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WO2003031376A1 - Synthese en phase solide de 1,5-benzodiazepine-2-one ou 1,5-benzothiazepine-2-one substitue - Google Patents

Synthese en phase solide de 1,5-benzodiazepine-2-one ou 1,5-benzothiazepine-2-one substitue Download PDF

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WO2003031376A1
WO2003031376A1 PCT/US2002/032496 US0232496W WO03031376A1 WO 2003031376 A1 WO2003031376 A1 WO 2003031376A1 US 0232496 W US0232496 W US 0232496W WO 03031376 A1 WO03031376 A1 WO 03031376A1
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resin
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formula
mmol
dmf
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George C. Morton
Joseph M. Salvino
Richard F. Labaudiniere
Timothy F. Herpin
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Aventis Pharmaceuticals Inc
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Aventis Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • 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-benzod ⁇ azepme-2-one and l,5-benzoth ⁇ azep ⁇ ne-2-one are present in numerous pharmacologically active compounds including for example ⁇ nterleukm-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)
  • ⁇ nterleukm-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
  • 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.
  • this invention is directed to a method of synthesizing substituted 1,5- benzodiazepine-2-one and l,5-benzothiazepine-2-one compounds of formula
  • X is NHR 4 or S or SO or SO 2
  • R 4 is hydrogen, aliphatic, aromatic, -C(O)-R 13 , SO2-R 14 , C(O)-N-R 15 or C(O)-0-R 16 ;
  • R 13 , R 14 , R 15 , R 16 are independently aliphatic or aromatic;
  • R 1 is aliphatic or aromatic
  • R 2 is aliphatic or aromatic
  • R 3 is NR 5 R 6 , R 5 is H, aliphatic or aromatic; R 6 is -C(O)-R 7 , SO 2 -R 8 or C(0)-N-R 9 or C(0)-0-R 10 ; and
  • R 7 , R 8 , R 9 , R 10 are independently aliphatic or aromatic.
  • a method for preparing such a compound comprises: (1) preparing a resin-bound protected 1 ,5-benzodiazepine-2-one compound of formula
  • L is absent or a linking group
  • R 12 is an aldehyde
  • P 1 is a base-labile nitrogen protecting group or a metal-labile nitrogen protecting group or a nucleophilic labile protecting group
  • R 5 is alkyl or aryl
  • R 7 ⁇ s alkyl or aryl
  • this invention compnses: (1) Reacting resm bound cysteme derivatives with o-halo-mtrobenzene derivatives to produce compounds of the general formula:
  • L is a solid support
  • L is a linking group Reducing the mtro-group to amme derivative
  • 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.
  • 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 R 1 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
  • solid support includes a solid support as described above which is affixed to a second inert support such as the pins described in Technical Manual, MultipinTM SPOC, Chiron
  • 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
  • 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.
  • N-protecting groups are 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,
  • 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-t ⁇ fluoroethoxycarbonyl, 2-tr ⁇ methyls ⁇ lylethxoycarbonyl, vmyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1,1-d ⁇ methylpropynyloxycarbonyl, benzyloxycarbonyl
  • 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,
  • 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- ⁇ sopropylallyloxycarbonyl, cinnamyloxycarbonyl, 4- mtrocmnamyloxycarbonyl, and the like.
  • Symmetrical diamine means a molecule with two identical ammo termini. Examples of symmetrical diammes include p ⁇ erazine, 4-ammo-aml ⁇ ne, and 4-am ⁇ nomethyl-benzylam ⁇ ne.
  • 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 heteroaryl
  • 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.
  • 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
  • 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.
  • 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).
  • 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).
  • 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-S0 2 -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-S ⁇ 2-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.
  • Amidino or “amidine” means a group of formula C-NR wherein R 17 is hydrogen; R 19 0 2 C- wherem R 19 is hydrogen, alkyl, aralkyl or heteroaralkyl; R 19 0-; R 19 C(0)-, cyano, alkyl, nitro, or amino, and R 18 is selected from hydrogen; alkyl; aralkyl; and heteroaralkyl.
