BACKGROUND OF THE INVENTION Solid-phase synthetic techniques, in which a reagent is immobilized on a polymeric material which is inert to the reagents and reaction conditions employed, as well as being insoluble in the media used, are important synthetic tools. A polymeric reagent has the advantage of ease of separation from low molecular weight reactants or products by filtration or selective precipitation. The polymeric reagent can also be used in excess to effect fast and quantitative reactions such as in the case of acylations, or a large excess of reactants may be used to drive the equilibrium of the reaction towards product formation to provide essentially quantitative conversion to product, as seen in solid phase peptide synthesis. A further advantage of supported reagents and catalysts is the fact that they are recyclable and that they lend easily to automated processes. In addition, supported analogs of toxic and odorous reagents are safer to use.

Substituted 1, 5-benzodiazepine-2-one and 1, 5-benzothiazepine-2-one are present in numerous pharmacologically active compounds including for example interleukin-1 (3 converting enzyme Inhibitors, (See International Application WO 9722619 and International Application WO 953508); treatment of arrhythmia, (See International Application WO 9640656); cholecystokinin receptor antagonists, (See International Application WO 9401421-Al) ; angiotensin II antagonists, (See International Application WO 9413651-A1). Thus, the development of new synthetic methodology for preparing substituted 1,5- benzodiazepine-2-one and 1, 5-benzothiazepine-2-one, particularly solid phase synthetic techniques which are especially useful for synthesis of large numbers of compounds through automated parallel synthesis or combinatorial library generation, is central to the rapid discovery of new therapeutic agents containing this functionality.

The solid phase synthesis of substituted 1, 5-benzodiazepine-2-one is described in Lee et al. , J. Org.

Chem. 1999,64, 3060, Schwartz et al. , J. Org. Chem. 1999,64, 2219; using 4-fluoro-3-nitrobenzoic acid as starting material and a carboxamide at position 7 as a point of attachment to the resin.

SUMMARY OF THE INVENTION The present invention involves the synthesis of 3-amino-1, 5-benzodiazepine-2-one derivatives in solution, attachment to a resin through the 1-amide nitrogen, and cleavage from the resin.

In its principle aspect, this invention is directed to a method of synthesizing substituted 1,5- benzodiazepine-2-one and 1, 5-benzothiazepine-2-one compounds of formula

wherein X is NHR4 or S or SO or SO2 R4 is hydrogen, aliphatic, aromatic,-C (O)-R", S02-R'4, C (O)-N-R15 or C (O)-O-R'6 ; Rl3, R'4, R'5, R'6are independently aliphatic or aromatic; R'is aliphatic or aromatic; R2 is aliphatic or aromatic R3 is NR5R6, R5 is H, aliphatic or aromatic; R6 is-C (O)-R', SO2-R8 or C (O)-N-R9 or C (O)-O-R'° ; and R', R8, R9, R'° are independently aliphatic or aromatic.

A method for preparing such a compound comprises: (1) preparing a resin-bound protected 1,5-benzodiazepine-2-one compound of formula

wherein is a solid support; L is absent or a linking group; R'2 is an aldehyde; and P'is a base-labile nitrogen protecting group or a metal-labile nitrogen protecting group or a nucleophilic labile protecting group, Rs is alkyl or aryl;

R'is alkyl or aryl ; (2) introducing R4 (3) removing P' (4) introducing R5 and R6 (5) isolating the substituted 1, 5-benzodiazepine-2-one derivative of the following formula:

In another aspect, this invention comprises: (1) Reacting resin bound cysteine derivatives with o-halo-nitrobenzene derivatives to produce compounds of the general formula:

wherein is a solid support; L is a linking group Reducing the nitro-group to amine derivative; (3) and then reacting the carboxylic acid group with the amine derivative to form the benzothiazepine skeleton; (4) optionally oxidizing the sulfide to the sulfone ; (5) reducing R2 ; (6) cleaving the substituted 1, 5-benzothiazepine-2-one derivative from the resin; and (7) introducing R6.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

"Diazacycloalkyl"means a non-aromatic monocyclic ring wherein the ring contains 2 nitrogen atoms and from about 3 to about 6 carbon ring atoms. The diazacycloalkyl is optionally substituted with

one or more"ring system substituents"which may be the same or different, and are as defined herein.

Representative diazacycloakyl include imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, and the like.

"Diazacycloakylcarboxamide"means a diazacycloalkyl as defined herein in which one of the ring carbon atoms is substituted with a carboxamide group or a carboxylic acid or a carboxylic ester, i. e. a group of formula-C (O)-ZH wherein Z is O or NR'and R'is H, aliphatic or aromatic.

"Solid support"means a substrate which is inert to the reagents and reaction conditions described herein, as well as being substantially insoluble in the media used. Representative solid supports include inorganic substrates such as kieselguhr, silica gel, and controlled pore glass; organic polymers including polystyrene, including 1-2% copolystyrene divinyl benzene (gel form) and 20-40% copolystyrene divinyl benzene (macro porous form), polypropylene, polyethylene glycol, polyacrylamide, cellulose, and the like; and composite inorganic/polymeric compositions such as polyacrylamide supported within a matrix of kieselguhr particles. See J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd. Ed. , Pierce Chemical Co. (Chicago, IL, 1984).

In addition, "solid support"includes a solid support as described above which is affixed to a second inert support such as the pins described in Technical Manual, MultipinTM SPOC, Chiron Technologies (1995) and references therein which comprise a detachable polyethylene-or polyproylene- based head grafted with an amino functionalized methacrylate copolymer and an inert stem.

In addition, "solid support"includes polymeric supports such as the polyethylene glycol supports described by Janda et al., Proc. Natl. Acad. Sci. USA, 92,6419-6423 (1995) and S. Brenner, WO 95/16918, which are soluble in many solvents but can be precipitated by the addition of a precipitating solvent.

"Linking group"and"linker"mean a group through which a functional group such as an alcohol, a carboxylic acid, an amine or an amide may be covalently linked to the solid support. The linking group is generally inert to the reagents and reaction conditions described herein. The linking group under chemical reatment can release the functional group from the resin at the end of the synthesis.

"Nitrogen protecting group"means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable.

The use of N-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, CF, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), incorporated herein by reference. Representative nitrogen protecting groups include formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl,

4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl, methoxycarbonyl, 2,2, 2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1, 1-dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), p-nitrophenylsulfinyl, p-nitrobenzyloxycarbonyl, 2, 4-dichlorobenzyloxycarbonyl, allyloxycarbonyl (Alloc), 1-isopropylallyloxycarbonyl, cinnamyloxycarbonyl and 4-nitrocinnamyloxycarbonyl, 9-fluorenylmethoxycarbonyl (fmoc), 9- (2-sulfo) fluorenylmethoxycarbonyl, 9- (2, 2-dibromo) -fluorenylmethoxycarbonyl and the like.

"Base-labile nitrogen protecting group"means a nitrogen protecting group as defined herein which is readily removed by treatment with an amine base. Representative base-labile nitrogen protecting groups include 9-fluorenylmethoxycarbonyl (fmoc), 9- (2-sulfo) fluorenylmethoxycarbonyl, 9- (2, 2-dibromo) -fluorenylmethoxycarbonyl and the like.

"Metal-labile nitrogen protecting group"means a nitrogen protecting group as defined herein which is readily removed by treatment with Pd (0). Representative Metal-labile nitrogen protecting groups include allyloxycarbonyl (Alloc), 1-isopropylallyloxycarbonyl, cinnamyloxycarbonyl, 4- nitrocinnamyloxycarbonyl, and the like.

"Symmetrical diamine"means a molecule with two identical amino termini. Examples of symmetrical diamines include piperazine, 4-amino-aniline, and 4-aminomethyl-benzylamine.

"Aliphatic"means a radical derived from a non aromatic C-H bond by removal of the hydrogen atom. The aliphatic radical may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkyloxyalkyl, aralkyloxycarbonylalkyl, aralkyl, aralkynyl, aralkyloxyalkenyl, heteroaralkenyl, heteroaralkyl, heteroaralkyloxyalkenyl, heteroaralkyloxyalkyl, heteroaralkynyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, and the like. "Aliphatic", as used herein, also encompasses the residual, non-carboxyl portion of natural and unnatural amino acids as defined herein.

"Aromatic"means a radical derived from an aromatic C-H bond by removal of the hydrogen atom. Aromatic includes both aryl and heteroaryl rings as defined herein. The aryl or heteroaryl ring may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aromatic groups include aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, and the like.

"Acyl"means an H-CO-or alkyl-CO-group wherein the alkyl group is as herein described.

Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2- methylpropanoyl, butanoyl and palmitoyl.

"Acylamino"is an acyl-NH-group wherein acyl is as defined herein.

"Alkenoyl"means an alkenyl-CO-group wherein alkenyl is as defined herein.

"Alkenyl"means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbon-carbon double bond. Preferred alkenyl groups have 2 to about 12 carbon atoms; more preferred alkenyl groups have 2 to about 4 carbon atoms. The alkenyl group is optionally substituted with one or more alkyl group substituents as defined herein. Representative alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

"Alkenyloxy"means an alkenyl-O-group wherein the alkenyl group is as herein described.

Representative alkenyloxy groups include allyloxy or 3-butenyloxy.

"Alkoxy"means an alkyl-O-group wherein the alkyl group is as defined herein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy, and the like.

"Alkoxyalkyl"means an alkyl-O-alkylene-group wherein alkyl and alkylene are as defined herein. Representative alkoxyalkyl groups include methoxyethyl, ethoxymethyl, n-butoxymethyl and cyclopentylmethyloxyethyl.

"Alkoxyalkoxy"means an alkyl-O-alkylenyl-O-group. Representative alkoxyalkoxy include methoxymethoxy, methoxyethoxy, ethoxyethoxy, and the like.

"Alkoxycarbonyl"means an ester group; i. e. an alkyl-O-CO-group wherein alkyl is as defined herein. Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t- butyloxycarbonyl, and the like.

"Alkoxycarbonylalkyl"means an alkyl-O-CO-alkylene-group wherein alkyl and alkylene are as defined herein. Representative alkoxycarbonylalkyl include methoxycarbonylmethyl, and ethoxycarbonylmethyl, methoxycarbonyl ethyl, and the like.

"Alkyl"means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl"means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl is optionally substituted with one or more"alkyl group substituents" which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, amino, carbamoyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl.

Representative alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl,

ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl.

"Alkylene"means a straight or branched bivalent hydrocarbon chain of 1 to about 6 carbon atoms. The alkylene is optionally substituted with one or more"alkylene group substituents"which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, carbamoyl, carboxy, cyano, aryl, heteroaryl or oxo. The alkylene is optionally interrupted by, i. e. , a carbon thereof is substituted for,-0-,- S (O) m (where m is 0-2), phenylene or-NR"- (where R"is lower alkyl). Preferred alkylene groups are the lower alkylene groups having 1 to about 4 carbon atoms. Representative alkylene groups include methylene, ethylene, and the like.

"Alkenylene"means a straight or branched bivalent hydrocarbon chain containing at least one carbon-carbon double bond. The alkenylene is optionally substituted with one or more"alkylene group substituents"as defined herein. The alkenylene is optionally interrupted by, i. e. , a carbon thereof is substituted for,-O-,-S (O) m (where m is 0-2), phenylene or-NR'- (where R'is lower alkyl).

Representative alkenylene include-CH=CH-, -CH2CH=CH-,-C (CH3) =CH-, -CH2CH=CHCH2-, and the like.

"Alkynylene"means a straight or branched bivalent hydrocarbon chain containing at least one carbon-carbon triple bond. The alkynylene is optionally substituted with one or more"alkylene group substituents"as defined herein. The alkynylene is optionally interrupted by, i. e. , a carbon thereof is substituted for,-O-, ~S (O) m (where m is 0-2), phenylene or-NR'- (where R'is lower alkyl).

