 3.1 (2g, 2.95mmol) in an 8:1 mixture of acetone/H2O (36mL), at r.t., were added N-methyl-morpholine-N-oxide (716mg, 2eq) and OsO4 4%/H2O (1.8mL, 0.leq). After 3.5 h the solvent was evaporated and a saturated solution of Na2SO3 was added. The product was extracted with EtOAc (2x20mL) and the combined organic extracts were dried over anh. Na2S04. The solids were filtered and the solvent was evaporated. The oil obtained was dissolved in a 9:1 mixture of THF/H2O (45mL) and NaIO4 (947mg, 1.5eq) was added. The reaction mixture was stirred at r.t. for 18 hr. It was then diluted with water and the product was extracted with EtOAc (3x20mL). The combined organic extracts were washed with brine and dried over anh. Na2SO4. The solids were filtered and the solvent was evaporated to give the title compound (1.932g, 2.85mmol, 96%), as a mixture of two diastereoisomers. NMR ('H, Acetone): Isomer 1: δ 8.15 (m, 2H), 7.72 (m, 5H), 7.44 (m, 6H), 6.19 (d, 1H), 5.27 (m, 1H), 4.41 (t, 1H), 4.08 (dd, 1H), 3.52 (m, 1H), 2.81 (m, 1H), 2.35 (m, 1H), 2.15 (s, 3H), 1.07 (s, 9 H). Isomer 2: 5 8.15 (m, 2H), 7.72 (m, 5H), 7.44 (m, 6H), 5.8-5.4 (m, 2H), 4-3.8 (m, 2H), 3.6-3.4 (m, 1H), 3-2.8 (m, 1H), 2.35 (m, 1H), 2.15 (s, 3H), 1.07 (s, 9H). MS (m/z): 680 [MH]+. Intermediate 33 5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5.6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine To a solution of intermediate 32 (1.93g, 2.84mmol) in anh. CH2C12 (50mL), at -78°C, were added Et3SiH (1.82mL, 4eq) and BF3-Et20 (1.58mL, 4.4eq). The reaction mixture was stirred 1 hr at -78°C and then was allowed to warm to r.t. and stirred for 18 hr. A saturated solution of NaHCO3 was then added and the product was extracted with CH2C12 (3x50mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to give the title compound (0.607g, 9.16mmol, 32%) as a white solid NMR ('H,CDC13): δ 7.98-7.94 (d, 1H), 7.88-7.80 (dd, 1H), 7.7-7.58 7.44-7.32 (m, 10H), 7.35-7.14 (d, 1H), 3.98-3.94 (dd, 1H), 3.73-3.55 (m, 1H), 3.63-3.59 (m, 1H), 3.44-3.36 338-3.3 (2m, 2H), 2.55-2.4 (m, 1H), 2.17-2.15 (s, 3H), 2.04-1.9 (m, 1H), 0.98 (s, 9H). MS (m/z): 664[MH]+. Intermediate 34 {4-Chloro-2-methyl-8-(2;4-bis-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyridor2.3- d]pyrimidin-5 -yl) -methanel To a solution of intermediate 33 (600mg, 0.91mmol) in anh. DMF (15mL), at r.t, under N2, was added Et3N-3HF (1.25mL, 8.4eq) and the reaction mixture was heated at 40°C for 6.5 h. It was then cooled down to r.t. and diluted with water. The product was extracted with Et2O (3x20mL). The combined organic extracts were washed with brine and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 6:4) to give the title compound (337mg, 0.8mmol, 88%) as a clear oil. NMR ('H, DMSO): δ 8.26-8.12 (m, 2H), 7.9-7.8 (d, 1H), 5.08-4.98 (t, 1H), 3.9-3.6 (2H), 3.7- 3.3 (2H), 3.24-3.10 (1H), 2.3 (m, 1H), 2.09 (s, 3H), 2.0-1.8 (m, 1H). MS (mlz): 426[MH]+. Intermediate 35 Methanesulfonic acid 4-chloro-2-methyl-8-(2,4-bis-trifluoromethyl-phenyl)-5.6.7.8- tetrahydro-pyrido[2,3-d]pyrimidin-5-ylmethyl ester To a solution of intermediate 34 (200mg, 0.47mmol), in anh. CH2C12 (l0mL), under N2, at 0°C, were added Et3N (0.26mL, 4eq) and MsCl (73μl, 2eq). The reaction mixture was warmed to r.t. and stirred for 18 hr. It was then diluted with water and the product was extracted with CH2C12 (3x20mL). The combined organic extracts were washed with brine and dried over anh. Na2SO4. The solids were filtered, the solvent evaporated and the crude product was purified by flash chromatography (silica gel, cHex/EtOAc 6:4) to give the title compound (203mg, 0.4mmol, 86%) as a clear oil. NMR ('HJDMSO): δ 8.3 8.14 (m, 2H), 7.95-7.8 (d+d, 1H), 4.56-4.20 (2H), 3.9-3.4 (m, 3H), 3.25 (s, 3H), 2.11 (s, 3H), 2.2-1.9 (m, 2H). MS (mlz): 504[MH]+. Intermediate 36 {4-Chloro-2-methyl-7-(2.4-bis-trifluoromethyl-phenyl)-6.7-dihydro-5H-pyrrolor[2.3-d]pyrimidin-5-yl} -acetaldehyde To a solution of intermediate 31 (0.6g, 0.886mmol) in anh. DMF (15mL), at r.L, under N2 was added Et3N-3HF (1.22mL, 8.4eq). The reaction mixture was stirred at r.L for 18 hr. The reaction mixture was diluted with water and the product was extracted with Et2O (3x20mL). The combined organic extracts were washed with brine and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 8:2) to give an alcohol intermediate (346mg, 89%) which was dissolved into anh. CH2C12 (15mL) and cooled down to 0°C. Et,N (0.44mL, 4eq) and MsCl (0.122mL, 2eq) were added, and the reaction mixture was warmed to r.L and stirred for 18 hr. The reaction mixture was diluted with water and the product was extracted with CH2C12 (3x20mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 8:2) to give a cyclic pyrrolidine intermediate (276mg, 83%). This intermediate was dissolved in an 8:1 mixture of acetone/H2O (18mL) and N-methyl-morpholine-N-oxide (230mg, 2eq) and OsO4 (403 μl, 0.1 eq) were added. The reaction mixture was stirred at r.t. for 6 h. The solvent was evaporated and a saturated solution of Na2SO3 was added. The product was extracted with EtOAc (3x20mL) and the combined organic extracts were dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was dissolved into a 9:1 mixture of THF/H2O (15mL) and NaIO4 (210mg, 1.5eqJ was added. The reaction mixture was stirred at r.t. for 18 hr, then it was diluted with water and the product was extracted with EtOAc (3x20mL). The combined organic extracts were washed with brine and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated to give the title compound (250mg, 0.59mmol, 90%) as a clear oil. NMR ('H, CDC13): δ 9.86 (s, 1H), 8.05 (s, 1H), 7.93 (d, 1H), 7.5 (d, 1H), 4.24 (m, 1H), 3.93 (m, 1H), 3.65 (dd, 1H), 3.25 (dd, 1H), 2.93 (dd, 1H), 2.4 (s, 3H). MS (m/z): 424[MH]+. Intermediate 37 Methanesulfonic acid 2-{4-chloro-2-methyl-7-(2.4-bis-trifluoromethyl-phenyl)-6.7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}-ethyl ester To a solution of