WO2003031376A1 - Solid phase synthesis of substituted 1,5-benzodiazepine-2-one and 1,5-benzothiazepine-2-one - Google Patents

Abstract

A solid phase synthetic method for making substituted 1,5-benzodiazepine-2-one or 1,5-benzothiazepine-2-one. The method is useful for synthesis of large numbers of compounds through automated parallel synthesis or combinatorial library generation and is thus important to rapid discovery or new therapeutic agents containing the base structure of 1,5-benzodiazepine-2-one or 1,5-benzothiazepine-2-one.

Description

SOLID PHASE SYNTHESIS OF SUBSTITUTED l,5-BENZODIAZEPINE-2-ONE AND 1,5-

BENZOTHIAZEPINE-2-ONE

FIELD OF THE INVENTION This invention is directed to the solid phase synthesis of substituted l,5-benzodιazepιne-2-one and l,5-benzothιazepme-2-one. This application is based on and claims pnonty from U.S. Provisional Application 60/329,195 filed on December 10, 2001, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION Solid-phase synthetic techniques, in which a reagent is immobilized on a polymeric matenal which is inert to the reagents and reaction conditions employed, as well as bemg 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 polymenc reagent can also be used m 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 equihbnum 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 l,5-benzodιazepme-2-one and l,5-benzothιazepιne-2-one are present in numerous pharmacologically active compounds including for example ιnterleukm-1 J converting enzyme Inhibitors, (See International Application WO 9722619 and International Application WO 953508); treatment of arrhythmia, (See International Application WO 9640656); cholecystokinm receptor antagonists, (See International Application WO 9401421-Al); angiotensm II antagonists, (See International Application WO 9413651 -A 1) Thus, the development of new synthetic methodology for prepanng substituted 1,5- benzodιazepme-2-one and l,5-benzothιazepme-2-one, particularly solid phase synthetic techniques which are especially useful for synthesis of large numbers of compounds through automated parallel synthesis or combinatonal library generation, is central to the rapid discovery of new therapeutic agents containing this functionality.

The solid phase synthesis of substituted l,5-benzodιazeριne-2-one is descnbed in Lee et al , J Org Chem 1999, 64, 3060, Schwartz et al , J Org Chem 1999,64, 2219, using 4-fluoro-3-nιtrobenzoιc acid as starting material and a carboxarmde at position 7 as a point of attachment to the resin SUMMARY OF THE INVENTION

The present invention involves the synthesis of 3-amino-l,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 l,5-benzothiazepine-2-one compounds of formula

wherein

X is NHR⁴ or S or SO or SO₂

R⁴ is hydrogen, aliphatic, aromatic, -C(O)-R¹³, SO2-R¹⁴, C(O)-N-R¹⁵ or C(O)-0-R¹⁶;

R¹³, R¹⁴, R¹⁵, R¹⁶are independently aliphatic or aromatic;

R¹ is aliphatic or aromatic; R² is aliphatic or aromatic

R³ is NR⁵R⁶, R⁵ is H, aliphatic or aromatic; R⁶ is -C(O)-R⁷, SO₂-R⁸ or C(0)-N-R⁹ or C(0)-0-R¹⁰; and

R⁷, R⁸, R⁹, R¹⁰are 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; R¹² is an aldehyde; and

P¹ is a base-labile nitrogen protecting group or a metal-labile nitrogen protecting group or a nucleophilic labile protecting group, R⁵ is alkyl or aryl; R⁷ιs alkyl or aryl;

(2) introducing R⁴

(3) removing P¹

(4) introducing R⁵ and R⁶

(5) isolating the substituted l,5-benzodιazepme-2-one derivative of the following formula:

In another aspect, this invention compnses: (1) Reacting resm bound cysteme derivatives with o-halo-mtrobenzene derivatives to produce compounds of the general formula:

wherein

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

DETAILED DESCRIPTION OF THE INVENTION

Definitions of Terms

As used above, and throughout the descnption 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 nng 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(0)-ZH wherein Z is O or NR' and R¹ 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, Multipin™ 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, acyhsothiocyanate, aminocaproyl, benzoyl, methoxycarbonyl, 2,2,2-tπfluoroethoxycarbonyl, 2-trιmethylsιlylethxoycarbonyl, vmyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1,1-dιmethylpropynyloxycarbonyl, benzyloxycarbonyl

(CBZ), p-nitrophenylsulfmyl, p-nitrobenzyloxycarbonyl, 2,4-dιchlorobenzyloxycarbonyl, allyloxycarbonyl (Alloc),

1-ιsopropylallyloxycarbonyl, cinnamyloxycarbonyl and 4-nιtrocιnnamyloxycarbonyl,

9-fluorenylmethoxycarbonyl (fmoc), 9-(2-sulfo)fluorenylmethoxycarbonyl,

9-(2,2-dιbromo)-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 amme base. Representative base-labile nitrogen protecting groups include 9-fiuorenylmethoxycarbonyl (fmoc), 9-(2-sulfo)fluorenylmethoxycarbonyl,

9-(2,2-dιbromo)-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-ιsopropylallyloxycarbonyl, cinnamyloxycarbonyl, 4- mtrocmnamyloxycarbonyl, and the like.

"Symmetrical diamine" means a molecule with two identical ammo termini. Examples of symmetrical diammes include pφerazine, 4-ammo-amlιne, and 4-amιnomethyl-benzylamιne.

"Aliphatic" means a radical denved 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 denved 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.

"Acylammo" 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, z-butenyl, 3-methylbut-2-enyl, /z-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

"Alkenyloxy" means an alkenyl-O- group wherein the alkenyl group is as herein descnbed. 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, t-propoxy, n-butoxy, heptoxy, and the like.