Representative alkynylene include-C =C-,-C i-CH2-,-C {I-CH (CH3) -, and the like.

"Alkylsulfinyl"means an alkyl-SO-group wherein the alkyl group is as defined above. Preferred alkylsulfinyl groups are those wherein the alkyl group is lower alkyl.

"Alkylsulfonyl"means an alkyl-SO2-group wherein the alkyl group is as defined herein.

Preferred alkylsulfonyl groups are those wherein the alkyl group is lower alkyl.

"Alkylsulfonylcarbamoyl"means an alkyl-SO2-NH-CO-group wherein alkyl group is defined herein. Preferred alkylsulfonylcarbamoyl groups are those wherein the alkyl group is lower alkyl.

"Alkylthio"means an alkyl-S-group wherein the alkyl group is as defined herein. Preferred alkylthio groups are those wherein the alkyl group is lower alkyl. Representative alkylthio groups include methylthio, ethylthio, i-propylthio, heptylthio, and the like.

"Alkynyl"means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbon-carbon triple bond. Preferred alkynyl groups have 2 to about 12 carbon atoms. More preferred alkynyl groups contain 2 to about 4 carbon atoms. "Lower alkynyl"means alkynyl of 2 to about 4 carbon atoms. The alkynyl group may be substituted by one or more alkyl group

substituents as defined herein. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2- butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and the like.

"Alkynyloxy"means an alkynyl-O-group wherein the alkynyl group is defined herein.

Representative alkynyloxy groups include propynyloxy, 3-butynyloxy, and the like.

"Alkynyloxyalkyl"means alkynyl-O-alkylene-group wherein alkynyl and alkylene are defined herein.

NR17 <BR> <BR> #<BR> "Amidino" or "amidine" means a group of formula -C-NR18 wherein R17 is hydrogen; R19O2C- wherein R'9 is hydrogen, alkyl, aralkyl or heteroaralkyl ; Rl9O-; RX9C (o)-, cyano, alkyl, nitro, or amino, and R18 is selected from hydrogen; alkyl; aralkyl; and heteroaralkyl.

"Amino" means a group of formula Y1Y2N- wherein Y1 and Y2 are independently hydrogen; acyl; or alkyl, or Y1 and Y2 taken together with the N through which Y1 and Y2 are linked form a 4 to 7 membered azaheterocyclyl. Representative amino groups include amino (H2N-), methylamino, dimethylamino, diethylamino, and the like.

"Aminoalkyl"means an amino-alkylene-group wherein amino and alkylene are defined herein.

Representative aminoalkyl groups include aminomethyl, aminoethyl, dimethylaminomethyl, and the like.

"Aralkenyl"means an aryl-alkenylene-group wherein aryl and alkenylene are define herein.

Preferred aralkenyls contain a lower alkenylene moiety. A representative aralkenyl group is 2-phenethenyl.

"Aralkyloxy"means an aralkyl-O-group wherein aralkyl is defined herein. Representative aralkoxy groups include benzyloxy, naphth-1-ylmethoxy, naphth-2-ylmethoxy, and the like.

"Aralkyloxyalkyl"means an aralkyl-O-alkylene-group wherein aralkyl and alkylene are defined herein. A representative aralkyloxyalkyl group is benzyloxyethyl.

"Aralkyloxycarbonyl"means an aralkyl-O-CO-group wherein aralkyl is defined herein. A representative aralkoxycarbonyl group is benzyloxycarbonyl.

"Aralkyloxycarbonylalkyl"means an aralkoxycarbonyl-alkylene-wherein aralkyloxycarbonyl and alkylene are defined herein. Representative aralkoxycarbonylalkyls include benzyloxycarbonylmethyl, benzyloxycarbonylethyl.

"Aralkyl"means an aryl-alkylene-group wherein aryl and alkylene are defined herein. Preferred aralkyls contain a lower alkyl moiety. Representative aralkyl groups include benzyl, 2-phenethyl, naphthlenemethyl, and the like.

"Aralkyloxyalkenyl"means an aralkyl-O-alkenylene-group wherein aralkyl and alkenylene are defined herein. A representative aralkyloxyalkenyl group is 3-benzyloxyallyl "Aralkylsulfonyl"means an aralkyl-SO2-group wherein aralkyl is defined herein.

"Aralkylsulfinyl"means an aralkyl-SO-group wherein aralkyl is defined herein.

"Aralkylthio"means an aralkyl-S-group wherein aralkyl is defined herein. A representative aralkylthio group is benzylthio.

"Aroyl"means an aryl-CO-group wherein aryl is defined herein. Representative aroyl include benzoyl, naphth-1-oyl and naphth-2-oyl.

"Cycloalkyl"means a non-aromatic mono-or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more"ring system substituents"which may be the same or different, and are as defined herein. Representative monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative multicyclic cycloalkyl include 1-decalin, norbornyl, adamantyl, and the like. The prefix spiro before cycloalkyl means that geminal substituents on a carbon atom are replaced to form 1, 1-cycloalkyl.

"Cycloalkylene"means a bivalent radical derived from a cycloalkyl as defined herein by removal of a hydrogen atom from each of two ring atoms. Preferred cycloalkylenes have about 4 to about 8 carbon atoms. Preferred cycloalkylenene groups include 1,2-, 1,3-, or 1, 4- cis or trans-cyclohexylene.

"Cycloalkenyl"means a non-aromatic mono-or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkylene rings contain about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more"ring system substituents"which may be the same or different, and are as defined herein. Representative monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A representative multicyclic cycloalkenyl is norbornylenyl.

"Heterocyclenyl"means a non-aromatic monocyclic or multicyclic ring system of about 3 to about ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element (s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.

The heterocyclenyl is optionally substituted by one or more ring system substituents, wherein"ring system substituent"is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Representative monocyclic azaheterocyclenyl groups include 1,2, 3, 4-tetrahydropyridine, 1, 2-dihydropyridyl, 1, 4-dihydropyridyl, 1,2, 3,6-tetrahydropyridine, 1,4, 5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like.

Representative oxaheterocyclenyl groups include 3, 4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A representative multicyclic oxaheterocyclenyl group is

7-oxabicyclo [2.2. 1] heptenyl. Representative monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like "Heterocyclyl"means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element (s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl is optionally substituted by one or more"ring system substituents"which may be the same or different, and are as defined herein. Representative monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

"Aryl"means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more"ring system substituents"which may be the same or different, and are as defined herein. Representative aryl groups include phenyl and naphthyl.

"Heteroaryl"means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element (s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to about 6 ring atoms. The"heteroaryl"is optionally substituted by one or more"ring system substituents"which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide.

Representative heteroaryls include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1, 2-a] pyridine, imidazo [2, 1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2, 4-triazinyl, benzothiazolyl and the like.

"Fused arylcycloalkenyl"means a radical derived from a fused aryl and cycloalkenyl as defined herein by removal of hydrogen atom from the cycloalkenyl portion. Preferred fused arylcycloalkenyls are those wherein aryl is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein"ring system substituent"is as defined herein. Representative fused arylcycloalkenyl include 1, 2-dihydronaphthylene, indene, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkenylaryl"means a radical derived from a fused arylcycloalkenyl as defined herein by removal of hydrogen atom from the aryl portion. Representative fused cycloalkenylaryl are as described herein for a fused arylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arylcycloalkyl"means a radical derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkyl is optionally substituted by one or more ring system substituents, wherein"ring system substituent"is as defined herein. Representative fused arylcycloalkyl includes 1,2, 3,4- tetrahydronaphthyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkylaryl"means a radical derived from a fused arylcycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused cycloalkylaryl are as described herein for a fused arylcycloalkyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arylheterocyclenyl"means a radical derived from a fused aryl and heterocyclenyl as defined herein by removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused arylheterocyclenyls are those wherein aryl is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl portion of the fused arylheterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein"ring system substituent"is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused arylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.

Representative fused arylheterocyclenyl include 3H-indolinyl, lH-2-oxoquinolyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3, 4-dihydroisoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclenylaryl"means a radical derived from a fused arylheterocyclenyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused heterocyclenylaryl are as defined herein for a fused arylheterocyclenyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arylheterocyclyl"means a radical derived from a fused aryl and heterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused arylheterocyclyls are those wherein aryl is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclyl is optionally substituted by one or more

ring system substituents, wherein"ring system substituent"is as defined herein. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Representative preferred fused arylheterocyclyl ring systems include phthalimide, 1,4-benzodioxane, indolinyl, 1,2, 3, 4-tetrahydroisoquinoline, 1,2, 3,4-tetrahydroquinoline, 1H-2, 3-dihydroisoindolyl, 2,3-dihydrobenz [flisoindolyl, 1, 2,3, 4-tetrahydrobenz [g] isoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclylaryl"means a radical derived from a fused aryheterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Representative preferred fused heterocyclylaryl ring systems are as described for fused arylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylcycloalkenyl"means a radical derived from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion. Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl and the cycloalkenyl each contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein"ring system substituent"is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl include 5,6- dihydroquinolyl, 5, 6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro- 1 H-benzimidazolyl, 4, 5-dihydrobenzoxazolyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkenylheteroaryl"means a radical derived from a fused heteroarylcycloalkenyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkenylheteroaryl are as described herein for fused heteroarylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylcycloalkyl"means a radical derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylcycloalkyl is optionally substituted by one or more ring system substituents, wherein"ring system substituent"is as defined herein. The nitrogen atom of the heteroaryl portion of the fused

heteroarylcycloalkyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkyl include 5,6, 7,8-tetrahydroquinolinyl, 5,6, 7,8-tetrahydroisoquinolyl, 5,6, 7, 8-tetrahydroquinoxalinyl, 5,6, 7, 8-tetrahydroquinazolyl, 4,5, 6, 7-tetrahydro-1H-benzimidazolyl, 4,5, 6,7-tetrahydrobenzoxazolyl, 1 H-4-oxa-1, 5-diazanaphthalen-2-onyl, 1, 3-dihydroimidizole- [4, 5] -pyridin-2-onyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkylheteroaryl"means a radical derived from a fused heteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkylheteroaryl are as described herein for fused heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylheterocyclenyl"means a radical derived from a fused heteroaryl and heterocyclenyl as defined herein by the removal of a hydrogen atom from the heterocyclenyl portion.

Preferred fused heteroarylheterocyclenyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl or heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein"ring system substituent"is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.

Representative fused heteroarylheterocyclenyl include 7,8-dihydro [1, 7] naphthyridinyl, 1,2- dihydro [2,7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4, 5-c] pyridyl, 1, 2-dihydro-1, 5-naphthyridinyl, 1, 2-dihydro-1, 6-naphthyridinyl, 1, 2-dihydro-1, 7-naphthyridinyl, 1, 2-dihydro-1, 8-naphthyridinyl, 1, 2-dihydro-2,6-naphthyridinyl, and the like, in which the bond to the parent moiety is through a non aromatic carbon atom.