  • ammo groups include ammo (H 2 N-), 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.
  • Alkenyl 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.
  • Alkyloxy means an aralkyl-O- group wherem aralkyl is defined herein.
  • Representative aralkoxy groups include benzyloxy, naphth-1-ylmethoxy, naphth-2-ylmethoxy, and the like.
  • Alkyloxyalkyl means an aralkyl-0-alkylene- group wherein aralkyl and alkylene are defined herein.
  • a representative aralkyloxyalkyl group is benzyloxyethyl.
  • Alkyloxycarbonyl 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.
  • Alkyloxyalkenyl means an aralkyl-O-alkenylene- group wherein aralkyl and alkenylene are defined herein A representative aralkyloxyalkenyl group is 3-benzyloxyallyl.
  • Alkylsulfonyl means an aralkyl-S0 2 - group wherem aralkyl is defined herein
  • Aralkylsulfinyl means an aralkyl-SO- group wherem aralkyl is defined herein.
  • Alkylthio 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 tr ⁇ ns-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.
  • 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,
  • Representative monocyclic azaheterocyclenyl groups include 1,2,3,4- tetrahydropyndine, 1,2-d ⁇ hydropyndyl, 1 ,4-d ⁇ hydropyndyl, 1,2,3,6-tetrahydropynd ⁇ ne, 1,4,5,6-tetrahydropyr ⁇ rn ⁇ dme, 2-pyrrohnyl, 3-pyrrol ⁇ nyl, 2- ⁇ m ⁇ dazohnyl, 2-pyrazolmyl, and the like.
  • Representative oxaheterocyclenyl groups include 3,4-d ⁇ hydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like.
  • a representative multicychc oxaheterocyclenyl group is 7-oxab ⁇ cyclo[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-d ⁇ oxolanyl, 1,4-d ⁇ oxanyl, 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, t ⁇ azolyl, 1 ,2,4-th ⁇ ad ⁇ azolyl, pyrazmyl, pyndazmyl, qumoxahnyl, phthalaz yl, ⁇ m ⁇ dazo[l,2-a]pynd ⁇ ne, ⁇ m ⁇ dazo[2,l-b]th ⁇ azolyl, benzofurazanyl, mdolyl, azamdolyl, benzimidazolyl, benzothienyl, qumolmyl, imi
  • 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-d ⁇ hydronaphthylene, 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.
  • 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-d ⁇ ox ⁇ de.
  • Representative preferred fused arylheterocyclyl rmg systems include phthahmide, 1 ,4-benzod ⁇ oxane, mdolmyl, 1,2,3,4-tetrahydro ⁇ soqumol ⁇ ne, 1,2,3,4-tetrahydroqu ⁇ nolme, lH-2,3-d ⁇ hydro ⁇ so ⁇ ndolyl, 2,3-d ⁇ hydrobenz[f] ⁇ somdolyl, l,2,3,4-tetrahydrobenz[g] ⁇ soqu ⁇ nohnyl, 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-d ⁇ hydro ⁇ soqumolyl, 5,6-d ⁇ hydroqu ⁇ noxalmyl, 5,6-dihydroqumazolmyl, 4,5-d ⁇ hydro- 1 H-benzimidazolyl,
  • 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 ⁇ ng atoms.
  • 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-tetrahydroqumol ⁇ nyl, 5,6,7,8-tetrahydro ⁇ soqumolyl, 5,6,7,8-tetrahydroqu ⁇ noxahnyl, 5,6,7,8-tetrahydroqu ⁇ nazolyl, 4,5,6,7-tetrahydro-lH-benz ⁇ m ⁇ dazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, lH-4-oxa-l,5-d ⁇ azanaphthalen-2-onyl, 1 ,3-d ⁇ hydro ⁇ m ⁇ d ⁇ zole-[4,5]-py ⁇ d ⁇ n-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-d ⁇ ox ⁇ de.