"Alkoxyalkyl" means an alkyl-0-alkylene- group wherein alkyl and alkylene are as defined herein. Representative alkoxyalkyl groups include methoxyethyl, ethoxymethyl, «-butoxymethyl and cyclopentylmethyloxyethyl .

"Alkoxyalkoxy" means an alkyl-O-alkylenyl-0- 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 m the chain. Preferred alkyl groups have 1 to about 12 carbon atoms m 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, acylammo, aroylammo, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl Representative alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, H-propyl, t-propyl, n-butyl, t-butyl, «-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(0)_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, -0-, -S(0)_m (where m is 0-2), phenylene or -NR'- (where R' is lower alkyl). Representative alkynylene include -C ≡=€-, -C ≡≡€-CH₂-, -C ≡ -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-S0₂-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-Sθ2-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, t-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, w-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 wherem alkynyl and alkylene are defined herein.

NR17

" 18

"Amidino" or "amidine" means a group of formula C-NR wherein R¹⁷ is hydrogen; R¹⁹0₂C- wherem R¹⁹ is hydrogen, alkyl, aralkyl or heteroaralkyl; R¹⁹0-; R¹⁹C(0)-, cyano, alkyl, nitro, or amino, and R¹⁸ is selected from hydrogen; alkyl; aralkyl; and heteroaralkyl.

1 2 1 2 "Ammo" means a group of formula Y Y N- wherem Y and Y are independently hydrogen;

1 2 1 2 acyl; or alkyl, or Y and Y taken together with the N through which Y and Y are linked form a 4 to 7 membered azaheterocyclyl. Representative ammo groups include ammo (H₂N-), methylammo, dimethylammo, diethylamino, and the like.

"Ammoalkyl" means an amino-alkylene- group wherem ammo and alkylene are defined herein. Representative ammoalkyl groups include aminomethyl, ammoethyl, dimethylammomethyl, and the like.

"Aralkenyl" means an aryl-alkenylene- group wherem 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 wherem aralkyl is defined herein. Representative aralkoxy groups include benzyloxy, naphth-1-ylmethoxy, naphth-2-ylmethoxy, and the like.

"Aralkyloxyalkyl" means an aralkyl-0-alkylene- group wherein aralkyl and alkylene are defined herein. A representative aralkyloxyalkyl group is benzyloxyethyl.

"Aralkyloxycarbonyl" means an aralkyl-O-CO- group wherem aralkyl is defined herein. A representative aralkoxycarbonyl group is benzyloxycarbonyl. "Aralkyloxycarbonylalkyl" means an aralkoxycarbonyl-alkylene- wherem aralkyloxycarbonyl and alkylene are defined herein. Representative aralkoxycarbonylalkyls include benzyloxycarbonylmethyl, benzyloxycarbonylethyl.

"Aralkyl" means an aryl-alkylene- group wherem 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-S0₂- group wherem aralkyl is defined herein "Aralkylsulfinyl" means an aralkyl-SO- group wherem aralkyl is defined herein.

"Aralkylthio" means an aralkyl-S- group wherem 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 multicychc nng 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 multicychc cycloalkyl include 1-decalm, norbornyl, adamantyl, and the like. The prefix spiro before cycloalkyl means that gemmal substituents on a carbon atom are replaced to form 1,1 -cycloalkyl.

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

"Cycloalkenyl" means a non-aromatic mono- or multicychc 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 multicychc cycloalkenyl is norbornylenyl.

"Heterocyclenyl" means a non-aromatic monocyclic or multicychc nng system of about 3 to about nng atoms, preferably about 5 to about 10 ring atoms, m which one or more of the atoms in the nng 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 "rmg 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-dιoxιde. Representative monocyclic azaheterocyclenyl groups include 1,2,3,4- tetrahydropyndine, 1,2-dιhydropyndyl, 1 ,4-dιhydropyndyl, 1,2,3,6-tetrahydropyndιne, 1,4,5,6-tetrahydropyrιrnιdme, 2-pyrrohnyl, 3-pyrrolιnyl, 2-ιmιdazohnyl, 2-pyrazolmyl, and the like. Representative oxaheterocyclenyl groups include 3,4-dιhydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A representative multicychc oxaheterocyclenyl group is 7-oxabιcyclo[2.2.1]heptenyl. Representative monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like

"Heterocyclyl" means a non-aromatic saturated monocyclic or multicychc ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, m which one or more of the atoms m the nng system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heterocyclyls contain about 5 to about 6 nng atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a nng 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 pipendyl, pyrrolidinyl, piperazinyl, morphohnyl, thiomorphohnyl, thiazohdmyl, 1,3-dιoxolanyl, 1,4-dιoxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