"Fused heterocyclenylheteroaryl"means a radical derived from a fused heteroarylheterocyclenyl as defined herein by the removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclenylheteroaryl are as described herein for fused heteroarylheterocyclenyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylheterocyclyl"means a radical derived from a fused heteroaryl and heterocyclyl as defined herein, by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused heteroarylheterocyclyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylheterocyclyl is

optionally substituted by one or more ring system substituents, wherein"ring system substituent"is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclyl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Representative fused heteroarylheterocyclyl include 2, 3-dihydro-lH pyrrol [3,4- b] quinolin-2-yl, 1,2, 3,4-tetrahydrobenz [b] [1, 7] naphthyridin-2-yl, 1,2, 3,4-tetrahydrobenz [b] [1, 6] naphthyridin-2-yl, 1,2, 3, 4-tetrahydro-9H-pyrido [3,4-b] indol-2yl, 1,2, 3, 4-tetrahydro-9H-pyrido [4,3-b] indol-2yl, 2, 3,-dihydro-lH-pyrrolo [3,4-b] indol-2-yl, 1H-2, 3,4, 5-tetrahydroazepino [3,4-b] indol-2-yl, 1H-2, 3,4, 5-tetrahydroazepino [4,3-b] indol-3-yl, 1H-2, 3,4, 5-tetrahydroazepino [4,5-b] indol-2 yl, 5,6, 7,8-tetrahydro [1, 7] napthyridinyl, 1, 2,3, 4-tetrhydro [2,7] naphthyridyl, 2,3-dihydro [1, 4] dioxino [2,3-b] pyridyl, 2,3-dihydro [1, 4] dioxino [2, 3-b] pryidyl, 3, 4-dihydro-2H-1-oxa [4, 6] diazanaphthalenyl, 4,5, 6,7-tetrahydro-3H-imidazo [4,5-c] pyridyl, 6,7-dihydro [5,8] diazanaphthalenyl, 1, 2,3, 4-tetrahydro [1, 5] napthyridinyl, 1,2, 3,4-tetrahydro [1, 6] napthyridinyl, 1,2, 3,4-tetrahydro [1, 7] napthyridinyl, 1, 2,3, 4-tetrahydro [1, 8] napthyridinyl, 1, 2,3, 4-tetrahydro [2,6] napthyridinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclylheteroaryl"means a radical derived from a fused heteroarylheterocyclyl as defined herein, by removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclylheteroaryl are as described herein for fused heteroarylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Aralkynyl"means an aryl-alkynylene-group wherein aryl and alkynylene are defined herein.

Representative aralkynyl groups include phenylacetylenyl and 3-phenylbut-2-ynyl.

"Aryldiazo"means an aryl-N=N-group wherein aryl is defined herein. Representative aryldiazo groups include phenyldiazo and naphthyldiazo.

"Arylcarbamoyl"means an aryl-NHCO-group, wherein aryl is defined herein.

"Benzyl"means a phenyl-CH2-group. Substituted benzyl means a benzyl group in which the phenyl ring is substituted with one or more ring system substituents. Representative benzyl include 4- bromobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, and the like.

"Carbamoyl" means a group of formula Y1Y2NCO- wherein Y1 and Y2 are defined herein.

Representative carbamoyl groups include carbamyl (H2NCO-), dimethylaminocarbamoyl (Me2NCO-), and the like.

"Carboxy"and"carboxyl"mean a HO (O) C- group (i. e. a carboxylic acid).

"Carboxyalkyl"means a HO (O) C-alkylene- group wherein alkylene is defined herein.

Representative carboxyalkyls include carboxymethyl and carboxyethyl.

"Cycloalkyloxy"means a cycloalkyl-O-group wherein cycloalkyl is defined herein.

Representative cycloalkyloxy groups include cyclopentyloxy, cyclohexyloxy, and the like.

"Diazo"means a bivalent-N=N-radical.

"Ethylenyl"means a-CH=CH-group.

"Halo"or"halogen"mean fluoro, chloro, bromo, or iodo.

"Heteroaralkenyl"means a heteroaryl-alkenylene-group wherein heteroaryl and alkenylene are defined herein. Preferred heteroaralkenyls contain a lower alkenylene moiety. Representative heteroaralkenyl groups include 4-pyridylvinyl, thienylethenyl, pyridylethenyl, imidazolylethenyl, pyrazinylethenyl, and the like.

"Heteroaralkyl"means a heteroaryl-alkylene-group wherein heteroaryl and alkylene are defined herein. Preferred heteroaralkyls contain a lower alkylene group. Representative heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like.

"Heteroaralkyloxy"means an heteroaralkyl-O-group wherein heteroaralkyl is defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxy.

"Heteroaralkyloxyalkenyl"means a heteroaralkyl-O-alkenylene-group wherein heteroaralkyl and alkenylene are defined herein. A representative heteroaralkyloxyalkenyl group is 4-pyridylmethyloxyallyl.

"Heteroaralkyloxyalkyl"means a heteroaralkyl-O-alkylene-group wherein heteroaralkyl and alkylene are defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxyethyl.

"Heteroaralkynyl"means an heteroaryl-alkynylene-group wherein heteroaryl and alkynylene are defined herein. Preferred heteroaralkynyls contain a lower alkynylene moiety. Representative heteroaralkynyl groups include pyrid-3-ylacetylenyl, quinolin-3-ylacetylenyl, 4-pyridylethynyl, and the like.

"Heteroaroyl"means an means a heteroaryl-CO-group wherein heteroaryl is defined herein.

Representative heteroaroyl groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, pyridinoyl, and the like.

"Heteroaryldiazo"means an heteroaryl-N=N-group wherein heteroaryl is as defined herein.

"Heteroarylsulphonylcarbamoyl"means a heteroaryl-SO2-NH-CO-group wherein heteroaryl is defined herein.

"Heterocyclylalkyl"means a heterocyclyl-alkylene-group wherein heterocyclyl and alkylene are defined herein. Preferred heterocyclylalkyls contain a lower alkylene moiety. A representative heteroaralkyl group is tetrahydropyranylmethyl.

"Heterocyclylalkyloxyalkyl"means a heterocyclylalkyl-O-alkylene group wherein heterocyclylalkyl and alkylene are defined herein. A representative heterocyclylalkyloxyalkyl group is tetrahydropyranylmethyloxymethyl.

"Heterocyclyloxy"means a heterocyclyl-O-group wherein heterocyclyl is defined herein.

Representative heterocyclyloxy groups include quinuclidyloxy, pentamethylenesulfideoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy, 7-oxabicyclo [2.2. 1] heptanyloxy, hydroxytetrahydropyranyloxy, hydroxy-7-oxabicyclo [2.2. 1] heptanyloxy, and the like.

"Hydroxyalkyl"means an alkyl group as defined herein substituted with one or more hydroxy groups. Preferred hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"N-oxide"means group.

"Oxo"means a group of formula O=, "Phenoxy"means a phenyl-O-group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

"Phenylene"means a-phenyl-group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

"Phenylthio"means a phenyl-S-group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.

"Pyridyloxy"means a pyridyl-O-group wherein the pyridyl ring is optionally substituted with one or more ring system substituents as defined herein.

"Ring system substituent"means a substituent which optionally replaces a hydrogen CH or NH constituent of an aromatic or non-aromatic ring system. Ring system substituents are selected from the group consisting of aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo, heteroaryldiazo, amidino, Y1Y2N-, Y1Y2N-alkyl-, Y1Y2NCO- or Y1Y2NSO2-, wherein Y1 and Y2 are independently hydrogen, alkyl, aryl, and aralkyl, or where the substituent is Y1Y2N- or Y1Y2N-alkyl- then one of Y1 and Y2 is acyl or aroyl and the other of Y1 and Y2 is hydrogen, alkyl, aryl, and aralkyl.

When a ring system is saturated or partially saturated, the"ring system substituent"further comprises methylene (H2C=), oxo (O=) and thioxo (S=).

"Sulfamoyl"means a group of formula YlY-NS02-wherein Y1 and y2 are defined herein.

Representative sulfamoyl groups are sulfamoyl (H2NS02-) and dimethylsulfamoyl (Me2NSO2-).

Preferred Embodiments The solid phase synthesis of substituted 1, 5-benzodiazepine-2-one compounds according to this invention is outlined in Scheme 1 wherein R', R4, R5, R6, R", R, P'and L are defined herein. The groups R', R4, R5, R6, R", R12 may be further substituted and may contain functional groups suitable for further chemical transformations while attached to the resin. It is understood that when these functional groups possess reactivity such that they could potentially interfere with the reactions described below, such functional groups should be suitably protected. For a comprehensive treatise on the protection and deprotection of common functional groups see T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), incorporated herein by reference.

Scheme 1 According to the foregoing Scheme 1, the amino resin 2 is prepared by reductive amination of a resin of formula la with an amine of formula HNR11 using, for example sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride in acetic acid/DMF, or by nucleophilic displacement of the leaving group (LG) from the resin of formula lb with an amine of formula HNR"in the presence of base. Preferred leaving groups are Br and Cl.

Preferred resins suitable for reductive alkylation with an amine of formula HNR"include :

3, 5-dimethoxy-4-formyl-phenoxymethyl-copoly (styrene-divinylbenzene)-resin (BAL resin), designated herein as

3-methoxy-4-formyl-phenoxymethl-copoly (styrene-divinylbenzene)-resin, designated herein as

Preferred resins suitable for alkylation with an amine of formula NHR'include: 4- (chloromethyl) phenoxymethyl-copoly (styrene-divinylbenzene) -resin, designated herein as 4- (4-bromomethyl) phenoxymethyl-copoly (styrene-divinylbenzene) -resin, designated herein as 4-bromomethyl-3-nitro-benzamidomethyl-copoly (styrene-divinylbenzene) -resin (Baldwin, J. Am. Chem.

Soc. 1995,117, 5588), designated herein as

Coupling of the amino resin 2 with a bromo-chloro-or iodo-carboxylic acid derivative, halo- R'2-COOH, in a suitable organic solvent such as dimethylformamide, dichloromethane, DMSO or THF using methods and reagents well-known in the art of amide bond formation results in formation of the resin-bromo-chloro-or iodoamide 3. Coupling times range from about 2 to about 12 hours, depending upon bromo-chloro-or iodo-carboxylic acid derivative to be coupled, activating agent, solvent and temperature. The coupling is accomplished at from about-10 °C to about 50 °C, preferably at about ambient temperature. The carboxylic acid moiety is activated with an appropriate activating agent such as isopropyl chloroformate in the presence of N-methylpiperidine ; diisopropylcarbodiimide (DIC) in the

presence of 1-hydroxybenzotriazole (HOBT); bis (2-oxo-3-oxazolidinyl) -phosphonic chloride (BOP-Cl) in the presence of triethylamine ; 2- (1H-benzotriazole-1-yl)-1. 1. 33-tetramethyluronium tetrafluoroborate (TBTU) in the presence of diisopropylethyl amine; N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide (DCC); or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (Pybrop), and the like. Alternatively, the carboxylic acid moiety of bromo-chloro-or iodo-carboxylic acid derivative may be converted to a reactive derivative such as the acid bromide, chloride or fluoride or a symmetrical or mixed anhydride which is then reacted with the amino resin. Preferred bromo-chloro-or iodo-carboxylic acid derivatives include bromo-acetic acid, chloroacetic acid, iodoacetic acid, bromobenzooic acid, chlorobenzoic acid, iodobenzoic acid, bromobutyric acid, chlorobutyric acid, iodobutyric acid and the like. More preferred bromo-chloro-or iodo-carboxylic acid derivatives is bromo-acetic acid.