intermediate 36 (250mg, 0.59mmol) in a 9:1 mixture of CH2Cl2/MeOH (15mL), at 0°C, under N2, was added NaBH4 (44mg, 2eq). The reaction mixture was stirred for 30 min at 0°C. Cone. HC1 was added until pH = 7 was reached. The reaction mixture was then diluted with water and the product was extracted with CH2C12 (3x20mL). The combined organic extracts were washed with brine and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated to give a white solid (alcohol intermediate, 231mg, 0.54mmol, 93%) which was dissolved in anh. CH2C12 (15mL). The reaction mixture was cooled at 0°C, then Et3N (302 μ1, 4eq) and MsCl (85 μ.1, 2eq) were added. The reaction mixture was stirred at r.t. for 18 hr, then it was diluted with water and the product was extracted with CH2C12 (3x20mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 6:4) to give the title compound (252mg, 0.50mmol, 93%) as a clear oil. NMR ('H, CDC13): δ 8.05 (bs, 1H), 7.94 (bd, 1H), 7.53 (bd, 1H), 4.42 (m, 2H), 4.07 (t, 1H), 3.83 (dd, 1H), 3.71 (m, 1H), 3.04 (s, 3H), 2.46 (m, 1H), 2.43 (s, 3H), 2.13 (m, 1H). MS (m/z): 504[MH]+. Intermediates 38 and 39 (S)-2-Acetoxy-propionic acid 4-chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyl)-5.6.7.8- tetrahydro-pyridor[2.3-d]pyrimidin-5(S)-ylmethyl ester and (S)-2-Acetoxy-propionic acid 4- chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyl)-5.6.7.8-tetrahydro-pyridor[2.3- d]pyrimidin-5(R)-ylmethyl ester To a solution of intermediate 34 (320mg, 0.753mmol) in CH2Cl2 (7mL) at 0°C, under N2, were added DMAP (230mg, 2.5eq), Et3N (0.73mL, 7eq) and (S)-2-acetoxyprcpiony chloride (0.6ImL, 6.4eq). The reaction mixture was stirred at 0°C for 30 min, wanned to r.t and diluted with a saturated solution of NaHCO3. The product was extracted with CH2C12 (3x30mL) and the combined organic extracts were dried over anh. Na2SO4. The solids were filtered and the solvent was evaporated. The crude product was purified by flash cnromatography (silica gel, cHex/EtOAc 8:2). The two diastereoisomers were separated by preparative chiral hplc: intermediate 38 (97mg, 0.l8mmol, d.e. = 97%) and intermediate 39 (89.7mg, 0.17mmol, d.e.>99%) were obtained as white solids. NMR ('H, Acetone ): Intermediate 38: δ 8.22-8.13 (m, 2H), 7.96-7.8 (d+d, 1H), 5.06 (m, 1H), 4.56-4.34 (m, 2H), 4.07-3.54 (m, 3H), 2.34-2.05 (m, 2H), 2.7 (s, 3H), 2.06 (s, 3H), 1.48 (d+d, 3H). Intermediate 39: 5 8.22-8.14 (m, 2H), 7.96-7.81 (d+d, 1H), 5.06 (m, 1H), 4.5-4.3 (m, 2H), 4.1-3.54 (m, 3H), 2.7 (s, 3H), 2.3-2.0 (m, 2H), 2.13 (s, 3H), 1.47 (d,3H). MS (mlz): 540[MH]+. Filter Rhodyne Daicel CHIRALPAK AD 25 2 500 HPLC: Preparative: n-hexane-IPA 90/10 v/v 6.5 DAD 225, 292 21.8, r.t. (min) 26.5, r.t. (min) Filter Rhodyne CHIRALPAK AD 25 4.6 5 r.t. Pre-column/Guard column: Column type: Column length [cm]: Internal diameter [mm]: Injection volume [μl]: Mobile phase: Flow rate [mL/min]: Detector type: Wavelength [nm]: Intermediate 38: Intermediate 39: Analytical: Pre-column/Guard column: Column type: Column length [cm]: Internal diameter [mm]: Particle size [μm]: Column temperature [C]: 20 n-hexane/isopropylalcohol 90/10 v/v 1.0 DAD 225 6.88, r.t (min) Filter Rhodyne CHIRALPAK AD 25 4.6 r.L Autosampler temperature [C] r.t. Injection volume [μ1]: Mobile phase: Flow rate [mL/min]: Detector type: Wavelength [nm]: Intermediate 38: Pre-column/Guard column: Column type: Column length [cm]: Internal diameter [mm]: Column temperature [°C]: Autosampler temperature [°C] Mobile phase: n-hexane/2- Propanol 90/10 v/v 47 Flow rate [mL/min]: 1.0 Detector type: DAD Wavelength [nm]: 220-350 Intermediate 39: 8.29, r.t. (min) Intermediate 40 {4-Chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyl)-5.6.7.8-tetrahydro-pyridor2.3- d]]pyrimidin-5(S)-yl}-methanol To a solution of intermediate 38 (90mg, 0.167mmol) in a 4:1 mixture of THF/H2O (5mL), at 0°C, was added LiOH (14mg, 2eq) and the reaction mixture was stirred for 50 min. It was then diluted with water and the product was extracted with Et20 (2xl0mL) and with EtOAc (Ixl0mL). The combined organic extracts were dried over anh. Na2SO4. The solids were filtered, the solvent was evaporated and the crude product was purified by flash chromatography (silica gel, cHex/AcOEt 6:4) to give the title compound (65mg, 0.l5mmol, 92%, e.e. = 97%) as a clear oil. NMR ('H, DMSO): δ 8.3-8.1 (m, 2H), 7.88-7.81 (d+d, 1H), 5.00 (broad, 1H), 3.9-3.6 (m, 2H), 3.7-3.3 (m, 2H), 3.2-3.1 (m, 1H), 2.3 (m, 1H), 2.09 (s, 3H), 2.00-1.8 (m, 1H). MS (m/z): 426[MH]+ HPLC: Analytical Pre-column/Guard column: Filter Rhodyne Column type: Daicel GHIRALPAK AD Column length [cm]: 25 Internal diameter [mm]: 0.46 Column temperature [C]: r.t. Autosampler temperature [C] r.t. Injection volume [μl]: 20 Mobile phase: n-hexane/IPA/EtOH Step 1: Time-Reserv.A-ReservB: 95/3.5/1.5 Flow rate [mL/min]: 1.0 Detector type: DAD Wavelength [nm]: 225 Intermediate 40: 10.28, r.L (min) Intermediate 41 Methanesulfonic acid 4-chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyI)-5.6.7.8- tetrahydro-pyrido[2.3-d]pyrimidin-5(S)ylmethyl ester To a solution of intermediate 40 (62mg, 0.145mmol) in anh. CH2C12 (5mL), at 0°C, under N2, were added Et3N (80μl, 4eq) and MsCl (23μl, 2eq). The reaction mixture was brought to r.t, stirred for 1 h. and then diluted with water. The product was extracted with CH2C12 (3x20mL) and the combined organic extracts were washed with brine and dried ovar anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 6:4) to give the title compound (67mg, 0.l3mmol, 92%, e.e. = 95%) as a clear oil. 48 NMR ('H, DMSO): δ 8.3-8.14 (m, 2H), 7.94-7.83 (d, 1H), 4.55-4.20 (2H), 3.94-3.4 (m, 3H), 3.25 (s, 3H), 2.11 (s, 3H), 2.25-1.94 (m, 2H). MS (m/z): 504[MH]+ HPLC: Analytical Autosampler temperature [AC] r.t. Pre-column/Guard column: Column type: Column length [cm]: Internal diameter [mm]: Particle size [μm]: Column temperature [C]: Injection volume [μl]: Mobile phase: Flow rate [mL/min]: Detector type: Wavelength [nmj: Intermediate 41: Filter Rhodyne CHIRALPAKAD 25 4.6 5 r.t. 20 n-hexane/EtOH/IPA 73.5/1.5/25 v/v 1.0 DAD 225 6.52, r.t. (min) Intermediate 42 (4-Chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyn-5.6.7.8-tetrahydro-pyrido[2.3- d]pyrimidin-5(R)-yl)-methanol To a solution of intermediate 39 (83mg, 0.154mmol) in a 4:1 mixture of THF/H2O (5mL), at 0°C, was added LiOH (14mg, 2eq) and the reaction mixture was stirred for 20 min. It was then diluted with water and the product was extracted with Et2O (2x1 0mL) and with EtOAc (1x1 0mL), and the combined organic extracts were dried over anh. Na2SO4. The solids were filtered, the solvent was evaporated and the crude product was purified by flash chromatography (silica gel, cHex/EtOAc 7:3) to give the title compound (61mg, 0.14mmol, 93%, e.e.