"Aryl" means an aromatic monocyclic or multicychc nng 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 "nng 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 multicychc ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 nng atoms, m which one or more of the atoms in the nng system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to about 6 nng 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 nng atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyrazinyl, furanyl, thienyl, pyridyl, pynmidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, tπazolyl, 1 ,2,4-thιadιazolyl, pyrazmyl, pyndazmyl, qumoxahnyl, phthalaz yl, ιmιdazo[l,2-a]pyndιne, ιmιdazo[2,l-b]thιazolyl, benzofurazanyl, mdolyl, azamdolyl, benzimidazolyl, benzothienyl, qumolmyl, imidazolyl, thienopyndyl, qumazohnyl, thienopynmidyl, pyrrolopyndyl, lmidazopyπdyl, lsoqumolmyl, benzoazaindolyl, 1,2,4-tnazmyl, 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-dιhydronaphthylene, indene, and the like, m 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-l-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 "nng 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-dιoxιde. Representative preferred fused arylheterocyclyl rmg systems include phthahmide, 1 ,4-benzodιoxane, mdolmyl, 1,2,3,4-tetrahydroιsoqumolιne, 1,2,3,4-tetrahydroquιnolme, lH-2,3-dιhydroιsoιndolyl, 2,3-dιhydrobenz[f]ιsomdolyl, l,2,3,4-tetrahydrobenz[g]ιsoquιnohnyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclylaryl" means a radical denved from a fused aryheterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Representative preferred fused heterocyclylaryl rmg 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 denved from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion Preferred fused heteroarylcycloalkenyls are those wherem the heteroaryl and the cycloalkenyl each contain about 5 to about 6 nng 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 nng system substituents, wherein "nng 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-dιhydroιsoqumolyl, 5,6-dιhydroquιnoxalmyl, 5,6-dihydroqumazolmyl, 4,5-dιhydro- 1 H-benzimidazolyl,

4,5-dιhydrobenzoxazolyl, 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 πng atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a nng atom. The fused heteroarylcycloalkyl is optionally substituted by one or more nng system substituents, where "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-tetrahydroqumolιnyl, 5,6,7,8-tetrahydroιsoqumolyl, 5,6,7,8-tetrahydroquιnoxahnyl, 5,6,7,8-tetrahydroquιnazolyl, 4,5,6,7-tetrahydro-lH-benzιmιdazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, lH-4-oxa-l,5-dιazanaphthalen-2-onyl, 1 ,3-dιhydroιmιdιzole-[4,5]-pyπdιn-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 denved from a fused heteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkylheteroaryl are as descnbed 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 nng system substituents, wherem "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-dιoxιde. Representative fused heteroarylheterocyclenyl include 7,8-dιhydro[l,7]naphthyπdιnyl, 1,2- dιhydro[2,7]naphthyπdιnyl,

6,7-dιhydro-3H-ιmιdazo[4,5-c]pyπdyl, l,2-dιhydro-l,5-naphthyndmyl, l,2-dιhydro-l,6-naphthyndmyl, l,2-dιhydro-l,7-naphthyndmyl, l,2-dιhydro-l,8-naphthyndmyl, l,2-dιhydro-2,6-naphthyndmyl, and the like, in which the bond to the parent moiety is through a non aromatic carbon atom.

"Fused heterocyclenylheteroaryl" means a radical denved 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 nng 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 nng system substituents, wherem "nng 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-dιoxιde. Representative fused heteroarylheterocyclyl include 2,3-dιhydro-lH pyrrol[3,4- b]quιnolm-2-yl,

1,2,3,4-tetrahydrobenz [b][l,7]naphthyndιn-2-yl, 1,2,3,4-tetrahydrobenz [b][l,6]naphthyndιn-2-yl, 1 ,2,3,4-tetrahydro-9H-pyndo[3,4-b]ιndol-2yl, 1 ,2,3,4-tetrahydro-9H-pyndo[4,3-b]ιndol-2yl, 2,3,-dιhydro-lH-pyrrolo[3,4-b]mdol-2-yl, lH-2,3,4,5-tetrahydroazepιno[3,4-b]ιndol-2-yl, lH-2,3,4,5-tetrahydroazepmo[4,3-b]ιndol-3-yl, lH-2,3,4,5-tetrahydroazepmo[4,5-b]mdol-2 yl, 5,6,7,8-tetrahydro[l,7]napthyndmyl, l,2,3,4-tetrhydro[2,7]naphthyndyl, 2,3-dιhydro[l,4]dιoxιno[2,3-b]pyπdyl, 2,3-dιhydro[l,4]dιoxmo[2,3-b]pryιdyl, 3,4-dιhydro-2H-l-oxa[4,6]dιazanaphthalenyl, 4,5,6,7-tetrahydro-3H-ιmιdazo[4,5-c]pyπdyl, 6,7-dιhydro[5,8]dιazanaphthalenyl, l,2,3,4-tetrahydro[l,5] napthyπdmyl, 1 ,2,3 ,4-tetrahydro[ 1 ,6]napthyndιnyl, 1 ,2,3 ,4-tetrahydro[ 1 ,7]napthyndmyl, l,2,3,4-tetrahydro[l,8]napthyndιnyl, l,2,3,4-tetrahydro[2,6]napthyndιnyl, 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, wherem aryl is defined herein.

"Benzyl" means a phenyl-CH₂- group. Substituted benzyl means a benzyl group in which the phenyl rmg is substituted with one or more ring system substituents. Representative benzyl include 4- bromobenzyl, 4-methoxybenzyl, 2,4-dιmethoxybenzyl, and the like. "Carbamoyl" means a group of formula Y 1 Y2 NCO- wherem Y 1 and Y2 are defined herein.

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

"Carboxy" and "carboxyl" mean a HO(0)C- group (ι e. a carboxylic acid). "Carboxyalkyl" means a HO(O)C-alkylene- group wherem alkylene is defined herein. Representative carboxyalkyls include carboxymethyl and carboxyethyl.

"Cycloalkyloxy" means a cycloalkyl-O- group wherem 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-pyndylvιnyl, thienylethenyl, pyndylethenyl, 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, pyndylmethyl, lmidazolylmethyl, pyrazinylmethyl, and the like. "Heteroaralkyloxy" means an heteroaralkyl-O- group wherem heteroaralkyl is defined herein. A representative heteroaralkyloxy group is 4-pyndylmethyloxy.