The suitably protected 1, 5-benzodiazepine-2-one scaffold 4 is prepared in solution according to the method described in Shinozaki et al. Preparation and formulation of benzodiazepine derivatives as gastrin and cholecystokinin antagonists. PCT Int. Appl. WO 9825911 Al. Suitable protecting groups P'include base cleavable protecting groups, metal cleavable protecting groups and nucleophile cleavable protecting groupa. Suitable base cleavable protecting groups include 9-fluorenylmethoxycarbonyl, 9- (2- sulfo) fluorenylmethoxycarbonyl and 9- (2, 2-dibromo) -fluorenylmethoxycarbonyl, and the like, which are removed by treatment with, for example, piperidine, morpholine, dicyclohexylamine, dimethylaminopyridine, diisopropylethylamine, tetrabutylamonium fluoride, and the like in a suitable solvent such as DMF. Other suitable protecting groups are metal-labile nitrogen protecting groups which include allyloxycarbonyl, 1-isopropylallyloxycarbonyl, cinnamyloxycarbonyl and 4- nitrocinnamyloxycarbonyl, and the like which are removed by treatment with Ni (CO) 4, in DMF/H2O ; Pd (Ph3P) 4 and Bu3SnH in acetic acid; Pd (Ph3P) 4 and morpholine; Pd (Ph3P) 2CI2 and Bu3SnH in 4- nitrophenol; Pd2 (dba) 3-CHC13 in HCO2H ; and the like. Other suitable protecting groups are nucleophile labile protecting groups such as phtalimide, or N-2,3-diphenylmaleimide which can be removed with nucleophiles such as hydrazine, phenylhydrazine or methylamine in organic solvents such as isopropanol.

A more preferred nitrogen protecting group is phtalimide which can be removed with hydazine in isopropanol.

The resin (3) is reacted with the protected 1, 5-benzodiazepine-2-one scaffold (4) in presence of a base in an organic solvent such as dichloromethane or dimethylformamide. Preferred bases include potassium tert-butoxide, sodium hydride, n-butyllithium, lithium bis-trimethylsilyl acetamide, lithium diispropylamide and the like. More prefered base is potassium tert butoxide.

The group of formula R4 is then introduced into the resin-bound 1, 5-benzodiazepine-2-one derivative (5) to form the 5 substituted 1, 5-benzodiazepine-2-one derivative (6). When R4 is a group of formula-C (O)-Rl3 the acylation is accomplished by reaction of the resin (5) with the acid chloride of formula R13-C (O)-Cl in an organic solvent and in presence of base. A preferred solvent is pyridine which also acts as a base.

When R4 is a group of formula-C (O)-N'5 acylation is also accomplished using the isocyanate of formula R'5NCO in an organic solvent.

When R4 is-SO2R'4 sulfonylation is accomplished using a sulfonyl chloride of formula 4 in the presence of a base such as pyridine or N-methylmorpholine in an inert organic solvent such as dichloromethane. A preferred solvent is pyridine which also acts as a base.

When R4 is-C (O)-O-R'6 acylation is accomplished using a chloroformate of formula CIC (O)-O- Rl6 in the presence of a base such as pyridine or N-methylmorpholine in an inert organic solvent such as dichloromethane. A preferred solvent is pyridine which also acts as a base.

When R4 is aliphatic or aromatic, alkylation is accomplished using a bromide R4-Br, chloride R4- Cl or idodide R4-I in presence of a base such as triethylamine or diisopropylethylamine in an organic solvent.

The nitrogen protecting groups P'is then selectively removed by treatment of the resin-bound (5) substituted 1, 5-benzodiazepine-2-one compound (6) with a base, metal or a nucleophile to form the resin- bound compound (7).

The group of formula R5 is then optionally introduced into the resin-bound 2-amino-1, 5- benzodiazepine-2-one or 3-amino-1, 5-benzodiazepine-2-one (7) to form the resin-bound N-alkylated-1,5- benzodiazepine-2-one compound (8). When Rus ils H, no reaction is performed. When R is alkyl, alkylation can be accomplished by reductive amination, or by the so called"Fukayama"method.

Reductive amination is accomplished by treatment with an aldehyde in an organic solvent such as trimethyl orthoformate or dimethyl formamide in presence of a reducing agent such as sodium triacetoxy borohydride, sodium cyanoborohydride, sodium borohydride, lithium aluminium hydride and the like.

The reaction can either be run in one pot or the reaction with the aldehyde and the reducing agent can be run consecutively. The"Fukayama method"involves the conversion of the amine to the 2-nitro-, the 4- nitro or the 2,4-nitrophenyl sulfonamide by treatment with the corresponding sulfonyl chloride in a suitable organic solvent such as DCM or THF in presence of a base such as triethylamine or diisopropylethylamine. The sulfonamide is alkylated by reaction with an alcohol R4-OH in presence of a phosphine reagent such as triphenyl or tributyl phosphine and diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) in an organic solvent. The 2-nitro-, 4-nitro or 2,4-nitrophenyl sulfonamide is then hydrolyzed by reaction with ethanethiol and diazabicyclo- [4, 7] -undecene (DBU) in tetrahydrofuran to furnish the resin (7).

The group of formula R6 is then introduced into the resin-bound 2-amino-1, 5-benzodiazepine-2-one or 3- amino-1, 5-benzodiazepine-2-one (7) to form the resin-bound N-alkylated-1, 5-benzodiazepine-2-one compound (8).

When R6 is a group of formula-C (O)-R7 the acylation is accomplished using methods and reagents commonly used in the art of amide bond formation as described above for the conversion of (2) to (3). When R6 is a group of formula-C (O)-NHR9 formation of the urea is accomplished using the isocyanate of formula RNCO.

When R6 is-SO2R8 sulfonylation is accomplished using a sulfonyl chloride of formula CISO2R9 in the presence of a base such as pyridine or N-methylmorpholine in an inert organic solvent such as dichloromethane. When R6 is-C (O)-OR'° acylation is accomplished using a chloroformate of formula C1C (O) OR'° in the presence of a base such as pyridine or N-methylmorpholine in an inert organic solvent such as dichloromethane.

Treatment of the resin-bound substituted 1, 5-benzodiazepine-2-one compound (9) with acid, preferably trifluoracetic acid in dichloromethane, results in formation of the trisubstituted 1,5- benzodiazepine-2-one derivative (10).

In a more preferred aspect of the foregoing process, 1, 5-benzodiazepine-2-one scaffold (4) The solid phase synthesis of substituted 1, 5-benzothiazepine-2-one is described in scheme 2 where R', R and R6 are described herein.

Scheme 2 According to the foregoing scheme 2, cysteine is attached on the resin through a linking group which can release a primary amine. Suitable linkers to release an amine group are for example carbonate or chloroformate derivatives of Wang resin. A preferred carbonate resin is p- Nitrophenyl carbonate Wang (4- (4- (4-nitrophenylcarbonate) hydroxymethyl) phenoxymethyl- copoly (styrene-divinylbenzene) -resin available from Novabiochem, USA designated herein as:

Coupling of the carbonate resin (11) (LG is a leaving group) with cisteine in an organic solvent such as dimethyl formamide or dichloromethane in presence of bis-trimethylsilylacetamide results in the formation of (12).

The thiol group of cysteine is reacted with an ortho-bromo, ortho-chloro or ortho-fluoro nitrobenzene derivative (13) (Y= Br, Cl, F) in an organic solvent such as dimethylformamide in presence of a base such as triethylamine or diisopropylethylamine to produce (14). The nitro group of intermediate (14) is converted to the amine (15) using standard reagents for the reduction of aromatic nitro groups such as tin dichloride hydrate in dimethyl formamide, sodium borohydride and copper acetoacetate or sodium dithionite in ethanol. Preferred conditions include as tin dichloride hydrate in dimethyl formamide.

Cyclisation of (15) to the benzothizepine (16) is accomplished using methods and reagents commonly used in the art of amide bond formation as described above for the conversion of 2 to 3.

The 1, 5-benzothazepine-2-one (15) can optionally be oxidised to the corresponding sulfone (16) using standard reagents for sulfide to sulfone oxidation in an inert organic solvent such as dichloromethane.

These reagents include m-CPBA (meta-chloroperbenzoic acid), hydrogen peroxide in acetic acid or potassium persulfate. Preferred conditions include m-CPBA in dichloromethane.

Treatment of the resin-bound substituted 1, 5-benzothiazepine-2-one compound (18) with acid, preferably trifluoracetic acid in dichloromethane, results in formation of the substituted 1, 5-benzothiazepine-2-one compound (19).

The 3 amino-group of the 1, 5-benzothiazepine-2-one compound (19) is then optionally further substituted to form (20). When R6 is a group of formula-C (O)-R' the acylation is accomplished using methods and reagents commonly used in the art of amide bond formation as described above for the conversion of (2) to (3). When R6 is a group of formula-C (O)-NHR9 formation of the urea is accomplished using the isocyanate of formula R9NCO.

When R6 is-SO2Rg, sulfonylation is accomplished using a sulfonyl chloride of formula CISO2R9 in the presence of a base such as pyridine or N-methylmorpholine in an inert organic solvent such as dichloromethane. When R6 is-C (O)-OR'° acylation is accomplished using a chloroformate of formula CIC (O) OR'° in the presence of a base such as pyridine or N-methylmorpholine in an inert organic solvent such as dichloromethane.

Preferred conditions for introduction of R6 are conditions which involve a resin bound reagent and allow for simple purification applicable to automation. Example of such reagents are the tetrafluorophenol resin, the Marshall resin and the EDC-resin.

The more preferred embodiement is to use the tetrafluorophenol-resin (TFP resin) (21) as depicted in scheme 3. Carboxylic acids R6COOH are attached to the resin to form derivative (22) using standard methods in the art of ester bond conditions such as DIC/DMAP in dichloromethane. Sulfonyl chlorides C1S02R8 are attached to the resin using for example triethylamine or pyridine dichloromethane. The resin (21) is washed of all excess reagent and then reacted with 0.8 equivalents of amine-trifluoroacetate salt in presence of a resin bound base such as resin bound triethylammonium carbonate (Argonaut Technologies, CA, USA) in an organic solvents such as DMF. The 3-substituted 1, 5-benzothiazepine-2- one derivative (20) is then isolated by filtration and evaporation.

Scheme 3 The process of this invention is especially useful for the rapid synthesis of combinatorial libraries containing a large number of diazacycloalkyl carboxamide compounds.

"Combinatorial library"or"chemical library"mean an intentionally created collection of differing molecules which can be prepared synthetically and screened for biological activity in a variety of different formats (e. g. , libraries of soluble molecules; and libraries of compounds tethered to resin beads, silica chips, or other solid supports). The term is also intended to refer to an intentionally created collection of stereoisomers.

"Combinatorial synthesis"or"combinatorial chemistry"refers to an ordered strategy for the synthesis of diverse compounds by sequential addition of reagents which leads to the generation of large chemical libraries. Thus, combinatorial chemistry refers to the systematic and repetitive, covalent connection of a set of different"building blocks"of varying structures to each other to yield large arrays of diverse molecular entities.

The synthesis of a representative library is of N, N-disubstituted diazacylocalky carboxamide compounds using the process of this invention is outlined in Scheme 4.

Scheme 4 a) Divide into x portions o-L-CHO OS-L-N-R11 1a b) react with x amine 2 c) combine the x portions R1 Reactwith halo-R12-COOH < ( L-N'i R12-N NH React with benzodiazepine (-L-N R12-N NH P scaffold (4) 5 NP1 5 a) Divide intoy portions O XR1 O b) react with y R4 groups' L-N_ _R12-N N-R4 c) combine the y portions ~ R11 4/ 6 ° NP, 6 nu1 O 0 Rl a) Divide into z portions RemoveS L-N -N N-R4 R12 I b) react with z R6 groups R'l 1 C) combine the, y portions 7 NH2 Ru ru p' O , Cleave g L-N R12-N N-R4 com nds HN--R12-N N-R4 individually R11 R6/N--H 10 R6/N--R5 As shown in Scheme 4, a single portion of resin (la) is divided into x smaller portions containing approximately equal amounts of resin. Each portion of resin (la) is then reductively aminated as described in Scheme 1 above with a different amine of formula HNR", where x corresponds to the total

number of different amines. Alternatively, a resin of formula (lb) may be reacted with x different nucleophilic amines of formula HNR"as described in Scheme 1 above to form x portions of resin (24) (X is HNR") each of which contains a different R". The group X which is substituted with NR"is referred to herein as the first combinatorial position. The x portions are then recombined into a single portion and the amines are acylated with Br-R'2-COOH. The bromide is then displaced with the 1,5- benzothiazepine scaffold to form a mixture of resin-bound monoprotected 1, 5-benzodiazepine compounds (5) containing x different groups at the first combinatorial position.