>99%) as a clear oil. NMR ('H, DMSO): δ 8.26-8.12 (m, 2H), 7.9-7.8 (d, 1H), 5.08-4.98 (t, 1H), 3.9-3.6 (m, 2H), 3.7-3.3 (m, 2H), 3.24-3.1 (m, 1H), 2.3 (m, 1H), 2.09 (s, 3H), 2.00-1.8 (m, 1H). MS (mlz): 426[MH]+. HPLC: Analytical Pre-column/Guard column: Filter Rhodyne Column type: CHIRALPAK AD Column length [cm]: 15 Internal diameter [mm]: 4.6 Injection volume [uj] 10 Mobile phase: n-hexane/Ethanol/IPA Step l: Time-Reserv.A-Reserv.B:95/1.5/3.5 v/v Flow rate [mL/min]: 1.0 Detector type: DAD Wavelength [nm] : 225 Intermediate 42: 9.417, r.t. (min) Intermediate 43 Methanesulfonic acid 4-chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyl)-5.6.7.8- tetrahydro-pvrido[2.3-td]pyrimidin-5(R)-ylmethyl ester To a solution of intermediate 42 (58mg, 0.136mmol) in anh CH2C12 (5mL), at 0°C, under N2, were added Et3N (76μl, 4eq) and MsCl (21μ.l, 2eq). The reaction mixture was brought to r.t, stirred for 1 h. and then diluted with water. The product was extracted with CH2C12 (3x20mL) and the combined organic extracts were washed with brine and dried over anh. Na2SO4. The solids were filtered, the solvent evaporated and the crude product was purified by flash chromatography (silica gel, cHex/EtOAc 7:3) to give the title compound (57.6mg, 0.ll mmol, 85%, e.e.>99%) as a clear oil. NMR ('H, DMSO): δ 8.3-8.14 (m, 2H), 7.95-7.8 (d, 1H), 4.56-4.20 (2H), 3.9-3.4 (m, 3H), 3.25 (s, 3H), 2.11 (s, 3H), 2.2-1.9 (m, 2H). MS (m/z): 504[MH]+. HPLC: Analytical Pre-column/Guard column: Filter Rhodyne Column type: CHIRALPAK AD Column length [cm]: 25 Internal diameter [mm]: 4.6 Particle size [μm]: 3 Injection volume [μl]: 10 Mobile phase: n-hexane/Ethanol/IPA Step 1: Time-Reserv.A-Reserv.B: 75/1.5/23.5 v/v Flow rate [mL/min]: 1.0 Detector type DAD Wavelength [nm]: 225 Intermediate 43: 4.703, r.t. (min) Intermediate 44 3-(2.4-Dichloro-phenyl)-2-hydroxy-6-nitromethyI-cyclohex-l -enecarboxylic acid methyl ester To a solution of intermediate 23 (26mg, 0.087mmol) in an anh. mixture of Et2O/THF (0.SmL/0.lmL) was added nitromethane (0.005mL, 1.1 eq) and Amberlyst A21 (weekly basic resin; 260mg). The solvent was slowly evaporated at r.t without agitation. After 2.5 hr, the dry resin was diluted with Et2O and decanted It was rinsed further with Et2O (7x) and the combined organic fractions were evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc, 9:1) to give the title compound (25mg, 80%) as a clear oil. NMR. ('H, CDC13): δ 12.72 (s, 1H), 7.41 (d, III), 7.24 (dd, III), 7.03 (d, 1H), 4.64 (dd, 1H), 430 (t, 1H), 4.07 (bm, 1H), 3.87 (s, 3H), 3.58 (m, 1H), 2.08 (bm, 1H), 1.85 (bm, 3H). MS (m/z): 359 [MH]+ (2 Cl). Intermediate 45 8-(2.4-Dichloro-phenyI)-2-methyl-5-nitromethy]-5.6.7.8-tetrahydro-quinazolin-4-ol Sodium (21mg, 3.1eq) was added portionwise to anh. MeOH (1.5mL) under N2. After consumption of metallic sodium, acetamidine hydrochloride (96mg, 3.3eq) was added. After 10 min of stirring, the precipitated NaCl was filtered off and washed with anh. MeOH (2mL). The solution of free acetamidine was added to intermediate 44 (106mg, 0.294mmol) and the mixture was stirred at r.t. for 18 hr. The solvent was evaporated and the crude product was purified by flash chromatography (silica gel, EtOAc/cHex 8:2) to give the title compound as a clear oil (8 Img, 75%). MS (m/z): 368 [MH]+ (2 Cl). Intermediate 46 4-Chloro-8-(2,4-dichloro-phenyl)-2-methyl-5-nitromethyl-5,6,7,8-tetrahydro-quinazoline A solution of intermediate 45 (73mg, 0.198mg) in POC13 (2mL) was heated at reflux for 2.5 hr. POCl3 was evaporated and the residue was taken up in CH2C12. The organic phase was washed with cone. NH4OH, the phases were separated and the aqueous layer was extracted with CH2C12 (3x1 0mL). The combined organic extracts were washed with sat.aq. NaCl and dried over anh. Na2SO4. The solids were filtered and the solvent was evaporated. The crude title compound (68mg, 89%) was used as such in the next step. MS(/;;/z):386[MH]+(3Cl). Intermediate 47 4-Chloro-8-(2.4-dichloro-phenyl)-2-methyl-5.6.7.8-tetrahydro-quinazoline-5-carbaldehyde To a stirred solution of intermediate 46 (64mg, 0.166mmol) in anh. MeOH (ImL), at -10°C, under N2, was added methanolic KOH (0.1M, 2.3mL) dropwise. After stirring at -10°C for 15 min, a solution of KMnO4 (18mg, 0.7eq) and MgSO4 (20mg, leq) in H2O (2.5mL) was added dropwise (reaction temperature kept below 0°C). The reaction mixture was stirred at 0°C for 24 hr. It was then filtered on Celite, and the Celite cake washed with CH2C12. The solvent was evaporated and the aqueous phase extracted with CH2C12 (Sxl0mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated. The crude oil obtained was purified by flash chromatography (silica gel, cHex/EtOAC 9:1----> 8:2). The title compound was obtained as a 65:35 mixture of diastereomers (27mg, 46%, clear oil). MS (mlz): 355 [MH]+ (3 Cl). EXAMPLE 1 Synthesis of representative compounds of structure (1-1) 5-(2.4-Dichlorophenyl)-l -(l-ethyl-propyl)-7-methyl-1 .2,2a,3.4.5-hexahydro-l .5.6.8-tetraaza-acenaphthylene (l-l-l) A solution of intermediate 19 (14mg) in pure 3-pentylamine (60μ1) was stirred at 120°C for 8 hr. The reaction mixture was then diluted with water and extracted with Et2O (3xl0mL). The combined organic extracts were washed once with water, once with brine and dried over anh. Na2SO4. The solids were filtered, the solvent evaporated and the crude pale yellow oil was purified by flash chromatography (silica gel, cHex/EtOAc 8:2) to give the title compound as a pale yellow oil (5.9mg). 