"Heteroaralkyloxyalkenyl" means a heteroaralkyl-O-alkenylene- group wherein heteroaralkyl and alkenylene are defined herein. A representative heteroaralkyloxyalkenyl group is 4-pyndylmethyloxyallyl . "Heteroaralkyloxyalkyl" means a heteroaralkyl-O-alkylene- group wherem heteroaralkyl and alkylene are defined herein. A representative heteroaralkyloxy group is 4-pyndylmethyloxyethyl

"Heteroaralkynyl" means an heteroaryl-alkynylene- group wherem heteroaryl and alkynylene are defined herein. Preferred heteroaralkynyls contain a lower alkynylene moiety. Representative heteroaralkynyl groups include pyπd-3-ylacetylenyl, qumolm-3-ylacetylenyl, 4-pyndylethynyl, and the like.

"Heteroaroyl" means an means a heteroaryl-CO- group wherem heteroaryl is defined herein. Representative heteroaroyl groups include thiophenoyl, mcotinoyl, pyrrol-2-ylcarbonyl, pyndinoyl, and the like.

"Heteroaryldiazo" means an heteroaryl-N=N- group wherein heteroaryl is as defined herein "Heteroarylsulphonylcarbamoyl" means a heteroaryl-S0₂-NH-CO- group wherem heteroaryl is defined herein.

"Heterocyclylalkyl" means a heterocyclyl-alkylene- group wherem 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 quinuchdyloxy, pentamethylenesulfideoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrohdinyloxy, tetrahydrofuranyloxy, 7-oxabιcyclo[2.2. l]heptanyloxy, hydroxytetrahydropyranyloxy, hydroxy-7-oxabιcyclo[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. o- l ₊

"N-oxide" means a ^{^}~ N ~ group.

"Oxo" means a group of formula O=,

"Phenoxy" means a phenyl-O- group wherem the phenyl nng is optionally substituted with one or more nng system substituents as defined herein.

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

"Phenylthio" means a phenyl-S- group wherem the phenyl rmg is optionally substituted with one or more ring system substituents as defined herein. "Pyndyloxy" means a pyndyl-O- group wherein the pyndyl nng is optionally substituted with one or more rmg 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 nng system. Rmg 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, amidmo, Y*Y²N-, Y¹Y²N-alkyl-, Y¹ Y²NCO- or Y¹ Y²NS02-, wherem Y¹ and Y²are independently hydrogen, alkyl, aryl, and aralkyl, or where the substituent is Y 1 Y2 N- or Y 1 Y2 N-alkyl-

1 2 1 2 then one of Y and Y is acyl or aroyl and the other of Y and Y is hydrogen, alkyl, aryl, and aralkyl.

When a πng system is saturated or partially saturated, the "ring system substituent" further comprises methylene (H2C=), oxo (0=) and thioxo (S=). "Sulfamoyl" means a group of formula Y YT FSO₂- wherein Y and Y are defined herein. Representative sulfamoyl groups are sulfamoyl (H₂NSO₂-) and dimethylsulfamoyl (Me₂NSO -).

Preferred Embodiments The solid phase synthesis of substituted l,5-benzodiazepine-2-one compounds according to this invention is outlined in Scheme 1 wherem R¹, R⁴, R⁵, R⁶, R¹¹, R¹², P¹ and L are defined herein. The groups R¹, R⁴, R⁵, R⁶, R¹¹, R¹²may 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 animation of a resin of formula la with an amme of formula HNRl 1 using, for example sodium tnacetoxyborohydnde, sodium cyanoborohydnde or sodium borohydnde in acetic acid/DMF, or by nucleophilic displacement of the leaving group (LG) from the resm of formula lb with an amme of formula HNR" in the presence of base. Preferred leaving groups are Br and CI.

Preferred resins suitable for reductive alkylation with an amine of formula HNR¹¹ include: 3,5-dιmethoxy-4-formyl-phenoxymethyl-copoly(styrene-dιvmylbenzene)-resm (BAL resin), designated herein as

3-methoxy-4-formyl-phenoxymethl- copoly(styrene-dιvιnylbenzene)-resm, designated herein as

Preferred resins suitable for alkylation with an amme of formula NHR¹ include: 4-(chloromethyl)phenoxymethyl-copoly(styrene-dιvmylbenzene)-resm, designated herein as

^O C ,

4-(4-bromomethyl)phenoxymethyl-copoly(styrene-dιvιnylbenzene)-resm, designated herein as

4-bromomethyl-3-nιtro-benzamιdomethyl- copoly(styrene-dιvmylbenzene)-resιn (Baldwin, J. Am. Chem. Soc. 1995, 117, 5588), designated herein as

Coupling of the ammo resin 2 with a bromo- chloro- or iodo- carboxylic acid derivative, halo- R¹²-COOH, in a suitable organic solvent such as dimethylformamide, dichloromethane, DMSO or THF using methods and reagents well-known m the art of amide bond formation results in formation of the resin-bromo- chloro- or lodoamide 3. Coupling times range from about 2 to about 12 hours, depending upon bromo- chloro- or iodo- carboxylic acid denvative 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-methylpipeπdine; diisopropylcarbodnmide (DIC) in the presence of 1 -hydroxybenzotnazole (HOBT); bιs(2-oxo-3-oxazohdmyl)-phosphonιc chloride (BOP-C1) in the presence of tπethylamme; 2-(lH-benzotπazole-l-yl)-1.1.3.3-tetramethyluromum tetrafluoroborate (TBTU) in the presence of dnsopropylethyl amine; N-hydroxysuccimmide in the presence of dicyclohexylcarbodnmide (DCC); or bromo-tns-pyrrohdino-phosphonium hexafluorophosphate (Pybrop), and the like. Alternatively, the carboxylic acid moiety of bromo- chloro- or iodo- carboxylic acid denvative may be converted to a reactive derivative such as the acid bromide, chlonde or fluoride or a symmetrical or mixed anhydride which is then reacted with the ammo resm. Preferred bromo- chloro- or iodo- carboxylic acid denvatives include bromo-acetic acid, chloroacetic acid, lodoacetic acid, bromobenzooic acid, chlorobenzoic acid, lodobenzoic acid, bromobutync acid, chlorobutync acid, lodobutync acid and the like. More preferred bromo- chloro- or iodo- carboxylic acid denvatives is bromo-acetic acid.