  • Representative fused heteroarylheterocyclenyl include 7,8-d ⁇ hydro[l,7]naphthy ⁇ d ⁇ nyl, 1,2- d ⁇ hydro[2,7]naphthy ⁇ d ⁇ nyl,
  • 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-d ⁇ ox ⁇ de.
  • Representative fused heteroarylheterocyclyl include 2,3-d ⁇ hydro-lH pyrrol[3,4- b]qu ⁇ nolm-2-yl,
  • 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.
  • Alkynyl means an aryl-alkynylene- group wherein aryl and alkynylene are defined herein.
  • Representative aralkynyl groups include phenylacetylenyl and 3-phenylbut-2-ynyl.
  • Representative aryldiazo groups include phenyldiazo and naphthyldiazo.
  • Arylcarbamoyl means an aryl-NHCO- group, wherem aryl is defined herein.
  • Benzyl means a phenyl-CH 2 - 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-d ⁇ methoxybenzyl, and the like.
  • Carbamoyl means a group of formula Y 1 Y2 NCO- wherem Y 1 and Y2 are defined herein.
  • carbamoyl groups include carbamyl (H NCO-), dimethylaminocarbamoyl (Me 2 NCO-), and the like.
  • Carboxy and “carboxyl” mean a HO(0)C- group ( ⁇ 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.
  • 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-pyndylv ⁇ nyl, 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 py ⁇ d-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.
  • Heteroarylsulphonylcarbamoyl means a heteroaryl-S0 2 -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-oxab ⁇ cyclo[2.2. l]heptanyloxy, hydroxytetrahydropyranyloxy, hydroxy-7-oxab ⁇ cyclo[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.
  • 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, a
  • one of Y and Y is acyl or aroyl and the other of Y and Y is hydrogen, alkyl, aryl, and aralkyl.
  • “Sulfamoyl” means a group of formula Y YT FSO 2 - wherein Y and Y are defined herein. Representative sulfamoyl groups are sulfamoyl (H 2 NSO 2 -) and dimethylsulfamoyl (Me 2 NSO -).
  • 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 HNR 11 include: 3,5-d ⁇ methoxy-4-formyl-phenoxymethyl-copoly(styrene-d ⁇ vmylbenzene)-resm (BAL resin), designated herein as
  • Preferred resins suitable for alkylation with an amme of formula NHR 1 include: 4-(chloromethyl)phenoxymethyl-copoly(styrene-d ⁇ vmylbenzene)-resm, designated herein as
  • 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-methylpipe ⁇ dine; diisopropylcarbodnmide (DIC) in the presence of 1 -hydroxybenzotnazole (HOBT); b ⁇ s(2-oxo-3-oxazohdmyl)-phosphon ⁇ c chloride (BOP-C1) in the presence of t ⁇ ethylamme; 2-(lH-benzot ⁇ azole-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.
  • an appropriate activating agent such as isoprop
  • 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-benzod ⁇ azep ⁇ ne-2-one scaffold 4 is prepared in solution according to the method described in Shmozaki et al. Preparation and formulation of benzodiazepme denvatives as gast ⁇ n and cholecystokinin antagonists. PCT Int. Appl. WO 9825911 Al.
  • Suitable protecting groups P 1 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-d ⁇ bromo)-fluorenylmethoxycarbonyl, and the like, which are removed by treatment with, for example, pipe ⁇ dme, morphol e, dicyclohexylamme, dimethylaminopy ⁇ dine, dnsopropylethylamine, tetrabutylamomum fluoride, and the like in a suitable solvent such as DMF.
  • a suitable solvent such as DMF.