5-(2,4-Dichlorophenyn-l-(2-ethyl-buryl)-7-methyl-l,2,2a.3,4.5,5a 8b-octahydro-1,5,6,8-tetraaza-acenaphthylene (1-1-2) A solution of intermediate 19 (l0.0mg) in pure 2-ethyl-n-butylamine (l00μl) was stirred in a sealed vial at 120°C for 7 hr. The reaction mixture was then cooled down to r.t. and directly purified by flash chromatography (silica gel, Toluene/EtOAc 95:5) to give the title compound as pale yellow oil (1.9mg). 5-(2.4-Dichlorophenyl)-l-(2-methoxy-l-methoxymethyl-ethyl)-7-methyl-1.2.2a.3,4.5.5a.8b-octahydro-1.5.6.8-tetraaza-acenaphthylene (1-1-3) A solution of intermediate 19 (16.5mg) in pure 2-methoxy-l-(methoxymethyl)ethylamine (52.6mg) was stirred at 150°C (screw cap vial) for 4 hr. The reaction mixture was then cooled down to r.t. and directly purified by flash chromatography (silica gel, Toluene/EtOAc 6:4) to obtain the title compound as a pale yellow oil (4.2mg). 7-Methyl-l-(l-propylbutyl)-5-(2,4-bis-trifluoromethyl-phenyl)-1,2,2a.3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene (1-1-4) Intermediate 35 (135mg, 0.27mmol) and 4-aminoheptane (0.5mL, 12eq) were heated at 130°C (screw cap vial) for 3 hr. The reaction mixture was then cooled down to r.t. and diluted with CH2C12. The solvent was evaporated and the crude product was purified by flash chromatography (sililca gel, cHex/EtOAc 9:1) to give the title compound (29.4mg, 0.06mmol, 23%) as a yellow solid. Enantiomeric Resolution First enantiomer 7-Methyl-l-(l-propylbutyl)-5-(2,4-bis-trifluoromethyl-phenyl)-1.2.2a(S).3.4.5-hexahydro- 1.5.6.8-tetraaza-acenaphthylene Intermediate 41 (60mg, 0.119mmol) and 4-aminoheptane (178μl, l0eq) were heated at 130°C (screw cap vial) for 3 h. The reaction mixture was diluted with CH2C12 and the solvent was evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to give the title compound (19.4mg, 0.04mmol, 33%, e.e. = 95%) as a clear oil. HPLC: Analytical Column type: CHIRALPAK OD Column length [cm]: 25 Internal diameter [mm]: 4.6 Column temperature [C]: 35 injection volume [μl]: 10 Mobile phase: Co2/EtOH (0.15% Ipa) 85/15 Flow rate [mL/min]: 2.5 Detector type: UV Wavelength [nm]: 225 Column pressure [bar]: 150 Title compound: 2.55, r.t. (min) 'H-NMR and MS data are.the same as reported in the following Table 1 for compound 1-1-4 Second enantiomer 7-Methyl-1 -(1-propylbutyl)-5-(2.4-bis-trifluoromethyl-phenyl)-1.2.2a(R)3.4.5-hexahydro- 1.5.6.8-tetraaza-acenaphthylene Intermediate 43 (55mg, 0.l09mmol) and 4-aminoheptane (163μl, l0eq) were heated at 130°C (screw cap vial) for 3 h. The reaction mixture was diluted with CH2C12 and the solvent was evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to give the title compound (25.7mg, 0.053mmol, 49%, e.e.>99%) as a clear oil. HPLC: Analitical Column type: . CH1RALPAK OD Column length [cm]: 25 Internal diameter [mm]: 4.6 Column temperature [C]: 35 Injection volume [μl]: 10 Mobile phase: CO2/EtOH (0.15% Ipa) 85/15 Flow rate [mL/min]: 2.5 Detector type: UV Wavelength [nm]: 225 Column pressure [bar]: 150 Title compound: 2.12, r.t. (min) 'H-NMR and MS data are the same as reported in the following Table 1 for compound 1-1-4 5-(2.4-Dichlorophenyl)-7-methyl-l-(1-propylbutyl)-1,2.2a.3.4.5-hexahydro-1.5.6,8-tetraaza-acenaphthylene (1-1-5) A solution intermediate 19 (20mg, 0.046mmol) in 4-aminoheptane (l00μL) was heated at 130°C (screw cap vial) for 18 hr. The amine was evaporated and the residue was directly purified by flash chromatography (silica gel, toluene/EtOAc, 9:1 —» 8:2) to give the title compound as a clear oil (7mg, 0.017mmol, 36%). Enanriomeric resolution First enantiomer 5-(2.4-DichlorophenyI)-7-methyl-l-(1-propylbuty)-1.2,2a-(S).3.4.5.5a.8b-octahydro-1.5.6.8- tetraaza-acenaphthylene Intermediate 47 (120mg, 0.276mmol) and 4-aminoheptane (0.412mL, 10eq) was stirred at 130°C (screw cap vial) for 18 hr. Then it was diluted with CH2C12 (5mL) and the solvent was evaporated. The resulting crude product was purified by flash chromatography (silica gel, cHex/EtOAc 9.5:0.5) to afford the title compound (62mg, 53%, ee%>99%) as a clear oil. HPLC: Analytical: Pre-column/Guard column: Rheodyne filter Column type: CHIRALPAK AD Column lenght (cm): 25 Internal diameter (mm): 4.6 Particle size (μm): 5 Column temperature (°C): r.t. Autosampler temperature: (°C): r.t. Injection volume (μL): 20 Mobile phase: n-Hexane/tert-butanol 90/10 a/a Flow rate (mL/min): 1 Detector type: DAD Wavelenght (nm):. 220-350 Title compound: 10.2rt(min) 'H-NMR and MS data are the same as reported in the following Table 1 for compound 1-1-5. Second enantiomer 5-(2.4-Dichlorophenyl)-7-methyl-l-(l-propylbutyl)-1.2.2a-(R),3,4.5.5a.8b-octahydro-I.5.6.8- tetraaza-acenaphthylene Intermediate 49 (130mg, 0.298mmol) and 4-aminoheptane (0.342mL, l0eq) were stirred at 130°C (screw cap vial) for 18 hr. Then it was diluted with CH2C12 (5mL) and the solvent was evaporated. The resulting crude product was purified by flash chromatography (silica gel, cHex/EtOAc 9.5:0.5) to afford the title compound (74mg, 59%, ee%=90%) as a clear oil. HPLC: Analytical: Pre-column/Guard column: Rheodyne filter Column type: CHIRALPAK AD Column lenght (cm): 25 Internal diameter (mm): 4.6 Particle size (μm): 5 Column temperature (°C): r.t. Autosampler temperature: (°C): r.t Injection volume (μL): 20 Mobile phase: n-Hexane/tert-butanol 90/10 a/a Flow rate (mL/min): 1 Detector type: DAD Wavelenght (nm): 220-350 Title compound: 7.5, rt (min), 90%. !H-NMR and MS data are the same as reported in the following Table 1 for compound 1-1-5. All