The suitably protected l,5-benzodιazepιne-2-one scaffold 4 is prepared in solution according to the method described in Shmozaki et al. Preparation and formulation of benzodiazepme denvatives as gastπn and cholecystokinin antagonists. PCT Int. Appl. WO 9825911 Al. Suitable protecting groups P¹ 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-dιbromo)-fluorenylmethoxycarbonyl, and the like, which are removed by treatment with, for example, pipeπdme, morphol e, dicyclohexylamme, dimethylaminopyπdine, dnsopropylethylamine, tetrabutylamomum 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-ιsopropylallyloxycarbonyl, cinnamyloxycarbonyl and 4- nitrocmnamyloxycarbonyl, and the like which are removed by treatment with Nι(CO)₄, in DMF/H₂0; Pd(Ph₃P)₄ and Bu₃SnH in acetic acid; Pd(Ph₃P)₄ and morpholme; Pd(Ph₃P)₂Cl₂ and Bu₃SnH in 4- mtrophenol; Pd₂(dba)₃-CHC1₃ in HC0₂H, and the like. Other suitable protecting groups are nucleophile labile protecting groups such as phtahmide, or N-2,3-dιphenylmaleιmιde which can be removed with nucleophiles such as hydrazme, phenylhydrazme or methylamine in organic solvents such as isopropanol. A more preferred nitrogen protecting group is phtahmide which can be removed with hydazme in isopropanol

The resm (3) is reacted with the protected l,5-benzodιazepme-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 hydnde, n-butylhthium, lithium bis-tπmethylsilyl acetamide, lithium dnspropylamide and the like. More prefered base is potassium tert butoxide. The group of formula R⁴ is then introduced into the resm-bound l,5-benzodιazepιne-2-one derivative (5) to form the 5 substituted l,5-benzodιazepιne-2-one derivative (6). When R⁴ is a group of formula-C(0)-R¹³ the acylation is accomplished by reaction of the resin (5) with the acid chloride of formula R13-C(0)-C1 in an organic solvent and m presence of base. A preferred solvent is pyndme which also acts as a base.

When R⁴ is a group of formula-C(O)-N¹⁵ acylation is also accomplished using the isocyanate of formula R¹⁵NCO in an organic solvent.

When R⁴ is -S0₂R¹⁴ sulfonylation is accomplished using a sulfonyl chloride of formula C1S0₂R¹⁴ in the presence of a base such as pyndine or N-methylmorpholme in an inert organic solvent such as dichloromethane. A preferred solvent is pyndme which also acts as a base.

When R⁴ is -C(0)-0-R¹⁶ acylation is accomplished using a chloroformate of formula ClC(0)-0- R¹⁶ in the presence of a base such as pyndine or N-methylmorphohne in an inert organic solvent such as dichloromethane. A preferred solvent is pyndine which also acts as a base.

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

The nitrogen protecting groups P¹ is then selectively removed by treatment of the resm-bound (5) substituted l,5-benzodιazepme-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 resm-bound 2-amιno-l,5- benzodιazepme-2-one or 3-amιno-l,5-benzodιazepme-2-one (7) to form the resm-bound N-alkylated-1,5- benzodιazepme-2-one compound (8) When R⁵ is H, no reaction is performed. When R⁵ is alkyl, alkylation can be accomplished by reductive animation, or by the so called "Fukayama" method. Reductive animation is accomplished by treatment with an aldehyde in an organic solvent such as tnmethyl orthoformate or dimethyl formamide in presence of a reducing agent such as sodium tnacetoxy borohydnde, sodium cyanoborohydnde, sodium borohydnde, lithium aluminium hydnde 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-nιtro-, the 4- nitro or the 2,4-nιtrophenyl 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 tnethylamine or diisopropylethylamme. The sulfonamide is alkylated by reaction with an alcohol R⁴-OH presence of a phosphine reagent such as tnphenyl or tπbutyl phosphine and diethylazodicarboxylate (DEAD) or dnsopropylazodicarboxylate (DIAD) in an organic solvent. The 2-nιtro-, 4-nιtro or 2,4-nιtrophenyl sulfonamide is then hydrolyzed by reaction with ethanethiol and dιazabιcyclo-[4,7]-undecene (DBU) in tetrahydrofuran to furnish the resm (7) The group of formula R⁶ is then introduced into the resin-bound 2-amino-l,5-benzodiazepine-2-one or 3- amino-l,5-benzodiazepine-2-one (7) to form the resin-bound N-alkylated-l,5-benzodiazepine-2-one compound (8).

When R⁶ is a group of formula-C(0)-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(0)-NHR⁹ formation of the urea is accomplished using the isocyanate of formula R^NCO.