The mixture of resin-bound monoprotected 1, 5-benzodiazepine compounds (5), is then divided into y portions, y different groups R4 are introduced at the second combinatorial position using the procedures described in Scheme 1 above and the y portions are recombined to form a single portion, referred to herein as the second combinatorial mixture, comprising a mixture of resin bound 5-substituted 1,5-benzodiazepine compounds (6) containing all possible combinations of the x R"groups and y R4 groups.

P'is then removed from the second combinatorial mixture, the resulting mixture of resin-bound 1,5-benzodiazepine compounds is divided into z portions and z different groups R6 are introduced into the third combinatorial position as described above to form z portions of resin-bound 1,5-benzodiazepine compounds (9).

The resin-bound 1,5-benzodiazepine compounds (9) are then cleaved from the resin as described in Scheme 1 above to give a library of substituted 1, 5-benzodiazpine compounds containing all possible combinations of groups at each of the combinatorial positions. Using the procedure described above, a library of 7,290 compounds may be readily prepared from reagents corresponding to 18 R"groups, 9 R4 groups and 45 R6 groups.

The progress of the combinatorial synthesis may be monitored by use of identifier tags.

"Identifier tag"denotes a physical attribute that provides a means whereby one can identify a chemical reaction. The identifier tag serves to record a step in a series of reactions used in the synthesis of a chemical library. The identifier tag may have any recognizable feature, including for example: a microscopically or otherwise distinguishable shape, size, mass, color, optical density, etc.; a differential absorbance or emission of light; chemical reactivity; magnetic or electronic properties; or any other distinctive mark capable of encoding the required information, and decipherable at the level of one (or a few) molecules. Identifier tags can be coupled to the solid support. Alternatively, the"identifier tag"can be coupled directly to the compound being synthesized, whether or not a solid support is used in the synthesis. In the latter embodiment, the identifier tag can conceptually be viewed as also serving as the "support"for synthesis.

In a preferred embodiment, a radio-frequency identifier tag is associated with each compound in the library. In a library preparation monitored by use of radio-frequency tags, each compound is made in

a polypropylene container with mesh side walls (MicroKan, available from Irori, La Jolla, California, USA) in which resin and a radio frequency tags are placed. The overall synthesis is programmed in a computer which incorporate a scanning station to track the RF-tags. As the MicroKans are scanned for the first time, a library member is assigned to each code. Along with this assignment the MicroKans are directed toward the vessel for the first combinatorial step. They are then reacted as a batch with the first set of combinatorial reagents. After the first combinatorial reaction, the MicroKans are pooled, and the scanner is then used to direct the cans into the vessels corresponding to their second combinatorial step. And so on for all the combinatorial steps. At the end of the synthesis, the final scan assigns a plate number and a well location to each compound in the library.

It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.

The foregoing may be better understood by reference to the following examples, which are presented for illustration and are not intended to limit the scope of this invention.

Example 1 Preparation of BAL Resin 4-Hydroxy-2,6-dimethoxybenzaldehyde (127.53 g, 700.0 mmol) is dissolved in anhydrous dimethylformamide (3.0 L). Sodium hydride (26.4 g of 60% sodium hydride in oil, 660.0 mmol) is added slowly in portions to the stirring solution at ambient temperature under a flow of nitrogen gas. After the sodium hydride addition is complete, the reaction is stirred at ambient temperature for 30 minutes.

Chloromethylpolystyrene resin (100.0 g of 2.0 mmol/g loaded 150-300 um beads from Polymer Laboratories) is added to the ruby red solution and the resulting suspension is stirred at ambient temperature for 30 minutes under nitrogen. The nitrogen line is removed and replaced with a needle to vent the reaction. The reaction flask is placed in an incubator shaker and mixed for two days at 50 °C.

The reaction flask is removed from the oven, cooled in an ice bath, and water (500 ml) is added. The resin is filtered off and washed with 1 : 1 dimethylformamide/methanol (3x), dimethylformamide (3x), dichloromethane (3x) and methanol (3x). The resin is then placed in a vacuum oven an dried at ambient temperature for about 2 days. The resin loading is determined to be approximately 1.0 mmol/g.

Example 2 Preparation of 5-phtalimido-1 5-benzodiazepine-2-one a-Boc, a, b-diamino propionic acid (100g, 490 mmol) was dissolved in DMF (1L). Triethylamine (200 ml, 1.3 mol) was added followed by 2-fluoronitrobenzene (200 ml, 1.84 mol). The mixture was stirred overnight at 80°C. The mixture was then poured into ethyl acetate (2L), and extracted with 1N NaOH (3x500 ml). The combined aqueous extracts were acidified with 2N HCl (1L) and extracted with ethyl acetate (3x 500 ml). The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to afford 218 g of an orange oil which solidified upon standing.

The crude mixture was dissolved in methanol (1L), 10% palladium on charcoal (4g, 3.7 mmol) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 36h. The mixture was filtered over celite and concentrated to afford 230 g of a black oil. This crude product was dissolved in DMF (1.4L), cooled to 0°C and EDC (112g, 585 mmol) was added. The mixture was allowed to room temperature and stirred overnight. The mixture was poured in ethyl acetate (2.5 L), washed with water (4 x500 mL), brine (500 mL) and dried over sodium sulfate. The mixture was concentrated to afford 134 g of a black oil. The first two aqueous extracts were combined and extracted with ethyl acetate. The combined organic phase were dried over sodium sulfate and concentrated to afford a black oil which was dried under vacuum for 3 days. Both crude mixture were purified by chromatography (ethyl acetate: hexane 1: 9 the 5: 5 then 7: 3) to afford 98g (72% over 3 steps) of the 5-Boc-1, 5-benzodiazepine-2- one as a white powder.

The 5-Boc-1, 5-benzodiazepine (98g, 355 mmol) was stirred in a 1: 1 mixture or TFA : DCM (1.2 L) for lh.

The mixture was evaporated and the residue was azeotroped twice with toluene. The residue was dried under vacuum for 12h. The residue was then suspended in toluene (1.2 L), triethylamine (154 ml, 1 mol) was added followed by phtalic anhydride (52.9 g, 319 mmol). The flask was equipped with a Dean Stark apparatus and a condenser, and the mixture was heated at 110°C overnight. The mixture was cooled

to O°C, and then filtered to afford 73 g (64%) of 5-phtalimido-1, 5-benzodiazepine-2-one a bright yellow powder.

Example 3 Preparation of 1-((2terahydrofurfurvl-methyl) acetamide). 3-furan-(2carboxvl) amide 5 (4- trifluoromethylbenzyl)-1, 5-benzodiazepine-2-one.

Reductive Amination on the BAL resin: BAL resin (300 mg, 0.24 mmol) was swelled in a 1 % acetic acid in DMF solution (3 ml).

Tetrahydrofurfuryl amine (130 mg, 1.92 mmol) and sodium triacetoxyborohydride (448 mg, 1.92 mmol) were added sequentially. The reaction was shaken at RT for 5 hours. For workup, the reaction was drained and the resin was washed with 10% Et3N in DMF (1X), DMF (3X), DCM (3X) and Et20 (lX).

The resin was then dried overnight with a stream of nitrogen gas.

Acylation with bromoacetic acid.

300 mg of the precedent resin was suspended in anhydrous DCM (SL), bromoacetic acid (337 mg, 2.4 mmol) was added followed by DIC (380 mg, 2.4 mmol). The mixture was stirred overnight at room temperature, drained and the resin was washed with DCM (1X), DMF (3X), DCM (3X) and Et2O (lX).

The resin was then dried overnight with a stream of nitrogen gas and then for 48h in a vacuum oven.

Alkylation with Benzodiazepine Scaffold.

300mg of the precedent resin was reacted in oven dried glassware. The Benzodiazepine scaffold (147 mg, 0.48 mmol) was dissolved in anhydrous DMF and potassium t-butoxide (0.46 mL of a 1.0 M solution in THF) was added. The mixture was stirred 30 min. at room temperature and the resin was added in one

portion. The mixture was shaken overnight at room temperature, drained and the resin was washed with DMF (3X), DCM (3X) and Et2O (lX). The resin was then dried overnight with a stream of nitrogen gas.

Alkylation at N-4.

300mg of the precedent resin was suspended in anhydrous DMF (5 mL), 4-trifluoromethylbenzyl chloride (640 mg, 3.3 mmol) was added along with DIPEA (0. 5 ml, 3.3 mmol) and potassium iodide (950 mg, 3. 3 mmol). The mixture was stirred overnight at 80°C. For workup, the resin was drained and washed with DMF (3X) and H20 (1X), THF (1X), H20 (1X), THF (2X), DCM (3X) and isopropanol (1X).

Removal of Phtalimide Protecting group.

300 mg of the precedent resin was suspended in 25% hydrazine monohydrate in isopropanol (5 mL), and stirred at 50°C for 4h. The mixture was drained and the resin was washed with isopropanol (3X), ), DMF (2X), DCM (3X). The resin was stirred overnight in DCM, drained and washed with Et20 (lX). The resin was then dried overnight with a stream of nitrogen gas.

Acylation of primarv amine with carboxylic acids 300mg of the precedent resin was suspended in NMP (5 mL), 2-furoic acid (260 mg, 2.4 mmol) was added followed by EDC (460 mg, 2.4 mmol) and DIEA (0.83 ml, 4.8 mmol). The mixture was shaken overnight at room temperature. For workup, the resin was drained and washed with DMF (3X), THF (2X), DCM (3X) and ether (1X). The resin was then dried overnight with a stream of nitrogen gas Cleavage : To 300 mg of the precedent resin, a solution of 50% TFA in DCM (5 ml) was added. The mixture was shaken for lh, drained, the resin was rinsed with DCM (lmL), and the resulting solution was concentrated under reduced pressure to afford 98mg of the title compound (90%).

Example 4 Preparation of 1- ( (cvclohexyl) acetamide), 3-dansylsulfonamide, 5acetyl-1, 5-benzodiazepine-2-one.

Reductive Amination on the BAL resin: BAL resin (300 mg, 0.24 mmol) was swelled in a 1 % acetic acid in DMF solution (3 ml).

Cyclohexylamine (190 mg, 1.92 mmol) and sodium triacetoxyborohydride (448 mg, 1.92 mmol) were added sequentially. The reaction was shaken at RT for 5 hours. For workup, the reaction was drained and the resin was washed with 10% Et3N in DMF (1X), DMF (3X), DCM (3X) and Et20 (lX). The resin was then dried overnight with a stream of nitrogen gas.

Acylation with bromoacetic acid.

300 mg of the precedent resin was suspended in anhydrous DCM (SL), bromoacetic acid (337 mg, 2.4 mmol) was added followed by DIC (380 mg, 2.4 mmol). The mixture was stirred overnight at room temperature, drained and the resin was washed with DCM (IX), DMF (3X), DCM (3X) and Et20 (lX).

The resin was then dried overnight with a stream of nitrogen gas and then for 48h in a vacuum oven.

Alkylation with Benzodiazepine Scaffold.

300mg of the precedent resin was reacted in oven dried glassware. The Benzodiazepine scaffold (147 mg, 0.48 mmol) was dissolved in anhydrous DMF and potassium t-butoxide (0.46 mL of a 1.0 M solution in THF) was added. The mixture was stirred 30 min. at room temperature and the resin was added in one portion. The mixture was shaken overnight at room temperature, drained and the resin was washed with DMF (3X), DCM (3X) and Et20 (lX). The resin was then dried overnight with a stream of nitrogen gas.