the analytical data are set forth in the following Table 1. Table 1 (Table Removed) EXAMPLE 2 Synthesis of representative compounds of structure (1-2) 9-(2.4-Dichloropheriyl)-4-(1-ethylpropyl)-2-methyl-5.6.6a.7.8.9-hexahydro-4H-1.3.4-triazaphenalene (isomer 1) and 9-(2.4-Dichlorophenyl)-4-(l-ethylpropyl)-2-methyl-5.6.6a.7.8.9-hexahydro-4H-1.3.4-triazaphenalene (isomer 2) (2-1-1) Intermediate 25 (isomer 11 was dissolved in anh. CH2C12 (6mL) and treated with O3 (5g/hr) at -78°C for 20 min. Dimethylsulflde (ImL) was added and the mixture was allowed to warm to r.t. and stirred overnight. Then the reaction mixture was dried over Na2SO4, the solids were filtered and the solvent evaporated. The crude aldehyde (106mg) was obtained as a 1:1 mixture of two diastereoisomers and used without further purification. To a solution of the aldehyde prepared above (30mg) in anh. MeOH (ImL), 1-ethyl-propylamine (0.0l0mL) was added and the reaction mixture was stirred at r.t. for 3 hr. A 1M solution of NaBH3CN in THF (0.162mL) was then added and the mixture was stirred at r.t. for 65 hr. Another aliquot of 1M NaBH3CN in THF (0.080mL) was added and the reaction was stirred at r.t: for 3 hr. The solvent was evaporated and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (4x10mL) and the combined organic extracts were washed with brine (2x1 OmL), dried over anh. Na2SO4.The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, CH2Cl2/EtOAc 7:3) to give the title compound (16mg) as a mixture of two diastereoisomers. The two diastereoisomers were separated by preparative TLC (1% NH4OH in toluene/EtOAc 95:5) to give isomer 1 (5.4mg) and isomer 2 (5.6mg) as yellow oils. All the analytical data are set forth in the following Table 2. Table 2 (Table Removed) EXAMPLES Synthesis of representative compounds of structure (1-3) 5-Cyclopropylmethyl-l -(2.4-dichlorophenyl)-7-methyl-l ,2.2a.3 4,5-hexahydro-l .5.6.8-tetraaza-acenaphthylene (3-1-1) To a solution of intermediate 10 (20mg) in anh. CH3OH (ImL) was added (aminomethyl)cyclopropane (5μl, leq).The reaction was stirred at r.t. for 90 min and then NaBH3CN l.0M/THF (113μl) was added. The mixture was stirred for an additional 18 hr at r.t. and quenched with H2O (l0mL). The product was extracted with EtOAc (2x15mL), the combined extracts were dried over anh. Na2SO4, filtered and concentrated to dryness in vacua. Flash chromatography of the crude product (silica gel, cHex/EtOAc 9:1) gave the title compound (5mg) as a colourless oil. l-(2.4-Dichlorophenyl)-5-(2-methoxyethyl)-7-methyl-1.2.2a.3.4.5-hexahydro-1.5.6.8-tetraaza-acenaphthylene (3-1-2) To a solution of intermediate 10 (16mg) in anh. THF (ImL) was added 2-methoxy-ethylamine (4μ1). The reaction was stirred at r.t. for 90 min and then NaBH3CN l.0M/THF (90μl) was added. The mixture was stirred for an additional 18 hr at r.t. and quenched with H2O (l0mL). The product was extracted with EtOAc (2x15mL). The combined extracts were dried over anh. Na2SO4, filtered and concentrated to dryness in vacuo. The crude product was dissolved in anh. THF (2mL) and TEA (30μl) was added. The reaction mixture was heated to reflux for 10 hr and quenched with H2O. The product was extracted with EtOAc (2xl0mL). The combined extracts were dried over anh. Na2SO4, filtered and concentrated to dryness in vacuo. 2mg (12%) of the title compound were obtained as a light beige oil after prep-TLC purification (eluted 3 times: 1: cHex 100%, 2: cHex/EtOAc 75:25, 3: cHex/EtOAc 50:50). l-(2.4-Dichloropheny)-5-(l-ethylpropyl)-7-methyl-1.2.2a.3.4.5-hexahydro-1.5.6.8-tetraaza-acenaphthylene (3-1-3) To a solution of intermediate 10 (20mg) in anh. THF (ImL) was added 1-ethyl-propylamine (6.5μl). The reaction mixture was stirred at r.t. for 90 min and then NaBH3CN l.0M/THF (112μl) was added. The mixture was stirred for an additional 18 hr at r.t. and quenched with water (l0mL). The product was extracted with EtOAc (2xl0mL). The combined extracts were dried over anh. Na2SO4 filtered and concentrated to dryness in vacuo. The crude product was dissolved in anh. toluene (2mL) and heated to reflux for 18 hr. The reaction mixture was diluted with H2O (l0mL) and extracted with EtOAc (3x10mL). The combined organic extracts were dried over anh. Na2SO4, filtered and concentrated to dryness in vacuo to give the title compound (1.6mg, 7%).) as a colourless oil after prep-TLC purification (cHex/EtOAc 75:25). 1-(2.4-Dichlorophenyl)-5-(2-ethylbutyl)-7-methyl-1.2.2a,3.4.5-hexahydro-1.5.6.8-tetraaza-acenaphthylene (3-1-4) To a solution of intermediate 10 (35.5mg) in anh. MeOH (2mL) was added 2-ethylbutylamine (0.014mL) at r.t., under N2. The reaction mixture was stirred at r.t. for 90 min. NaBH3CN (1 N solution in THF, 0.2mL) was then added at r.t. and the reaction mixture was heated to 70°C for 3 hr. It was then allowed to cool to r.t and H2O (5mL) was added. The organic solvent was evaporated under reduced pressure and the aqueous suspension was extracted with EtOAc (3x5mL). The combined organic layers were washed with sat. aq. NaCl (5mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex 100%----> cHex/EtOAc 95:5) to yield the title compound as a yellow solid (0.0l8g). l-(2.4-Dichlorophenyl)-7-methyl-5-(l-propylbutyl)-1,2.2a,3,4,5-hexahydro-1.5,6,8-tetraaza-acenaphthvlene (3-1-5) A solution intermediate 30 (20mg, 0.046mmol) in 4-aminoheptane (l00μL) was heated at 130°C (screw cap vial) for 6.5 hr, and then at r.t. for 18 hr. The amine was evaporated and the residue was directly purified by flash chromatography (silica gel, cHex/EtOAc, 9:1) to give the title compound as a clear oil (9mg, 0.021mmol, 47%). 7-Methyl-5-(l-propylbutyl)-l-(2.4-bis-trifluoromethyl-phenyl)-l,2.2a,3,4.5-hexahydro-1.5,6,8-tetraazaacenaphthylene (3-1-6) Intermediate 37 (230mg, 0.457mmol) and 4-aminoheptane (0.68mL, l0eq) were heated at 130°C (screw cap vial) for 14 hr. The reaction mixture was diluted with CH2C12 and the solvent were evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 95:5) to give the title compound (54mg, 0.1 Immol, 24%) as a white solid. 