When R⁶ is -S0₂R⁸ sulfonylation is accomplished using a sulfonyl chloride of formula C1S0₂R⁹ 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)-OR¹⁰ acylation is accomplished using a chloroformate of formula

C1C(0)0R¹⁰ 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 l,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, l,5-benzodiazepine-2-one scaffold (4)

The solid phase synthesis of substituted 1 ,5-benzothiazepine-2-one is described in scheme 2 where R¹, R² 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-tnmethylsilylacetamide results m the formation of (12). The thiol group of cysteme is reacted with an ortho-bromo, ortho-chloro or ortho-fluoro nitrobenzene derivative (13) (Y= Br, CI, F) in an organic solvent such as dimethylformamide in presence of a base such as tnethylamine or diisopropylethylamme to produce (14). The nitro group of intermediate (14) is converted to the amme (15) using standard reagents for the reduction of aromatic nitro groups such as tin dichloπde hydrate m dimethyl formamide, sodium borohydnde and copper acetoacetate or sodium dithiomte in ethanol. Preferred conditions include as tin dichlonde hydrate in dimethyl formamide.

Cychsation 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 l,5-benzothazepιne-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 resm-bound substituted l,5-benzothιazepme-2-one compound (18) with acid, preferably tπfluoracetic acid in dichloromethane, results in formation of the substituted l,5-benzothιazepιne-2-one compound (19) The 3 ammo-group of the l,5-benzothιazepme-2-one compound (19) is then optionally further substituted to form (20). When R⁶ is a group of formula-C(0)-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(0)-NHR⁹ formation of the urea is accomplished using the isocyanate of formula R^NCO. When R⁶ is -S0₂R⁸, sulfonylation is accomplished using a sulfonyl chloride of formula C1S0₂R⁹ m the presence of a base such as pyndine or N-methylmorpholine in an inert organic solvent such as dichloromethane. When R⁶ is -C(0)-OR¹⁰ acylation is accomplished using a chloroformate of formula C1C(0)0R¹⁰ in the presence of a base such as pyndine or N-methylmorphohne 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 l,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-dιsubstιtuted diazacylocalky carboxamide compounds using the process of this invention is outlined in Scheme 4.

Scheme 4 a) Divide into x portions

(s)— L-CHO » S r— L-N-R11 1a b) react with x amine 2^H c) combine the x portions

a) Divide into z portions

Remove P1 b) react with z R6 groups c) combine the y portions

As shown in Scheme 4, a single portion of resin (la) is divided into x smaller portions containing approximately equal amounts of resm Each portion of resm (la) is then reductively aminated as described in Scheme 1 above with a different amme 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 ammes of formula HNR¹¹ as described in Scheme 1 above to form x portions of resin (24) (X is HNR") each of which contains a different R¹¹. The group X which is substituted with NR¹¹ 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-R¹²-COOH. The bromide is then displaced with the 1,5- benzothiazepine scaffold to form a mixture of resin-bound monoprotected 1,5-benzodιazepιne compounds (5) containing x different groups at the first combinatorial position.

The mixture of resm-bound monoprotected 1,5-benzodιazepme 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 recombmed to form a single portion, referred to herein as the second combinatonal mixture, compnsing a mixture of resm bound 5-substιtuted 1,5-benzodιazepιne compounds (6) containing all possible combinations of the x R¹¹ groups and y R⁴ groups.

P¹ is then removed from the second combinatorial mixture, the resulting mixture of resin-bound 1 ,5-benzodιazepιne 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 resm-bound 1,5-benzodιazepme compounds (9).

The resin-bound 1,5-benzodιazepme compounds (9) are then cleaved from the resm as described in Scheme 1 above to give a library of substituted 1,5-benzodιazpιne 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 R¹¹ groups, 9 R4 groups and 45 R⁶ groups.

The progress of the combinatonal 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 Iron, La Jolla, California, USA) in which resm 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 combinatonal reagents. After the first combinatonal 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 Resm

4-Hydroxy-2,6-dιmethoxybenzaldehyde (127.53 g, 700.0 mmol) is dissolved in anhydrous dimethylformamide (3.0 L). Sodium hydride (26.4 g of 60% sodium hydnde 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 hydnde addition is complete, the reaction is stirred at ambient temperature for 30 minutes. Chloromethylpolystyrene resm (100.0 g of 2.0 mmol/g loaded 150-300 um beads from Polymer Laboratones) 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-phtahmιdo-l ,5-benzodιazepιne-2-one

a-Boc,a,b-dιammo propiomc acid (lOOg, 490 mmol) was dissolved in DMF (IL). Tnethylamine (200 ml, 1.3 mol) was added followed by 2-fluoronιtrobenzene (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 IN NaOH (3x500 ml). The combined aqueous extracts were acidified with 2N HCl (IL) and extracted with ethyl acetate (3x 500 ml). The combined ethyl acetate extracts were dned over sodium sulfate and concentrated to afford 218 g of an orange oil which solidified upon standing.

The crude mixture was dissolved in methanol (IL), 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), bnne (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 dned under vacuum for 3 days. Both crude mixture were punfied by chromatography (ethyl acetate :hexane 1 :9 the 5-5 then 7:3) to afford 98g (72% over 3 steps) of the 5-Boc-l,5-benzodιazepme-2- one as a white powder.

The 5-Boc-l,5-benzodιazepιne (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), tnethylamine (154 ml, 1 mol)was added followed by phtahc anhydnde (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 0°C, and then filtered to afford 73 g (64%) of 5-phtalimido-l,5-benzodiazepine-2-one a bright yellow powder.

Example 3

Preparation of l-((2terahydrofurfuryl-methyl acetamide). 3-furan-(2carboxyl)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 (IX), 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 (5L), 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.