Acylation at N-4.

300mg of the precedent resin was suspended in anhydrous Pyridine (4 mL), acetyl chloride (930 mg, 12 mmol) was added followed by a spoonful of DMAP. The mixture was shaken overnight at 80°C. For

workup, the resin was drained and washed with DMF (4X), 20% aq THF (3X), THF (2X), DCM (3X) and isopropanol (1X).

Removal of Phtalimide Protecting group.

300 mg of the precedent resin was suspended in 25% hydrazine monohydrate in isopropanol (5 mL), and stirred at 50°C for 4h. The mixture was drained and the resin was washed with isopropanol (3X), ), DMF (2X), DCM (3X). The resin was stirred overnight in DCM, drained and washed with Et20 (lX). The resin was then dried overnight with a stream of nitrogen gas.

Sulfonylation of primary amine.

300mg of the previous resin was suspended in DCM (5 mL), dansyl chloride (624 mg 2.4 mmol) was added followed by Et3N (391 ml, 2.8 mmol). The mixture was stirred overnight at room temperature. For workup, the resin was drained and washed with DMF (3X), THF (2X), DCM (3X) and ether (1X). The resin was then dried overnight with a stream of nitrogen gas.

Cleavage: To 300 mg of the precedent resin, a solution of 50% TFA in DCM (5 ml) was added. The mixture was shaken for lh, drained, the resin was rinsed with DCM (ImL), and the resulting solution was concentrated under reduced pressure to afford 98mg of the title compound (90%).

Example 5 Preparation of Compound of Formula Cysteine carbamate resin: The nitro-phenol carbonate resin (320 g, 544.0 mmol) was swelled in anhydrous DMF (SL) in a 12L three-necked round bottom flask. Argon gas was bubbled through this slurry for one hour while stirring with an overhead stirrer. In a second 3L three-necked round bottom flask, anhydrous DMF (500 ml) and BSA (1. 5L) were added. This solution was degassed for one hour by bubbling argon gas through the

solution. The DL-cysteine was then introduced into the three-necked flask. After stirring for 30 minutes, all of the cysteine had dissolved up into solution. This cysteine solution was then canulated into the 12L flask containing the resin slurry. The reaction was stirred overnight at room temperature under argon. For the workup, the reaction solution was drained off under argon. The resin was then washed with DMF (2X), 10% AcOH in DMF (3X), DMF (2X), THF (2X), DCM (2X) and diethyl ether (2X) under argon.

The resin was dried overnight with a stream of argon gas.

4-Bromo-3-nitrobiphenyl coupling : 300 mg of cysteine resin (with a loading of 1.2 mmol/g) were placed into a PP Jones'tube fitted with an argon line. The tube was flushed with argon. Degassed anhydrous DMF (6 ml) was added to the tube.

While under argon, DBU (0.54 ml, 3.6 mmol) was added. After vortexing for approximately 5 minutes, the 4-bromo-3-nitrobiphenyl (1.00 g, 3.6 mmol) was then added. The reaction was vortexed under argon for several hours. The argon lines were then removed, the reaction capped tightly and stirred overnight at room temperature. For the workup, the reaction solution was drained off under argon. The resin was then washed with DMF (3X), 10% HOAc in DMF (2X), 20% aqueous THF (2X), THF (2X), DCM (2X) and diethyl ether (1X). It was dried overnight with a stream of nitrogen gas.

Reduction of nitro group : 300 mg of the halo-nitrobenzene coupled resin (with a loading of 1.2 mmol/g) were placed into a PP Jones'tube. DMF (6 ml) and tin dichloride dihydrate (0.81 g, 3.6 mmol) were added to the tube. The reaction was stirred at 50 degrees centigrade overnight. For the workup, the reaction solution was drained off. The resin was then washed with DMF (3X), aqueous THF (1X), THF (2X), DCM (2X), and diethyl ether (1X). It was dried overnight with a stream of nitrogen gas.

Cyclization to benzothiazepine ring system : 300 mg of the reduced resin (with a loading of 1.2 mmol/g) were placed into a PP Jones'tube. The resin was swelled in anhydrous NMP (6 ml). EDC (0.35 g, 1.8 mmol) was added and the reaction was stirred overnight. For the workup, the resin was washed with DMF (1X), aqueous DMF (IX), DMF (1X), aqueous THF (1X), THF (2X), DCM (2X) and diethyl ether (1X). It was dried overnight with a stream of nitrogen gas.

Acylation with 1-bromo-3-methylbutane : 300 mg of the cyclized resin (with a loading of 1. 2 mmol/g) were placed into a PP Jones'tube. The resin was swelled with anhydrous DMF (6 ml). The DBU (0. 54ml, 3.6 mmol) was added and the reaction was stirred for 15 minutes. The 1-bromo-3-methylbutane

(0.43 ml, 3.6 mmol) was then introduced. KI (0.60 g, 3.6 mmol) was added last. The reaction was stirred overnight at room temperature. For the workup, the reaction solution was drained off and the resin was washed with DMF (2X), 10% HOAc in DMF (2X), 20% aqueous THF (2X), THF (2X), DCM (2X) and diethyl ether (1X). It was dried overnight with a stream of nitrogen gas.

Loading piperonylic acid onto TFP resin: TFP resin (20g with a loading of 1.25 mmol/g) was introduced into a 250 ml glass peptide vessel. The resin was swelled in DMF (120 ml). The piperonylic acid (41.53 g, 250 mmol), DMAP (3.05 g, 25 mmol) and DIC (39.14 ml, 250 mmol) were then added sequentially. The reaction was mixed on a wrist shaker overnight. For the workup, the reaction solution was drained off and the resin was washed with DMF (3X), THF (3X), DCM (3X), and diethyl ether (1X). The resin was dried in a vacuum oven at room temperature overnight.

Cleaving and free basing : 300 mg of the alkylated resin were cleaved with a 50% TFA/DCM solvent mixture for one hour and then concentrated down. The resulting residue was azeotroped with DCM to remove the remaining traces of TFA. MP-Carbonate resin (411 mg, 1.08 mmol) and DMF (4 ml) were added to the residue (approximately 0.360 mmol of product). After vortexing for several seconds to dissolve up the cleaved compound, the reaction was allowed to sit at room temperature overnight. The liquid above the resin was transferred to another test tube through a filter tube using a Packard liquid handler. The resin was then washed twice with DMF (3 ml). Each of these washings was transferred to the collection tube giving approximately 9 ml total of a benzothiazepine free amine stock solution.

Reaction with TFP resin: The above benzothiazepine free amine stock solution was reacted with the piperonylic acid acylated TFP resin. 400 uL of this stock solution were added to approximately 15 mg of acylated TFP resin. The reaction was mixed on an orbital shaker at room temperature for three days. The product suspension was filtered through a filter plate into a collection plate using a Tomtec. The product was concentrated down in a GeneVac at 65 degrees centigrade to give the desired product in 96% purity.

Example 6 Preparation of Compound of Formula Cystine carbamate resin: The nitro-phenol carbonate resin (320 g, 544.0 mmol) was swelled in anhydrous DMF (SL) in a 12L three-necked round bottom flask. Argon gas was bubbled through this slurry for one hour while stirring with an overhead stirrer. In a second 3L three-necked round bottom flask, anhydrous DMF (500 ml) and BSA (1. 5L) were added. This solution was degassed for one hour by bubbling argon gas through the solution. The DL-cysteine was then introduced into the three-necked flask. After stirring for 30 minutes, all of the cysteine had dissolved up into solution. This cysteine solution was then canulated into the 12L flask containing the resin slurry. The reaction was stirred overnight at room temperature under argon. For the workup, the reaction solution was drained off under argon. The resin was then washed with DMF (2X), 10% AcOH in DMF (3X), DMF (2X), THF (2X), DCM (2X) and diethyl ether (2X) under argon.

The resin was dried overnight with a stream of argon gas.

Synthetic chloro-nitrobenzene amide: 4-Chloro-3-nitrobenzoyl chloride (0.79 g, 3.6 mmol) was partially dissolved up into anhydrous DCM (5 ml). Upon addition of DIEA (0.75 ml, 4.3 mmol), all of the benzoyl chloride dissolved up into solution.

The reaction solution was cooled in an ice bath and the butylamine (0.43 ml, 4.3 mmol) was slowly added. After the addition was complete, the ice bath was removed. The reaction was then stirred for approximately 6 hours at room temperature. It was concentrated down and the residue was used directly in the coupling step without further purification.

Synthetic chloro-nitrobenzene butylamide coupling: 300 mg of cysteine resin (with a loading of 1.2 mmol/g) were placed into a PP Jones'tube fitted an argon line. The tube was flushed with argon. Degassed anhydrous DMF (6 ml) was added to the flask. While under argon, DBU (0.54 ml, 3.6 mmol) was added. After stirring for approximately 5 minutes, the crude 4-bromo-3-nitrobenzene butylamine product (3.6 mmol) was then added. The reaction was stirred under argon for several hours. The argon lines were then removed, the reaction capped tightly and stirred overnight at room temperature. For the workup, the reaction solution was drained off under argon. The

resin was then washed with DMF (3X), 10% HOAc in DMF (2X), 20% aqueous THF (2X), THF (2X), DCM (2X) and diethyl ether (IX). It was dried overnight with a stream of nitrogen gas.

Reduction of nitro group : 300 mg of the halo-nitrobenzene coupled resin (with a loading of 1.2 mmol/g) were placed into a PP Jones'tube. DMF (6 ml) and tin dichloride dihydrate (0.81 g, 3.6 mmol) were added to the flask. The reaction was stirred at 50 degrees centigrade overnight. For the workup, the reaction solution was drained off. The resin was then washed with DMF (3X), aqueous THF (1X), THF (2X), DCM (2X), and diethyl ether (1X). It was dried overnight with a stream of nitrogen gas.

Cyclization to benzothiazepine ring system : 300 mg of the reduced resin (with a loading of 1.2 mmol/g) were placed into a PP Jones'tube. The resin was swelled in anhydrous NMP (6 ml). EDC (0.35 g, 1.8 mmol) was added and the reaction was stirred overnight. For the workup, the resin was washed with DMF (1X), aqueous DMF (1X), DMF (1X), aqueous THF (1X), THF (2X), DCM (2X) and diethyl ether (1X). It was dried overnight with a stream of nitrogen gas.

Oxidation to sulfone: 300 mg of the cyclized resin (with a loading of 1.2 mmol/g) were swelled in DCM (6 ml). MCPBA (0.50 g of 50% pure reagent, 0.15 mmol) was added and the reaction was stirred at room temperature for 5.5 hours. For the workup, the reaction solution was drained off and the resin was washed with DCM (2X), aqueous THF (2X), THF (2X) and diethyl ether (1X). It was dried overnight with a stream of nitrogen gas.

Alkylation reaction: 300 mg of the oxidized resin (with a loading of 1.2 mmol/g) were placed into a PP Jones'tube. The resin was swelled with anhydrous DMF (6 ml). The DBU (0. 54ml, 3.6 mmol) was added and the reaction was stirred for 15 minutes. The 3- (4-tert-butylphenyl)-5-chloromethyl-1, 2,4-oxadiazole (0.90 g, 3.6 mmol) was then introduced. KI (0.60 g, 3.6 mmol) was added last. The reaction was stirred overnight at room temperature. For the workup, the reaction solution was drained off and the resin was washed with DMF (2X), 10% HOAc in DMF (2X), 20% aqueous THF (2X), THF (2X), DCM (2X) and diethyl ether (1X).

It was dried overnight with a stream of nitrogen gas.