5-Cyclopropylmethyl-l-(2,4-dichlorophenyl)-7-methyl-4-propyl-1.2,2a.3.4.5-hexahydro-1.5.6,8-tetraazaacenaphthylene (3-1-7) To a suspension of CuBr-Me2S (48mg, 5eq) in anh. Et2O (0.8mL) at -50°C, under N2, was added PrMgBr 1M/THF (0.188mL, 4eq) dropwise under vigorous stirring. The dark yellow mixture was stirred for 45 min at -50°C and was then cooled to -78°C. BF3-Et20 (0.024mL, 4eq) was added and the reaction mixture was stirred for 20 min at -78°C. A solution of intermediate 28 (19mg, 0.047mmol) in anh. THF (0.5mL) was added and the reaction temperature was allowed to rise to r.t. over 3 hr. After a total reaction time of 4 hr, a 1:1 mixture of cone. NR4OH and sataq. NR4C1 (2mL) was added and the mixture was stirred for 15 min. Water and EtOAc were added, the phases were separated and the aqueous layer was extracted with EtOAc (3x10mL). The combined organic extracts were washed with water and dried over anh, Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 9:1). The title compound was obtained as a light yellow oil (3mg, 0.007mmol, 15%). 4-Butyl-5-cyclopropylmethyI-l-(2.4-dichlorophenyl)-7-methyl-1.2,2a.3.4.5-hexahydro-l.5.b.S-tetraazaaeenaphthvlene (5-1-8) To a suspension of CuBrMe2S (72mg, 4.3eq) in anh. Et2O (ImL) at -50°C, under N2, was added dropwise n-BuLi 1.6M/hexanes (021mL, 4.15eq) under vigorous stirring. The dark brown mixture was stirred for 40 min at -50°C, was then cooled at -78°C and BF3-Et2O (0.043mL, 4.]5eq) was added. After stirring for 15 minutes at —78°C, a solution of intermediate 28 (33mg, 0.08lmmol) in anh. THF (0.5mL) was added and the reaction temperature was allowed to rise to r.t. over 3 hr. After a total reaction time of 3.5 hr, a 1:1 mixture of cone. NH4OH and a sat.aq. NE4Cl (ImL) was added and the mixture was stirred for 15 min. Water and EtOAc were then added, the phases were separated and the aqueous layer was extracted with EtOAc (3xl0mL). The combined organic extracts were washed with water and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 9:1). The title compound (isomer 1: syn) was obtained as a pale yellow oil (16mg, 0.037mmol, 46%). A small percentage of the anti isomer 2 was also isolated. 5-Cyclopropylmethyl-l-(2,4-dichIorophenyl)-7-methyl-4-propoxy-l,2,2a.3.4,5-hexahydro-1,5,6,8-tetraazaacenaphthylene (3-1-9) To a suspension of CuBr-SMe2 (27mg, 2eq) in anh. Et2O (0.2mL), at -60°C, under N2, was added a solution of propyl magnesium bromide (0.2mL, 2eq: prepared by the addition of Mg (27mg, l.lmmol) and propyl bromide in anh. Et2O (1.5mL), at r.t., under N2, for 1 hr). The yellow heterogeneous reaction mixture was diluted with an additional 0.2mL of anh. Et2O and stirred at -60°C for 30 min. It was then cooled down to -78°C and BF3-Et2O (17 μL, 2eq) was added. After 10 min at -78°C, a solution of intermediate 28 (27mg, 0.067mmol) in anh. THF (0.4mL) was added and the reaction mixture was slowly warmed to r.t. (4 hr). It was then diluted with a 1:1 mixture of cone. NH4OH/sat.aq. NH4Cl and stirred at r.t. for 10 min. The aqueous phase was then extracted with CH2C12 (4x20mL) and the combined organic extracts were washed with H2O (2x20mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude compound was purified by flash chromatography (silica gel, 9:1 ----> 7:3 cHex/EtOAc). The title compound was obtained as a clear oil (4mg, 0.009mmol, 14%) 4.5-Dibutyl-l-(2,4-dichlorophenvl)-7-methyl-1.2.2a.3.4,5-hexahydro-1.5.6.8-tetraazaacena-phthylene (3-1-101 To a suspension of CuBrMezS (65mg, 4.3eq) in anh. Et2O (ImL) cooled to—50°C, under N2, a 1.6 M solution of BuLi (0.184mL, 0.295mmol, 4eq) was added dropwise under vigorous stirring. The dark brown,mixture was stirred for 40 min between -50°C and —40°C, then it was cooled to -78°C and BF3-Et2O (0.037mL, 4eq) was added. After stirring for 15 min at -78°C, intermediate 28 was added (30mg, 0.074mmol) dissolved in anh. THF (O.5mL) and the reaction temperature was allowed to rise to r.t over 3 hr. After a total reaction time of 3.5 hr, a 1:1 mixture of NH2,OH and a saturated solution of NH4Cl (ImL) was added and the mixture was stirred for 15 min. Then water and EtOAc were added, the phases were separated and the aqueous layer was extracted with EtOAc (3x10mL). The combined organic extracts were washed with water and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated The crude product (28mg) was purified by flash chromatography (cHex/EtOAc 9:1). The title compound (12mg, 0.028mmol, 37%) was obtained as a colourless oil. All the analytical data are set forth in the following Table 3. Table 3 (Table Removed) EXAMPLE 4 Synthesis of representative compounds of structure 5-(2,4-Dichlorophenyn-l-(1-ethylpropyl)-7-methyl-l,2,2a3,4,5-hexahydro-1,6,8-triaza-acenaphthylene (4-1-1) To a solution of intermediate 47 (22mg, 0.062mmol) in anh. MeOH (ImL), under N2, at r.t., was added 1-ethyl propylamine (9μL, 1.25eq) and the reaction mixture was stirred at r.t. for 1.25 hr. NaBH3CN l.0M/THF (0.15mL, 2.4eq) was then added and the reaction mixture was stirred at r.t. for 2 hr, then at -18°C for 4 days. The solvent was evaporated and the residue partitioned between EtOAc/H2O. The phases were separated and the aqueous layer was extracted with EtOAc (3x5mL). The combined organic extracts were washed with sat.aq. NaCl (lx5mL) and dried over anh. Na2SO4. The solids were filtered and.the solvent evaporated The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 9:1 ---> 8:2). The title compound was obtained as a clear oil (3mg, 0.008mmol, 12%). All the analytical data are set forth in the following Table 4. Table 4 (Table Removed) EXAMPLE 5 CRF Binding Activity CRF binding affinity has been determined in vitro by the compounds' ability to displace I25I-oCRF and I25I-Sauvagine for CRF1 and CRF2 SPA, respectively, from recombinant human CRF receptors expressed in Chinese Hamster Ovary (CHO) cell membranes. For membrane preparation, CHO cells from confluent T-flasks were collected in SPA buffer (HEPES/KOH 50mM, EDTA 2mM; MgCl2 l0mM, pH 7.4.) in 50mL centrifuge tubes, homogenized with a Polytron and centrifuged (50'000g for 5min at 4°C: Beckman centrifuge with JA20 rotor). The pellet was resuspended, homogenized and centrifuged as before. The SPA experiment has been carried out in Optiplate by the addition of 100 μL the reagent mixture to l μL of compound dilution (100% DMSO solution) per well. The assay mixture was prepared by mixing SPA buffer, WGA SPA beads (2.5mg/mL), BSA (Img/mL) and membranes (50 and 5 μg of protein/mL for CRF1 and CRF2 respectively) and 50 pM of radioligand. The plate was incubated overnight (>18 hr) at room temperature and read with the Packard Topcount with a WGA-SPA I25I counting protocol. EXAMPLE 6 CRF functional assay Compounds of the invention were characterised in a functional assay for the determination of their inhibitory effect. Human CRF-CHO cells were stimulated with CKF and the receptor activation was evaluated by measuring the accumulation of cAMP. CHO cells from a confluent T-flask were resuspended with culture medium without G418 and dispensed in a 96-well plate, 25'000c/well, 100 μL/well and incubated overnight. After the incubation the medium was replaced with 100 uL of cAMP IBMX buffer warmed at 37°C (5mM KC1, 5mM NaHCO3, 154mM NaCl, 5mM HEPES, 2.3mM CaCl2, ImM MgCl2; Ig/L glucose, pH 7.4 additioned by Img/mL BSA and ImM IBMX) and lμL of antagonist dilution in neat DMSO. After 10 additional minutes of incubation at 37°C in a plate incubator without CO2, lμL of agonist dilution in neat DMSO was added. As before, the plate was incubated for 10 minutes and then cAMP cellular content was measured by using the Amersham RPA 538 kit All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above. The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims: claim: 1. A method of forming a pot for an array of hollow fibre membranes comprising the steps of: -placing the ends of said fibre membranes in a mould; -forming a first layer of curable resin material in a non-cured state around said fibre membrane ends, - applying a second layer of polyurethane resin material to said first layer prior to full curing of said first layer, said second layer of polyurethane resin material being chemically reactive with said first layer material to form an adhesive bond therebetween; -at least partially curing both layers and removing the pot formed from said mould, wherein said second layer material is of higher flexibility than said first layer material when each layer is fully cured. 2. A method as claimed in claim 1, wherein the curable resin material is an epoxy resin. 3. A method as claimed in any one of claims 1 to 2, comprising producing the second layer of higher flexibility by adding one or more flexibilising agents to the components of the material forming the first layer of lower flexibility. 4. A method as claimed in any one of claims 1 to 3, comprising the step of the monitoring the curing process of the first layer to determine the optimal time in which to apply the second layer thereto. 5. A method as claimed claim 4, wherein the step of monitoring comprises monitoring the temperature changes within said first layer to determine the state of the curing process. 6. A method as claimed anyone of the preceding claims, comprising the step of providing a potting sleeve(23) within said mould to receive the first and second layers of material, said potting sleeve having adhesion means to assist adhesion of said materials thereto. 7. A method as claimed in claim 6, wherein said adhesion means comprises roughening the surface of the sleeve in contact with said materials. 8. A method as claimed in claim 7, wherein said adhesion means comprises one or more protrusions and/or indentations formed on the surface of the sleeve in contact with said materials. 9. An apparatus for potting hollow fibre membranes comprising: - a mould (5) for receiving the ends (6) of said hollow fibre membranes(7); -means (11) for forming a first layer of curable resin material in a non-cured -state around said fibre membrane ends in said mould, -means (15) for applying a second layer of a polyurethane resin material to said first layer prior to full curing of said first layer, said second layer polyurethane resin material being chemically reactive with said first layer material to form an adhesive bond therebetween and said second layer polyurethane resin material being of higher flexibility than said first layer material when each layer is fully cured. 10. Apparatus as claimed in claim 9, wherein the mould comprises separate means for flowing said first and second layer materials into the mould. 11. Apparatus as claimed in claim 9 or 10, wherein said materials are fed into a centrifuge before being flowed along a conduit or tube into the mould. 12. Apparatus as claimed in claim 11, wherein said centrifuge has separate sections to receive the respective first and second layer materials. 13. Apparatus as claimed in claim 11, wherein the adhesion means comprises roughening the surface of the sleeve in contact with said materials. 14. Apparatus as claimed in claim 13, wherein the adhesion means comprises one or more protrusions and/or indentations (25) formed on the surface of the sleeve in contact with said materials. 15. A method of forming a pot for an array of hollow fibre membranes substantially as hereinbefore described with reference to any one of the embodiments of the invention illustrated in the accompanying drawings. 16. Apparatus for potting hollow fibre membranes substantially as hereinbefore described with reference to any one of the embodiments of the invention illustrated in the accompanying drawings.