  • suitable protecting groups are metal-labile nitrogen protecting groups which include allyloxycarbonyl, 1- ⁇ sopropylallyloxycarbonyl, cinnamyloxycarbonyl and 4- nitrocmnamyloxycarbonyl, and the like which are removed by treatment with N ⁇ (CO) 4 , in DMF/H 2 0; Pd(Ph 3 P) 4 and Bu 3 SnH in acetic acid; Pd(Ph 3 P) 4 and morpholme; Pd(Ph 3 P) 2 Cl 2 and Bu 3 SnH in 4- mtrophenol; Pd 2 (dba) 3 -CHC1 3 in HC0 2 H, and the like.
  • nucleophile labile protecting groups such as phtahmide, or N-2,3-d ⁇ phenylmale ⁇ m ⁇ de 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-benzod ⁇ azepme-2-one scaffold (4) in presence of a base in an organic solvent such as dichloromethane or dimethylformamide.
  • a base in an organic solvent such as dichloromethane or dimethylformamide.
  • Preferred bases include potassium tert-butoxide, sodium hydnde, n-butylhthium, lithium bis-t ⁇ methylsilyl acetamide, lithium dnspropylamide and the like. More prefered base is potassium tert butoxide.
  • the group of formula R 4 is then introduced into the resm-bound l,5-benzod ⁇ azep ⁇ ne-2-one derivative (5) to form the 5 substituted l,5-benzod ⁇ azep ⁇ ne-2-one derivative (6).
  • R 4 is a group of formula-C(0)-R 13 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.
  • R 4 is a group of formula-C(O)-N 15 acylation is also accomplished using the isocyanate of formula R 15 NCO in an organic solvent.
  • R 4 is -S0 2 R 14 sulfonylation is accomplished using a sulfonyl chloride of formula C1S0 2 R 14 in the presence of a base such as pyndine or N-methylmorpholme in an inert organic solvent such as dichloromethane.
  • a base such as pyndine or N-methylmorpholme
  • an inert organic solvent such as dichloromethane.
  • a preferred solvent is pyndme which also acts as a base.
  • R 4 is -C(0)-0-R 16 acylation is accomplished using a chloroformate of formula ClC(0)-0- R 16 in the presence of a base such as pyndine or N-methylmorphohne in an inert organic solvent such as dichloromethane.
  • a base such as pyndine or N-methylmorphohne
  • an inert organic solvent such as dichloromethane.
  • a preferred solvent is pyndine which also acts as a base.
  • R 4 is aliphatic or aromatic
  • alkylation is accomplished using a bromide R 4 -Br, chloride R 4 - CI or idodide R 4 -I in presence of a base such as tnethylamine or diisopropylethylamme in an organic solvent.
  • the nitrogen protecting groups P 1 is then selectively removed by treatment of the resm-bound (5) substituted l,5-benzod ⁇ azepme-2-one compound (6) with a base, metal or a nucleophile to form the resin- bound compound (7).
  • the group of formula R 5 is then optionally introduced into the resm-bound 2-am ⁇ no-l,5- benzod ⁇ azepme-2-one or 3-am ⁇ no-l,5-benzod ⁇ azepme-2-one (7) to form the resm-bound N-alkylated-1,5- benzod ⁇ azepme-2-one compound (8)
  • R 5 is H, no reaction is performed.
  • 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-n ⁇ tro-, the 4- nitro or the 2,4-n ⁇ trophenyl 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 R 4 -OH presence of a phosphine reagent such as tnphenyl or t ⁇ butyl phosphine and diethylazodicarboxylate (DEAD) or dnsopropylazodicarboxylate (DIAD) in an organic solvent.
  • a phosphine reagent such as tnphenyl or t ⁇ butyl phosphine and diethylazodicarboxylate (DEAD) or dnsopropylazodicarboxylate (DIAD) in an organic solvent.
  • the 2-n ⁇ tro-, 4-n ⁇ tro or 2,4-n ⁇ trophenyl sulfonamide is then hydrolyzed by reaction with ethanethiol and d ⁇ azab ⁇ cyclo-[4,7]-undecene (DBU) in tetrahydrofuran to furnish the resm (7)
  • DBU d ⁇ azab ⁇ cyclo-[4,7]-undecene
  • the group of formula R 6 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).
  • R 6 is a group of formula-C(0)-R 7 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).
  • R 6 is a group of formula-C(0)-NHR 9 formation of the urea is accomplished using the isocyanate of formula R ⁇ NCO.
  • R 6 is -S0 2 R 8 sulfonylation is accomplished using a sulfonyl chloride of formula C1S0 2 R 9 in the presence of a base such as pyridine or N-methylmorpholine in an inert organic solvent such as dichloromethane.
  • R 6 is -C(O)-OR 10 acylation is accomplished using a chloroformate of formula
  • 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:
  • 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 dichlo ⁇ de hydrate m dimethyl formamide, sodium borohydnde and copper acetoacetate or sodium dithiomte in ethanol.
  • aromatic nitro groups such as tin dichlo ⁇ de 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-benzothazep ⁇ ne-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.
  • R 6 is a group of formula-C(0)-NHR 9 formation of the urea is accomplished using the isocyanate of formula R ⁇ NCO.
  • R 6 is -S0 2 R 8
  • sulfonylation is accomplished using a sulfonyl chloride of formula C1S0 2 R 9 m the presence of a base such as pyndine or N-methylmorpholine in an inert organic solvent such as dichloromethane.
  • R 6 is -C(0)-OR 10 acylation is accomplished using a chloroformate of formula C1C(0)0R 10 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 R 6 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 R 6 COOH 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.
  • 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.
  • 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-d ⁇ subst ⁇ tuted diazacylocalky carboxamide compounds using the process of this invention is outlined 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.
  • a resin of formula (lb) may be reacted with x different nucleophilic ammes of formula HNR 11 as described in Scheme 1 above to form x portions of resin (24) (X is HNR”) each of which contains a different R 11 .
  • the group X which is substituted with NR 11 is referred to herein as the first combinatorial position.
  • the x portions are then recombined into a single portion and the amines are acylated with Br-R 12 -COOH.
  • the bromide is then displaced with the 1,5- benzothiazepine scaffold to form a mixture of resin-bound monoprotected 1,5-benzod ⁇ azep ⁇ ne compounds (5) containing x different groups at the first combinatorial position.
  • the mixture of resm-bound monoprotected 1,5-benzod ⁇ azepme compounds (5) is then divided into y portions, y different groups R 4 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-subst ⁇ tuted 1,5-benzod ⁇ azep ⁇ ne compounds (6) containing all possible combinations of the x R 11 groups and y R 4 groups.
  • P 1 is then removed from the second combinatorial mixture, the resulting mixture of resin-bound 1 ,5-benzod ⁇ azep ⁇ ne compounds is divided into z portions and z different groups R 6 are introduced into the third combinatorial position as described above to form z portions of resm-bound 1,5-benzod ⁇ azepme compounds (9).
  • the resin-bound 1,5-benzod ⁇ azepme compounds (9) are then cleaved from the resm as described in Scheme 1 above to give a library of substituted 1,5-benzod ⁇ azp ⁇ ne compounds containing all possible combinations of groups at each of the combinatorial positions.
  • a library of 7,290 compounds may be readily prepared from reagents corresponding to 18 R 11 groups, 9 R4 groups and 45 R 6 groups.
  • 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.
  • 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.
  • a radio-frequency identifier tag is associated with each compound in the library
  • each compound is made in a polypropylene container with mesh side walls (MicroKanTM, 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.
  • a library member is assigned to each code.
  • the MicroKansTM are directed toward the vessel for the first combinatorial step. They are then reacted as a batch with the first set of combinatonal reagents.
  • the MicroKansTM 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.
  • 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 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.
  • a-Boc,a,b-d ⁇ ammo propiomc acid (lOOg, 490 mmol) was dissolved in DMF (IL). Tnethylamine (200 ml, 1.3 mol) was added followed by 2-fluoron ⁇ trobenzene (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.
  • IL 2N HCl
  • ethyl acetate extracts were dned over sodium sulfate and concentrated to afford 218 g of an orange oil which
  • 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-benzod ⁇ azepme-2- one as a white powder.
  • the 5-Boc-l,5-benzod ⁇ azep ⁇ ne (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.
  • 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 Et 2 0(lX). The resin was then dried overnight with a stream of nitrogen gas.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a 18 x 9 x 45 7290 member library was produced using the Iron system. BAL resm was loaded in 7290 microkans.
  • microkans 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 tnacetoxyborohyd ⁇ de (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).
  • 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.
  • microkans were sorted into cleavage racks. A solution of TFA (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.
  • 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.
  • 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.
  • the argon lines were then removed, the reaction capped tightly and stirred overnight at room temperature.
  • 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.
  • 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.
  • 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 (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.
  • 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.
  • 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.
  • 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

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Abstract

L'invention concerne une méthode de synthèse en phase solide destinée à produire un 1,5-benzodiazépine-2-one ou 1,5-benzothiazépine-2-one substitué. La méthode de l'invention est utile pour la synthèse d'un grand nombre de composés pouvant être obtenus par synthèse parallèle automatisée ou production d'une bibliothèque combinatoire. Elle est donc importante pour la découverte rapide de nouveaux agents thérapeutiques contenant la structure de base de 1,5-benzodiazépine-2-one ou de 1,5-benzothiazépine-2-one.
PCT/US2002/032496 2001-10-12 2002-10-10 Synthese en phase solide de 1,5-benzodiazepine-2-one ou 1,5-benzothiazepine-2-one substitue Ceased WO2003031376A1 (fr)

Applications Claiming Priority (4)

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US32919501P 2001-10-12 2001-10-12
US60/329,195 2001-10-12
GB0203379A GB0203379D0 (en) 2001-10-12 2002-02-13 Solid phase synthesis of substituted 1, 5-benzodiazepine-2-one and 1, 5-benzothiazepine-2-one
GB0203379.3 2002-02-13

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WO2016139181A1 (fr) 2015-03-02 2016-09-09 Apeiron Biologics Ag Dérivés tétrahydrothiazépine bicycliques utiles pour le traitement de maladies infectieuses et/ou néoplasiques
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US9815850B2 (en) 2016-02-05 2017-11-14 Denali Therapeutics Inc. Compounds, compositions and methods
WO2019246541A1 (fr) * 2018-06-21 2019-12-26 Dana-Farber Cancer Institute, Inc. Inhibiteurs d'egfr et leurs procédés d'utilisation
US11072618B2 (en) 2016-12-09 2021-07-27 Denali Therapeutics Inc. Compounds, compositions and methods
WO2022171745A1 (fr) * 2021-02-12 2022-08-18 F. Hoffmann-La Roche Ag Dérivés bicycliques de tétrahydroazépine pour le traitement du cancer
WO2023030295A1 (fr) * 2021-09-01 2023-03-09 先声再明医药有限公司 Inhibiteur de protéase 1 spécifique de l'ubiquitine
US11999750B2 (en) 2022-01-12 2024-06-04 Denali Therapeutics Inc. Crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-B][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide
US12466889B2 (en) 2020-12-17 2025-11-11 Hoffmann-La Roche Inc. Anti-HLA-G antibodies and use thereof

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MORTON G C ET AL: "Novel solid-phase synthesis of 1,5-benzothiazepine-4-one derivatives", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 41, no. 17, April 2000 (2000-04-01), pages 3029 - 3033, XP004196718, ISSN: 0040-4039 *
T. F. HERPIN ET AL.: "Synthesis of a 10000 member 1,5-benzodiazepine-2-one library by the directed sorting method", JOURNAL OF COMBINATORIAL CHEMISTRY, vol. 2, no. 5, 2000, pages 513 - 521, XP002225703 *

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WO2016140860A3 (fr) * 2015-02-25 2016-10-27 The Trustees Of Columbia University In The City Of New York Lieur peptidique pour la fixation de molécules thiol-réactives à des surfaces
RU2730524C2 (ru) * 2015-03-02 2020-08-24 Апейрон Биолоджикс Аг Бициклические тетрагидротиазепиновые производные, полезные для лечения неопластических и/или инфекционных заболеваний
US10472341B2 (en) 2015-03-02 2019-11-12 Apeiron Biologics Ag Bicyclic tetrahydrothiazepine derivatives useful for the treatment of neoplastic and/or infectious diseases
CN107889487B (zh) * 2015-03-02 2021-09-03 阿派隆生物制剂股份公司 用于治疗肿瘤和/或感染性疾病的双环四氢硫氮杂䓬衍生物
JP2018508527A (ja) * 2015-03-02 2018-03-29 アペイロン・バイオロジックス・アクチェンゲゼルシャフトＡＰＥＩＲＯＮ Ｂｉｏｌｏｇｉｃｓ ＡＧ 新生物疾患および／または感染性疾患の治療にとって有用な二環式テトラヒドロチアゼピン誘導体
CN107889487A (zh) * 2015-03-02 2018-04-06 阿派隆生物制剂股份公司 用于治疗肿瘤和/或感染性疾病的双环四氢硫氮杂*衍生物
WO2016139181A1 (fr) 2015-03-02 2016-09-09 Apeiron Biologics Ag Dérivés tétrahydrothiazépine bicycliques utiles pour le traitement de maladies infectieuses et/ou néoplasiques
US9815850B2 (en) 2016-02-05 2017-11-14 Denali Therapeutics Inc. Compounds, compositions and methods
US10131676B2 (en) 2016-02-05 2018-11-20 Denali Therapeutics Inc. Compounds, compositions and methods
US10604535B2 (en) 2016-02-05 2020-03-31 Denali Therapeutics Inc. Compounds, compositions and methods
US9896458B2 (en) 2016-02-05 2018-02-20 Denali Therapeutics Inc. Compounds, compositions and methods
US12358928B2 (en) 2016-02-05 2025-07-15 Denali Therapeutics Inc. Compounds, compositions and methods
US11072618B2 (en) 2016-12-09 2021-07-27 Denali Therapeutics Inc. Compounds, compositions and methods
US12180211B2 (en) 2016-12-09 2024-12-31 Denali Therapeutics Inc. Compounds, compositions and methods
US12161649B2 (en) 2018-06-21 2024-12-10 Dana-Farber Cancer Institute, Inc. Inhibitors of EGFR and methods of use thereof
WO2019246541A1 (fr) * 2018-06-21 2019-12-26 Dana-Farber Cancer Institute, Inc. Inhibiteurs d'egfr et leurs procédés d'utilisation
US12466889B2 (en) 2020-12-17 2025-11-11 Hoffmann-La Roche Inc. Anti-HLA-G antibodies and use thereof
WO2022171745A1 (fr) * 2021-02-12 2022-08-18 F. Hoffmann-La Roche Ag Dérivés bicycliques de tétrahydroazépine pour le traitement du cancer
JP2024506339A (ja) * 2021-02-12 2024-02-13 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト がんの治療のための二環式テトラヒドロアゼピン誘導体
WO2023030295A1 (fr) * 2021-09-01 2023-03-09 先声再明医药有限公司 Inhibiteur de protéase 1 spécifique de l'ubiquitine
US11999750B2 (en) 2022-01-12 2024-06-04 Denali Therapeutics Inc. Crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-B][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

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