Loading N-acetyl-L-proline onto TFP resin:

TFP resin (20g with a loading of 1.25 mmol/g) was introduced into a 250 ml glass peptide vessel. The resin was swelled in DMF (120 ml). The N-acetyl-L-proline (39.29 g, 250 mmol), DMAP (3.05 g, 25 mmol) and DIC (39.14 ml, 250 mmol) were then added sequentially. The reaction was mixed on a wrist shaker overnight. For the workup, the reaction solution was drained off and the resin was washed with DMF (3X), THF (3X), DCM (3X), and diethyl ether (1X). The resin was dried in a vacuum oven at room temperature overnight.

Cleaving and free basing : 300 mg of the alkylated resin were cleaved with a 50% TFA/DCM solvent mixture for one hour and then concentrated down. The resulting residue was azeotroped with DCM to remove the remaining traces of TFA. MP-Carbonate resin (411 mg, 1.08 mmol) and DMF (4 ml) were added to the residue (approximately 0.360 mmol of product). After vortexing for several seconds to dissolve up the cleaved compound, the reaction was allowed to sit at room temperature overnight. The liquid above the resin was transferred to another test tube through a filter tube using a Packard liquid handler. The resin was then washed twice with DMF (3 ml). Each of these washings was transferred to the collection tube giving approximately 9 ml total of a benzothiazepine free amine stock solution.

Reaction with TFP resin: The above benzothiazepine free amine stock solution was reacted with the N-acetyl-L-proline acylated TFP resin. 400 uL of this stock solution was added to approximately 15 mg of acylated TFP resin. The reaction was mixed on an orbital shaker at room temperature for three days. The product suspension was filtered through a filter plate into a collection plate using a Tomtec. The product was concentrated down in a GeneVac at 65 degrees centigrade to give the desired product in 87% purity.

Example 7 Preparation of a 7.290 Member 1*5-benzodiazepine Library A 18 x 9 x 45 = 7290 member library was produced using the Irori system. BAL resin was loaded in 7290 microkans.

Reductive Amination on the BAL resin: For each amine, 585 microkans (each microkan contained 12 mg of 0.8 mmol/g loaded BAL resin) were placed into a 3.0 L 3-necked round bottom flask fitted with an overhead stirrer. The resin in the microkans was swelled in a 1% acetic acid in DMF solution (800 ml). The amine (45.0 mmol) and sodium triacetoxyborohydride (10.5 g, 45.0 mmol) were added sequentially. The reaction was stirred at RT for 5 hours. For workup, each reaction was individually drained and washed with DMF (1X). All of the microkans were then combined and washed with 10% Et3N in DMF (1X), DMF (3X), DCM (3X) and Et20 (lX). The kans were then dried overnight with a stream of nitrogen gas.

Removal of the Foc-group of Rink Amide resin: 585 Microkans were stirred 2 h in 800 ml of a 1: 1 mixture of DMF and Piperidine. The Microkans were then washed with DMF (4x), DCM (3x) and Et20 (lX). The kans were then dried overnight with a stream of nitrogen gas Acylation with bromoacetic acid.

5265 Microkans were suspended in anhydrous DCM (SL), bromoacetic acid (73.18 g, 520 mmol) was added followed by DIC (82. 5g, 520 mmol). The mixture was stirred overnight at room temperature, drained and the Microkans were washed with DCM (1X),), DMF (3X), DCM (3X) and Et20 (lX). The kans were then dried overnight with a stream of nitrogen gas and then for 48h in a vacuum oven.

Alkylation with Benzodiazepine Scaffold.

5265 Microkans were reacted in oven dried glassware. The Benzodiazepine scaffold (33. 8g, 110 mmol) was dissolved in anhydrous DMF and potassium t-butoxide (105 mL of a 1.0 M solution in THF) was added. The mixture was stirred 30 min. at room temperature and the Microkans were added in one portion. The mixture was stirred overnight at room temperature, drained and the Microkans were washed with DMF (3X), DCM (3X) and Et2O (lX).). The kans were then dried overnight with a stream of nitrogen gas.

Alkylation at N-4.

For each alkyl halide, 810 Microkans were suspended in anhydrous DMF (1.2 L), the halide (792 mmol) was added along with DIPEA (60 ml, 396 mmol) and potassium iodide (115 g, 396 mmol). The mixture was stirred overnight at 80°C. For workup, each reaction was individually drained and washed with DMF (3X) and H20 (1X). All of the microkans were then combined and washed with THF (1X), H20 (1X), THF (2X), DCM (3X) and isopropanol (1X).

Acylation and sulfonylation at N-4.

For each acid chloride or sulfonyl chloride, 810 Microkans were suspended in anhydrous Pyridine (1.2 L), the acid chloride or sulfonyl chloride (404 mmol) was added followed by a spoonful of DMAP. The mixture was stirred overnight at 80°C. For workup, each reaction was individually drained and washed with DMF (2X). All of the microkans were then combined and washed with DMF (2X), 20% aq THF (3X), THF (2X), DCM (3X) and isopropanol (1X).

Urea Formation at N-4 810 Microkans were suspended in anhydrous Toluene (1.2 L), the isocyanate (404 mmol) was added. The mixture was stirred overnight at 40°C. For workup, each reaction was individually drained and washed with DMF (2X). All of the microkans were then combined and washed with DMF (2X), 20% aq THF (3X), THF (2X), DCM (3X) and isopropanol (IX).

Removal of Phtalimide Protecting group.

5265 Microkans were suspended in 25% hydrazine monohydrate in isopropanol (5L), and stirred at 50°C for 4h. The mixture was drained and the Microkans were washed with isopropanol (3X), ), DMF (2X), DCM (3X). The microkans were stirred overnight in DCM, drained and washed with Et20 (lX). The kans were then dried overnight with a stream of nitrogen gas.

Acylation of primary amine with carboxylic acids For each carboxylic acid, 234 Microkans were suspended in NMP (300 mL), the carboxylic acid (28 mmol) was added followed by EDC (5.38 g, 28 mmol) or HBTU (10.6 g, 28 mmol) and DIEA (9.76 ml, 56 mmol). For the amine salts, additional DIEA (4.8 ml, 28 mmol) were added. The mixture was stirred overnight at room temperature. For workup, each reaction was individually drained and washed with DMF (1X). All of the microkans were then combined and washed with DMF (3X), THF (2X), DCM (3X) and ether (1X). The kans were then dried overnight with a stream of nitrogen gas Sulfonvlation of primary amine.

For each sulfonyl chloride, 234 Microkans were suspended in DCM (300 mL), the sulfonyl chloride (28 mmol) was added followed by Et3N (3.91 ml, 28 mmol). The mixture was stirred overnight at room temperature. For workup, each reaction was individually drained and washed with DMF (1X). All of the microkans were then combined and washed with DMF (3X), THF (2X), DCM (3X) and ether (1X). The kans were then dried overnight with a stream of nitrogen gas.

Cleavage of compounds attached to Rink Amide resin: The microkans were sorted into cleavage racks. A solution of 10% TFA in DCM (1.5 ml) was added to each microkan. The mixture was shaken for lh, drained, the microkan was rinsed with DCM (1mL), and the resulting solution was concentrated under reduced pressure.

Cleavage of compounds containing the t-butyl ester: The microkans were sorted into cleavage racks. A solution of TFA (1.5 ml) was added added to each microkan. The mixture was shaken for lh, drained, the microkan was rinsed with DCM (ImL), and the resulting solution was concentrated under reduced pressure.

Cleavage of all other compounds:

The microkans were sorted into cleavage racks. A solution of 50% TFA in DCM (1.5 ml) was added added to each microkan. The mixture was shaken for lh, drained, the microkan was rinsed with DCM (1mL), and the resulting solution was concentrated under reduced pressure Representative reagents suitable for use in the foregoing library synthesis are listed in Tables 1,2 and 3.

Table 1 MFCD # Name RI 1 MFCD0000148 CYCLOHEXYLAMIN HZN 6 E 2 MFCD0000320 N- (3'-j ? H NN 1 AMINOPROPYL)-2- PYRROLIDINONE 3 MFCD0000537 TETRAHYDROFURF H2N, 3 URYLAMINE 4 MFCD0000810 BENZYLAMINE H2N O 6 5 MFCD0000811 3- 3 FLUOROBENZYLAMI F NE 6 MFCD0000811 3, 4-4 HzN \ I O 6 DIMETHOXYBENZY po H, 6 LAMINE 7 MFCD0000811 3-F 7 (TRIFLUOROMETHY H2N F F L) BENZYLAMINE 8 MFCD0000812 4-tin 1 CHLOROBENZYLAM INE 9 MFCD0000816 ETHYLAMIN H3C-IIW6 0 10 MFCD0000818 2-W 0 METHOXYETHYLAM INE 11 MFCD0000822 3 CH3 CH, 0 ISOPROPOXYPROPY LAMINE 12 MFCD0000822 3-HZN 4 PHENYLPROPYLAMI NE 13 MFCD0001169 BUTYLAMINE 0 14 MFCD0001504 3-AMINO-2, 4-H3C, CH3 3 Y Y 3 1 DIMETHYLPENTANE CH3 CH3 15 MFCD0003714 CYCLOPROPANEME (NH2 7 THYLAMINE 16 MFCD0004323 (S)-(+)-ALPHA-H, C-o m Han ou NH 8 (METHOXYMETHYL) PHENETHYLAMINE HYDROCHLORIDE 17 MFCD0005149 THIOPHENE-2-H2N t -' 5 ETHYLAMIN 18 RINK

Table 2 MFCD # Name R2 1 MFCD0000018 TERT-BUTYL H C CHw 8 BROMOACETATE 2 MFCD0000071 ACETYL CHLORIDE Cyo 9 H3c 3 MFCD0000074 3 ou ci 8 PHENYLPROPIONYL CHLORIDE 4 MFCD0000127 CYCLOPROPANECA 7 RBONYL CHLORIDE Cl 5 MFCD0000199 PHENYL 4 ISOCYANATE I 0 6 MFCD0000745 P-° zu 0 TOLUENESULFONYL CHLORIDE F 7 MFCD0004077 4-F F ce 2 (TRIFLUOROMETHY F L) BENZYL CHLORIDE 8 MFCD0005948 3-II- CIS'' 2 METHYLTHIOPROPI ONYL CHLORIDE 9 NOTHING NOTHING H Table 3 MFCD # Name R1 1 BA09001 Boc-isonipecotic acid |BOe-N3COOH | J 2 BA09602 Boc- (4-piperidyl)-L- B.-. - proline 3 BA11701 R, S-Boc-2-,- Boc-N 0 carboxymorpholine 4 BA11801 R, S-Boc-1, 3-digydro-2H- Zizi isoindole carboxylic acid COOH 5 BA12701 Boc-4-phenyl-piperidine- Hot-N X _ -y 4-carboxylic acid 6BA12901 Boc-nipecotic-acid IBocNU JJ 7 MFCD0000128 CYCLOPROPANECAR 7 BOXYLIC ACID HO 8 MFCD0000239 BENZOIC ACID HO Ho 8 9 MFCD0000249 3, 4-o<_c Ho \ 2 DICHLOROBENZOIC ci ACID 10 MFCD0000250 3, 5-H3C 2 DIMETHOXYBENZOI o zu CH3 C ACID HO 11 MFCD0000253 4-PHENOXYB Ho 11. L 9 ACID 12 MFCD0000271 3, 3- 7 DIPHENYLPROPIONIC ACID o 13 MFCD0000323 2-FUROIC ACID HOR3 8 8 14 MFCD0000398 DANSYL CHLORIDE ACH 5 5 CH, 15 MFCD0000428 N, N-g ICH3 HO NCH3 3 DIMETHYLGLYCINE 16 MFCD0000434 4 < 7 HYDROXYPHENYLAC ETIC ACID 17 MFCD0000435 4-BIPHENYLACETIC 1 ACID 18 MFCD0000439 4- H. CH, HO CH 7 (DIMETHYLAMINO) CI NNAMIC ACID 19 MFCD0000526 HYDANTOIN-5-aN} ß zon 7 ACETIC ACID Y 0 20 MFCD0000584 2-HO43 o \ I 8 BENZOFURANCARBO XYLIC ACID 21 MFCD0000651 1-mec HN 5 PIPERIDINEPROPIONI HO C ACID 22 MFCD0000746 ETHANESULFONYL 3 0 CHLORIDE 23 MFCD0001231 BENZOTRIAZOLE-5- 8 CARBOXYLIC ACID NOH 24 MFCD0001261 3 HO rCH3 NVCH 1 (DIETHYLAMINO) PRO PIONIC ACID HYDROCHLORIDE 25 MFCD0001690 3- (3, 4- O OH 9 METHYLENEDIOXYP HENYL) PROPIONIC ACID 26 MFCDO002055 4-N--fo 2 ACETAMIDOBUTYRI C ACID 27 MFCD0003615 ACETIC ACIDE" 2 cl, zu 28 MFCD0003724 BOC-SER-OH HO9OH HO OH zu H3C CH, JE 29 MFCD0003729 BOC-BETA-ALA-OH H XoJLNOH 1 1 30 MFCD0003732 BOC-L-PROLINE Q) toH 4 \-OH . CH, 31 MFCD0003825 BOC-GLU (OTBU)-OH", o' o 7 oc H, c c"91 32 MFCD0005163 THIANAPHTHENE-2-HO<3 o 6 CARBOXYLIC ACm 33 MFCD0005165 4-METHYL-2-c", ZOU 3 PHENYL-1, 2, 3-o TRIAZOLE-5- CARBOXYLIC ACID 34 MFCD0005166 S-,, 9 s ci 7 CHLOROTHIOPHENE- 2-SULFONYL CHLORIDE 35 MFCD0005216 MAYBRIDGE SPB 6 02696 uN ho HO 36 MFCD0005228 MAYBRIDGE KM S-ci 4 03980 o 37 MFCD0005280 MAYBRIDGE BTB oo i 5 07063 NHN OH 38 MFCD0006804 MAYBRIDGE KM o= =o 9 06358 XNx s Ho 39 MFCD0006824 2-METHYLPYRAZINE-3WYN) NO 1 5-CARBOXYLIC ACID OH 40 MFCD0007544 (METHYLTHIO) ACETI o 4 C ACID H3C-S OH 41 MFCD0007559 4 OH 1 (DIMETHYLAMINO) P ou HENYLACETIC ACID H, CNCH, 42 MFCD0007690 BOC-5-<cX gt N 'OM H 3 AMINOVALERIC ACID 43 MFCDO015615 ISOXAZOLE-5-HO '-\ 1 CARBOXYLIC ACID o 44 MFCD0017383 4-METHYL-1, 2, 3-,./ "\ o 0 THIADIAZOLE-5-N's' OH CARBOXYLIC ACID 45 NOTHING H Example 8 Preparation of a 15,000 Member 1, 5-benzothiazepine-2-one Library Cystine carbamate resin: The nitro-phenol carbonate resin (320 g, 544.0 mmol) was swelled in anhydrous DMF (5L) in a 12L three-necked round bottom flask. Argon gas was bubbled through this slurry for one hour while stirring with an overhead stirrer. In a second 3L three-necked round bottom flask, anhydrous DMF (500 ml) and BSA (1. 5L) were added. This solution was degassed for one hour by bubbling argon gas through the solution. The DL-cysteine was then introduced into the three-necked flask. After stirring for 30 minutes, all of the cysteine had dissolved up into solution. This cysteine solution was then canulated into the 12L flask containing the resin slurry. The reaction was stirred overnight at room temperature under argon. For the workup, the reaction solution was drained off under argon. The resin was then washed with DMF (2X), 10% AcOH in DMF (3X), DMF (2X), THF (2X), DCM (2X) and diethyl ether (2X) under argon.

The resin was dried overnight with a stream of argon gas.

Synthetic halo-nitrobenzene amides:

4-Chloro-3-nitrobenzoyl chloride (33.3 g, 151.4 mmol) was partially dissolved up into anhydrous DCM (200 ml). Upon addition of DIEA (31.6 ml, 181.7 mmol), all of the benzoyl chloride dissolved up into solution. The reaction solution was cooled in an ice bath and the amine (181.7 mmol) was slowly added.

After the addition was complete, the ice bath was removed. The reaction was then stirred for approximately 6 hours at room temperature. It was concentrated down and the residue was used directly in the coupling step without further purification.

Synthetic halo-nitrobenzene ureas: 4-Fluoro-3-nitrophenyl isocyanate (27.5 g, 151. 0 mmol) was dissolved into anhydrous DCM (200 ml).

This solution was cooled in an ice bath and the amine (181.2 mmol) was slowly added. After the addition was complete, the ice bath was removed. The reaction was then stirred for approximately 6 hours at room temperature. It was concentrated down and the residue was used directly in the coupling step without further purification.

Halo-nitrobenzene coupling: For each halo-nitrobenzene, 42 Macrokans (each containing 300 mg of cysteine resin with a loading of 1.2 mmol/g) were placed into a 1L three-necked flask fitted with an overhead stirrer and argon line. The flask was flushed with argon for 30 minutes. Degassed anhydrous DMF (250 ml) was added to the flask.

While stirring the Macrokans under argon, DBU (22.6 ml, 151.2 mmol) was added. After stirring for approximately 5 minutes, the halo-nitrobenzene (151.2 mmol) was then added. The reaction was stirred under argon for several hours. The argon lines were then removed, the reaction capped tightly and stirred overnight at room temperature. For the workup, the reaction solution was drained off under argon. The Macrokans were then washed with DMF (3X), 10% HOAc in DMF (2X), 20% aqueous THF (2X), THF (2X), DCM (2X) and diethyl ether (1X). The kans were dried overnight with a stream of nitrogen gas.

Reduction of nitro group : 924 Macrokans (each containing 300 mg of resin with a loading of 1.2 mmol/g) were placed into a 12L three-necked round bottom flask fitted with an overhead stirrer and a heating mantle. DMF (6L) and tin dichloride dihydrate (750.5 g, 3326.4 mmol) were added to the flask. The reaction was stirred at 50 degrees centigrade overnight. For the workup, the reaction solution was drained off. The resin was then washed with DMF (3X), aqueous THF (1X), THF (2X), DCM (2X), and diethyl ether (IX). The kans were dried overnight with a stream of nitrogen gas.

Cvclization to benzothiazepine ring system :

924 Macrokans (each containing 300 mg of resin with a loading of 1.2 mmol/g) were placed into a 12L three-necked round bottom flask fitted with an overhead stirrer and a heating mantle. The resin in the kans was swelled in anhydrous NMP (6L). EDC (318.9 g, 1663.2 mmol) was added and the reaction was stirred overnight. For the workup, the kans were washed with DMF (1X), aqueous DMF (1X), DMF (1X), aqueous THF (1X), THF (2X), DCM (2X) and diethyl ether (1X). The kans were dried overnight with a stream of nitrogen gas.

Oxidation to sulfone: The resin in 420 Macrokans (each containing 300 mg of resin with a loading of 1.2 mmol/g) were swelled in DCM (4L). MCPBA (208.7 g of 50% pure reagent, 604.8 mmol) was added and the reaction was stirred at room temperature 5.5 hours. For the workup, the reaction solution was drained off and the resin was washed with DCM (2X), aqueous THF (2X), THF (2X) and diethyl ether (1X). The kans were dried overnight with a stream of nitrogen gas.

Alkylation reaction: For each alkyl halide, 44 Macrokans (each containing 300 mg of resin with a loading of 1.2 mmol/g) were placed into a 1L three-necked round bottom flask fitted with an overhead stirrer. The resin in the kans was swelled with anhydrous DMF (350 ml). The DBU (23.7 ml, 158.4 mmol) was added and the reaction was stirred for 15 minutes. The alkyl halide (158. 4 mmol) was then introduced. KI (158. 4 mmol) if needed was added last. The reaction was stirred overnight at room temperature. For the workup, the reaction solution was drained off and the kans were washed with DMF (2X), 10% HOAc in DMF (2X), 20% aqueous THF (2X), THF (2X), DCM (2X) and diethyl ether (1X). The kans were dried overnight with a stream of nitrogen gas.

TFP resin loading : For each carboxylic acid, TFP resin (20g with a loading of 1.25 mmol/g) was introduced into a 250 ml glass peptide vessel. The resin was swelled in DMF (120 ml). The carboxylic acid (250 mmol), DMAP (3.05 g, 25 mmol) and DIC (39.14 ml, 250 mmol) were then added sequentially. The reaction was mixed on a wrist shaker overnight. For the workup, the reaction solution was drained off and the resin was washed with DMF (3X), THF (3X), DCM (3X), and diethyl ether (IX). The resin was dried in a vacuum oven at room temperature overnight.

Archiving, cleaving and free basing : For each Macrokan, the cap was removed and the resin and tag were poured into a 16X100 mm glass test tube. Twenty two racks of 40 tubes each were archived in the Irori system. For each tube, the resin was

cleaved with a 50% TFA/DCM solvent mixture for one hour and then concentrated down. The resulting residue was azeotroped with DCM to remove the remaining traces of TFA. MP-Carbonate resin (411 mg, 1.08 mmol) and DMF (4 ml) were added to the residue (approximately 0.360 mmol of product per kan) in each test tube.

After vortexing for several seconds to dissolve up the cleaved compounds, the reaction was allowed to sit at room temperature overnight. The liquid above the resin was transferred to another test tube through a filter tube using a Packard liquid handler. The resin was then washed twice with DMF (3 ml). Each of these washings was transferred to the collection tube giving approximately 9 ml total of a benzothiazepine free amine stock solution.

Reaction with TFP resin: Each set of 80 benzothiazepine free amine stock solutions (two racks of 40 tubes each) was reacted with 20 acylated TFP resins. 400 uL of each stock solution was added to approximately 15 mg of acylated TFP resin per well. (Note: Each 80 well plate contained the same TFP activated acid resin in each well but a different amine in each well). The reactions were mixed on an orbital shaker at room temperature for three days. The product suspension was filtered through filter plates into two daughter plates using a Tomtec. The products were concentrated down in Savants and GeneVacs at 65 degrees centigrade.

Table 4,5 and 6 list the reagents used in combinatorial positions 1,2 and 3 in this library.

Table 1 Structure Ber 0 0 o-a c cH. 0 c I °vx o-0 0 CH + cri 3 O +-0 + 0 O 0N-Q 0'N N6 0 C, zizi O-O o-o Cl N Cl F o-cite 0 N N N - [vJ ; N OH OH 0 O Q. H H H H It. 0 °~, O I, cf"i3 C) O N. N NHa w I IO F O_+ N It+ F 0 Cl cl, cl 0 N I j N O N CH3 O N'O-3 - N- o oJ F'F 0 N F cri Cl 1. H r CI N oCl I y N Table 2 Structure 3 cl ci <o)- H CL C H3 H3C+Br Cl r 3 N < "CI N \C H3c 0 \-CH3 N O CH Cl Ct \j/ \ CH3 N CI N CH3 BrO w H3C ci ci / ce ci ci s CI CH3 CTH Cul N/\ CI CI--HsC ci 11-o CRI Hic O H3C Table 3 Structure HO » t rY X J>N 0 0 0 H N 0 HO 0 0 Chkd n d"3 O HIC HO 0 H3C OH 0 H3c 3 O O O H3C CH, O /, CI 0 ci CH3 H33x0 Ho cl '00H-CCHpo On HO c. -0 N 0 0' ho ON CH3 HO 0 ou on 0OH 0