Documents:

1490-DELNP-2003-Abstract-(03-12-2008).pdf

1490-DELNP-2003-Abstract-(14-11-2008).pdf

1490-delnp-2003-abstract-(18-12-2008).pdf

1490-delnp-2003-abstract.pdf

1490-delnp-2003-assignment.pdf

1490-DELNP-2003-Claims-(03-12-2008).pdf

1490-DELNP-2003-Claims-(14-11-2008).pdf

1490-delnp-2003-claims-(18-12-2008).pdf

1490-delnp-2003-claims.pdf

1490-DELNP-2003-Correspondence Others-(16-02-2012).pdf

1490-DELNP-2003-Correspondence-Others-(03-12-2008).pdf

1490-DELNP-2003-Correspondence-Others-(09-01-2009).pdf

1490-DELNP-2003-Correspondence-Others-(10-04-2008).pdf

1490-DELNP-2003-Correspondence-Others-(14-11-2008).pdf

1490-delnp-2003-correspondence-others-(18-12-2008).pdf

1490-delnp-2003-correspondence-others.pdf

1490-DELNP-2003-Description (Complete)-(03-12-2008).pdf

1490-delnp-2003-description (complete)-(18-12-2008).pdf

1490-delnp-2003-description (complete).pdf

1490-DELNP-2003-Drawings-(09-01-2009).pdf

1490-delnp-2003-drawings-(18-12-2008).pdf

1490-delnp-2003-drawings.pdf

1490-DELNP-2003-Form-1-(03-12-2008).pdf

1490-DELNP-2003-Form-1-(14-11-2008).pdf

1490-delnp-2003-form-1-(18-12-2008).pdf

1490-delnp-2003-form-1.pdf

1490-DELNP-2003-Form-16-(16-02-2012)-1.pdf

1490-DELNP-2003-Form-16-(16-02-2012).pdf

1490-delnp-2003-form-18.pdf

1490-DELNP-2003-Form-2-(03-12-2008).pdf

1490-DELNP-2003-Form-2-(14-11-2008).pdf

1490-delnp-2003-form-2-(18-12-2008).pdf

1490-delnp-2003-form-2.pdf

1490-DELNP-2003-Form-3-(03-12-2008).pdf

1490-DELNP-2003-Form-3-(10-04-2008).pdf

1490-delnp-2003-form-3.pdf

1490-DELNP-2003-Form-5-(03-12-2008).pdf

1490-delnp-2003-form-5-(18-12-2008).pdf

1490-delnp-2003-form-5.pdf

1490-DELNP-2003-GPA-(10-04-2008).pdf

1490-DELNP-2003-GPA-(16-02-2012).pdf

1490-delnp-2003-gpa.pdf

1490-delnp-2003-pct-101.pdf

1490-delnp-2003-pct-409.pdf

1490-DELNP-2003-Petition-137-(03-12-2008).pdf

1490-delnp-2003-petition-138.pdf

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