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 (IX), THF (IX), H20 (IX), THF (2X), DCM (3X) and isopropanol (IX).

Removal of Phtahmide 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 primary 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 (IX). 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 -((cyclohexyl)acetamide). 3-dansylsulfonamide, 5acetyl-1.5-benzodiazepine-2-one.

Reductive Ammation on the BAL resin:

BAL resm (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 tnacetoxyborohydπde (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 (IX), DMF (3X), DCM (3X) and Et₂0(lX). The resm 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 (5L), 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 resm was washed with DCM (IX), DMF (3X), DCM (3X) and Et₂0(lX). The resm was then dned overnight with a stream of nitrogen gas and then for 48h m a vacuum oven.

Alkylation with Benzodiazepine Scaffold.

300mg of the precedent resm was reacted in oven dned 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 mm. at room temperature and the resin was added in one portion. The mixture was shaken overnight at room temperature, drained and the resm was washed with DMF (3X), DCM (3X) and Et₂0(lX). The resin was then dned overnight with a stream of nitrogen gas.

Acylation at N-4.

300mg of the precedent resin was suspended m anhydrous Pyndine (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 (IX).

Removal of Phtahmide Protecting group. 300 mg of the precedent resin was suspended in 25% hydrazme 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 resm was stirred overnight m DCM, drained and washed with Et₂0(lX). The resin was then dned overnight with a stream of nitrogen gas.

Sulfonylation of primary amme.

300mg of the previous resm 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 (IX). The resm 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 nnsed with DCM (lmL), 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 mtro-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.

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% HO Ac 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 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 (IX), THF (2X), DCM (2X), and diethyl ether (IX). It was dried overnight with a stream of nitrogen gas.

Cyclization to benzothiazepme 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 (IX), aqueous DMF (IX), DMF (IX), aqueous THF (IX), THF (2X), DCM (2X) and diethyl ether (IX). It was dried overnight with a stream of nitrogen gas.

Alkylation with l-bromo-3-rnethylbutane:

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 l-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% HO Ac 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.

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 (IX). 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 benzothiazepme free amine stock solution.

Reaction with TFP resin:

The above benzothiazepme 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

Cysteme carbamate resm:

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

Synthetic chloro-mtrobenzene amide- 4-Chloro-3-nιtrobenzoyl chlonde (0.79 g, 3.6 mmol) was partially dissolved up into anhydrous DCM (5 ml). Upon addition of DJEA (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-mtrobenzene butylamide coupling:

300 mg of cysteme 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-nιtrobenzene 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 resm 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 resm (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 (IX), THF (2X), DCM (2X), and diethyl ether (IX). It was dned overnight with a stream of nitrogen gas.

Cvchzation to benzothiazepme nng system:

300 mg of the reduced resin (with a loading of 1.2 mmol/g) were placed into a PP Jones' tube. The resm 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 resm was washed with DMF (IX), aqueous DMF (IX), DMF (IX), aqueous THF (IX), THF (2X), DCM (2X) and diethyl ether (IX). 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 (IX). It was dried overnight with a stream of nitrogen gas.

Alkylation reaction.

300 mg of the oxidized resm (with a loading of 1.2 mmol/g) were placed into a PP Jones' tube. The resm 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-l,2,4-oxadιazole (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 (IX). It was dried overnight with a stream of nitrogen gas.

Loading N-acetyl-L- prohne onto TFP resin: TFP resm (20g with a loading of 1.25 mmol/g) was introduced into a 250 ml glass peptide vessel. The resm was swelled in DMF (120 ml). The N-acetyl-L-prohne (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 wnst shaker overnight. For the workup, the reaction solution was drained off and the resm was washed with DMF (3X), THF (3X), DCM (3X), and diethyl ether (IX). The resin was dned m a vacuum oven at room temperature overnight.

Cleaving and free basing:

300 mg of the alkylated resm were cleaved with a 50% TFA/DCM solvent mixture for one hour and then concentrated down. The resulting residue was azeofroped with DCM to remove the remaining traces of TFA. MP-Carbonate resm (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 benzothiazepme free amme stock solution.

Reaction with TFP resin: The above benzothiazepme free amme stock solution was reacted with the N-acetyl-L-prohne 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 Gene Vac at 65 degrees centigrade to give the desired product in 87% purity.

Example 7 Preparation of a 7.290 Member 1.5-benzodιazepιne Library

hydrazme

A 18 x 9 x 45 = 7290 member library was produced using the Iron system. BAL resm was loaded in 7290 microkans.

Reductive Animation on the BAL resin:

For each amme, 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 tnacetoxyborohydπde (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 (IX). All of the microkans were then combined and washed with 10% Et3N in DMF (IX), DMF (3X), DCM (3X) and Et₂0(lX). The kans were then dned overnight with a sfream of nitrogen gas.

Removal of the Fmoc-group of Rmk Amide resm: 585 Microkans were stirred 2 h m 800 ml of a 1 :1 mixture of DMF and Piperidme. The Microkans were then washed with DMF (4x), DCM (3x) and Et₂0(lX). The kans were then dned overnight with a stream of nitrogen gas

Acylation with bromoacetic acid. 5265 Microkans were suspended in anhydrous DCM (5L), 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 (IX), ), 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 m anhydrous DMF and potassium t-butoxide (105 mL of a 1.0 M solution in THF) was added. The mixture was stirred 30 mm. 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 Et₂0(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 (IX). All of the microkans were then combined and washed with THF (IX), H20 (IX), THF (2X), DCM (3X) and isopropanol (IX).

Acylation and sulfonylation at N-4.

For each acid chloride or sulfonyl chloride, 810 Microkans were suspended in anhydrous Pyndine (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 (IX).

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 Phtahmide 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 (IX). All of the microkans were then combined and washed with DMF (3X), THF (2X), DCM (3X) and ether (IX). The kans were then dried overnight with a stream of nitrogen gas

Sulfonylation 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 (IX). All of the microkans were then combined and washed with DMF (3X), THF (2X), DCM (3X) and ether (IX). 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 (lmL), 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 (lmL), 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 (lmL), 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

Table 2

Table 3

Example 8 Preparation of a 15.000 Member 1.5-benzothiazepine-2-one Library

Cysteine 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-nιtrobenzoyl 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 amme (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-nιtrophenyl isocyanate (27.5 g, 151.0 mmol) was dissolved into anhydrous DCM (200 ml). This solution was cooled m an ice bath and the amme (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 m 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 1 L 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 stirnng 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 (IX). 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 resm was then washed with DMF (3X), aqueous THF (IX), THF (2X), DCM (2X), and diethyl ether (IX) The kans were dned ovemight with a stream of nitrogen gas

Cvchzation to benzothiazepme 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 resm 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 (IX), aqueous DMF (IX), DMF (IX), aqueous THF (IX), THF (2X), DCM (2X) and diethyl ether (IX). The kans were dried overnight with a stream of nitrogen gas.

Oxidation to sulfone:

The resm in 420 Macrokans (each containing 300 mg of resin with a loading of 1.2 mmol/g) were swelled m 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 (IX). 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 mto a IL three-necked round bottom flask fitted with an overhead stirrer. The resm m 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 (IX). The kans were dried overnight with a stream of nitrogen gas

TFP resm loading:

For each carboxylic acid, TFP resm (20g with a loading of 1 25 mmol/g) was introduced mto 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 resm was washed with DMF (3X), THF (3X), DCM (3X), and diethyl ether (IX) The resm 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 m the Iron 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 azeofroped 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) m 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 benzothiazepme free amine stock solution.

Reaction with TFP resm:

Each set of 80 benzothiazepme free amme stock solutions (two racks of 40 tubes each) was reacted with 20 acylated TFP resms. 400 uL of each stock solution was added to approximately 15 mg of acylated TFP resm per well. (Note: Each 80 well plate contained the same TFP activated acid resin in each well but a different amme 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

Table 2

Table 3

Claims

WE CLAIM:

A method of synthesizing compounds of formula:

wherem

R¹ is aliphatic or aromatic,

R⁴ is hydrogen, aliphatic, aromatic, -C(0)-R¹³, S02-R¹⁴, C(0)-N-R¹⁵ or C(0)-0-R¹⁶,

R¹³, R¹⁴, R¹⁵, R¹⁶are independently aliphatic or aromatic,

R⁵ is H, aliphatic or aromatic,

R⁶ is -C(0)-R⁷, S0₂-R⁸or C(0)-N-R⁹or C(0)-0-R¹⁰,

R⁷, R⁸, R⁹, R¹⁰ are independently aliphatic or aromatic, and

R¹¹ is L-R¹⁷, L is absent or alkylene, R¹⁷ is aliphatic, aromatic, cycloalkyl or heterocyclyl,

R¹² is alkylene, said method comprising:

( 1 ) preparing a resin-bound protected 1 ,5 -benzodiazepine-2-one compound of formula

wherem

is a solid support, L is absent or a linking group, Pi is a base-labile nitrogen protecting group or a metal-labile nitrogen protecting group or a nucleophilic labile protecting group;

(2) introducing R⁴ to afford a compound of formula

(3) removing P_! to afford a compound of formula

(4) introducing R⁶ to afford a compound of formula

(6) isolating the substituted l,5-benzodiazepine-2-one derivative of the following formula:

2. A method according to claim 1, further comprising between step (3) and step (4) an additional step: (4a) infroducing R⁶ to afford a compound of formula

which leads to a final product of formula

A method of claim 1, wherein said substituted l,5-benzodiazepine-2-one derivative isolated in step (5) is:

4. A method of claim 1, wherein said substituted l,5-benzodiazepine-2-one derivative isolated in step (5) is

5. A method of synthesizing compounds of formula

Wherein

X is S, SO or S02,

Ri and R₂ are independently aliphatic or aromatic,

R⁶ is -C(0)-R⁷, S0₂-R⁸ or C(0)-N-R⁹or C(0)-0-R¹⁰, and

R⁷, R⁸, R⁹, R^l0are independently aliphatic or aromatic, said method comprising:

(2) reacting resin bound cysteine derivatives with o-halo-nitrobenzene derivatives to produce compounds of formula:

wherein

is a solid support and L is a linking group, (2) reducing the nitro-group to amine derivative to afford compounds of formula

(3) reacting the carboxylic acid group with the amine derivative to form a benzothiazepine skeleton of formula

(4) introducing R₂ to afford substituted l,5-benzothiazepine-2-one derivatives of formula

(5) cleaving the substituted l,5-benzothiazepine^'-2-one derivative from the resin;

(6) introducing R⁶ to afford final 1 ,5-benzothiazepine-2-one derivative of formula

6. A method of claim 5, further comprising an additional step (3a) between step (3) and step (4):

(3 a) oxidizing the sulfide to the sulfone to afford compounds of formula

7. A method of claim 5, further comprising an additional step (3a) between step (3) and step (4):

(3a) converting the sulfide to the sulfoxide to afford compounds where X is SO.

A method of claim 5, wherein said final l,5-benzothiazepine-2-one derivative is:

9. A method of claim 6, wherein said final l,5-benzothiazepine-2-one derivative is: