NZ329822A - Pyrrole derivatives bound to a fibrinogen receptor antagonist template - Google Patents

Pyrrole derivatives bound to a fibrinogen receptor antagonist template

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Publication number
NZ329822A
NZ329822A NZ329822A NZ32982298A NZ329822A NZ 329822 A NZ329822 A NZ 329822A NZ 329822 A NZ329822 A NZ 329822A NZ 32982298 A NZ32982298 A NZ 32982298A NZ 329822 A NZ329822 A NZ 329822A
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New Zealand
Prior art keywords
methyl
oxo
mmol
alkyl
galkyl
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NZ329822A
Inventor
Ali Fadia El-Fehail
William Bondinell
William Francis Huffman
M Amparo Lago
Richard Mcculloch Keenan
Chet Kwon
William Henry Miller
Thomas Nguyen
Dennis T Takata
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Smithkline Beecham Corp
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Publication of NZ329822A publication Critical patent/NZ329822A/en

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Abstract

Compounds are disclosed which are vitronectin receptor antagonists useful in the treatment of inflammation, cancer and cardiovascular disorders, such as atheroscerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis. These compounds comprise a fibrinogen receptor antagonist template linked to a heterocyclic moiety. The compound claimed according to formula (III). W is CHRga-U-CHRgb-V- or formula (IV) A is a fibrinogen receptor antagonist template (illustrated according to formula (a) to (i) Wherein R1 and R1, are R* or R, or together are =O; R2 and R2, are R* or R, or together are =O; R3 and R3, are R* or R, or together are =O; R4 and R4, are R* or R, or together are =O; R5 and R5, are R* or R, or together are =O; R is at least one substituent chosen from the group of R7, or Q-C1-4alkyl, Q-C1-4alkenyl, Q-C2-4alkynyl, optional substituted by one or more =O, R11 or R7; and R* is H, Q-C1-6alkyl, Q-C1-6oxoalkyl, Q-C2-6oxoalkyl, Q-C2-6oxoalkenyl, Q-C3-4oxoalkynyl, Q-C2-4oxoalkynyl, Q-C3-6oxoalkynyl, Ar or Het, optional substituted by one or more R11 The rest of the constituents are common substituents as described.

Description

New Zealand Paient Spedficaiion for Paient Number 329822 NEW ZEALAND PATENTS ACT, 1953 Divided out of No 290008 Dated- 29 June 1995 COMPLETE SPECIFICATION VITRONECTIN RECEPTOR ANTAGONISTS We, SMITHKLINE BEECHAM CORPORATION, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of Amenca, of One Franklin Plaza, Philadelphia, Pennsylvania 19103, United States of Amenca, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly descnbed in and by the following statement - (followed by page la) WO 96/00730 PCT/US9S/08306 TITLE Vitronectin Receptor Antagonists FIELD OF THE INVENTION This invention relates to phaimaceutically active compounds which inhibit the vitronectin receptor and are useful for the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis BACKGROUND OF THE INVENTION Integnns arc a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include gpllb /Ilia, the fibrinogen receptor, and avfl3, the 15 vitronectin receptor The fibrinogen receptor gpUb /ma is expressed on the platelet surface and it mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding wound. Philips, etaL, Blood., 1988, 71, 831. The vitronectin receptor av6} is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions The 0,6, 20 receptor expressed on the membrane of osteoclast cells mediates the bone resportion process and contributes to the development of osteoporosis Ross, et al, J Biol Cherru, 1987,262, 7703 The ayB3 receptor expressed on human aortic smooth muscle cells stimulates their migration into neoibtuna, which leads to the fonnauon of atherosclerosis and restenosis after angioplasty B~own, et al, Cardiovascular \\ Res, 1994, 28, 1815 Additionally, a recent study haj shown that a avSj antagonist il is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels Brooks, et al., Cell, 1994, 79, 1157 Thus, agents that would block the vitronectin receptor would be useful in treating diseases mediated by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer -la- The vitronectin receptor is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tn-peptide Arg-Gly-Asp (or RGD) motif Thus, Horton, et al, Exp Cell Res 1991,195, 368, disclose that RGD-contaimng peptides and an anti-vitronectin receptor antibody 5 (23C6) inhibit dentine resorption and cell spreading by osteoclasts In addition, Sato, et al, J Cell BioL 1990, 111, 1713 disclose that echistatin, a snake venom peptide which contains the RGD sequence, is a potent inhibitor of bone resorption m tissue culture, and inhibits attachment of osteoclasts to bone Fisher, et aL, Endocrinology 1993,132,1411, has further shown that echistatin inhibits bone \ resorption in vivo in the rat Bertohni et al, J Bone Mm Res., 6, Sup. 1, S146,252 have shown that cylco-S.S-N^acetyl-cysteinyl-N^methyl-argininyl-^iycyl-aspartyl-penicillamine inhibits osteoclast attachment to bone EP 528 587 and 528 586 report substituted phenyl derivatives which inhibit osteoclast mediated bone resorption.
Alig et al, EP 0 381 033 Hartman, et al, EP 0 540,334, Blackburn, et al., WO 93/08174, Bondmell, et al, WO 93/00095, Blackburn, et al. WO 95/04057, Egbertson, et al, EP 0 478 328, Sugihara, et al EP 529,858, Porter, et al, EP 0 542 363, and Fisher, et al., EP 0 635 492 disclose certain compounds that are useful for inhibiung the fibrinogen receptor. It has now been discovered that certain appropriately substituted compounds are potent inhibitors of the vitronectin receptor In particular, it has been discovered that such compounds are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor and such compounds contain a fibrinogen receptor antagonist template SUMMARY OF THE INVENTION This invention comprises compounds of the formula (I)-(V) as described hereinafter, which have pharmacological activity for the inhibition of the vitronectin receptor and are useful in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis This invention is also a pharmaceutical composition comprising a compound according to formula (I)-(V) and a pharmaceutic ally earner This invention is also a method of treating diseases which are mediated by the vitronectin receptor In a particular aspect, the compounds of this invention are 5 useful for treating atherosclerosis, restenosis, mflammauon, cancer and diseases wherein bone resorption is a factor, such as osteoporosis DETAILED DESCRIPTION This invention comprises novel compounds which are more potent inhibitors 10 of the vitronectin receptor than the fibnnogen receptor The compounds of the instant invention compnse a fibnnogen receptor antagonist template that is linked to a nitrogen-containing five-membered nng, which is optionally fused to an aromatic six-membered nng The fibnnogen receptor antagonist template is substituted by an aliphatic substituent which contains an acidic moiety. It is preferred that about 15 fourteen intervening covilent bonds via the shortest intramolecular path will exist between the acidic group of the fibnnogen receptor antagonist template and the nitrogen of the optionally fused five-membered nng As used herein, the term "fibnnogen receptor antagonist template" means the core structure of a fibrinogen receptor antagonist, said core being substituted by an 20 acidic group and said core being linked to an organic group substituted with a basic nitrogen moiety A fibnnogen receptor antagonist is an agent thai inhibits the binding of fibnnogen to the platelet-bound fibnnogen receptor GPHb-DIa It is an object of this invention that a fibnnogen receptor antagonist is converted to a vitronectin receptor antagonist by replacing the organic group substituted with a 25 basic nitrogen moiety in a fibnnogen receptor antagonist with an optionally fused nitrogen-containing five-membered nng, preferably an imidazole nng and, most preferably, a benzimidazole nng This invention comprises compounds of formula (I)-(V).
W- *x< (I) or (H) w- or or J n re (iv) wherein W is CHRSa-U- CHRSb-V- or n v- or (V) ^n-—(ch^, A is a fibrinogen receptor antagonist template, U and V are absent or CO, CRf2, C(=CRf2), S(0)k, O, NR1, CR'OR1, CR'(0Rk)CR'2, CR'2CR'(0Rk), C(0)CR'2, CR'2C(0), CONR1, NR'CO, OC(O), C(0)0, C(S)0, OC(S), C(S)NR', NR'C(S), S(0)2NR', NRIS(0)2 N=N, NRW, NR'CR'2, NR'CR^, CR'20, OCR'2, C&C or CR'=CR\ G is NRe, S or O, R' is H, Ci-6alkyl, Het-Co-6alkyl, C3-7cycloalkyl-Co-6allcyl or Ar- Co-6alkyl, Rk is R', -C(0)R', or -C(0)0Rf, R' is is H, Ci-6alkyl, Het-Co-6alkyl, C3-7cycloalkyl-Co_6alkyl, Ar- Co-6alkyl, or Ci-6alkyl substituted by one to three groups chosod from halogen, CN, NR'j, OR', SR', COjR1, and CON(R% 32982 Rf is H, C^alkyl or Ar-C,.6alkyl; Re is H, Ci-6alkyl, Ar-Ci-6alkyl, Het-Ci-6alkyl, C3-7cycloalkyl-C i-flalkyl, or (CHjXCOJR*. k is 0,1 or 2, q is 1 or 2, a is 0,1 or 2, b is 0,1 or 2, Rb and Rc are independently selected from H, Ci-^alkyl, Ar-Q)-6alkyl, Het- Co-6alkyl, or C3-6cycloalkyl-C0-6alkyl, halogen, CF3, OR, S(0)kR, COR, NO2, N(Rf)2, C0(NR)2, CH2N(Rf">2, or Rb and Rc are joined together to form a five or six membered aromatic or non-aromatic carbocyckc or heterocyclic nng, optionally substituted by up to three substituents chosen from halogen, CF3, Ci_4alkyl, OR, S(0)kR, COR, COzR OH, NO2, N(R )2, CO(NR )2, and CH2N(R )2, or methylenedioxy. or a pharmaceutical!)' acceptable salt thereof, with the proviso that* (I) when A is l,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-lH-l,4-benzodiazepine-2-acetic acid, then W is not -(CH,)2 3NHCO- attached at the 1-position of an imidazole nng, and (II) when A is l,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl>lH-l,4'-benzodiazepme-2-acetic acid, then W is not -(CH.). NHCO- attached at the 4(5)-posmon of an imidazole nng Flic compounds of toraiula (111) arc claimed in the present patent specification The compounds ot lormula (I), (II) and (IV) wherein G is NRe are claimed in New Zealand Patent Specillcation No 290008 and the compounds of formula (II) wherein G is S or O are claimed m New Zealand Patent Specification No 329656 Also included in this invention are pharmaceutical^ acceptable addition salts, complexes or prodrugs of the compounds of this invention Prodrugs are considered to be any covalently bonded earners which release the acuve parent drug according to formula (I) in vtvo In cases wherein the compounds of this invention may have one 01 more chiral centers, unless specified, this invention includes each unique nonracemic compound which may be synthesized and resolved by 329822 conventional techniques In cases m which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention In cases wherein compounds may exist in tautomeric forms, such as O or' I keto-enol tautomers, such as -—and , and each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or locked in one form by appropriate substitution with R' The compounds of formula (I) - (V) inhibit the binding of vitronectin and other RGD-contaimng peptides to the vitronectin (ovP3) receptor Inhibition of the 10 vitronectin receptor on osteoclasts inhibits osteoclastic bone resorption and is useful in the treatment of diseases wherein bone resorption is associated with pathology, such as osteoporosis Additionally, since the compounds of the instant invention inhibit vitronectin receptors on a number of different types of cells, said compounds would be useful in the treatment of inflammation and cardiovascular diseases, such 15 as atherosclerosis and restenosis, and would be useful as anti-metastatic and antitumor agents In a particuar embodiment, the compounds of this invention are of the b C formula (H), wherern R and R are joined to form an aromauc nng containing up to b C two nitrogen atoms In a preferred embodiment R and R are joined to form an opuonally subsututed phenyl nng according to formula (Ha) wherein G is N-R', S or 0 f n-co Suitably W is -(CHR8)aNR'CO- or £ IIJILUcmuai property off/cF] OF N2 1 J 7 DEC m9 RECEIVED Preferably W is -CHRSNR'CO- Suitably R' is H, Cj-galkyl, C3-7cycloalkyl, Ar or Cj-6alkyl substituted by one to three groups chosen from halogen, CN, NR*2, OR*, SR1, C02R1, and CON(Rx)2. Ar, Het or C3.7cycloalkyl In particular, R' is H, methyl, butyl, 5 cyanomethyl, carboxymethyl, phenylethyl or benzimidazolylmethyl Suitably R\ Ry and Rz are independently chosen from Cj^alkyl, methoxy, mtro, tnfluoromethyl, fluoro, chloro, ammo or Rx and Ry are adjacent to one another and are joined to form a methylenedioxy group Preferably G is NRe Suitably Rc is H, Q-4alkyl, Ar, Het or Chalky! substituted by Ar or Het.
More suitably, Re is H, methyl or benzimidazolylmethyl In another specific embodiment, Rb and Rc form a six membered aromatic nng containing one or two nitrogen atoms according to formulas (Ilb-d) (lib) (He) (Ed) wherein G, R' and R' arc as above for formula (Ha) In another aspect this mvenuon is an intermediate compound of formula XXX r' wherein Pr1 is a nitrogen protecting group, Rf is H, C^alkyl or AiCwaIkyl, a' is 1-3, and R\ R' and R* are independently chosen from H, halogen, SRf, ORf, CF3, N(Rf)2, NO, and C^alkyl Preferred nitrogen protecting groups are alky! and aryl carboxyhc PCT/TJS95/08306 acid groups, and alkyloxycarbonyl or arylmethyloxycarbonyl groups, such as the acetyl, BOC and Cbz group Typically RS is H or methyl.
Specifically, the compounds of this invention are comprised of a nitrogen-containing optionally fused five-membered nng, a linking group W, and a fibnnogen receptor antagonist template A. In particular, the fibnnogen receptor antagonist template A is as defined in Bondinell, et al, WO 93/00095, published January 7, 1993, of the sub-formula (VI) A (VI) A1 to A5 form an accessible substituted seven-membered nng, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosen firom the group of O, S and N wherein S and N may be opUonallj oxidized, D1 to D4 form an accessible substituted six membered nng, opuonally containing up to two nitrogen atoms, R is at least one substituent chosen from the group of R7, or Q-C j -4alkyl, Q-C2-4alkenyl, Q-C2-4alkynyl, opuonally subsututed by one or more of =0, R11 or R7.
R* is H, Q-C|.6alkyl, Q-Ci.60xoalkyl, Q-C2-6alkenyl, Q-C3-40X0alkenyl, Q-C3_40X0alkynyl, Q-C2-4alkynyl, C3-6cycloalkyl, Ar or Het, optionally subsututed 20 by one or more of R11, Q is H, Cs.gcycloalkyi, Het or Ar, - R7 is -COR8; COCR'2R9, -C(S)R8, -S(0)m0R\ -S(0)mNR'R", -PO(OR'), ( J -PO(OR')2, -B(OR')2, -N02 and Tet, R8 is -OR', -NR'R", -NR'S02R', -NR'OR', -0CR,2C(0)0R,1 -0CR'20C(0)-25 R', -0CR'2C(0)NR,2, CF3 or AA1, R9 is -OR', -CN, -S(0)rR\ S(0)mNR'2, -C(0)R' C(0)NR'2 or -C02R', 3,2x^.8 2 2 R11 is H, halo, -OR12, -CN, -NR'R12, -N^2. -CF3. CF3S -CONR'2, Q-Co-6alkyl-, Q-C^oxoalkyl-, Q-C2-6alkenyl-, Q-C2-6alkynyI-, Q-Q^alkyloxy-, Q-Co-6alkylamino- or Q-Co.6alkyl-S(0),-, R12 is R', -C(0)R', -C(0)NR'2, -C(O)0R15, -S(0)mR' or S(0)mNR'2, R15 is H, Ci_6alkyl or Ar-Qwalkyl, R' is H, Ci-6alkyl, C3-7cycloalkyl-Co^alkyl or Ar-Co-4alkyl, R" is R\ -C(0)R' or -C(0)0R15, AA1 is an amino acid attached through its amino group and having its carboxyl group optionally protected, m is 1 or 2, and r is 0 or 2, or pharmaceutical^ acceptable salts thereof, with the proviso that (i) when A is l,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)-lH-l,4-benzodiazepine-2-acetic acid, then W is not -(CH,)2 3NHCO- attached at the 1-position of an imidazole nng, and (11) when A is 1,2,4,5-tetrahydro-3-oxo-4-(2-pheny<ethyl)-1H-1,4-benzodiazepme-2-acetic acid, then W is not -(CPL), NHCO- attached at the 4(5)-position of an imidazole nng With reference to formula (VI), suitably, Al is CRlRl", CR*, NR5, N, O or S(0)x, A2 is CR2R2, CR2, NR2, A3 is CR3R3', CR3, NR3, N, O or S(0)x, A4 is CR4R4', CR4, NR4, or N.
A5 is CR5R5 , CR5, NR5, N, O or S(0)x, D'-D4 are CR1!, CR^ or N, R1 and R1' are R* or R, or together are =0, R2 and R2' are R*, R or =0, R3 and R3' are R*, R or =0, R4 and R4 are R*, R or =0, R5 and R5' are R*, R or =0, and x is 0 to 2 9- 'NTELLLU UML HHUPtfiTY OFRCEI OF HI 1:1 I ? DEC 1999 -RECEIVED 9 32982 More suitably, A1 is CR'R1', CR1, NR1, N, O or S, A2 is CR2R2', NR2 or CR2, A3 is CR3R3', A4 is CR4R4', CR4, NR4, or N, A5 is CR5R5', CR5, NR5, N, or O, D1 and D4 are CH, one of D2 or D3 is CH and the other is CH or N, one of R2 or R4 are R and the other is H, R3, R3' and R5, R5' are =0 or R*, H, R1 and R1' are R* or 5 R, and R2' and R4' are H Preferably, A1 is CHR', CR1, NR", N or S, A2 is CR2 or CR2R2', A3 is CR3R3', A4 is CR4R4' or NR4, A3 is CR'R5' and D'-D4 are CH in which R1 is R* or R, R2 and R2' are R* R or together are =0, RJ and R3' are R+, R or together are 10 =0, R4 and R4' are R*, R or together are =0, R5 and R5' are R*, R or together are In one embodiment. A1 is CR1. A2 is CR2, A3 is C=0, A4 is NR4, and A5 are CHRS m which R1 is R* or R, R2 is R* or R, R4 is R* or R, R5 is R* or R In another embodiment A1 is NR1. A2 is CHCR2, A3 is CR3R3' and A4 is NR4, and A5 are C=0 in which R1 is R* or R. R2 is R*. R, R1 and R3' are R*, R or together are C=0, R4 is R* or R In yet another embodiment. A' and A'are C=0, A2 is NR2, A3 is CHR3' and A^ is NR5 m which R2 is R* or R R3' is R* or R, R^ is R* or R oi =0 In a preferred embodiment A1 is NR1 A: is CHR\ A3 is C=0, A4 is NR' and A5 is CHR5 in which R1 is R* or R. R2 is R* or R, R* is R* or R =o Representative sub-fonnulas of (VI) are given by each of formulas (Vla)- (VL) below (VId) (Vie) (Vlf) (VIg) (Vlh) (VIi) Specific embodiments of this invention wherein the fibnnogen receptor antagonist template A is of the sub-formula (VI) are named in Examples 1-75 Preferred compounds of this invention are 10 (2S)-7-[[[N-(2-benzumdazolyl)methyl-N-methyljamino]carbonyl]-4-methyl-',-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid, -7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-aceuc acid, (±)-7-[[[2-(4-Azabenzimidazolyl)methyi]methylamino]carbonyl]-4-(2-15 methoxyethyl)-3-oxo-2,3,4,5-tetrahydro- 1H-1,4-beazodiazepme-2-acetic acid, (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid, -7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-20 2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetic acid, (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl- 2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid, -7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid, -7-[[[N-(2-benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid, (zt)-7-[[[2-(benzimidazolyI)methyl]amino]carbonyl-4-[2-(3,4- methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro- 1H-1,4-benzodiazepine-2-acetic acid, and (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid The most preferred fibrinogen receptor antagonist template is of the sub-formula (Via), wherein CR2Rr is CHCH,C02H, CR3Rr is C=0, and CR*Ry is CH, Vitronectin fibrinogen receptor antagonism is particularly pronounced when the A-W- substituent is attached to the 7-position of the 3-oxo-2,3,4,5-tetrahydro-lH-1,4-benzodiazepme nng system (±)-8-[[[(2-Benzimidazolyl)methyl]amino]-carbony l]-4-methy l-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid has a Ki of greater than 50 micromolar in the m vitro vitronectin binding assay descnbed hereinbelow In the formula below the defimtions for the substituents are as defined m formulas (I)-(IV), unless specified otherwise Another embodiment of a preferred fibnnogen receptor template A is represented by the 1,4-benzodiazepme 2,5-dione of sub-formula (VII), O wherein R- Y is H, Cj^alkyl, Cj^alkoxy, Cj^aikoxycarbonyl, F, CI, Br, I, CF3, OR^, 5(0)^^ CORf, NO2, N(Rf)2, CO(NRf)2, CH2N(R^)2, methylenedioxy, CN, C02Rf, QC(0)Rf, or NHC(0)Rf, R" is (CHt)qCOJRf Re 1S H< cl-6alkyl, Ar-Cj.galkyl, Het-C^alkyl, C3_7cycloalkyl-C1_6alkyl, or (CH2)kC02Rg, Rf is H, Cj^alkyl or Ar-C^alkyl, k is 0, 1 or 2, and q is 1 or 2 The preparation and the use of this sub-structure m prepanng fibnnogen receptor antagonists of this sub-formula is detailed in Bondinell, et al, WO 93/00095 published January 7,1993 and Blackburn, et al, WO 93/08174, published 5 Apnl 29,1993 Table I, below, summanes other preferred fibnnogen receptor templates that are included within the scope of the present invention Such templates are Table I one of Al or A2 is -Z-C02Rf or Z-CON(Rf)2, Z is -CH2-, -0(CH2)q-. -NRf(CH2)q-, -S(CH2)q, -CH2CH2-, -CH(CH3)CH2-, -(CH2)3-, -CH=CH-, -C(CH3)=CH-, CH2-CH=CH-or CH=CHCH2, and Y is H, Ci-4alkyl, Ci-4alkoxy, Ci_4alkoxycarbonyl, F, CI, Br, I, CF3, ORf, S(0)kRf, CORf, NO2, N(Rf)2, CO(NRf)2, CH2N(Rf)2, methylenedioxy or Z-CO- rvnr> or Wherein R21 and R^2 independently are H or -Z-CO2R or Z-CON(Rf)2 with the proviso that Rf, in Alig, et al., EP 0 381 033, published August 8,1990 The preferred fibnnogen receptor template A in formula (VJ3I) is f-. a Specific embodiments of this aspect of the invention are 4-[2-[[[l-[(Benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl] phenoxyacetic acid, (±)-4-[[2-[(Ben?imiriazoI-2-yl)methylJmethylaminoj-l-hydroxyethyl]-l,2-phenylene dioxydiacetic acid, 4-[2-[[(Benzimidazol-2-yl)methyl]methylamino]acetyl]-l,2-phenyienedioxydiacetic acid, or 3-[[4-[[[(Benzimidazol-2-yl)methy]anuno]cai-bonyl]phenyl]amjno]propiomc acid Y R°SOzNH wherein r.6 is aryl, Cj.ioalkyl, C3_6cycloalkyl, C^ioaralkyl, Ci_ioalkoxyalkyl, Ci.ioalkaiyl, C ^j Qalkylthioalky 1, Cj.ioalkoxythioalkyl, C^joalkylamino, C4.2oaralkylamino, Ci_ioalkanoylamino, C4.joaraikanoylamino, Cj.ioalkanoyl, C4.1 Qaralkanoyl, or Ci_iocarboxyalkyl, Y is H, Cj_4alkyl, Cj^alkoxy, C1 _4alkoxycarbonyl, F, CI, Br, I, CF3, OR^, S(0)kRf, CORf, N02, N(Rf)2, CO(NRf)2, CH2N(Rf)2, methylenedioxy, CN, C02Rf, 0C(0)Rf, or NHC(0)Rf, Rf is H, Cj.galkyl or Ar-C^alky!, and k is 0, 1 or 2, m Egbertson, et al, EP 0 478 328, published Apnl 1, 1992 1 7 DEC 1999 RECEfypp 329822 The preferred compounds of formula (IX) are those wherein is aryl, Cj. joalkyl, C3_6cycloalkyl, or C4_ioaralkyl A specific embodiment of this aspect of the invention is (S)-(2-butylsulfonyl-amino)-3-[4-(3-benzimidazo-2-yl)propyloxy)]phenyipropiomc IX} r9 — m1 m2 ( g1—chco,rf \—/ v_y wherein M1 is CH or N, M2 is CH or N, with the proviso that when M1 is CH, is N, G' is N nr N®R", Rf is H, C^alkyl or Ar-Cj.galkyl, and RS is H, Cj.galkyl, Het-Co^alkyl, C3_7cycloalkyl-Co_6alkyl or Ar- Q^alkyl, in Eldred, et al, EP 0542 363, published May 19, 1993 Preferred embodiments of the vitronecun receptor antagonists containmg the substructure of formula (X) are those wherein G' is N an M1 is N. A compound containing this substructure, namely 4-[4-[l-(2-methylbenzimidazolyl)pipendinyI]]-pipendmeaceuc acid, has a Ki of greater than 50 micromolar in the in vitro vitronecun binding assay descnbed hereinbelow (XI) .oh -m1 m2 ch2co2r' wherein M1 is CH or N, MJ is CH or N, with the proviso that when M1 is CH, M3 is N; and Rf is H Cj.galkyl or Ar-Cj.galkyl, in Porter, et al., EP 0 537 980, published Apnl 21, 1993 t X xxx M3 ^Rh 5 wherein M1 is CH or N; Y is H, Ci_4alkyl, C^alkoxy, C i^alkoxycarbonyl, F, CI, Br, I, CF3, ORf, SCO^R*, CORf, NO2, N(Rf)2, C0(NR^)2, CH2N(R^)2» methylenedioxy, CN, C02Rf, 0C(0)Rf orNHC(0)Rf, M3 is CH, or C=0; R" is (CHj^COjRf Rf is H, C^alkyl or Ar-Cj.galkyl, k is 0, 1 or 2, and q is 1 or 2, in Klinnick, et al, EP 0 635,492, published January 25, 1995 QOID O JR* wherein Y is H, Ci_4alkyl, Cj^alkoxy, C^alkoxycarbonyl, F, CI, Br, I, CF3, OR^, S(0)kRf, CORf, N02, N(Rf)2, CO(NRf)2, CH2N(Rf)2, methylenedioxy, CN, 25 C02Rf, 0C(0)Rf, or NHC(0)Rf; Rh is (CH^COjRf; h cr N B is h3c , or Rf is H, Cj^alkyl or Ar-Cj.galkyl, k is 0, 1 or 2, and n is 0 or 3, m Blackburn, et al, WO 95/04057, pubbshed February 9, 1995 ,JIUUuiuVSPER7Y^® J 7 DEC 1999 BECEIVf n rxivi 329822 •n •l-c02r9 O wherein L* is -C(0)NRB-(CH2>, -C(0)-(CH2)q-, NRfc-(CH2)q-, -0-(CH2)q-, or 10 S(0)k-(CH2)q-, Rg is H, C,.6alkyl, Het-C0_6alkyl C3 7cycloalkyl-C0.6alkyl or Ar-C^alkyl, k is 0, 1 or 2, and q is 1 or 2, in Hartman, et al, EP 0 540 331, published May 5, 1993 (XV) /—\ -n n—ch—c02r° CO^o wherein Rg is H, Chalky 1, Het-C0^alkyl, C3 7cycloalkyl-C0^alkyl or Ar-C0 6alkyl, m Sugihara, et al, EP 0 529,858, published March 3, 1993 Y is H, CMalkyl, CMalkoxy, CMalkoxycarbonyl, F, CI, Br, I, CF3, 0Rf, S(0\RF, CORfl, N02, NCR1),, CO(NR'):, CH2N(Rf)2, methylenedioxy, CN, C02Rf, 5 0C(0)Rf, or NHC(0)Rf, Rg is H, Chalky! Het-C0^alkyl, C3 7cycloalkyl-C0^alkyl or Ar-C0^alkyl, Rf is H, CMalkyl, or Ar-C^alkyl, and k is 0, 1 or 2, m Hmimeisbach, et al, EP 0 483 667, published May 6, 1992 rxvip wherein Rg is H, C, 6alkyl, Het-C0 6alkyl, C3 7cycloalkyl-C0^alkyl or Ar-C0^alkyl, and q is 1 or 2, m Linz, et al, EP 0 567 968, published November 3, 1993 fXVIID z- z* co2r9 Rd wherein R" is Het-C^alkyl, and Z", Z'" independently are hydrogen, C,_,alkyl, halo, ORf, CN, S(0)kRf, 5 COjRf, or OH, in Bovy, et al, EP 0 539 343, pubbshed Apnl 28, 1993 The above descriptions of fibnnogen receptor templates for use in the present invention were taken from pending pubbshed patent appkcations Reference should 10 be made to such patent applications for their full disclosures, including the methods of prepanng said templates and specific compounds using said templates, the entire disclosure of such patent applications being incorporated herein by reference Table n, below, descnbes other fibnnogen receptor antagonists, whose core 15 structures would be useful in carrying out the instant invention Reference should be made to the patent application > and other publications for their full disclosures, including the methods of preparing said templates and specific compounds usmg said templates, the entire disclosure of the noted patent applications and other pubkcations being incorporated herein by reference Since it is contemplated that 20 any fibnnogen receptor antagonist that is linked to an optionally fused nitrogen-containing five-membered nng will possess the novel utility descnbed herein, the list below does not limit the scope of the present invention Table n Adir et Compagnie FR 928004, June 30,1992, Fauchere, J L, et al EP 0578535, June 29, 1993, Fauchere, J-L, et al Descnbes X-RGDW-OH analogs, where X contains a cationic amine CA 2128560, Jan ^24, 1995, Godfroid, J-J, et al, substituted piperazines Asahi Breweries, Ltd.
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WO 92/17196, Mar 30,1992, S I Klein et al Descnbes X-Gly-Asp-Val-OH analogs.
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EP 614360, Sept 14, 1994, Bovy, P. R., et al 5 WO 9420457, (Der 94-302907/37) Sep 15,1994, Tjoeng, F S. et al Amindmophenyl compounds with central nng WO 9421602, (Der 94-316876/39), Sept 29,1994, Tjoeng, F S , et al Descnbes guamdinoalkylanunocarbonylaminoacid denvatives WO 9422820, Oct 13, 1994, Abood, N. A , et al * Descnbes 10 amidmophenylpyrollidinonyl-P-Ala denvatives EP 630366, Dec 28, 1994, Bovy, P R, et al US 5378727, Jan 3,1995, Bovy, P R et al K. F Fok, et al, Int J Peptide ProL Res, 38,124-130, 1991, SAR of RGDY analogs J A Zablocki, et al J.Med Chem 35,4914-4917, 1992, SAR summary of guanidinoalkanoyl-Asp-Phe analogs Tjoeng, F S , Fok, K F., Zupec, M E, Garland, R B , Miyano, M., Panzer-BCnodle, S , King, L W, Taite, B B , Nicholson, N S., Feigen, L P ; Adams, S P, Peptide Mimetics of the RGD Sequence, In Peptides, Chem and Biol Proc 20 12th Amer Peptide Symp, J A Smith and J E Rivier, Ed., ESCOM, Leiden, 1992, 752 Nicholson, N., Taite, B , Panzer-Knodle, S., Salyers, A , Haas, N, Szalony, J , Zablocki, J; Feigen, L, Glenn, K., Keller, B ; Broschat, K., Henn, M., Jacqmin, P; lesne, M, An Orally Active Glycoprotein Hb/DIa Antagonist -25 SC-54684, Thromb Haem., 69,975,1993 Sumitomo Pharm. Co. Ltd WO 9501336, June 6, 1994, Bceda, Y, et at, Descnbes pipendinyloxyacetyl-Tyr-pipendinyloxyacetic acid denvatives Sumitomo Seiyaku KK JP 06025290, (Der 94-077374/10) Feb 1,1994 Descnbes multimenc RGDT Taisho Pharm. (Teijin, Ltd) JP 05230009, (Der 93-317431/40, Feb 24,1992 Descnbes amidmo-Cbz-meta-5 aminophenylpropionate JP 9235479, Feb 24,1992 Descnbes Amidinophenylcarbamates (PFD4C06), WO 94/17804, Aug 18,1994, Mizushima, Y Pharm Comp for Treating Cerebral Thrombosis (EP 634171), Jan 18,1995, Nizushxma, M Pharm Comp for Treating Cerebral 10 Thrombosis Prostaglandins Takeda EP 0529858, Apr. 3,1993, H Sugihara, et al Descnbes amidmobenzoyl-Gly-Piperazinone analogs 15 EP 606881, Jul 20,1994, Cyclic peptides with beta and gamma turns EP 614664, Sept 14,1994, Miyake, A, et al Qumolonecarboxylic Acids as cell adhesion inhibitors Tanabe WO 89/07609, T J Lobl, et al Descnbes RGD analogs WO 92/00995, July 9,1991, T J Lobl, et al Descnbes cyclic RGD analogs WO 93/08823, Nov 6, 1991, T C McKenzie Descnbes guanidmoalkanoyl-Gly-Asp-X analogs CA 2087021, Jan 10,1991, Lobl, T J, et al Descnbes cyclic RGD analogs 25 WO92/08464,Nov 15,1991,T C McKenzie,etal Descnbes Telios / La Jolla Cancer Research US 4578079, Nov 22, 1983, E Ruoslahti, and M Pierschbacher Descnbes X-RGD-Y analogs US 4614517, June 17,1985, E Ruoslahti, and M. Pierschbacher Descnbes X-RGD-Y analogs P CT/O S95/08306 US 4792,525, June 17,1985, E Ruoslahti, and M. Pierschbacher. Descnbes X-RGD-Y analogs US 4879237, (Der 90-154405/20) May, 24, 1985, Descnbes X-RGD-Y analogs WO 91/15515, (Der 91-325173/44) Apr 6,1990, descnbes cyclic RGD analogs US 5041380,1991, E Ruoslahti, and M Pierschbacher Descnbes RGD-X analogs WO 95/00544 Jan 5, 1995, Craig, W S., et al Cheng, S , Craig, W. S., Mullen, D , Tschopp, J F., Dixon, D., Pierschbacher, M. F, Design and Synthesis of Novel Cyclic RGD-Contaimng Peptides as Highly Potent and Selective Integnn (XjjbPs Antagonists, J Medicm Chem., 0 37, 1, 1994 Collen, D ; Lu, H R , Stassen, J -M , Vreys, I, Yasuda, T, Bunting, S , Gold, H K, Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/nia Inhibitors in Animal Models of Platelet-Mediated Thrombosis, Thrombosis and Haemostasis, 71, 95,1994 Temple U.
WO 9409036, (Der 94-151248/18), Apr. 28, 1994, Describes disintegnn peptides.
TerumoKK 3 JP 6279389, Oct 4,1994, Obama, H, et al. Describes 3-(4- amidmophenyloxymethyl)phenylamidopropionic acid analogs (ala Roche I-35) Karl Thomae / Boehringer Icgelheim EP 0483667, May 6, 1992, Himmelsbach, F, et al: Descnbes amidinobiphenyl-oxymethyl-2-pyrrohdinone-acetic acid EP 0496378, Jan. 22, 1992, Himmelsbach, F., et al.: Descnbes amidmobiphenyl-aminocarbonylcyclohexylcarboxyhc acid analogs EP 0503548, Sep 16, 1992, Himmelsbach, F., et al. Descnbes amidinophenyl- 3 pyrrolidinone-phenylpropionic acid analogs.
FCT/CS95/08306 AU A-86926/91, May 7, 1992, Himmelsbach, F et al Descnbes armdinopheiiyl compounds EP 0528369, Feb 24,1993, Austel, V , et al Descnbes amidmobiphenyl-oxymethyl-2-pyrTolidinone-acetic acid 5 EP 0537696, Apr 21,1993 Linz, G , et al Descnbes amidinophenyl-pyndazine analogs DE 4124942, Jan 28,1993, Himmelsbach, F et al Descnbes amidino- tnarylproionic acid analogs DE 4129603, Mar 11,1993, Pieper, H, et al Descnbes amidmobiphenyl-0 benzimidazole EP 0547517 Al, (Der 93-198544) June 23,1993, Soyka, R, et al • Describes pyndyl compounds EP 0567966, Nov 3, 1993, Himmelsbach, F., et al Descnbes amidmobiphenyl-oxymethyl-2-pyrrokdinone-acetic acid 5 EP 0567967, Nov 3 1993, Weisenberger, J, et al Descnbes amidinobiphenyl-oxymethyl2-pyrrolidinone-acetic acid EP 0567968, Nov 3, 1993, Linz, G, et al. Descnbes amidmobiphenyl-lactam-acetic acid and amidinophenyllactamphenylpropionic acid analogs EP 0574808, June 11,1993, Pieper, H, et al Descnbes amidmobiphenyl-X-aceuc 3 acid ester analogs Der 93-406657/51, Austel, V., et al. Descnbes amidmobiphenyl analogs. EP 587134, (Der 94-085077/11) Mar 16,1994, Himmerlsbach, F D D , et al, Descnbes aimdinophenyltnazolone analogs EP 589874, Apr. 6,1994, Grell, W, et al 5 (P534005), DE 4234295, Apr 14, 1994, Pieper, H , et al, Descnbes heteroaryl-azacyclohexylcarboxyhc acid analogs EP 0592949, Apr 20,1994, Pieper, H D, et al, Descnbes amidinophenyl- 4pipendinamido-4-cyclohexylcarboxyhc acid analogs EP 596326, May, 11,1994, Maier, R et al 3 DE 4241632, June 15,1994, Himmelsbach, F, et al, Descnbes pipendinophenylamido-phenylpropionyl analogs EP 0604800 A, Jul 6, 1994, Himmelsbach, F. et al, Descnbes pipendmophenylamido-phenylalanine denvatives DE 4302051, (Der 94-235999/29) July, 28, 1994, descnbes compounds containing a 2H-pyrazol-5-one EP 0608858 A, Aug, 3,1994, Linz, G D, et al., Descnbes amidmo-biphenyl compounds DE 4304650, (Der 94-256165/32), Aug, 18, 1994, Austel, V , et al., descnbes compounds with a 5,6 template EP 611660, Aug, 24,1994, Austel, V, et al., Descnbes tncyclic template 0 DE 4305388, (Der 94-264904/33), Aug 25, 1994, Himmelsbach, F, et al, Descnbes 6,6 and 7,6 templates (P5D4005), EP 612741, (Der 94-265886/33), Aug 31,1994, Himmelsbach, F., et al., Descnbes 6,6 and 7,6 templates EP 0639575 A, Feb. 22,1995, Linz, G, et al Descnbes tetrahydrothiazolo-5 [5,4,c]pyndine cation replacements DE 4324580, Jan 26,1995, Linz, G et al EP 0638553, Feb 15,1995, Himmelsbach, F, et al F Hiummelsbach, V. Austel, G Kruger, H Pieper, H Weisenberger, T H Muller, and W G Eisert, in XHth Int Symp on Med Chem. Basel, Book of 3 Abstracts, 47,1992 V Austel, W Eisert, F. Himmelsbach, G Kruger, G. Linz, T Muller, H Pieper, and J Weisenberger, Natl Mtg Amer. Chem Soc Book of Abstracts, Denver, Div Med. Chem., 1993.
Muller, T H, Schurer, H, Waldmann, L, Bauer, E , Himmelsbach, F, Bmder, K., 5 Orally Activity of BIBU 104, a Prodrug of the Non-peptide Fibrinogen Receptor Antagonist BIBU 52, in Mice and Monkeys, Thromb. Haem., 69, 975, 1993 Univ. California 3 WO 94/14848, July, 7, 1994, Zanetti, M RGD peptides from CDR PCT/US9S/08306 Univ. New York WO 94/00144, June 29,1993, Ojima, I. et al. Descnbes RGD peptide multimers.
Yeda Res. and Dev. Co.
WO 93/09795, (Der 93-182236/22), Lido, O et al Descnbes Guanidinopentanoic acid analogs Zeneca WO 9422834, Oct 13,1994, Wayne, M G, et al Descnbes pyndinopiperazino-0 phenylcarbonyl-amino acids WO 9422835, Oct. 13,1994, Wayne, M G, et al Descnbes pyndmopipendmo- amidophenylacetic acids EP 632016, Jan 4, 1995, Brewster, A G ,etal Descnbes pyridinopropionylh>drazinylbenzoyl analogs 5 EO 632019, Jan 4, 1995, Brown, G, Shute, R E EO 632020, Jan 4, 1995, Brown, G, Shute, R E.
In cases wherein the compounds of this invention may have one or more chiral centers, unless specified, this invention includes each umque nonracemic 0 compound which may be synthesized and resolved by conventional techniques In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention The meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence 5 Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to descnbe the compounds of this invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as descnbed in Eur J Biochcm., 158,9 (1984) Ci-4alkyl as applied herein means an optionally substituted alkyl group of 1 3 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Ci-^alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof Co_4alkyl and Co~6alkyl additionally indicates that no alkyl group need be present (e.g, that a covalent bond is present) Any Ci-4alkyl or Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Cj.g oxoalkyl may be optionally substituted with the group Rx, which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques Suitable groups for Rx are Ci-4alkyl, OR*, SR*, Cj_4alkyl, Ci-4alkylsulfonyl, Ci-4alkylsulfoxyl, -CN, N(R*)2, CH2N(R*)2, -NO2, -CF3, -C02R'3 -CON(R 1)2, -CORl, -NR1C(0)R1, OH, F, CI, Br, I, or 10 CF3S(0)r, wherern r is 0 to 2.
Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents, such as those defined above for alkyl, especially Ci_4alkyl, Ci_4alkoxy, Ci-4alkthio, tnfluoroalkyl, OH, F, CI, Br or I Het, or heterocycle, indicates an optionally substituted five or six membered monocyclic nng, or a nine or ten-membered bicyclic nng containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis Illustrative heterocycles are benzofuryl, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indohne, 20 morpholine, pipendme, piperazme, pyrrole, pyrrohdme, tetrahydropyndine, pyndine, thiazole, thiophene, qumoline, isoquinohne, and tetra- and perhydro-qumoline and isoquinoline Any accessible combination of up to three substituents on the Het ring, such as those defined above for alkyl that are available by chemical synthesis and are stable are within the scope of this invention 25 C3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds Typical of C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl Any combination of up to three substituents, such as those defined above for alkyl, on the cycloalkyl nng that is available by conventional chemical synthesis and is stable, is within the scope of this invention When Rb and Rc are joined together to form a five- or six-membered aromatic or non-aromatic carbocychc or heterocyclic nng fused to the nng to which 5 Rb and Rc are attached, the nng formed will generally be a five- or six-membered heterocycle selected from those listed above for Het, or will be a phenyl, cyclohexyl or cyclopentyl nng Preferably Rb and Rc will be -D1=D2-D3=D4 wherein D1 - D4 are independently CH, N or C-Rx with the proviso that no more than two of D1 - D4 are N Most preferably, when R^ and Rc are joined together they form the group -10 CH=CH-CH=CH- Certain radical groups are abbreviated herein t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical, BrZ refers to the o-bromobenzyloxycarbonyl radical, C1Z refers to the o-chlorobenzyloxycarbonyl radical, Bzl refers to the benzyl radical, 4-MBzl refers to the 4-methyl benzyl radical, Me refers to methyl, Et refers to ethyl, Ac refers to acetyl, Alk refers to Cj^alkyl, Nph refers to 1- or 2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl Certain reagents are abbreviated herein DCC refers to dicyclohexylcarbodumide, DMAP refers to dimethylaminopyndine, DIEA refers to dusopropylethyl amine, EDC refers to l-(3-dimethylaminopropyl)-3-ethylcarbodumide, hydrochlonde HOBt refers to 1-hydroxybenzotnazole, THF refers to tetrahydrofuran, DEEA refers to dnsopropylethylamine, DME refers to dimethoxyethane, DMF refers to dimethylformamide, NBS refers to N-bromosuccirumide, Pd/C refers to a palladium on carbon catalyst, PPA refers to 1-propanephosphomc acid cyclic anhydnde, DPPA refers to diphenylphosphoryl azide, BOP refers to benzotnazol-l-yloxy-tns(dimethyl-ammo)phosphonium hexafluorophosphate, HF refers to hydrofluonc acid, TEA refers to tnethylamme, TFA refers to tnfluoroacetic acid, PCC refers to pyndinium chlorochromate Compounds of the formula (I)-(V) are prepared, for example, by reacting a compound of formula (XIX) with a compound of formula (XX), wherein L* and L2 are groups which may react to form a covalent bond m the moiety W, by methods generally known m the art. rVq jt l2 jt w-a 5 Rc N + L'-A ► rC N (xn) (xx) . (i) v Typical methods include coupling to form amide bonds, nucleophilic displacement reactions and palladium catalyzed couplings For instance, when W contains an ether or amine linkage, the bond may be formed by a displacement reaction, and one of L^ and L2 will contain an ammo or hydroxy group and the other will contain a displaceable group, such as a chloro, bromo or lodo group When W contains an amide bond, typically one of L* and L2 will contain an amino group, and the other will contain a carboxyhc acid group In another approach, L* may be an aryl or heteroaryl bromide, iodide or tnfluoromethylsulfonyioxy derivative and L2 may contain an amino group and the amide linkage may be formed by palladium-catalyzed ammocarbonylation with carbon monoxide m a suitable solvent such as dimethylformamide or toluene It will be apparent that the precise identity of L1 and L2 will be dependent upon the site of the linkage being formed General methods for prepanng the linkage -(CHR")rU-(CHR")s-V- are descnbed, for example, in EP-A 0 372 486 and EP-A 0 381 033 and EP-A 0 478 363, which are incorporated herein by reference For instance, if V is CONH, L1 may be -NH2, L2 may be OH (as m an acid) or CI (as in an acid chlonde), and R6" may be W-(CR'2)q-Z-(CR'RI0)rU-(CR'2)s-C'(0), with any functional groups opuonally protected. For example, R6" may be (benzyloxycarbonyl-amidino)benzoyl- or (Na-Boc,N8uan-Tos)argmyl- When L2 is OH, a coupling agent is used Similarly, if V is NHCO, L1 may be -CO2H or CO-C1, L2 may be -NH2, and R6" may be W-(CR'2)q-Z-(CR,R10)rU-(CR,2)s- For example, R6" may be (benzyloxycarbonyl-amidino)phenyl, (benzyloxycarbonylammo)methylben2yl- or 6-(benzyloxycarbonylamino)hexyl-5 Where V is NHSO2, L1 may be SO2CI, L2 may be -NH2 and R6" may be as above Where V is S02NH, L1 may be -NH2 and L2 may be SO2CI Methods to prepare such sulfonyl chlorides are disclosed, for instance, in J Org Chem., 23, 1257(1958) If V is CH=CH, L1 may be -CHO, L2 may be CH=P-Ph3 and R6" may be W-10 (CR,2)q-Z-(CR,R10)r-U-(CR,2)s- Alternately, L1 may be CH=P-Ph3, L2 may be CHO, e g, R6" may be W-CCR^q-Z^CR'R1 °)r-U-(CR,2)s-1 -CHO Where V is CH2CH2 may be obtained by reduction of a suitably protected compound wherern V is CH=CH Where V is CH2O, CH2N or Cs c, V may be -OH, -NH or 15 -C= C H,respectively; L2 may be -Br, and R6" may be W-(CR'2)q-Z-(CR,R10)r-U-(CR,2)s" For example, R6" may be (benzyloxycarbonylamino)-methylbenzyl- or 2-(N-benzyl-4-pipendinyl)-ethyl. Similarly where U or V is OCH2, NR'CH2 or C=C, L1 may be -CH2Br and L2 may be -OH, -NH or -C= C H, respectively Alternately, when U or V is C, L1 may 20 be Br, I or CF3SO3, L2 may be C^CH and the coupling may be catalyzed by palladium and a base.
Compounds wherein V is CHOHCH2 may be prepared from a suitably protected compound where V is CH=CH by the procedure disclosed in J Org Chem, 54,1354 (1989) Compounds wherein V is CH2CHOH may be obtained from a suitably protected compound where V is CH=CH by hydroboration and basic oxidation as disclosed in Tet Lett, 31, 231 (1990) Compounds of the formula (I)-(V), wherern tne fibnnogen receptor antagonist template is of the formula (VI) are prepared by the general methods descnbed in Schemes I-m 3 a) EDC, HOBT, (i-Pr)2NEt, DMF, 2-aminomethylbenzimidazole, b) SOCI2, reflux, c) 2-aminobenzinudazole, pyndine, CH2CI2, d) 1 0 N LiOH, aqueous THF, e) 10 acidification Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro- 1H-1,4-benzodiazepine-2-acetate (1-1), prepared as descnbed by Bondinell, et al (WO 93/00095), is converted to an activated form of the carboxyhc acid using, for 15 example, EDC and HOBT or SOCI2, and the activated form is subsequently reacted with an appropnate amine to afford the corresponding amide 1-2 Many additional methods for converting a carboxyhc acid to an amide are known, and can be found FCT/US95/08306 in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol I - VI (pubhshed by Wiley-Interscience) The methyl ester of 1-2 is hydrolyzed using aqueous base, for example, aqueous LiOH m THF or aqueous NaOH in methanol, and the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HC1, to afford the carboxyhc acid 1-3 Alternatively, the intermediate carboxylate salt can be isolated, if desired co2ch3 Scheme II b.c boc n—c02ch3 O J- H N—C02CH3 \=/ e /CH3 f.g CH, / 3 a) (E0C)20, DMAP, CH3CN, b) SOCl2, toluene, 70°C, c) H2, 10 % Pd/C, 2,6-lutidir.e, THF, d) 2-(ammomethyl)benzimidazole, NaBHsCN, MeOH, e) formaldehyde, NaBH3CN, AcOH, CH3CN, f) LiOH, THF, H20, g) acidification Conversion of the carboxyhc acid moiety of 1-Scheme II to an aldehyde can be accomplished by standard methodology, as descnbed in "Compendium of Organic Synthetic Methods" (published by Wiley-Interscience) For example, after protection of the aniline nitrogen as its re/f-butyl carbamate, the carboxyhc acid is converted to the corresponding acid chlonde with a suitable reagent, such as thionyl 10 chlonde The /ert-butyl carbamate is lost under these conditions The resulting acid chlonde is then reduced to aldehyde 3-Scheme II by hydrogenation over a suitable catalyst, for instance palladium on carbon in the presence of 2,6-lutidine The aldehyde 3-Scheme II is then converted to the amine 4-Scheme II by reaction with 2-(aminomethyl)benzimidazole in the presence of a suitable reducing agent, such as 15 sodium cyanoborohydnde Alternative methods for converting an aldehyde to an amine are descnbed in "Compendium of Organic Synthetic Methods" (published by Wiley-Interscience) The basic nitrogen atoms of 4-Scheme II are methylated under modified Eschweiler-Clarke conditions (Sondengam, B L etal, Tetrahedron Letters 1973, 261, Borsch, R. F, Hassid, A I / Org Chem. 1972,57,1673) Thus, 20 reaction of 4-Scheme II with formaldehyde m the presence of a suitable reducing agent, such as sodium cyanoborohydnde, gives 5-Scheme II Saponification of the methyl ester of 5-Scheme II by the methods descnbed earlier gives 6-Scheme II The methyl ester of 4-Scheme II can be cleaved similarly Scheme III / O a CI O co2ch3 b cozch3 1 2 CI co2h 3 a) NCS, DMF, 80 °C; b) see Scheme 1 Halogenation of the aromatic moiety of 1-Scheme III can be accomplished with an appropriate elctrophihc halogenatmg reagent, such as N-chlorosuccimmide The resulting chlorinated derivative, 2-Scheme HI, is then conveted to 3-Scheme m by the methods descnbed in Scheme I The core 6-7 fused nng system is prepared of formula (VI) by methods well known in the ait, e.g, Hynes, etal, J Het Chem., 1988,25, 1173, Muller, et al, Helv Chun. Acta., 1982,65, 2118, Mon, et al, Heterocycles, 1981, 16, 1491 Similarly, methods for prepanng benzazepines, 1,4-benzothiazepines, 1,4-15 benzoxazepines and 1,4-benzodiazepines are known and are disclosed, for instance, in Bondinell, et al, International Patent Application WO 93/00095 A representative method for prepanng the benzodiazepine nucleus is given by Schemes IV and V A representative method for prepanng a benzazepine nucleus is given by Scheme VI A representative method for prepanng a benzothiazepme is 20 given by Scheme VII An benzoxazepme nucleus may be prepared m the same manner as Scheme VII, except substituting a benzyl alcohol for a benzyl thiol Scheme IV R- 02N cho NaCNBH R^NHj O-N 'NH ho2C\ ^ R'N-Boc couple OgN N J NH-t-Boc 1)acid < ► 2) DMSO/90 DIEA H, Pd/C WO 96/00730 PCT/US95/08306 Scheme V CO 2CH 3 i --C. O2N^ n!,j ^ril _ rh h 2, pd/c CO 2CH 3 'v'v01 H*N-V °"YY ^N—(. OX")*0 P rucnntj !, _2" DMSO/TEA H Boc-HN .CN H CO 2CH 3 H 2, Raney-Ni j NaOCH 3 Boc-HN Scheme VI t-BuO 2c>^^sn^-ch 3 l"Bu0 2C"s^snv^-CH 2Br tx..--- XX.. — B 11 49 Scheme VII 1)bh 3 2) CBr 4,Ph 3P HF 02n XX sh o2n /=\ ho 2c co 2h h2n 1) (ch 30) 2so 2 2) h 2. pd/c co 2ch 3 The simple tn-substituted benzene starting materials are commercially available or prepared by routine methods well known in the art Schemes VIII-XI are illustrative of the methods for prepanng certain 25 compounds of the instant invention In schemes VIII - X, a covalent bond of the group W is prepared by a nucleophihc displacement reaction.
In Scheme Vm, 4-[2-(methylamino)acetyl]phenol hydrochlonde {Reel. Trav Chim. Pays-Bas 1949,68, 960) is N-protected with a suitable nitrogen protecting group, such as a ferr-butoxycarbonyl (BOC) group, to provide the N-protected 30 denvative 2-Scheme Vm -50 H3C Scheme VIII • hci boc boc C02Bn 2 O H3C •hci XX 0 COjjBn O COsBn O C02H a) (B0C)20, NaOH, 1,4-dioxane, H2O, b) BrCH2C02Bn, K2CO3, acetone, c) 4 M HCI m 1,4-dioxane, d) 2-(chloromethyl)ben2imida2ole, Et3N, CH3CN, CH2CI2, e) H2, 5% Pd/C, MeOH Other standard nitrogen protecting groups, such as those descnbed in Greene "Protective Groups in Organic Synthesis", may be chosen such that the protecting group employed is compatible with the subsequent chemistry and can be removed selectively under conditions which will not interfere with other functionality in the 5 molecule Alkylation of the phenol moiety of compound 2-Scheme VHI to afford the aryloxyacetic acid denvative 3-Scheme Vm can be accomplished by reaction with a haloacetic acid ester, for instance benzyl bromoacetate, under basic conditions in a neutral solvent Generally, K2CO3 in refluxmg acetone or 2-butanone gives acceptable results, but other bases, such as L12CO3 or CS2CO3, and other solvents, 10 such as DMF, THF, or DME, might also be used The nitrogen protecting group of 3-Scheme VHI is removed under conditions appropnate for selective deprotection of the specific protecting group employed For example, the BOC group of 3-Scheme Vin can be removed under acidic conditions, such as 4 M HC1 in 1,4-dioxane or TFA m CH2CI2, to afford amine 4-Scheme VjQI as the corresponding ammonium 15 salt Conversion of compound 4-Scheme Vm to the bis-benzimidazole denvative 5-Scheme VIII can be accomplished by alkylation with 2-(chloromethyl)benzimidazole m a solvent mixture of CH3CN and CH2CI2 in the presence of Et3N Subsequent removal of the ester group of compound 5-Scheme Vm under appropnate conditions gives compound 6-Scheme Vm The conditions 20 selected for ester removal must be appropnate for the specific ester present as well as compatible with the other functionality in the molecule For instance, the benzyl ester of 5-Scheme VHI can be removed by hydrogenolysis in the presence of a suitable catalyst, such as Pd on carbon, in an inert solvent, generally MeOH, EtOH, or acetic acid, to afford 6-Scheme Vm 25 In Scheme DC, commercially available andrenolone hydrochlonde (1-Scheme 2) is N-protected as discussed in Scheme 1 to provide the Cbz denvative 2-Scheme 2 -52 PCI7US95/08306 Scheme IX CBz CBz '\/Co2CH3 c C02ch3 h3c ^ u 2ch3 o-^ co2ch3 W-U^C02CH3 o co2ch3 o„ o- ,co2h co2h a) CbzCl, NaOH, toluene, H2O, b) B1CH2CO2CH3, K2CO3, acetone, c) H2,10% Pd/C, EtOAc, MeOH, d) 2-(chloromethyl)benzimidazoIe, Et3N, CH3CN, CH2CI2, e) 1 0NLiOH,THF,H2O.
Dialkylation of 2-Scheme IX by reaction with a haloacetic acid ester, for instance methyl bromoacetate, under basic conditions m a neutral solvent, provides the 1,2-phenylenedioxydiacetic acid denvauve 3-Scheme IX K2CO3 in refluxing acetone generally gives acceptable results, but other bases and solvents, such as -53 those discussed in Scheme VIII, might also be used. Removal of the nitrogen protecting group of 3-Scheme IX by hydrogenolysis over a Pd/C catalyst in a solvent mixture of EtOAc and MeOH is accompanied by concomitant reduction of the ketone to afford aminoalcohol 4-Scheme IX N-alkylation of compound 4-Scheme 5 IX with 2-(chloromethyl)benzimidazole in a solvent mixture of CH3CN and CH2CI2 in the presence of Et3N gives the mono-benzimidazole derivative 5-Scheme IX Subsequent removal of the ester group of 5-Scheme IX under appropnate conditions, as discussed in Scheme VIE, gives compound 6-Scheme IX. Generally, a methyl ester, such as that present in 5-Scheme IX, is removed by hydrolysis m the 10 presence of an alkali metal hydroxide, such as LiOH, NaOH, or KOH, in an aqueous solvent, typically MeOH, EtOH, or THF.
In Scheme X, commercially available andrenolone hydrochlonde (1-Scheme X) is N-protected as descnbed in Scheme Vm to provide the BOC denvative 2-Scheme X Scheme X " XX OH 1 OH \ H3C -54 ch3 o - O CO2CH3 aJH3 9 ^,C02CH3 f O CO2CH3 7 a) (BOQ2O, NaOH, 1,4-dioxane, H2O, b) BrCH2C02CH3, K2CO3, acetone, c) 4 M HC1 in 1,4-dioxane; d) l-(BOC)-2-(bromomethyl)benzimidazole, Et3N, THF, CH2CI2, e) TFA, CH2CI2; f) 1 0 N LiOH, THF, H2O Dialkylation of 2-Scheme X as discussed in Scheme IX affords 3-Scheme X The nitrogen protecting group of 3-Scheme X is removed as discussed in Scheme Vm to afford amine 4-Scheme X as the corresponding ammonium salt Alkylation of 4-Scheme X with l-BOC-2-(bromomethyl)benzimidazole in a solvent mixture of THF and CH2CI2 in the presence of Et3N gives the mono-benzimidazole denvative 5-Scheme X Subsequent removal of the BOC group of 5-Scheme X as discussed in Scheme VIE delivers 6-Scheme X. Removal of the ester group of 6-Scheme X as discussed in Schemes 1 and 2 gives 7-Scheme IX Alternatively, the ester group of 5-Scheme X might be removed first, followed by removal of the BOC group In Scheme XI, the moiety "W is prepared by an amide coupling reaction -55 Scheme XI a) ethyl acrylate, HOAc, b) SOCI2; c) 2-(anunomethyl)benzimida2ole, DIEA, CH2CI2, d) NaOH, H2O, MeOH Initially, ethyl 3-[4-(carboxy)phenyl]amino]propionic acid (2-Scheme XI) is prepared by Michael-type addition of 4-(caiboxy)anihne (1-Scheme XI) to ethyl acrylate m acetic acid as descnbed in Chem. Ber., 91,2239,1958. The carboxyl m compound 2-Scheme XI is converted to the acid chlonde with thionyl chloride, and 25 the acid chlonde is condensed with 2-(ammomethyl)benzimidazole dihydrochlonde hydrate with diisopropylethylamine in dichlorometkane to form compound 3-Scheme XI The ethyl ester 3-Scheme XI is saponified with sodium hydroxide in aqueous methanol to give compound 4-Scheme XI; alternatively the ester can be converted to the carboxyhc acid with other metal hydroxides or carbonates m a 30 suitable solvent -56 wo 96/00730 pct/us95/08306 Scheme XII 1) Hj/Pd/C MeOH 2) CIC02(iBu) Et3N ,NH2 n-BuSO,NH CO,Me N A 1 n-BuSO NH X nh2 1d 3) HOAc reflux LiOH, THF n-BuS02NH C02H ig The starting material for the formula lg-Scheme XII compounds are 5 prepared following the procedures m Egbertson et al., J Med Chem., 1994,37, 2557-555/which discloses general methods to alkylate the phenol of an N-protected tyrosine derivative, remove the N-protecung group, and sulfonylate the amine Using benzyl 4-bromobutyrate as the alkylating agent, intermediate Id-Scheme XH was prepared Removal of the benzyl ester and reaction with ortho-10 phenylenedianune under standard conditions afforded the benzimidazole lf-Scheme XII Finally, saponification of the methyl ester yielded the target compound 1 g-Scheme XII Intermediate compounds of formula (XXX) may be prepared from suitably protected amino acids and phenyl- 1,2-diammes or 2-mtro-amhnes which are 15 commercially available or prepared by methods available to those skilled in the art according to the Scheme (XHI) and (XTV) -57 PCT/US95/C83G6 Scheme XIII Pr1-NR'-(CH2)a-C02H a Pr1 -NR'-(CH2)a-CO-0 -CO-O^^ R\< RyJT R V R* nh2 nh2 i/- R N ^—(CH2)aNR'-Pr1 H b Ry^.NHCO(CH2)aNR,-Pr1 — R'i-ANH pX N"2 a) isobutyl chloroformate, THF, NEt3, b) A, AcOH Scheme XIV Pr1-NR'-(CH2)a-C02H Pr1-NR'-(CH2)a-CO-a Ry~ R* Cc nh2 no2 R\ AVI R n )—(CH2)aNR'-Pr1 XtT Ry^.NHCO(CH2)aNR'.Pr1 R'iA no2 a) thionyl chlonde, b) Fe, AcOH, A Amide coupling reagents as used herein denote reagents which may be used to form peptide bonds Typical coupling methods employ carboduimdes, activated -58 PCT/US9S/08306 anhydrides and esters and acyl haiides Reagents such as EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chlonde are typical Coupling methods to form peptide bonds are generally well known to the art The methods of peptide synthesis generally set forth by Bodansky et al, THE 5 PRACTICE OF PEPTIDE SYNTHESIS, Spnnger-Verlag, Berlin, 1984, Ah et al in J Med. Chem., 29,984 (1986) and J Med. Chem, 30, 2291 (1987) are generally illustrative of the technique and are incorporated herein by reference Typically, the amine or aniline is coupled via its free amino group to an appropnate carboxyhc acid substrate using a suitable carbodumide coupling agent, 10 such as N,N' dicyclohexyl carbodumide (DCC), optionally in the presence of catalysts such as l-hydroxybenzotnazole (HOBt) and dimethylammo pyndine (DMAP) Other methods, such as the formation of activated esters, anhydndes or acid haiides, of the free carboxyl of a suitably protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine, optionally in 15 the presence of a base, are also suitable For example, a protected Boc-amino acid or Cbz-amidino benzoic acid is treated in an anhydrous solvent, such as methylene chlonde or tetrahydrofuran(THF), m the presence of a base, such as N-methyl morphohne, DMAP or a tnalkylamine, with isobuty! chloroformate to form the "activated anhydnde", which is subsequently reacted with the free amine of a second 20 protected ammo acid or aniline The compounds of formula (XIX) and (XX) are commercially available or are prepared by methods known in the art such as illustrated herein disclosed m standard reference books, like the Compendium of Organic Synthetic Methods, 25 Vol I-VI (Wiley-Interscience) A generally applicable route to benzimidazoles is disclosed in Nestor et al, J Med Chem 1984,27,320 Representative methods for prepanng compounds of formula (XX) are also common to the art and may be found, for instance, in EP-A 0 381 033 Acid addition salts of the compounds are prepared in a standard manner in a 30 suitable solvent from the parent compound and an excess of an acid, such as hydrochlonc, hydrobromic, hydrofluonc, sulfunc, phosphonc, acetic, tnfluoroacetic, -59 maleic, succinic or methanesulfonic Certain of the compounds form inner salts or zwittenons which may be acceptable Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containmg the appropnate cation, or with an appropnate 5 organic amine Cations such as Li+, Na+, K+, Ca*4", Mg"1-1" and NH4+ are specific examples of cations present in pharmaceutical^ acceptable salts This invention also provides a pharmaceutical composition which comprises a compound according to formula (I)-(V) and a pharmaceutical^ acceptable earner. Accordingly, the compounds of formula (I)-(V) may be used in the manufacture of a 10 medicament Pharmaceutical compositions of the compounds of formula (I)-(V) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration Powders may be reconstituted by addition of a suitable diluent or other pharmaceutical^ acceptable earner pnor to use. The liquid formulation may be a buffered, isotomc, aqueous solution Examples of 15 suitable diluents are normal isotomc saline solution, standard 5% dextrose m water or buffered sodium or ammonium acetate solution Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained m a metered dose inhaler or nebulizer for insufflation It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, 20 polyethylene glycol, mannitol, sodium chlonde or sodium citrate Alternately, these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration Pharmaceutically acceptable solid or liquid earners may be added to enhance or stabilize the composition, or to facilitate preparation of the composition Solid earners include starch, lactose, calcium 25 sulfate dihydrate, terra alba, magnesium stearate or steanc acid, talc, pectin, acacia, agar or gelatin Liquid earners mclude syrup, peanut oil, olive oil, saline and water The earner may also include a sustained release matenal such as glyceryl monostearate or glyceryl distearate, alone or with a wax The amount of solid earner vanes but, preferably, will be between about 20 mg to about I g per dosage 30 unit The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, €0 WO 96/00730 PCT/US9S/08306 when necessary, for tablet forms, or milling, mixing and filling for hard gelatin capsule forms When a liquid earner is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension Such a liquid formulation may be administered directly p o or filled into a soft gelatin capsule 5 For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository The compounds descnbed herein are antagonists of the vitronectin receptor, and are useful for treating diseases wherern the underlying pathology is attributable 10 to hgand or cell which interacts with the vitronectin receptor For instance, these compounds are useful for the treatment of diseases wherein loss of the bone matrix creates pathology. Thus, the instant compounds are useful for the treatment of ostoeporosis, hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilization or 15 sex hormone deficiency The compounds of this invention are also believed to have utility as antitumor, anti-angiogemc. antiinflammatory and anti-metastatic agents, and be useful in the treatment of atherosclerosis and restenosis The compound is administered either orally or parenterally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption, or 20 other such indication. The pharmaceutical composition containing the peptide is administered at an oral dose of between about 0 1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0 5 to about 20 mg/kg For acute therapy, parenteral administration is preferred. An intravenous infusion of the peptide in5% dextrose in water or normal saline, or a 25 similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0 01 to about 100 mg/kg, preferably between 0.1 and 20 mg/kg. The compounds are administered one to four times daily at a level to achieve a total daily dose of about 0 4 to about 400 mg/kg/day The precise level and method by which 30 the compounds are administered is readily determined by one routinely skilled m the 61r an by comparing the blood level of the agent to the concentration required to have a therapeutic effect The compounds may be tested in one of several biological assays to determine the concentration of compound which is required to have a given 5 pharmacological effect Inhibition of vitronectin binding Solid-Phase [3HJ-SK&F-107260 Binding to avp3 Human placenta or human platelet avP3 (0 1-03 mg/mL) in buffer T (containing 2 mM CaCl2 and 1% 10 octylglucoside) was diluted with buffer T containing 1 mM CaCl2, 1 mM MnCl2, 1 mM MgCl2 (buffer A) and 0.05% NaN3, and then immediately added to 96-well ELIS A plates (Coming, New York, NY) at 0 1 mL per well 0.1 - 0 2 |ig of avP3 was added per weli The plates were incubated overnight at 4°C At the time of the experiment, the wells were washed once with buffer A and were incubated with 15 0 1 mL of 3.5% bovine serum albumin in the same buffer for 1 hr at room temperature. Following incubation the wells were aspirated completely and washed twice with 0 2 mL buffer A Compounds were dissolved in 100% DMSO to give a 2 mM stock solution, which was diluted with binding buffer (15 mM Tns-HCl (pH 7 4), 100 mM NaCl, 20 1 mM CaCl2,1 mM MnCl2, J mM MgCl2) to a final compound concentration of 100 pM This solution is then diluted to the required final compound concentration Various concentrations of unlabeled antagonists (0.001 -100 fiM) were added to the wells in triplicates, followed by the addition of 5 0 nM of [^HJ-SK&F-107260 (65 -86 Ci/mmol).
The plates were incubated for 1 hr at room temperature Following incubation the wells were aspirated completely and washed once with 0 2 mL of ice cold buffer A m a well-to-well fashion THe receptors were solubilized with 0 1 mL of 1% SDS and the bound [^H]-SK&F-107260 was determined by liquid scintillation counting with the addition of 3 mL Ready Safe m a Beckman LS Liquid Scintillation Counter, with 40% efficiency Nonspecific binding of [3h]-SK&F- 62 107260 was determined in the presence of 2 (iM SK&F-107260 and was consistently less than 1 % of total radioligand input The IC50 (concentration of the antagonist to inhibit 50% binding of [3H]-SK&F-107260) was determined by a nonlinear, least squares curve-fitting routine, which was modified from the LUNDON-2 program 5 The Kx (dissociation constant of the antagonist) was calculated according to the equation = IC50/( 1 + L/Kd), where L and Kd were the concentration and the dissociation constant of [3H]-SK&F-107260, respectively Compounds of the present invention inhibit vitronectin binding to SK&F 107260 in the concentration range of about 0 001 to 50 micromolar 0 Compounds of this invention are also tested for in vitro and in vivo bone resorption in assays standard in the art for evaluating inhibition of bone formation, such as the pit formation assay disclosed in EP 528 587, which may also be performed using human osteoclasts in place of rat osteoclasts, and the ovarectomized rat model, descnbed by Wronski et al, Cells and Materials 1991, Sup 1,69-74.
Vascular smooth muscle cell migration assay Rat or human aortic smooth muscle cells were used The cell migration was monitored in a Transwell cell culture chamber by usmg a polycarbonate membrane 0 with pores of 8 um (Costar) The lower surface of the filter was coated with vitronecun Cells were suspended m DMEM supplemented with 0 2% bovine serum albumin at a concentration of 2 5 - 5 0 x 10^ cells/mL, and were pretreated with test compound at vanous concentrahons for 20 mm at 20°C The solvent alone was used as control 0 2 mL of the cell suspension was placed m the upper compartment of 5 the chamber The lower compartment contained 0 6 mL of DMEM supplemented with 0 2% bovine serum albumin Incubation was earned out at 37°C in an atmosphere of 95% air/5% CO2 for 24 hr After incubation, the non-migrated cells on the upper surface of the filter were removed by gentle scraping The filter was then fixed in methanol and stained with 10% Giemsa stain Migration was measured D either by a) counting the number of cells that had migrated to the lower surface of 63- the filter or by b) extracting the stained cells with 10% acetic acid followed by determining the absorbance at 600 nM PARATHYRQIDECTOMTZED RAT MODEL Each experimental group consists of 5-6 male Sprague-Dawley rats The rats are parathyroidectomized (by the vendor, Tacomc Farms) 7 days pnor to use Twenty four hours pnor to use, circulating ionized calcium levels are measured in whole blood immediately after it has been withdrawn by tail venipuncture into hepannized tubes Rats 10 are included if ionized Ca level (measured with a Ciba-Cormng model 634 calcium pH analyzer) is _1.2 mM/L The rats are then put on a diet of calcium-free chow and deiomzed water At the start of the experiment the rats weigh approximately lOOg Baseline Ca levels are measured and the rats are administered control vehicle (saline) or compound (dissolved in saline) as a single intravenous (tail vein) bolus injection followed 15 immediately by a single subcutaneous injection of either human parathyroid hormone 1-34 peptide (hPTHl-34, dose 0.2mg/kg in saline/0.1% bovine serum albumen, Bachem, Ca) or the PTH vehicle. The calcemic response to PTH (and any effect of compound on this response) is measured 2h after compound/PTH administration.
RAT ULNA DRIFT MODEL Each experimental group consists of 8-10 male Sprague-Dawley or Wistar rats of approximately 30-40g body weight at the start of the experiment. The agent being tested is administered by an appropnate route as single or multiple daily doses for a penod of 25 seven days. Pnor to administration of the first dose, the rats are given a single dose of a fluorescent marker (tetracycline 25mg/kg, or calcein lOmg/kg) that labels the position of bone forming surfaces at that point in time. After dosing of compound has been completed, the rats are killed and both fore limbs are removed at the elbow, the foot is removed at the ankle and the skin removed The sample is frozen and mounted vertically 30 on a microtome chuck. Cross sections of the midshaft region of the ulna are cut in the ciyostaL The rate of bone resorption is measured morphometncally in the medial-dorsal 64 portion of the cortical bone The measurement is done as follows the amount of bone resorbed at the penosteal surface is equal to the distance by which the penosteal surface has advanced towards the fluorescent label which had been incorporated at the endosteal bone formation surface on day zero, this distance is calculated by subtracting the width of 5 bone between the label and the penosteal surface on day 7 from the width on day zero, the resorption rate in microns per day is calculated by dividing the result by 7 HUMAN OSTEOCLAST RESORPTION ASSAY ("PIT ASSAY") • Aliquots of osteoclastoma-denved cell suspensions are removed from hquid nitrogen strorage, wanned rapidly at 37°C and washed xl in RPMI-1640 medium by centnfugation (lOOOrpm, 5 mins at 4°C) • Aspirate the medium and replace it with munne anti-HLA-DR antibody, diluted 15 1 3 in RPMI-1640 medium. Incubate for 30 mins on ice and mix the cell suspension frequently • The cells are washed x2 with cold RPMI-1640 by centnfugation (lOOOrpm, 5 nuns at 4°C) and the cells are transferred to a sterile 15 ml centnfuge tube The number of mononuclear cells are enumerated in an improved Neubauer counting chamber • Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, are removed from their stock bottle and placed into 5 ml of fresh medium (this washes away the toxic azide preservative) The medium is removed by immobilizing the beads on a magnet and is replaced with fresh medium • The beads are mixed with the cells and the suspension is incubated for 30 mins on ice The suspension is mixed frequently • The bead-coated cells are immobilized on a magnet and the remaining cells (osteoclast-nch fraction) are decanted into a stenle 50 ml centnfuge tube €5 • Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts This wash process is repeated xlO The bead-coated cells are discarded • The osteoclasts are enumerated in a counting chamber, using a large-bore disposable plastic pasteur to charge the chamber with the sample • The cells are pelleted by centnfugation and the density of osteoclasts adjusted to 1.5x1 OVml in EMEM medium, supplemented with 10% fetal calf serum and 1 7g/htre of sodium bicarbonate • 3ml ahquots of the cell suspension (per treatment) are decanted into 15ml centnfuge tubes The cells are pelleted by centnfugation • To each tube 3ml of the appropnate treatment are added (diluted to 50 uM in the EMEM medium). Also included are appropnate vehicle controls, a positive control (87MEM1 diluted to 100 ug/ml) and an isotype control (IgG2a diluted to 100 ug/ml). Incubate at 37°C for 30 mms *0 5ml ahquots of the cells are seeded onto stenle dentine slices m a 48-well plate and incubated at 37°C for 2 hours Each treatment is screened in quadruplicate • The slices are washed in six changes of warm PBS (10 ml / well in a 6-well plate) and then placed into fresh treatment or control Incubate at 37°C for 48 hours Tartrate resistant acid phosphatase (TRAP) procedure (selective stain for cells of the osteoclast lineage) • The shces are washed in phosphate buffered saline and fixed in 2% gluteraldehyde 30 (in 0 2M sodium cacodylate) for 5 mins. 66 • They are washed in water and incubated in TRAP buffer for 5 mins at 37°C • Following a wash in cold water they are incubated in cold acetate buffer / fast red garnet for 5 nuns at 4°C • Excess buffer is aspirated, and the slices are air dried following a wash in water • The TRAP positive osteoclasts are enumerated by bright-field microscopy and are then removed from the surface of the dentine by sonication • Pit volumes are determined using the Nikon/Lasertec ILM21W confocal microscope Inhibition of RGD-mediated GPIIb-IIIa binding Purification of GPIIb-IIIa Ten units of outdated, washed human platelets (obtained from Red Cross) were lyzed by gentle stirring in 3% octylglucoside, 20 mM Tns-HCl, pH 7 4,140 mM NaCl, 2 mM CaCl2 at 4°C for 2 h The lysate was centnfuged at 100,000g for 1 h The supernatant obtained was applied to a 5 mL lentil lectin sepharose 4B column (E Y Labs) preequihbrated with 20 mM Tns-HCl, pH 7 4, 100 mM NaCl, 2 mM CaCl2, 1% octylglucoside (buffer A) After 2 h incubation, the column was washed with 50 mL cold buffer A The lectm-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose All procedures were performed at 4°C The 25 GPHb-IHa obtained was >95% pure as shown by SDS polyacrylamide gel electrophoresis Incorporation of GPIIb-IIIa in Liposomes A mixture of phosphatidylsenne (70%) and phosphatidylcholine (30%) 30 (Avanti Polar Lipids) were dned to the walls of a glass tube under a stream of nitrogen Punfied GPHb-IHa was diluted to a final concentration of 0 5 mg/mL and mixed with the phospholipids m a protein phospholipid ratio of 1 3 (w w) The mixture was resuspended and sonicated in a bath sonicator for 5 mm The mixture was then dialyzed overnight using 12,000-14,000 molecular weight cutoff dialysis 67 WO 96/00730 PCT/US95/08306 tubing against a 1000-fold excess of 50 mM Tns-HCl, pH 7 4,100 mM NaCl, 2 mM CaC12 (with 2 changes) The GPHb-IIIa-containing hposomes wee centnfuged at 12,000g for 15 mm and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg/mL The hposomes were stored at -70C until 5 needed Competitive Binding to GPIIb-IIIa The binding to the fibnnogen receptor (GPIIb-IIIa) was assayed by an indirect competitive binding method using [3H]-SK&F-107260 as an RGD-type ligand The binding assay was performed in a 96-well filtration plate assembly (Milhpore Corporation, Bedford, MA) using 0 22 um hydrophilic durapore membranes The wells were precoated with 0.2 mL of 10 jig/mL poly lysine (Sigma Chemical Co, St. Louis, MO) at room temperature for 1 h to block nonspecific binding Vanous concentrations of unlabeled benzadiazapmes were added to the wells in quadruplicate [3H]-SK&F-107260 was applied to each well at a final concentration of 4 5 nM, followed by the addition of 1 pg of the punfied platelet GPIIb-IIIa-containing hposomes The mixtures were incubated for 1 h at room temperature The GPIIb-IIIa-bound [3HJ-SK&F-107260 was seperated from the unbound by filtration using a Milhpore filtration manifold, followed by washing with ice-cold buffer (2 tunes, each 0.2 mL) Bound radioactivity remaining on the filters was counted in 1.5 mL Ready Solve (Beckman Instruments, FuIIerton, CA) m a Beckman Liquid Scintillation Counter (Model LS6800), with 40% efficiency.
Nonspecific binding was determined in the presence of 2 |iM unlabeled SK&F- 107260 and was consistently less than 0 14% of the total radioactivity added to the samples All data points are the mean of quadruplicate determinations Competition binding data were analyzed by a nonlinear least- squares curve fitting procedure This method provides the IC50 of the antagonists (concentration of the antagonist which inhibits specific binding of [3H]-SK&F- 107260 by 50% at equilibnum) The IC50 is related to the equihbnum dissociation constant (Ki) of the antagonist based on the Cheng and Prusoff equation Ki = IC50/(l+L/Kd), where L is the concentration of [3HJ-SK&F-107260 used in the 68 PCT/CS9S/08306 competit've binding assay (4.5 nM), and Kd is the dissociation constant of [3H]-SK&F-J07260 which is 4.5 nM as determined by Scatchard analysis Compounds of the present invention inhibit the vitronectin binding to SK&F 007260 with a Ki at the vitronectin receptor that is about ten-fold greater than that 5 for the fibnnogen receptor Preferred compounds have a Ki at the vitronectin receptor that is thirty-fold greater than that at the fibnnogen receptor. The most preferred compounds have a Ki at the vitronectin receptor that is a hundred-fold greater than that at the fibnnogen receptor. 69- The examples which follow are intended to in no way limit the scope of this invention, but are provided to illustrate how to make and use the compounds of this invention Many other embodiments will be readily apparent to those skilled in the art Examples General Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Broker AM 250 or Bruker AC 400 spectrometer. CDCI3 is deutenochloroform, DMSO-dg is hexadeutenodimethylsulfoxide, and CD3OD is 10 tetradeutencimethanol Chemical shifts are reported in parts per million (8) downfield frcm the internal standard tetramethylsilane Abbreviations for NMR data are as follows s=singlet, d=doublet, t=tnplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad J indicates the NMR coupling constant measured in Hertz Continuous wave infrared (IR) spectra were 15 recorded on a Perkm-Elmer 683 infrared spectrometer, and Fourier transform infrared (FOR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer IR and FTTR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm-1). Mass spectra were taken on either VG 70 FE, PE Syx API HI, or VG ZAB HF instruments, using fast atom 20 bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkm-Elmer 240C elemental analyzer Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected All temperatures are reported m degrees Celsius Analtech Sihca Gel GF and E Merck Silica Gel 60 F-254 thin layer plates 25 were used for thin layer chromatography Both flash and gravity chromatography were earned out on E. Merck Kieselgel 60 (230-400 mesh) silica gel Analytical and preparative HPLC were earned out on Rainin or Beckman chromatographs ODS refers to an octadecylsilyl denvatized silica gel chromatographic support 5 ji Apex-ODS indicates an octadecylsilyl denvatized silica gel chromatographic support 30 having a nominal particle size of 5 ji, made by Jones Chromatography, Littleton, Colorado YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co Ltd, Kyoto, Japan PRP-1® is a polymenc (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co, Reno, Nevada) Cehte® is a filter aid composed of acid-washed diatomaceous 35 silica, and is a registered trademark of Manville Corp, Denver, Colorado 70 PCT/US9S/08306 Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate, methyl (2S)-7-carboxy-4-methyi-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate, methyl (2R)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate, methyl (±)-7-carboxy-4-5 isopropyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetate, methyl (±)-7-carboxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro- 1H-1,4-benzodiazepme-2-acetate, and methyl (±)-8-carboxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate were prepared by the method of Bondinell, et al, WO 93/00095 2-(Ammomethyl)imidazo!e was prepared according to the procedure in 10 Annalen 1968, 718, 249 Preparation 1 Preparation of methvl C±)-7-carboxv-4-f2-methoxvethvl)-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetate 15 a) tert-Butyl 3-[(2-methoxyethyl)amino]methyl-4-nitrobenzoate A mixture of tert-butyl 3-methyl-4-mtrobenzoate (WO 93/00095, 14 96 g, 63 05 mmol), NBS (16.83 g, 94 58 mmol), benzoyl peroxide (1.53 g, 6.31 mmol), and CCI4 (315 mL) was heated at reflux After 18.5 h, the reaction was cooled thoroughly in ice and filtered to remove the precipitated succmimide The filtrate 20 was concentrated to leave a yellow oil.
This yellow oil was dissolved m dry THF (315 mL), and 2-methoxyethylamine (16 4 mL, 189 2 mmol) was added all at once The orangish-yellow solution was stirred at RT for 40 mm, then was concentrated to remove the THF The residue was diluted with Et20 (630 mL) and washed sequentially with 1.0 25 N NaOH (125 mL) and H20 (125 mL) The combined aqueous layers were back-extracted with Et20 (300 mL), and the combined organic layers were washed with bnne (125 mL) and dned (MgS04) Concentration and silica gel chromatography (3 2 EtOAc/hexanes) gave the a tie compound (10 30 g, 53%) as a yellow oil TLC Rf (1 1 EtOAc/hexanes) 0 43, >H NMR (250 MHz, CDCI3) 5 8 22 (d, J=1 7 Hz, 30 1H), 7 99 (dd, J=8 4,1 7 Hz, 1H), 7 92 (d, J=8 4 Hz, 1H), 4 08 (s, 2H), 3 51 (t, J=5 1 Hz, 1H), 3 36 (s, 3H), 2 82 (t, J=5 1 Hz, 2H), 1 61 (s, 9H), FTIR (CCI4) 1723, 1530, 1369, 1302, 1162,1116, 842 cm*1; MS (ES)m/e311 (M+H)+,255 (M+H-C4H8)+ b) ten-Butyl 3-[[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl)]amino]methyl-4-mtrobenzoate Di-tert-butyl dicarbonate (7.97 g, 36 51 mmol) was added all at once to a solution of tert-butyl 3-[(2-methoxyethyl)amino]methyl-4-nitrobenzoate (10 30 g, 5 33.19 mmol) in CHCI3 (165 mL) at RT After 16 h, the reaction was concentrated and reconcentrated from hexanes (to remove CHCI3) Silica gel chromatography (20% EtOAc/hexanes) gave the title compound (13 21 g, 97%) as a yellow oil TLC Rf (20% EtOAc/hexanes) 0 49, JH NMR (250 MHz, CDCI3) 8 7 85-8 15 (m, 3H), 4 75-4.95 (m, 2H), 3.35-3 65 (m, 4H), 3.25 (bs s, 3H), 1 60 (s, 9H), 1 15-1.80 (m, 10 9H), FTIR (CCI4) 1723,1701,1531,1368, 1304,1161, 1119 cm'1, MS (ES) m/e 428 2 (M+NH4)+, 411 2 (M+H)+, 355.2 (M+H - C4H8)+, 311.2 (M+H - C4H8 -C02)+ c) tert-Butyl 4-amino-3-[[N-(2-methoxyethyl)-N-(tert-15 butoxycarbonyl)]amino]methyl benzoate % Pd/C (3.42 g, 3.22 mmol) was added to a solution of tert-butyl 3-[[N-(2-methoxyethyl)-N-(tert-butoxycaibonyl)]anuno]methyI-4-mtrobenzoate (13.21 g, 32 18 mmol) in EtOAc (320 mL), and the mixture was shaken on a Parr apparatus at RT under H2 (55 psi) After 4 h, the reaction was filtered through Celite®, and the 20 filtrate was concentrated to afford the title compound (12 16 g, 99%) as a colorless foam TLC Rf (20% EtOAc/hexanes) 0 34, *H NMR (250 MHz, CDCI3) 8 7 68-7 77 (m, 2H), 6 56 (d, J=8 9 Hz, 1H), 5 00 (br s, 2H), 4 46 (s, 2H), 3 38-3 52 (m, 2H), 3.32 (s, 3H), 3.20-3.35 (m, 2H), 1 57 (s, 9H), 1 48 (s, 9H), FTIR (CCI4) 3490, 3340, 3230, 1703,1673,1642,1367,1284,1149,1170 cm*1, MS (ES) m/e 403 2 25 (M+Na)+, 3812 (M+H)+, 325.2 (M+H - C4H8)+, 281 (M+H - C4H8 - CO^*, 269 0 (M+H - 2 x QH8)+, 225 0 (M+H - 2 x C4H8 - CO^ d) t-Butyl (±)-4-[2-( 1,4-dimethoxy-1,4-dioxobutyl)amino]-3-[[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl)]amino]methylbenzoate A soluuon of tert-butyl 4-amino-3-[[N-(2-methoxyethyl)-N-(tert- butoxycarbonyl)]ammo]methylbenzoate (12 16 g, 31 96 mmol) and dimethylacetylene dicarboxylate (4 3 mL, 35 2 mmol) in MeOH (65 mL) was heated at reflux for 45 mm, then was cooled to RT The resulting solution was combined with MeOH (260 mL) and 10% Pd/C (6 80 g, 6 4 mmol), and the mixture was 35 shaken on a Parr apparatus at RT under H2 (50 psi) After 6 5 h, the reaction was filtered through Celite®, and the filtrate was concentrated on the rotavap The 72 WO 96/00730 PCT/US95/08306 residue was reconcentrated from CHCI3 (to remove MeOH), then was chromatographed on sdica gel (30% EtOAc/hexanes) The tide compound (15 03 g, 90%) was obtained as a faintly yellow oil TLC Rf (30% EtOAc/hexanes) 0 39; *H NMR (250 MHz, CDCI3) 5 7 82 (dd, J=8 6,2 0 Hz, IH), 7 72 (d, J=2 0 Hz, IH), 5 6 63 (d, J=8 6 Hz, IH), 6.35-6 55 (m, IH), 4 55-4 70 (m, IH), 4 52 (1/2 AB, J=15 1 Hz, IH), 4 40 (1/2 AB, J=15 1 Hz, IH), 3 71 (s, 3H), 3 69 (s, 3H), 3 35-3 50 (m, 2H), 3.31 (s, 3H), 3 20-3.30 (m, 2H), 2 98 (dd, J=16.2, 6 7 Hz, IH), 2 84 (dd, J=16 2,6 8 Hz, IH), 1 56 (s, 9H), 1 48 (s, IH), FTIR (CC14) 3312,1748,1704, 1670,1610,1367,1297,1142, 1172 cm-1, Me (ES) m/e 547.2 (M+Na)+ 525 2 10 (M+H)+, 469 2 (M+H - C4H8)+, 425 2 (M+H - C4H8 - C02)+ e) Methyl (±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetic acid TFA (140 mL) was added all at once to a solution of t-butyl (±)-4-[2-(l,4-15 dimethoxy-1,4-dioxobutyl)ammo]-3-[[N-(2-methoxyethyl)-N-(tert- butoxycarbonyl)]amino]methylbenzoate (15.03 g, 28 65 mmol) in anhydrous CH2CI2 (140 mL) at 0°C, and the faintly yellow solution was warmed to RT After 2 h, the solution was concentrated on the rotavap, and the residue was reconcentrated from toluene (to remove residual TFA) The resulting oil was combined with 20 toluene (280 mL) and Et3N (20 mL, 143 mmol), and the mixture was heated to reflux A light yellow, homogeneous solution was produced After 23.5 h, the reaction was concentrated on the rotavap to leave a solid residue This was dissolved in a minimum of MeOH (ca 720 mL) at reflux, diluted with H20 (720 mL), and acidified with glacial AcOH (8 mL) The solution was cooled to RT, then 25 was cooled in the refrigerator. After several h, more glacial AcOH (24 mL) was added The mixture was kept in the refrigerator overnight then was filtered The solid was washed sequentially with MeOH and Et20, then was dried in high vacuum to afford the title compound (6 40 g, 66%) as a nearly colorless powder mp 228-230°C, TLC Rf (10% MeOH/CHCI3) 0 51, »H NMR (250 MHz, DMSO-d6) 5 7 59 30 (d, J=1 9 Hz, IH), 7 54 (dd, J=8 5, 1 9 Hz, IH), 6 50-6 60 (m, 2H), 5 43 (d, J=16 6 Hz, IH), 5 12-5 22 (m, IH), 4 04 (d, J=16 6 Hz, IH), 3 60 (s, 3H), 3 20-3 70 (m, 4H), 3 08 (s, 3H), 2 83 (dd, J=16 7,8 8 Hz, IH), 2 65 (dd, J=16 7, 5 3 Hz, IH), MS (ES) m/e 359 0 (M+Na)+, 337 0 (M+H)+ The mother liquors were concentrated on the rotavap to ca 500 mL, cooled, and filtered to afford additional title compound 35 (1 51 g, total=7 91 g, 82%) as a light yellow solid mp 226-229 5°C 73 Preparation 2 Using the procedures of Preparation 1, except substituting 3,4-methylenedioxyphenethyiamine for 2-methoxyethylamine, the following compound was prepared a) Methyl (±)-7-carboxy-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate NMR (DMSO-d6) 5 7.51 (dd, J=8 6,2 Hz, IH), 7.45 (s, IH), 6.57 (m, 2H), 6 49 (m, 2H), 5 87 (s, 2H), 5.32 (d, J=16 5 Hz, IH), 5 07 (m, IH), 3 78 (d, J=16 5 Hz, IH), 3 62 (s, 3H), 3.56 (m, 2H), 2 88 (dd, J=16 7, 8 8 Hz, IH), 2 60 (m, 3H) Preparation 3 Preparation of methyl f±V7-carboxv-3-oxo-2.3.4.5-tetrahvdro-lH-1.4-benzodiazepme-2-acetate a) ten-Butyl 3-[[bis-(t-butoxycarbonyl)]amino]methyl-4-nitrobenzoate Di-tert-butyliminodicarboxylate (4.35 g, 20 0 mmol) was added to a suspension of sodium hydride (0.48 g, 20.0 mmol) in anhydrous DMF (30 mL) at RT After 30 minutes, a solution of t- butyl 3-bromomethyl-4-nitrobenzoate (6.3 g, 20 mmol) m DMF (15 mL) was added rapidly dropwise After 16 h, the solvent was evaporated and the residue partitioned between EtOAc (200 mL) and water (40 mL) The organic layer was extracted with water (3 x 50 mL) and brine (40 mL) and dried finally over Na2S04 Removal of solvent gave the crude product which was punfied on flash chromatography (15 85, EtOAc-Hexane) to give the title compound (81 5%) MS (ES) m/e 453 (M+H)+, lH NMR (400 MHz, CDCI3) 8 7 97-8 10 (m, 3H), 5 16 (s, 2H), 1 62 (s, 9H), 1 49 (s, 18H) b) ten-Butyl 4-amino-3-[[bis-(t-butoxycarbonyl)]ammo]methylbenzoate A solution of tert-butyl 3-[[bis-(t-butoxycarbonyl)]amino]methyl-4- nitrobenzoate (4 2 g, 9.3 mmol) in ethanol (150 mL) was hydrogenated at 40 psi in the presence of 10% Pd on C (0 40 g) After 30 minutes, catalyst was filtered and solvent removed to give the title compound in essentially quantitative yield MS (ES) m/e 423 (M+H)+, JH NMR (400 MHz, CDCI3) 8 7 82 (s, IH), 7 71 (d, J=8 4 Hz, IH), 6 56 (d, J=8 4 Hz, IH), 4 92 (br s, 2H), 4 68 (s, 2H), 1 62 (s, 9H), 1 49 (s, 18H) 74 c) (E/Z) tert-Butyl 4-[2-(l ,4-dimethoxy-1,4-dioxo-2-butenyl)amino]-3-[[bis-(t-butoxycarbonyl)]anuno]methylbenzoate A solution of tert-butyl 4-ammo-3-[[bis-(t-butoxycarbonyl)]amino]methyl benzoate (3 9 g, 9 2 mmol) and dimethylacetylene dicarboxylate (1 34 g, 9 4 mmol) 5 was refluxed 1 h and evaporated to dryness to give the title compound MS (ES) m/e 565 2 (M+H)+, NMR (400 MHz, CDCI3) 5 9 69 (s, IH), 7 91 (s, IH), 7 77 (m, IH), 6 75 (d, J=7.3 Hz, IH), 5 56 (s, IH), 4 92 (s, 2H), 3.77 (s, 3H), 3 59 (s, 3H), 1 62 (s, 9H), 1 49 (s, 18H) d) tert-Butyl (±)-4-[2-( 1,4-dimethoxy-1,4-dioxobutyl)amino]-3-[[bis-(t-butoxycarbonyl)]amino]methylbenzoate A solution of (E/Z) tert-butyl 4-[2-(l,4-dimethoxy-l,4-dioxo-2-butenyl)anuno]-3-[[bis-(t-butoxycarbonyl)]amino]methylbenzoate (5.2 g, 9 2 mmol) in methanol (150 mL) was hydrogenated at 40 psi in the presence of 10% Pd/C (0 75 15 g) After 2 h, the catalyst was removed by filtration, and the solvent was removed to provide the crude product Purification by flash chromatography gave the title compound (80%) MS (ES) m/e 567.2 (M+H)+, *H NMR (400 MHz, CDCI3) 8 7 82 (s, IH), 6 66 (d, J=8.5 Hz, IH), 6 39 (d, J=8.5 Hz, IH), 4.70 (d, J=4.5 Hz, 2H), 4 61 (m, IH), 3 72 (s, 6H), 2 82-2 99 (m, 2H), 1 62 (s, 9H), 1 49 (s, 18H) e) (±)-4-[2-( 1,4-Dimethoxy-1,4-dioxobutyl)amino]-3-(aminomethyl)benzoic acid, bis-(tnfluoroacetate) A solution of tert-butyl 4-[2-(l,4-dimethoxy-l,4-dioxobutyl)ammo]-3-[[bis-(t-butoxycarbonyl)]amino]methylbenzoate (4 0 g, 7 1 mmol) in a mixture of 25 methylene chlonde (100 mL) and tnfiuoroacetic acid (25 mL) was kept 16 h at RT The solvents were evaporated and the residue was triturated with ether to give the title compound m essentially quantitative yield MS (ES) m/e 310 2 (M+H)+, *H NMR (400 MHz, DMSO-dg) 8 8 25 (br s, 3H), 7 89 (s, IH), 7 79 (d, J=8 4 Hz, IH), 6 75 (d, J=8 4 Hz, IH), 6 25 (d, J=8 4 Hz, IH), 4 65 (m, IH), 4 05 (s, 2H), 3 69 (s, 30 3H), 3 65 (s, 3H), 2 89-3 07 (m, 2H) 0 Methyl (±)-7-carboxy-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate A solution of sodium methoxide m methanol (25 wt%, 6 7 mL, 30 mmol) was added to a solution of 4-[2-( 1,4-dimethoxy-1,4-dioxobutyl)amino]-3-35 (anunoinethyl)benzoic acid, bis-(tnfluoroacetate) (4 0 g, 7 0 mmol) at -10°C under argon After 30 minutes, the cold solution was quenched with acetic acid (15 mL) 75 The reaction mixture was kept one h at -20°C and filtered The filter cake was slurried in water (30 mL) and filtered to provide the title compound (65%). MS (ES) m/e 279 0 (M+H)+, JH NMR (400 MHz, DMSO-dg) 8 8 21 (t, J=5 4 Hz, IH), 7 55 (m, 2H), 6 55 (d, J=8 4 Hz, IH), 6 45 (s, IH), 5 05 (m, 2H), 3 76 (dd, J=15 8,7.5 5 Hz, IH), 2 82 (dd, 16 8,9 8 Hz, IH), 2 65 (dd, J=16.8,4 5 Hz, IH) Preparation 4 Preparation of 2-(methvlaminomethvDbenzimidazole dihvdrochlonde a) 2-[(tert-B utoxycarbonyl)sarcosyl]aminoaniline A solution of phenylenedianune (100 g, 0 924 mole) and Boc-sarcosine (175 g, 0 924 moie) m DMF (1750 mL) was cooled to -10°C under argon, and a solution of DCC (190 8 g, 0 924 mole) m CH2CI2 (1750 mL) was added in a slow stream 15 over 1 hr The temperature rose to 0°C during the addition The reaction was stirred overnight while the temperature was allowed to rise to RT The white precipitate was removed by filtration, and the filtrate was diluted with H2O (3 5 L) and saturated bnne (1 L) The CH2CI2 layer was separated and the aqueous phase was extracted with EtOAc (2 x 1 L). The combined organic layers were washed with H2O (1 L) 20 and bnne (0 5 L), then were concentrated to a yellow residue (341 g) This was triturated with EtOAc to afford the title compound (179 4 g, 70%) mp 134 - 136°C b) 2-[(N-tert-Butoxycarbonyl-N-methyI)aminomethyl]benzimidazole A solution of 2-[(tert-butoxycarbonyl)sarcosyl]aminoanihne (178 4 g, 0 639 25 mole) m THF (900 mL) and AcOH (900 mL) was heated to reflux under argon for 1 hr, then a vacuum was carefully applied to the reaction, and most of the THF was removed by distillation The residual solution was poured mto stirred ice water, and conc NH4OH (1150 mL) was added to adjust the pH to 10 An oil formed which ciystalhzed on stirring overnight The solid was filtered and dried at 50°C at 30 atmospheric pressure for two days to leave a yellow-white solid (167 g, 100%) mp 140 - 150°C Further drying at RT and atmospheric pressure gave the crude title compound (162 g, 97%) PCTAJS95/08306 c) 2-(Methylaminomethyl)benzimidazole dihydrochlonde A solution of 4 M HCl/dioxane (616 mL, 2 46 mole) and anisole (134 mL, 1 23 mole) was cooled to 0°C under argon, and a solution of 2-[(N-tert-5 butoxycarbonyl-N-methyl)aminomethyl]benzimidazole (161 g, 0 616 mole) in CH2CI2 (800 mL) was added m a slow stream over 30 min The temperature rose to 8°C dunng the addition, and a white precipitate began to foim before the addition was complete The reaction was stirred for 20 nun, then the title compound (66 6 g, 46%) was collected by filtration: mp 250 - 255 °C (dec) Anal Calcd for C9H1 jN3 10 2 HCl C, 46 17; H, 5 60, N, 17 95 Found C, 46 33, H, 5 68, N, 17 55 The filtrate was diluted with Et20, and the mixture was allowed to stand overnight Filtration gave additional title compound (62 g, total yield 128 6 g, 89%) as a pink solid mp 248 - 253°C (dec) Example 1 Preparation of C±)-7-nTf2-benzimidazolvl)methvnaminolcarbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdro-lH- 1.4-benzodiazepme-2-acetic acid a) Methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate 20 A mixture of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepme-2-acetate (0 57 g, 1 82 mmol) and thionyl chlonde (15 mL) was refluxed for 1 h The resulting orange solution was concentrated to dryness to leave a yellow-orange foam This was dissolved in CH2CI2 (10 mL) and added dropwise to a solution containing 2-(aminoinethyl)benzimidazole dihydrochlonde (1 2 g, 5 46 25 mmol), pyndme (0 72 g, 9 1 mmol), and tnethylamine (0 55 g, 5 46 mmol) in CH2CI2 (15 mL) at 0°C under argon The reaction mixture was then stirred m RT under argon After 25 5 h, CH2CI2 (200 mL) and 5% NaHC03 (50 mL) were added to the reaction mixture to give a light yellow precipitate which was filtered and air-dned to give the title compound (0 11 g, 14%) The filtrate was separated and the 30 organic layer was washed sequentially with 5% NaHC03 (50 mL) and H2O (50 mL), then was concentrated on the rotavap After tnturation with CH2CI2 and air-drying, a yellowish solid was collected to yield more of the title compound (0 35 g, 45%) lH NMR (250 MHz, CDCl3/DMSO-d6) 5 6 30-8 70 (m, 9H), 5 52 (d, T=16 Hz, IH), 5 14 (m, IH), 4 67 (d, J=5 Hz, 2H), 3 80 (d, J=17 Hz, IH), 3 63 (s, 3H), 77 2 97 (s, 3H), 2 85 (dd, J=16,9 Hz, IH), 2 64 (dd, J=17, 5 Hz, IH), MS (ES) m/e 422 2 (M+H)+ b) (±)-7-[[[(2-Benzimidazolyl)methyl]aimno]carbonyl]-4-methyl-3-oxo-2,3,4,5-5 tetrahydro-1H-1,4-benzodiazepine-2-acetic acid 1 0 N LiOH (0 57 mL, 0 57 mmol) was added dropwise at RT to a mixture of methyl (±)-7-[[[(2-benzinudazolyl)methyl]amino]carbonyI]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0 11 g, 0 26 mmol) m THF (4 mL) and H2O (5 mL) The resulting hght brownish-yellow solution was stirred for 21 5 h, 10 then was concentrated on the rotavap The resulting residue was lyophilized to give the crude product (0 11 g, 100%) as a yellowish powder Preparative HPLC (PRP-1® column, step gradient, 10-20% CH3CN/H2O-O 1% TFA) afforded the title compound *H NMR (250 MHz, DMSO-d6) 6 6 45-9 06 (m, 9H), 5 53 (d, J=16 Hz, IH), 5 13 (m, IH), 4 86 (d, J=5 Hz, 2H), 3 87 (d, J=17 Hz, IH), 2 95 (s, 3H), 2 80 15 (dd, J=17, 9 Hz, IH), 2 57 (dd, J=17,5 Hz, IH), MS (ES) m/e 408 2 (M+H)+ Anal Calcd for C21H21N5O4 • 4/3 CF3C02H H20 C, 49 22, H, 4 25, N, 12 13 Found C, 49 24, H, 4.22, N, 12.11 Example 2 Preparation of (,±V7-rrrr2-benzimidazolvnmethvllamino1carbonvll-3-oxo-4-C2-phenvlethvl)-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid a) Methyl (±)-7-[[[(2-benzimidazolyl)methyI]amino]carbonyI]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate EDC (230 mg, 1 2 mmol) was added to a stirred solution of methyl (±)-7-25 carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine-2- acetate (382 4 mg, 1 0 mmol), 2-(aminomethyl)benzinudazole dihydrochlonde (264 mg, 1 2 mmol), HOBT H2O (162 mg, 1 2 mmol), and diisopropylethylamine (0 70 mL, 4 0 mmol) in anhydrous DMF (5 mL) at RT After 19 h, the reaction was concentrated on the rotavap (high vacuum), and the residue was partitioned between 30 H2O (5 mL) and EtOAc (20 mL) The layers were separated and the organic layer was washed with H20 (5 mL) Drying (MgS04), concentration, and silica gel chromatography (load with 5% MeOH/CHCl3, gradient 5% MeOH in 1 1 EtOAc/CHCl3 (300 mL), then 10% MeOH/EtOAc (400 mL), then 10% MeOH/CHCls) gave the title compound (414 9 mg, 81%) as an off-white solid 35 TLC (10% MeOH/EtOAc) Rf 0 62, *H NMR (250 MHz, DMSO-d6) 8 8 72 (br t, J=5 6 Hz, IH), 7 35-7 75 (m, 4H), 7 00-7 35 (m, 7H), 6 56 (d, J=8 4 Hz, IH), 6 37 78 WO 96/00730 PCT/US95/08306 (br d, J=3 5 Hz, IH), 5 42 (d, J=16 6 Hz, IH), 5 08-5 20 (m, IH), 4 52-4 75 (m, 2H), 3 93 (d, J=16 6 Hz, IH), 3 45-3 72 (m, 2H), 3 61 (s, 3H), 2 83 (dd, J=16 7, 8 9 Hz, IH), 2 60-2 75 (m, 3H), MS (ES) 512.2 (M+H)+ b) (±)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetic acid A mixture of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (4131 mg, 0 81 mmol), ION LiOH (0 97 mL, 0 97 mmol), THF (4 mL), and H2O (3 mL) 10 was stirred at 40-45°C for 20 mm, and the resulting solution was stirred at RT for 17 h Acidification with TFA (019 mL, 2 4 mmol) and concentration left an off-white solid Recrystalhzation from CH3CN/H2O gave the title compound (343 2 mg, 69%) as a colorless powder HPLC (PRP-1®, 30% CH3CN/H2O-O 1% TFA) K'=l 5, IH NMR (400 MHz, CD3OD) 5 7 68-7 75 (m, 2H), 7 60 (dd, J=8 6,2 2 Hz, 15 IH), 7 51-7 58 (m, 2H), 7 49 (d, J=2.2 Hz, IH), 7.07-7.22 (m, 5H), 6 61 (d, J=8 6 Hz, IH), 5 46 (d, J=16 8 Hz, IH), 5 18 (dd, J=9 0,5 1 Hz, IH), 4 95 (s, 2H), 3 81 (d, J=16 8 Hz, IH), 3 61-3 78 (m, 2H), 2 94 (dd, J=16 8,9 0 Hz, IH), 2 71-2 83 (m, 2H), 2 65 (dd, J=16 8,5.1 Hz, IH), MS (ES) m/e 498 4 (M+H)+ Anal Calcd for C28H27N5O4 CF3CO2H 0.25 H20 C, 58 49, H, 4 66, N, 11.37 Found C, 20 58 52, H, 4 47, N, 1104.
Example 3 Preparation of (±')-4-isopropvl-7-nTf2-benzimidazolvl)methvnaminolcarbonvn-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid 25 a) Methyl (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro- IH- l,4-benzodiazepine-2-acetate EDC (173 mg, 0 90 mmol) was added to a stirred solution of methyl (±)-7-carboxy-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate (240 3 mg, 0 75 mmol), 2-(aminomethyl)benzimidazole dihydrochlonde (198 mg, 0 90 mmol), HOBT H20 (122 mg, 0 90 mmol), and dusopropylethylamme (0 52 mL, 3 0 mmol) in anhydrous DMF (4 mL) at RT After 20 h, the reaction was concentrated on the rotavap (high vacuum), and the residue was diluted with H2O (5 mL) to afford a gummy precipitate EtOAc (3 mL) was added and the mixture was stirred bnskly The precipitate remained gummy, but changed in form so that it was suspended as a mass in the solvents The solvents were drawn off with a pipet and the residue was suspended in MeOH (3 mL) and EtOAc (6 mL) The mixture was stirred briskly at RT for several min, then was cooled m ice and filtered The filter pad was washed with EtOAc and dried in high vacuum to leave the title compound (275 1 mg, 82%) as an off-white powder NMR (250 MHz, 20% CD3OD/CDCI3) 5 7 45-7 70 (m, 4H), 7 15-7 35 (m, 2H), 6 56 (d, J=9 1 Hz, IH), 5 5 22 (d, J=16 9 Hz, IH), 5 13 (app t, IH), 4 72-4 92 (m, IH), 4 72 (s, 2H), 4 03 (d, J=16 9 Hz, IH), 3 74 (s, 3H), 3 00 (d, J=16 4, 7 7 Hz, IH), 2 67 (dd, J=16 4, 6 0 Hz, IH), 1.21 (d, J=6 7 Hz, 3H), 1 03 (d, 3=6 8 Hz, 3H), MS (ES) 450 2 (M+H)+ b) (±)-4-Isopropyl-7-[[[(2-benzimidazolyl)metnyl]ammo]carbonyl]-3-oxo-2,3,4,5-10 tetrahydro-1H-1,4-benzodiazepine-2-acetic acid A mixture of methyl (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino] carbonyl]-3-oxo-23,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (275 1 mg, 0 61 mmol), 1 0 N LiOH (0.73 mL, 0 73 mmol), THF (3 mL), and H20 (2.3 mL) was stirred at 35°C for 45 min, and the resulting solution was stirred at RT After 15 17 5 h, the solution was filtered, and the filtrate was neutralized with 1 0 N HCl (0 73 mL) Since the product did not precipitate, the solution was acidified with TFA (0 2 mL) and concentrated The resulting solid was tnturated with H2O to leave a nearly colorless solid, which was dissolved with warming mil CH3CN/H20 The solution was cooled to RT and diluted with several volumes of 20 H20/0 1% TFA ODS chromatography (20% CH3CN/H20-0 1% TFA), concentration, and lyophilization gave the title compound (293 4 mg, 80%) as a colorless powder HPLC (PRP-1®, 20% CH3CN/H20-0 1% TFA) K'=2 5, JH NMR (400 MHz, CD3OD) 8 7 70-7 76 (m, 2H), 7 65 (d, J=2 2 Hz, IH), 7 61 (dd, J=8 5, 2 2 Hz, IH), 7 53-7 60 (m, 2H), 6 62 (d, J=8 5 Hz, IH), 5 33 (d, J=16 9 Hz, IH), 25 5 21 (dd, J=8.9, 5.2 Hz, IH), 4 97 (d, J=1 9 Hz, 2H), 4 72-4 85 (m, IH), 4 10 (d, J=16 9 Hz, IH), 2 96 (dd, J=16 8, 8 9 Hz, IH), 2 65 (dd, J=16.8,5 2 Hz, IH), 1 21 (d, J=6 7 Hz, 3H), 1 03 (d, J=6 8 Hz, 3H), MS (ES) m/e 436.2 (M+H)+ Anal Calcd for C23H25N504 I25CF3CO2H 1 25 H20 C, 51.00, H, 4 83, N, 11 66 Found C, 51 12, H, 4 91, N, 11 37 Example 4 Preparation of f±1-7-rnN-f2-benzothiazolvDmethvl-N-methvnamino1carbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid a) 2-Bromomethylbenzothiazole 35 A mixture of 2-methylbenzothiazole (2 0 g, 13 40 mmol), N- bromosuccmimide (2.39 g, 13 40 mmol), and AIBN (0 5 g, 3 04 mmol) in CCI4 (40 80 PCI7US95/08306 mL) was refluxed for 12h, then the mixture was cooled and filtered The filtrate was concentrated and purified by silica gel chromatography (5% EtOAc/hexane) to give the title compound (2 19 g, 72%) as a yellow oil 'H NMR (250 MHz, DMSO-d6) 8 5 12 (s, 2H), 7 5 (m, 2H), 8 01 (dd, J=7 9, 1 8 Hz, IH), 8 15 (dd, J=7 9, 1 8 Hz, 5 IH) b) 2-[(Methylamino)methyl]benzothiazole To a stirred solution of 2-bromomethylbenzothiazole (0 4 g 1 75 mmol) in THF (4 mL) was added 40% aqueous methylamine (0 30 g, 8 77 mmol) Stirring 10 was continued overnight, then the mixture was concentrated The residue was taken up in H20, neutralized with 2 5 N NaOH, and extracted with CH2CI2 The organic extracts were dried (MgS04) and concentrated to give the title compound (0.36 g, 80%) as a brown oil *H NMR (250 MHz, DMSO-d6) 8 2 70 (s, 3H), 4 71 (s, 2H), 7 55 (m, 2H), 8 0 (d, J=7 9 Hz, IH), 8 17 (d, J=7 9 Hz, IH) c) Methyl (±)-7-[[[N-(2-benzothiazolyl)methyl-N-methyl]amino]carbonyl]-4-methy l-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate A mixture of methyl (±)-7-carboxy-4-methyI-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (0 25 g, 0 855 mmol), 2-20 [(methylamino)methyl]benzothiazole (0 228 g, 1 283 mmol), EDC (0 31 g, 1.0026 mmol), HOBT H2O (0 14 g, 1 026 mmol), and diisopropylethylamme (0 30 mL, 1711 mmol) in dry DMF (5 mL) was stirred at RT in 20 h The reaction mixture was concentrated, and the residue was taken up in H20 and extracted with CH2CI2 The combined organic extracts were dried (MgS04) and concentrated Silica gel chromatography (5% MeOH/CH2Cl2) gave the title compound (0 289g, 75%) as a yellow oil NMR (400 MHz, DMSO-d6) 8 2 65 (dd, J=16 8, 5 0 Hz, IH), 2 82 (dd, J=16 8, 8 9 Hz, IH), 2 90 (s, 3H), 3 15 (s, 3H), 3 62 (s, 3H), 3 90 (d, J=16 1 Hz, IH), 4 90 (s, 2H), 5 13 (m, IH), 5 45 (d, J=16 1 Hz, IH), 6 29 (d, J=3 6 Hz, IH), 6 57 (d, J=8.3 Hz, IH), 7 19 (d, J=8 3 Hz, IH), 7.21 (s, IH), 7 45 (t, J=7 4 Hz, IH), 7 52 (r, J=7 4 Hz, IH), 8 00 (d, J=7 9 Hz, IH), 8 10 (d, J=7 9 Hz, IH) d) (±)-7-[[[N-(2-Benzothiazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid 2 5 N NaOH (3 0 mL) was added to a stirred solution of methyl (±)-7-[[[N-(2-benzothiazolyl)methyl-N-methyl] amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (0 289 g, 0 639 mmol) in MeOH (3 mL) at RT After 3 h, the mixture was concentrated, and the residue was acidified to pH 4 The colorless sohd was collected and triturated m Et20 to give the title compound (0 250 g, 89%) as a colorless sohd *H NMR (400 MHz, DMSO-dg) 8 2 55 (dd, J=16 8,5.0 Hz, IH), 2.75 (dd, J=16 8, 8 9 Hz, IH), 2 91 (s, 3H), 3 1 (s, 5 3H), 3 9 (d, J=16 1 Hz, IH), 4 9 (d, J=5 7 Hz, 2H), 5 10 (m, IH), 5 45 (d, J=16.1 Hz, IH), 6 29 (d, J=3 6 Hz, IH), 6.57 (d, J=8 3 Hz, IH), 7 19 (d, J=8 3 Hz, IH), 7 21 (s, IH), 7 45 (t, J=7 4 Hz, IH), 7.52 (t, J=7 4 Hz, IH), 8 00 (d, J=7.9 Hz, IH), 8 10 (d, J=7 9 Hz, IH), IR (KBr; 3500,3286, 3100,3000,1735, 1719,1662, 1652,1614, 1595, 1482,1392,827,765 cm"1, MS (ES) m/e 439 2 (M+H)+ Anal Calcd for 10 C22H22N4O4S 1 5 H20 C, 56.76, H, 5 41, N, 12 03 Found C, 56 37, H, 5 23, N, 11 86 Example 5 Preparation of f±V7-rrfN-(2-benzoxazolvl)methvl-N-methvnaminolcarbonvn-4-15 methvI-3-oxo-2.3.4.5-tetrahvdro-lH-l .4-benzodiazepine-2-acetic acid a) 2-Bromomethylbenzoxazole Following the procedure of Example 4(a), except using 2-methylbenzoxazole in place of 2-methylbenzothiazole, the tide compound (2.22 g, 70%) was prepared as a yellow oil JH NMR (250 MHz, DMSO-d^) 8 5 17 (s, 2H), 7 55 (m, 2H), 8 01 (d, 20 J=7 9,1 8 Hz, IH), 8 20 (dd, J=7 9, 1 8 Hz, IH) b) 2-[(Methylamino)methyl]benzoxazole Following the procedure of Example 4(b), except using 2-bromomethyl benzoxazole m place of 2-bromomethylbenzothiazole, the title compound (0 250 g, 25 71 %) was prepared as a brown oil *H NMR (400 MHz, DMSO-dg) 5 2 75 (s, 3H), 4 71 (s, 2H), 7 60 (m, 2H), 8 01 (d, J=7 9 Hz, IH), 8 17 (d, J=7 9 Hz, IH) c) Methyl-(±)-7-[[[N-(2-benzoxazolyl)methyl-N-methyl]amino]carbonyl]-4-methy]-3-oxo-2,3,4,5-tetrahydro-lH-1,4-benzodiazepine-2-acetate Following the procedure of Example 4(c), except using 2-[(methylamino) methyl]benzoxazole in place of 2-[(methylammo)methyl]benzothiazole, the title compound (0 342 g, 91 %) was prepared as a brown oil JH NMR (DMSO-dg) 8 2 65 (dd, J=16 8,5.0 Hz, IH), 2 82 (dd, J=16 8, 8 9 Hz, IH), 2 91 (s, 3H), 3 15 (s, 3H), 3 61 (s, 3H), 3 90 (d, J=16 1 Hz, IH), 4 91 (s, 2H), 5 15 (m, IH), 5 47 (d, 35 J=16 1 Hz, IH), 6 30 (d, J=3 6 Hz, IH), 6 57 (d, J=8 3 Hz, IH), 7.20 (m, 2H), 7 40 (m, 2H), 7 72 (t, J=7 4 Hz, 2H), 7 95 (s, IH) d) (±)-7-[[[N-(2-Benzoxazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetic acid Methyl-(±)-7-[[[N-(2-benzoxazolyl)methyl-N-methyl]amino]carbonyl]-4-5 methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepxne-2-acetate was saponified following the procedure of Example 4(d) Purification by silica gel chromatography (2 8 1 MeOH/CH2Cl2/Et3N) gave the title compound (0 231 g, 70%) as an off-white solid IH NMR (400 MHz, DMSO-d^) 5 2 45 (dd, J=16 8,5 0 Hz, IH), 2 70 (dd, J=16 8, 8 9 Hz, IH), 2 90 (s, 3H), 3.15 (s, 3H), 3 91 (d, J=16 1 Hz, IH), 4 90 (d, 10 J=5.7 Hz, 2H), 5 07 (m, IH), 5 45 (d, J=16 1 Hz, IH), 6 30 (d, J=3 6 Hz, IH), 6 58 (d, J=8 3 Hz, IH), 7 20 (m, 2H), 7 40 (m, 2H), 7 70 (m, 2H), IR (KBr) 3370,3100, 3000,1728,1653,1612,1575, 1485, 1455, 1397, 831,765 cm*1, MS (ES) m/e 421 (M -H)" Anal Calcd for C22H22N4O5 1 25 H20 C, 59 39, H, 5 45, N, 12 50 Found C, 59 43, H, 5 23, N, 12 14 Example 6 Preparation of (±)-7-riTN-r2-f5(6)-chlorobenzimidazolvl)methvll-N-methvllamino1 carbonvll-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazeoine-2-acetic acid a) 2-[[(N-tert-butoxycarbonyI-N-methyl)amino]methyl]-5(6)-chlorobenzimidazole 20 To a stirred and cooled (0°C) mixture of Boc-sarcosine (2.0 g, 10 571 mmol) and Et3N (1 12 g, 11 01 mmol) in anhydrous THF (25 mL) was added lsobutylchloroformate (151 g, 1101 mmol) After 1 h, 4-chloro-l,2-phenylenediamine (1.43 g, 10.571 mmol) was added Stimng was continued for 2 h, then aceuc acid (10 mL) was added, and the reaction was heated to reflux After 4 h, the mixture was cooled, concentrated, neutralized with 2 5 N NaOH, and extracted with CH2CI2 Drying (MgS04), concentration, and silica gel chromatography (1 % Me0H/CH2Cl2) gave the title compound (2 10 g, 67%) as a brown foam *H NMR (250 MHz, DMSO-d6) 5 1 45 (s, 9H), 2 95 (s, 3H), 4 60 (s, 2H), 7 10 (d, J=9 3 Hz, IH), 7 50 (d J-9 3 Hz, IH), 7 60 (s, IH) b) 5(6)-Chloro-2-[(methylamino)methyl]benzimidazole To a stirred solution of 2-[[(N-tert-butoxycarbonyl-N-methyl)amino]methyl]- (6)-chlorobenzimidazole (2 10 g, 7 101 mmol) m anhydrous CH2CI2 (20 mL) was added TFA (2.2 mL, 28 404 mmol) After stimng overnight, the mixture was concentrated, neutralized with 2 5 N NaOH, and extracted with CH2C12 The combined organic extracts were washed with bnne, dned (MgS04), and 83 concentrated to give the title compound (1 25 g, 90%) as a brown oil *H NMR (250 MHz, DMSO-d^) 5 2 35 (s, 3H), 3.88 (s, 2H), 7 17 (d, J=9 3 Hz, IH), 7 50 (d, J=9 3 Hz, IH), 7 55 (s, IH) c) Methyl (±)-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Following the procedure of Example 4(c), except substituting 5(6)-chloro-2-[(methylamino)methyl]benzimidazole for 2-[(methylamino)methyl]benzothiazole, the title compound (0 262 g, 59%) was obtained as an off-white solid after sihca gel 10 chromatography (5% MeOH/CH2Cl2) *H NMR (250 MHz, DMSO-d^) 5 2 65 (dd, J=16 8, 5 0 Hz, IH), 2 82 (dd, J=16 8, 8 9 Hz, IH), 2 91 (s, 3H), 3 15 (s, 3H), 3 61 (s, 3H), 3 91 (d, J=16 1 Hz, IH), 4 80 (d, J=5 7 Hz, 2H), 5 15 (m, IH), 5 47 (d, J=16 1 Hz, IH), 6 25 (d, J=3 6 Hz, IH), 6.55 (d, J=8 3 Hz, IH), 7.20 (m, 2H), 7 60 (m, 2H) d) (±)-7-[[[N-[2-(5(6)-Chlorobenzimidazolyl)methyl]-N-methyl]amino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid Methyl (±)-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2-acetate was 20 saponified following the procedure of Example 4(d) Trituration with Et0H/Et20 gave the title compound (0 100 g, 69%) as a colorless sohd NMR (400 MHz, DMSO-d<j) 5 2 55 (dd, J=16 8,5 0 Hz, IH), 2 75 (dd, J=16 8, 8.9 Hz, IH), 2 91 (s, 3H), 3 10 (s, 3H), 3 90 (d, J=16 1 Hz, IH), 4 9 (s, 2H), 5 10 (m, IH), 5 45 (d, 16 1 Hz, IH), 6 25 (s, IH), 6 57 (d, J=8 3 Hz, IH), 7 20 (m, 3H), 7 50 (d, J=9 3 Hz, IH), 25 7 60 (s, IH), 12 3 (br s, IH), 12 5 (br s, IH), MS (ES) m/e 456 0 (M+H)+ Anal Calcd for C22H22C1N504 C, 56 30, H, 5 05, N, 14 92 Found. C, 56 27, H, 5 30, N, 15 14 Example 7 Preparation of (±)-7-riTr2-mdolvl')methvllaminolcarbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid a) Indole-2'C^rboxamide A mixture of ethyl mdole-2-carboxylate (5 g, 26 5 mmol) and ammonium hydroxide (30 mL) was heated at 80°C in a sealed glass vessel overnight The 35 reaction was cooled and the title co npound (3 06g, 73%) was collected by filtration 84 PCT/USS5/08306 as a colorless solid lE NMR (400 MHz, DMSO-d6) 8 7 95 (br, IH), 7.61 (d, IH), / 41 (d, IH), 7 36 (br, IH), 7 12, (t, IH), 7 01 (t, IH) b) 2-Cyanomdole 5 A solution of indole-2-carboxamide (3.02 g, 18 8 mmol) m dichlorophenylphosphme oxide (20 mL) was heated at 80°C overnight The cooled reaction mixture was then poured over 100 mL ice and the pH was adjusted to 11 with 50% aqueous sodium hydroxide Extraction with ethyl acetate followed by concentration m vacuo gave an off-white sohd which was punfied by silica gel 10 chromatography (1 % MeOH/CH2Cl2) to yield the title compound (2 41 g, 90%) !H NMR (400 MHz, DMSO-d6) 8 7 68 (d, IH), 7 46 (d, IH), 7 36 (s, IH), 7.34 (t, IH), 7 14 (t, IH) c) 2-Ammomethylindole 15 LAH (42 mL, 1M solution in THF) was added dropwise through a syringe to a solution of 2-cyanoindole (2 0 g, 14 1 mmol) in anhydrous THF (20 mL) with cooling, and the resulting solution was stirred at RT under argon for 5 h H20 was added dropwise with cooling to destroy excess LAH, and the colorless precipitate was removed by filtration and washed with THF The filtrate was dried (K2CO3) 20 and concentrated to afford the title compound (2 11 g, quantitative) as a yellow sohd IH NMR (400 MHz, DMSO-dg) 87 41 (d, IH), 7 29 (d, IH), 6 97 (t, IH), 691 (t, IH), 6 20 (s, IH), 3.82 (s, 2H), 2 18 (br, IH) d) Methyl (±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-25 tetrahydro-lH-l,4-benzodiazepine-2-acetate EDC (1 53 g, 7 99 mmol) was added to a solution of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (2.13 g, 7.26 mmol), 2-aminomethylindole (1 06 g, 7 26 mmol), HOBT H20 (1 08 g, 7 99 mmol) and diisopropylethylamme (1 53 mL, 8 71 mmol) in anhydrous DMF (10 mL) 30 at RT After 20 h the reaction was concentrated on the rotavap (high vacuum) The residue was taken up in EtOAc and washed sequentially with H20 and 10% Na2C03 (2 x 30 mL) Drying (MgSO,*), concentration, and silica gel chromatography (2% MeOH/CH2CI2) gave the title compound (1 8 g, 60%) *H NMR (400 MHz, DMSO-d6) 8 8 56 (t, IH), 7 95 (s, IH), 7 59 (s, IH), 7 56 (d, IH), 7 43 (d, IH), 7 33 35 (d, IH), 7 01 (t, IH), 6 93 (t, IH), 6.55 (d, IH), 6 33 (br, IH), 6 25 (s, IH), 5 49 (d, IH), 5 14 (t, IH), 4.56 (d, 2H), 3 82 (d, IH), 3 61 (s, 3H), 2 92 (s, 3H), 2 75 (dd, IH), 2 53 (d, IH), MS(ES) m/e 421 2 (M+H)+ e) (±)-7-[[[(2-Indolyl)methyl]anuno]carbonyl]-4-rnethyl-3-oxo-2,3,4,5-tetrahydro-5 lH-l,4-benzodiazepine-2-acetic acid ION NaOH (1 mL, 1 0 mmol) was added dropwise to a solution of methyl (±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-1,4-benzodiazepine-2-acetate (0.35 g, 0 83 mmol) in THF (5 mL) and MeOH (2 mL) at RT The resulting mixture was stirred for 20 h then was concentrated The 10 residue was dissolved in H2O (20 mL) and acidified with TFA ODS chromatography (27% CH3CN/H2O-Q 1% TFA), concentration and lyophihzation gave the tide compound (100 mg, 30%) as an off-white sohd HPLC (ODS, 5-60% CH3CN/H2O-O 1% TFA gradient elution over 20 min) K-10 2, *H NMR (400 MHz, DMSO-dg) 5 8.55 (t, IH), 7 57 (s, IH), 7 56 (d, IH), 7 43 (d, IH), 7 33 (d, 15 IH), 7 01 (t, IH), 6 93 (t, IH), 6.55 (d, IH), 6 33 (br, IH), 6 25 (s, IH), 5 49 (d, IH), 5 08 (t, IH), 4.55 (d, 2H), 3.82 (d, IH), 2 92 (s, 3H), 2 75 (dd, IH), 2 53 (d, IH), MS (ES) m/e 407 2(M+H)+ Anal Calcd for C22H22N4O4 H20 C, 62.25, H, 5 70, N, 13 20 Found. C, 62.66, H, 5.64, N, 12 99 Example 8 Preparation of (2S)-7-nTf2-Benzimida7olvl)methvl]aniinolcarbonvll-4-methvl-3-oxo-2.3.4.5-tetrahvdro-lH-l .4-benzodiazepme-2-acetic acid a) Methyl (2S)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate 25 EDC (1 15 g, 6.02 mmol) was added to a solution of methyl (2S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (2 11 g, 5 02 mmol), 2-aminomethylbenzimidazole dihydrochlonde (1.15 g, 6.02 mmol), HOBT H2O (811 mg, 6.02 mmol), and diisopropylethylamine (1 76 mL, 10 mmol) in anhydrous DMF (25 mL) at RT After 21 h, the reaction was concentrated on the 30 rotavap (high vacuum), and the residue was taken up in CH2CI2 (240 mL) and washed with H2O The organic layer was dned (Na2S04), dissolved m xylenes, and reconcentrated to remove residual DMF The crude product was chromatographed on silica gel (MeOH/CHCl3) to give the title compound (1.1 g, 52%) PCT/US9S/08306 b) (2S)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetic acid 1 N NaOH (4 75 mL, 4 75 mmol) was added to a cold solution of methyl (2S)-7-[[[(2-benzimidazoiyl)methyl]amino]carbonylj~4-methyl-3-oxo-2,3,4,5-tetrahydro-5 1H-1,4-benzodiazepme-2-acetate (1 0 g, 2 38 mmol), MeOH (10 mL) and H20 (5 mL) The solution was stirred at room temperature for 18 hr and concentrated. ODS chromatography (CH3CN/H2O-O 1% TFA) gave the title compound (0 91 g, 94%) HPLC (5 Altex Ultrasphere ODS, 4 5 mm x 25 cm, 5%-60% CH3CN/H2O-O 1% TFA gradient over 20 mm) K'=5 7, !H NMR (400 MHz, DMSO-d6) 8 8 7-8.9 (t, 10 IH), 6 3-7 6 (m, 8H), 5 4-5 6 (d, IH), 5 0-5 1 (q, IH), 4 5-4 7 (d 2H), 3 8-3 9 (d, IH), 2 9-3 0 (s, 3H), 2 7-2 9 (dd, 2H), MS (ES) m/e 408 2 (M+H)+ Anal Calcd for C21H21N5O4 3 5 H20 C, 53 61, H, 6 00, N, 14 89 Found C, 53 38, H, 6 00, N, 14 55 [a]D -237° (c 0 1) Example 9 Preparation of f2RV7-nT(2-Benzimidazolvl)methvnamino1carbonvn-4-methyl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid a) Methyl (2R)-7-[[[(2-benzimidazoIyl)methyl]amino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate Following the procedure of Example 8(a), substituting methyl (2R)-7-carboxy-4-methyl-3-oxo-2,3,4,5-lH-l,4-benzodiazepine-2-acetate for the (2S) isomer, the tide compound (0 37 g, 86%) was prepared b) (2R)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid Following the procedure of Example 8(b), the compound of Example 9(a) is saponified to yield the utle compound (0.20 g, 57%) HPLC (5 Altex Ultrasphere ODS, 4 5 mm x 25 cm, 12% CH3CN/ H20-0 1% TFA) K'=4 7, JH NMR (400 MHz, DMSO-dg) 8 8 7-8 9 (t, IH), 6 3-7 6 (rn, 8H), 5 4-5 6 (d, IH), 5 0-5 1 (q, IH), 4 5-4 7 (d 2H), 3 8-3 9 (d, IH), 2 9-3 0 (s, 3H), 2 7-2 9 (dd, 2H), MS (ES) m/e 408 2 (M+H)+ Anal Calcd for C2iH2iN504 3 75 H20 C, 53 10, H, 6 05, N, 14 74 Found C, 52 86, H, 6 03, N, 14 39 [a]D= +205° (c 0 1) Example 10 Preparation of (±V7-frf(2-benzimidazolvl')methvllanunolcarbonvn-9-chloro-4-methvl-3-oxo-2.3.4.5-tetrahvdro-IH-1,4-benzodiazepine-2-acetic acid 87 PCTAJS95/08306 a) Methyl (±)-7-carboxy-9-chloro-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepme-2-acetate A solution of (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (1.0 g, 3 4 mmol), NCS (0 683 g, 4.0 mmol) in DMF (15 mL) was heated to 50°C for 18 h Water (150 mL) was added and the heterogeneous system was filtered The sohd was tnturated with CH2Cl2/MeOH (9 1,20 mL) for 1 h Filtration and drying m vacuo gave the title compound (0 61 g, 55%) *H NMR (400 MHz, DMSO-d6) 5 7 6-7 8 (m, 2H), 4 0-5 8 (m, 4H), 3 6-3 7 (s, 3H), 2 8-3 0 (m, 5H), MS (ES) m/e 327 0 (M+H)+ b) Methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate Following the procedure of Example 8(a), substituting methyl (±)-7-carboxy-9-chloro-4-methyl-3-oxo-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepme-2-acetate for 15 methyl (2S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate, and substituting 2-aminomethylbenzimidazole dihydrochlonde for 4-( 1-pipendmyl)pipendine, the title compound (0 68 g, 81%) was prepared c) (±)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-3-oxo-20 2,3,4,5-tetrahydro- IH- l,4-benzodiazepine-2-acetic acid Following the procedure of Example 8(b), methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetate was saponified and punfied to give the title compound (0 53 g, 84%) HPLC (5 Altex Ultrasphere ODS, 4 5 mm x 25 cm, 25 5%-60% CH3CN/H20-0 1 % TFA gradient over 20 nun) K'=6 5, *H NMR (400 MHz, DMSO-d6) 5 8 8-9.0 (t, IH), 7 0-8 0 (m, 8H), 3 9-5 7 (m, 6H), 2 9-3 0 (s, 3H), 2 7-2.9 (m, 2H); MS (ES) m/e 442 2 (M+H)+ Anal Calcd for C21H20CIN5O4 1 25 H2O C, 54 31, H, 4 88, N, 15 08 Found C, 54 77, H, 4 73, N, 14 68 I / Example 11 Preparation of (±')-8-rfT(2-Benzimidazolvl')methvnamino'lcarbonvl'l-2-methvl-3-oxo-2,3.4.5-tetrahvdro-1 H-2-benzazepme-4-acetic acid a) Methyl (±)-8-[[[(2-benznmdazolyl)methyl]amino]carbonyl]-2-methyI-3-oxo-2,3,4,5-tetrahydrc-lH-2-benzazepine-4-acetate 35 To a solution stirred under argon at room temperature of methyl (±)-8- carboxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate (0 30 g, 1 88 WO 96/00730 PCT/US95/08306 mmol), 2-aminomethylbenzimidazole dihydrochlonde (0 27 g, 1 2 mmol), HOBT H2O (0 17 g, 1 2 mmol), diisopropylethylamme (0 53 g, 4 mmol), and DMF (5 mL) was added EDC (0 24 g, 1.2 mmol) The resulting mixture was stirred for 18 h, then was concentrated to dryness, and the residue was partitioned between EtOAc and 5 H2O The organic phase was washed twice with H2O and once with bnne, dned (MgS04), and concentrated The residue was recrystallized firom boiling EtOAc to give the title compound (0 16 g, 37%) as a colorless sohd !h NMR (CDCI3) 8 9 95 (m, IH), 7 86 (d, J=8 Hz, IH), 7 79 (s, IH), 7 52 (m, 2H), 7 28 (m, 2H), 7.07 (d, J=8 1 Hz, IH), 5 16 (d, J=16 4 Hz, IH), 4.82 (m, 2H), 3 78 (m, IH), 3 69 (s, 3H), 10 3 65 (d, J=16 6 Hz, IH), 3.10-2 90 (m 3H), 2 87 (s, 3H), 2 40 (dd, J=16 9,5 4 Hz, IH) b) (±)-8-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepme-4-acetic acid 15 A solution of methyl (±)-8-[[[(2-benzimidazolyl)methyl]amino]cait>onyl]-2- methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate (0 10 g, 0 24 mmol), LiOH H2O (0 013 g, 0 31 mmol), THF (2 mL), and H2O (2 mL) was stirred at RT for 18 h, then was concentrated to dryness The residue was dissolved m H2O, and the solution was brought to pH 4-5 with 3N HCl The resulting precipitate was 20 collected by filtration and dned Recrystallization from boiling isopropanol gave the title compound (0 035 g, 36%) as a colorless sohd !H NMR (DMSO-d6) 8 9 13 (t, J=5 7 Hz, IH), 7 79 (m, IH), 7 48 (m, 2H), 7 23 (d, J=7 9 Hz, IH), 7 14 (m, 2H), 5 32 (d, J=16 9 Hz, IH), 4 69 (d, J=5 7 Hz, 2H), 4 03 (d, J=16 7 Hz, IH), 3 79 (m, IH), 3 14 (dd, J=18,2 Hz, IH), 2 90 (s, 3H), 2 70 (m, 2H), 2 38 (dd, J=11 4, 3 Hz, IH), MS (ES) m/e 407 (M+H)+ Anal Calcd for C22H22N4O4 1 5 H20 0 5 C3HgO C, 60 90, H, 6 31, N, 12 09 Found C, 60 68, H, 6 05, N, 12 05 Example 12 Preparation of (±)-8-lTfN-(2-benzimidazolvl)methvl-N-methvnaiiiinolcarbonvn-2-methvl-3-oxo-2.3.4.5-tetrahvdro-1 H-2-benzazepme-4-acetic acid a) Methyl (±)-8-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate Following the procedure of Example 11(a), methyl (±)-8-carboxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate was coupled with 2-(methylamino)methylbenzimidazole Chromatography on silica gel (5% MeOH/CH2Cl2) gave the title compound (67%) as a colorless foam *H NMR (CDCI3) 5 7 62 (m, 2H), 7 30 (m, 4H), 7 16 (d, J=8 3 Hz, IH), 5 31 (d, J=16 4 Hz, IH), 4 92 (d, J=14.5 Hz, IH), 4 87 (d, J=14 5 Hz, IH), 3 88 (m, 2H), 3 71 (s, 3H), 3 02 (s, 3H), 3 16 (s, 3H), 3 15-2 90 (m, 3H), 2 43 (dd, J=16 9, 5 3 Hz, IH) b) (±)-8-[[[N-(2-Benzimidazolyl)mediyl-N-methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-2-benzazepme-4-acetic acid Following the procedure of Example 11(b), methyl (±)-8-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate was saponified Extraction with CH2CI2, 10 concentration, and drying gave the title compound (52%) as a colorless solid *H NMR (DMSO-do) 5 7.59 (m, IH), 7 47 (d, J=8 Hz, IH), 7 35 (m, 2H), 7 15 (m, 3H), 5 25 (d, J=16 Hz, IH), 4.87 (d, J=14 Hz, IH), 4 08 (d, J=16 Hz, IH), 3 78 (m, IH), 3 10 (m, IH), 3 35 (s, 3H), 3 03 (s, 3H), 2 85-2 65 (m, 2H), 2 35 (dd, J=16,5 Hz, IH), MS (ES) m/e 421 2 (M+H)+ Anal Calcd for C23H24N4O4 HCl 1 2 CH2CI2 H20 C, 50 82, H, 5 18, N, 9 79 Found C, 50 96, H, 5 48, N, 9.55 Example 13 Preparation of (±V7-ITrN-(2-benzimidazolvl)methvI-N-methvllaminolcarbonvll-3-oxo-4-(2-phenvlethvl)-2.3.4.5-tetrahvdro- IH-1.4-benzodiazepme-2-acetic acid 20 a) Methyl (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyI]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate Following the procedure of Example 11(a), methyl (±)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine acetate and 2-(methylamino)methylbenzimidazole were coupled Chromatography on silica gel 25 (1 %-5% MeOH/CH2Cl2) gave the title compound (57%) as a colorless sohd JH NMR (CDCI3) 5 7.62 (m, 2H), 7 35-7 00 (m, 9H), 6 46 (d, J=8 Hz, IH), 5 24, (d, J=16 6 Hz, IH), 5 03 (m, IH), 4 95 (d, J=14 6 Hz, IH), 4 82 (d, J=14 6 Hz, IH), 4 51 (d, J=5 Hz, IH), 3 82 (m, IH), 3 74 (s, 3H), 3 58 (m, 2H), 3 17 (s, 3H), 2 99 (dd, J=16, 6 8 Hz, IH), 2 81 (m, 2H), 2 67 (dd, J=16,6 3, IH) b) (±)-7-[[[N-(2-Benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetic acid Methyl (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxo-4~( 2-phenylethy l)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate was 35 saponified according to the procedure of Example 11(b) Recrystallization from boiling isopropanol gave the title compound (57%) as a colorless sohd *H NMR 90 (DMSO-d6) 5 7 58 (m, IH), 7 47 (m, IH), 7 35-7 10 (m, 8H), 6 55 (d, J=8 Hz, IH), 6 23 (m, IH), 5 37 (d, J=16 Hz, IH), 5 05 (m, IH), 4 77 (s, 2H), 3 95 (m, IH), 3 58 (m, 2H), 3 05 (s, 3H), 2 65 (m, 2H), 2 58 (m, IH), MS (ES) m/e 512 2 (M+H)+ Anal Calcd for C29H29N5O4 2H2O C, 63 61; H, 6 07, N, 12.79 Found C, 5 63 33, H, 6 18, N, 12 58 Example 14 Preparation of (±)-7-frrN-^-benzinudazolvDmethvl-N-methvllammolmethvll-1.4-dimethvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid 10 a) Methyl (±)-l-(tert-butoxycarbonyl)-7-caiboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate A mixture of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-1 Abenzodiazepme-2-acetate (1 g, 3 42 mmol), di-tert-butyl dicarbonate (1 48 g, 6 8 mmol) and 4-dimethylaminopyndine (42 mg, 0 3 mmoi) in anhydrous CH3CN (30 15 mL) was stirred at RT for 3 h More di-tert-butyl dicarbonate (0 65 g, 3 mmol) was then added to the clear yellow solution and the reaction was stirred at RT for an additional h The reaction mixture was then quenched with water, the CH3CN was removed m vacuo, and the residue was extracted with EtOAc The organic layers were washed sequentially with saturated NH4CI and H20, then were dned (MgS04) 20 and concentrated in vacuo Silica gel chromatography (7/3 hexane/EtOAc-1% AcOH) gave the tide compound (1.05 g, 78%) as a white solid *H NMR (CDCl3) 400 MHz) 5 1 55 (s, 9H), 2 69 (dd, J=16,5 Hz, IH), 2.98 (dd, J=16,5 Hz, IH), 3 10 (s, 3H), 3 65-3 68 (m, IH), 3 72 (s, 3H), 5 16 (dd, J=5, 5 Hz, IH), 5 45 (d, J=16 4 Hz, IH), 6 52 (d, J=8 4 Hz, IH), 7 59 (d, J=1 4 Hz, IH), 7 78 (dd, J=8.4, 1 4 25 Hz, IH) b) Methyl (±)-7-formyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate Methyl (±)- l-(tert-butoxycarbonyl)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (400 mg, 1 02 mmol) was suspended in toluene and SOCl2 (3 mL) was added The reaction was heated at 80°C for 3 h The resulting solution was concentrated to dryness to leave a pale yellow solid The acid chlonde thus obtained was then suspended m THF (2 mL), and 2,6-lutidine (109 mg, 1 02 mmol) was added, followed by 10% Pd/C (40 mg) The resulting suspension was stirred under a H2 atmosphere overnight, then was filtered through a short pad of Celite® The filtrate was diluted with EtOAc and the solution was "WO 96/00730 PCT/US95/08306 cashed sequentially with 5% HCl and H20 Drying (MgSC>4) and concentration gave the title compound (139 mg, 60%) as a pale yellow sohd, which was used in the next step without further purification *H NMR (CDC13,400 MHz) 8 2 70 (dd, J=15 6,6 8 Hz, IH), 3 01 (dd, J=15 6, 6 4 Hz, IH), 3 08 (s, 3H), 3 75-3 82 (m, IH), 5 3 76 (s, 3H), 5 17 (dd, J=6 8,6 4 Hz, IH), 5 47 (d, J=16 4 Hz, IH), 6 59 (d, J=8 4 Hz, IH), 7 50 (s, IH), 7 58 (d, J=8 4 Hz, IH) c) Methyl (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]ammo]methyl]-l,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Methyl (±)-7-formyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetate (125 mg, 0 45 mmol) was suspended in anhydrous MeOH, then sodium acetate (111 mg, 1 35 mmol), 2-(aminomethyl)benzimidazole dihydrochlonde (100 mg, 0 45 mmol) and 4 A molecular sieves were added After 30 mm., sodium cyanoborohydnde (32 mg, 0 49 mmol) was added in 2 portions 15 over a penod of 30 nun The reaction mixture was allowed to stir at RT overnight, then the MeOH was removed under vacuum Formaldehyde (37 wt.% in H20,3 mL) was added, followed by CH3CN (3 mL), AcOH, and sodium cyanoborohydnde (34 mg, 0 49 mmol) After 40 mm. the reaction was concentrated under reduced pressure The residue was diluted with CH2C12, and the solution was washed with 20 saturated NaHC03 Drying (MgS04), concentration, and silica gel chromatography (55% CH2Cl2/20% EtOAc/20% hexane/5% MeOH) gave the title compound (55 mg, 29%) lH NMR (CDCI3,400 MHz) 8 2 33 (s, 3H), 2 63 (dd, J=16 0,5 0 Hz, IH), 2 74 (s, 3H), 3 03 (dd, J=16 0, 8.8 Hz, IH), 3 07 (s, 3H), 3 57 (br s, 2H), 3 68 (s, 3H), 3 87 (br s, 2H), 3 87 (d, J=16 4 Hz, IH), 4 71 (dd, J=8 8 Hz, 5 0, IH), 5.20 25 (d, J=16 4 Hz, IH), 6 94-6 97 (m, 2H), 7 20-7 26 (m, 5H), 7 57 (bs, IH), MS(ES) m/e 436 (M+H)+ d) (±)-7-[[[N-(2-Benzimidazolyl)methyl-N-methyl]amwo]methyl]-1,4-dimethyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetic acid LiOH (5 8 mg, 0 17 mmol) was added at RT to a solution of methyl (±)-7- [[[N-(2-benzimidazolyl)methyl-N-methyl]amino]methyl]-1,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (50 mg, 0 115 mmol) in THF (2 mL) and H20(3 mL) The reaction mixture was heated at 50°C for 30 nun, then was concentrated in vacuo The resulting residue was lyophilized to afford a pale yellow 35 solid which was punfied by preparative HPLC (11% CH3CN/H2O-O 1% TFA) to afford the title compound (30 mg, 31%) *H NMR (CD30D, 400 MHz) 8 2 57 (m, WO 96/00730 PCT/US95/08306 IH), 2 58 (s, 3H), 2 76 (s, 3H), 2 95 (dd, J =16,8 Hz, IH), 3 04 (s, 3H), 3 93 (d, J=16 3 Hz, IH), 4 07 (br s, 2H), 4.38 (br s, 2H), 4 67 (dd, J=8 4,7 OHz, IH), 5 18 (d, J=16 3 Hz, IH), 6 91 (d, J=8 4 Hz, IH), 7 12 (s, IH), 7 26 (d, J=8 4 Hz, IH), 7 42 (m, 2H), 7 64 (m, 2H), MS(ES) m/e 422 (M+H)+ Anal Calcd for C25H27N5O3 35CF3CO2H C, 42 51, H, 3 98, N, 8 26 Found C, 42 58, H, 4 27, N, 7 89 Example 15 Preparation of (±)-7-rrrN-r2-benzinudazolvDmethvl-N-methvllaminolcarbonvn-4-10 methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetic acid a) 2-(Methylaminomethyl)ben7amidazole dihydrochlonde Methylamine (5 0 g, 0 16 mole) was dissolved in a solution of Et20 (100 mL) and EtOH (5 mL) at 0°C, and 2-chloromethylbenzirrudazole (13 4 g, 0 08 mole) was added in small portions The reaction mixture was stiiTed at RT for 3 h, then 15 was allowed to stand at RT overnight More Et20 (200 mL) was added, and the reaction was cooled in an ice bath for 3 h before filtenng off the precipitate The filtrate was saturated with HCl and filtered, and the filtrate was concentrated Silica gel chromatography (step gradient, 10-25% MeOH/CH2Cl2) yielded the title compound (2 5 g, 13%) »H NMR (250 MHz, 5 1 DMSO-d6/CDCl3) 6 7 13-7 54 20 (m, 4H), 4 11 (s, 2H), 2 50 (s, 3H), MS (ES) m/e 162 0 (M+H)+ b) Methyl (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate Following the procedure of Example 1(a), except substituting 2-25 (methylanuno methyl)benzimidazole dihydrochlonde (1 2 g, 5 13 mmol) for the 2-(ammomethyl) benzimidazole dihydrochlonde, the crude title compound was prepared Silica gel chromatography (10% MeOH/CH2Cl2) yielded the title compound (0 29 g, 39%) as an off-white sohd 'H NMR (250 MHz, CDCI3) 8 6 44-7 62 (m, 9H), 5 41 (d, J=l6.2 Hz, IH), 5 07 (m, IH), 4 81 (m, 2H), 4.52 (d, J=5 2 Hz, 2H), 3 73 (s, 3H), 3 68 (d, J=16 6 Hz, IH), 3 04 (s, 3H), 2 96 (s, 3H), 2 93 (dd, J=17 1, 6 5 Hz, IH), 2 67 (dd, J=17 1, 6 3 Hz, IH), MS (ES) m/e 436 2 (M+H)+ c) (±)-7-[[[N-(2-Benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid Following the procedure of Example 1(b), the compound of Example 15(b) was saponified and punfied to give the title compound (0 21 g, 80%) MS (ES) m/e 422 2 (M+H)+ Anal Calcd for C22H23N5O4 4/3 CF3CO2H H20 C, 47 93, H, 4 22, N, 10 96 Found C, 47 88, H, 4.35, N, 10 96 Example 16 Preparation of f±V7-fn2-(2-benzimidazolvDethvllaminolcarbonvll-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetic acid a) 2-Aminoethylbenzimidazole diacetate A mixture containmg 2-cyanomethylbenzimidazole (2 0 g, 12 7 mmol), 10% Pd/C (1 0 g), and AcOH (40 mL) was hydrogenated at 42 psi for 6 h m a Parr 10 apparatus The reaction mixture was filtered through a bed of Celite® and concentrated to give the title compound (3 4 g, 95%) *H NMR (250 MHz, CDCI3) 8 7 04-8 13 (m, 7H), 3 17-3 39 (m, 4H), MS (ES) m/e 162 0 (M+H)+ b) Methyl (±)-7-[[[2-(2-benzimidazolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-15 2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate Following the procedure of Example 1(a), except substituting 2-aminoethyl benzimidazole diacetate (1 44 g, 5 13 mmol) for the 2-(aminomethyl)benzimidazole dihydrochlonde, the crude title compound was prepared. Silica gel chromatography (9% MeOH/CH2Cl2) yielded the title compound (0 64 g, 86%) as an off-white sohd 20 IH NMR (250 MHz, CDCI3) 8 6 20-8.23 (m, 9H), 5 50 (d, J=16 2 Hz, IH), 5 11 (m, IH), 3.70-3 81 (m, 3H), 3 64 (s, 3H), 3 11 (t, J=7 2 Hz, 2H), 2 98 (s, 3H), 2 86 (dd, J=16 8,8 0 Hz, IH), 2 63 (dd, J=16 8,5 0 Hz, IH), MS (ES) m/e 436 2 (M+H)+ c) (±)-7-[[[2-(2-Benzimidazolyl)ethyl]ammo]carbonyl]-4-methyl-3-oxo-2,3,4,5-25 tetrahydro-1H-1,4-benzodiazepme-2-acetic acid Following the procedure of Example 1(b), the compound of Example 16(b) was saponified and punfied to give the title compound (7.8 mg, 10%) MS (ES) m/e 422 0 (M+H)+ Anal Calcd for C22H23N5O4 2 CF3C02H 2 5 H20 C, 44 96, H, 4 35, N, 10 08 Found C, 44 79, H, 4 21, N, 10 08 Example 17 Preparation of (±')-7-lT(2-benzimidazolvl')amino'lcarbonvl'l-4-methvl-3-oxo-2.3A5-tetrahvdro-1H-1,4-benzodiazepine-2~acetic acid 94 PCT/US95/G8305 a) Methyl (±)-7-[[(2-benzinudazolyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Following the procedure of Example 1(a), except substituting 2-ammo benzimidazole (0 68 g, 5 13 mmol) for the 2-(aminomethyl)benzimidazole 5 dihydrochlonde, the crude title compound was prepared Silica gel chromatography (7% MeOH/CH2Cl2) yielded the title compound (0 48 g, 69%) as an off-white sohd IH NMR (250 MHz, CDCI3) 5 6 50-8 16 (m, 9H), 5 47 (d, J=16 3 Hz, IH), 5 24 (m, IH), 3 82 (d, J=4.5 Hz, IH), 3.65 (s, 3H), 2 60-3 01 (m, 6H), MS (ES) m/e 408 2 (M+H)+ b) (±)-7-[[(2-Benzimidazolyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid Following the procedure of Example 1(b), the compound of Example 32(a) was saponified and punfied to give the title compound (50 mg, 55%) MS (ES) m/e 394 2 (M+H)+ Anal Calcd for C20H19N5O4 4/3 CF3CO2H C, 49 91, H, 3 76, N, 12 84 Found C, 49 92, H, 3 83, N, 12 93 Example 18 Preparation of f2S>7-nTN-(2-benzirrudazolvPmethvl-N-methvnaminolcarbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4- benzodiazepine-2-acetic acid a) Methyl (2S)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetate Dusopropylethylamme (0 29 g, 2 25 mmol) was added in one portion to a stirred mixture of 2-(methylaminomethyl)benzimidazole bis(tnfluoroacetate) (18 mmol), methyl (2S)-7-carboxy-4-methyI-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (0 44 g, 1 50 mmol), EDC (0 34 g, 1 8 mmol) and HOBT H2O (0 24 g, 1 8 mmol) in DMF (8 mL) at RT under argon After 24 h, the solution was poured into a mixture of ice-water (90 g) and 5% NaHC03 (10 mL) The resulting precipitate was filtered and air-dned Flash chromatography (silica gel, MeOH/CH2Cl2) yielded the title compound (79%) !H NMR (400 MHz, CDC13) 86 51-7 60 (m, 9H), 5 41 (d, J-16 4 Hz, IH), 5 07 (m, IH), 4 82 (t, J=15 0 Hz, 2H), 4.50 (d, J=4.8 Hz, IH), 3 74 (s, 3H), 3 68 (d, J=16 6 Hz, IH), 3 15 (s, 3H), 2 96 (s, 3H), 2 93 (dd, J=17 1,6 5 Hz, IH), 2 67 (dd, J=16 1 6 5 Hz, IH), MS (ES) m/e 436 2 (M+H)+ 95 b) (2S)-7-[[[N-(2-Benzimidazolyl)methyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid Following the procedure of Example 1(b), the compound of Example 18(a) was saponified and punfied to give the title compound (0.11 g, 91 %) MS (ESMS) 5 m/e 422.2 (M+H)+ Anal Calcd for C22H23N5O4 3 H20 C, 55.57, H, 6 15; N, 14 73 Found C, 55 30, H, 6 13, N, 14.39 Example 19 Preparation of (±V4-Methvl-7-fffN-f2-n-methyl")benzirrudazolvDmethvl-N-10 methvllaminol carbonvll-3-oxo-2.3.4.5-tetrahvdro- IH-1.4-benzodiazepine-2-acetic acid a) 2-[[N-(tert-Butoxycarbonyl)-N-methyl]aminomethyl]benzimidazole Di-tert-butyl dicarbonate (1 12 g, 5 13 mmol) was added dropwise at 0°C to a mixture containing 2-(methylaminomethyl)benzimidazole dihydrochonde (1.0 g, 15 4 27 mmol), dioxane (25 mL), H20 (25 mL), and 1 N NaOH (12 8 mL, 12 8 mmol) After 2 h, the reaction was warmed to RT and stirred for 21 h The solvent was evaporated on the rotavap, and the pH was adjusted to 5 using 1 M NaHS04 The mixture was extracted with CH2C12 (2x80 mL), and the combined organic layers were washed with bnne (30 mL) and dned (MgS04) Concentration gave the title 20 product (0 7 g, 64%)• lH NMR (400 MHz, CDCI3) 8 7.59 (b, 2H), 7.26 (m, 3H), 4 57 (s, 2H), 2.98 (s, 3H), 1 50 (s, 9H); MS (ES) m/e 262 0 (M+H)+ b) 1 -Methyl-2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]benzimidazole A mixture of 2-[[N-(tert-butoxycarbonyl)-N-25 methyl]aminomethyl]benzimidazole (0.51 g, 1 95 mmol), NaH (0 12 g, 5 0 mmol), DMF (5 mL), and THF (20 mL) was stirred at RT under argon for 5 min, then methyl iodide (0 83 g, 5 86 mmol) was added The reaction mixture was stirred at RT for 170 mm, then was concentrated on the rotavap The residue was diluted with CH2C12 (100 mL), and the mixture was washed sequentially with H20 (30 mL), 5% 30 NaHC03 (30 mL), and bnne (30 mL) Drying (Na2S04) and concentration gave the tide compound (0.51,94%) IH NMR (250 MHz, CDCI3) 5 7 23-7 77 (m, 4H), 4 79 (s, 2H), 3.82 (s, 3H), 2 86 (s, 3H), 1.50 (s, 9H), MS (ES) m/e 276.2 (M+H)+ c) l-Methyl-2-(methylammomethyl)benzimidazole bis(tnfluoroacetate) A mixture of l-methyl-2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl] benzimidazole (0 51 g, 1 85 mmol) in 25% TFA/CH2C12 (20 mL) was stirred at RT 96 under argon for 20 min The solvent was removed on the rotavap and the residue was recrystalhzed from Et20/CH2Cl2 to give title compound (0.69 g, 92%) NMR (250 MHz, 5 1 CDC13 DMSO-d6) 5 7 24-7 68 (m, 4H), 4 56 (s, 2H), 3 84 (s, 3H), 2 84 (s, 3H), MS (ES) m/e 176 0 (M+H)+ d) Methyl (±)-4-methyl-7-[[[N-(2-(l-methyl)benzimidazolyl)methyl-N-methyl]amino] carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Following the procedure of Example 18(a), except substituting l-Methyl-2-(methylaminomethyl)benzimidazole bis(tnfluoroacetate) for 2,6-diaminopyndine, 10 the title compound (0 52 g, 77%) was prepared *H NMR (250 MHz, CDCI3) 8 6 50-7 80 (m, 9H), 5 43 (d, J=16.4 Hz, IH), 5 03-5 10 (m, 3H), 4 42 (d, J=4 7 Hz, IH), 3 88 (s, 3H), 3 74 (s, 3H), 3 68 (d, J=16 6 Hz, IH), 3 13 (s, 3H), 3 06 (s, 3H), 2 99 (dd, J= 16 2, 6 7 Hz, IH), 2 66 (dd, J= 16 2, 6 5 Hz, IH), MS (ES) m/e 450 2 (M+H)+ e) (±)-4-Methyl-7-[[[N-(2-(l-methyl)benzimidazolyl)methyl-N-methyl]amino] carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid Following the procedure of Example 1(b), the compound of Example 19(d) was saponified and punfied to give the title compound (0 13 g, 60%) MS (ES) m/e 436 2 (M+H)+ Anal Calcd for C23H25N5O4 1 5 H20 C, 59 73, H, 6 10, N, 15 14 Found C, 59.39, H, 6 05, N, 14 96 Example 20 Preparation of (±)-7-riT(2-(5(6)-methoxy)bcnzimidazolvl)methvnamino1carbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1,4-benzodiazepine-2-acetic acid a) N-[N-(Benzyloxycarbonyl)glycyl]-4-methoxy-2-mtroamLine N-(Benzyloxycarbonyl)glycine (2 72 g, 13 13 mmol) was dissolved in CH2CI2 and an excess of thionyl chlonde at room temperature After 2 h, the reaction was evaporated under vacuum and the residue was stnpped with toluene twice and dned under vacuum The white solid was taken into CH2CI2 and 4-methoxy-2-nitroanihne (2 1819 g, 12 98 mmol) was added as a solid, followed by tnethylamine (2 0 mL, 1 455 g, 14.38 mmol) The reaction was stirred at RT for 24 h, then was evaporated under vacuum The residue was dissolved in EtOAc and washed with aqueous IN NaHC03 The EtOAc layer was dned (MgS04) and concentrated under vacuum Thin layer chromatography analysis (1 1 1 hexanes/Et20/CH2Cl2) showed good conversion to the acylated matenal The crude 97 material was dissolved in 2 1 1 hexanes/Et20/CH2Cl2 initially, with the addition of enough Et20/CH2C12 and somcation/heatmg to dissolve all the solid material Silica gel chromatography (2 1 1 hexanes/Et20/CH2Cl2 (2L), then Ml hexanes/Et20/CH2Cl2 (1 5 L), then T^OICBqCXi) gave the title compound (3 3387 5 g, 72%) >H NMR (250 MHz, CDC13) 5 3 85 (s, 3H), 4 06 (d, 2H), 5 18 (s, 2H), 5 61 (t, IH), 7 2-7 4 (m, 6H), 7.65 (d, IH), 8 63 (d, IH). b) 2-[N-[(BenzyloxycarbonyI)amino}methyl]-5(6)-methoxybenzimidazole N-[N-(Benzyloxycarbonyl)glycyl]-4-methoxy-2-nitroanihne (1 0 g, 2 87 10 mmol) was dissolved in glacial acetic acid, and iron powder was added The mixture was heated in an oil bath at about 65 °C with stirring After 24 h, the reaction was evaporated under vacuum The residue was evaporated with toluene, dned under vacuum, and adsorbed onto silica gel Chromatography on a dry silica gel column (1 1 Et20/CH2Cl2 (1.5 L) followed by 5% MeOH/CH2Cl2) gave the title 15 compound (1 0063 g, 94%) *H NMR (250 MHz, CDC13) 5 3 78 (s, 3H), 4 57 (s, 2H), 5 05 (s, 2H), 6 8-7 5 (m, 8H), 10 85 (br s, IH), MS (ES) m/e 312.0 (M+H)+ c) 2-(Aminomethyl)-5(6)-methoxybenzunidazole 2-[N-[(Benzyloxycarbonyl)amino]methyl]-5(6)-methoxybenzimidazole 20 (1 0063 g, 3 23 mmol) was dissolved m MeOH, and 10% Pd/C was added The reaction was stirred at RT under H2 (balloon pressure) for 17 h, then was filtered through a bed of Celite® The filtrate was evaporated under vacuum to yield the title compound (4117 mg, 72%) as an oil 'H NMR (250 MHz, CDCI3) 5 3 75 (s, 3H), 4 05 (s, 2H), 5 59 (br s, 2H), 6 82 (dd, IH), 6 97 (d, IH), 7 40 (d, IH) d) Methyl (±)-7-[[[(2-(5(6)-methoxy)benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-1,4-benzodiazepine-2-acetate Methyl (±)-7 -carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate (245 4 mg, 0 84 mmol) was dissolved in DMF A solution 30 of EDC (169 3 mg, 0 88 mmol) m DMF was added, followed by HOBT H2O (112 1 mg, 0 83 mmol) A solution of 2-(Ammomethyl)-5(6)-methoxybenzimidazole (1 434 mg, 0 81 mmol) in DMF was then added, followed by diisopropylethylamme (0 2 mL, 1 44 mmol) The reaction was stirred at RT for 5 d, then was concentrated under vacuum The residue was evaporated once with 35 toluene The crude matenal was partitioned between H20 and EtOAc The aqueous phase was back-extracted with EtOAc, and the combined organic layers were dned (MgSC>4) and concentrated TLC (10% MeOH/CHCl3) showed two major products Silica gel chromatography (CHCI3 (0 25 L), then 3% MeOH/CHCl3) gave three fractions, fraction 3 gave the title compound (112 9 mg, 31%) 'H NMR (250 MHz, CD3OD) 5 3 06 (s, 3H), 3 70 (s, 3H), 3 80 (s, 3H), 4 74 (s, 2H), 5 28 (t, IH), 5 51 (d, 5 IH), 6 58 (d, IH), 6 85 (d, IH), 7 00 (s, IH), 7 48 (d, IH), 7 5-7 65 (m, 2H), MS (ES) m/e 452 2 (M+H)+ e) (±)-7-[[[(2-(5(6)-Methoxy)benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid 10 Methyl (±)-7-[[[(2-(5(6)-methoxy)benzimidazolyI)methyl]amino]carbonyl]- 4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodir.zepine-2-acetate (112 9 mg, 0 25 mmol) was dissolved in MeOH, and aqueous IN sodium hydroxide (0 5 mL, 0 5 mmol) was added The reaction was stirred at RT for two d, then was warmed m an oil bath at about 65 °C The solution was concentrated and the residue was 15 redissolved m aqueous MeOH The solution was neutralized with aqueous IN hydrochloric acid (0 5 mL, 0 5 mmol) and the mixture was evaporated under vacuum to remove most of the MeOH The precipitate which formed was collected on a sintered glass funnel and dned under high vacuum to afford the title compound (103 1 mg, 94%) TLC (3 1 1 n-Bu0H/Ac0H/H20) Rf= 0 62, MS (ES) m/e 438 2 20 (M+H)+ Anal Calcd for C22H23N5O5 2H20 C, 55 81, H, 5 75; N, 14 70 Found C, 55 69, H, 5 59, N, 14 41 Example 21 Preparation of (±V7-ITrN-r2-(4-azabenzimidazolvl')1methvl-N-25 methvllamino1carbonvn-4-methvI-3-oxo-2.3 4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid a) 2-Amino-3-[[N-(benzyloxycarbonyl)sarcosyi]amino]pyndine N-(Benzyloxycarbonyl)sarcosme (4 1 g, 18 5 mmol) was dissolved in dry THF, and tnethylamine (3 mL, 216 mmol) was added, followed by 30 isobutylchloroformate (2 5 mL, 19 27 mmol) The solution was cooled to about -20°C for 15 minutes, then a solution of 2,3-diaminopyndme (2 0767 g, 19 03 mmol) in dry THF was added slowly The reaction was kept stimng between -10°C to -20°C for 15 minutes, then was a'lowed to warm to RT After 3 d, the reaction was evaporated under vacuum, and the residue was partitioned between EtOAc and IN 35 NaHC03 The EtOAc phase was dned (MgS04) and evaporated under vacuum The residue was dissolved in glacial AcOH and was stirred in a oil bath at 70 °C 99 WO 96/00730 PCT/US95/08306 After 24 h, the reaction was removed from the oil bath, allowed to cool to RT, and concentrated under vacuum The residue was evaporated with toluene, then was chromatographed on silica gel (CHCI3, then 3% MeOH/CHCl3 , then 5% MeOH/CHCl3) to afford the title compound (1 13 g, 19%) *H NMR (250 MHz, 5 CDCI3) 5 3 05 (s, 3H), 3 99 (s, 2H), 4 82 (br s, IH), 6 5-6 65 (m, IH), 7 32 (s, 5H), 7 87 (d, IH), 8 84 (br s, IH), MS (ES) m/e 315 4 (M+H)+ b) 2-[[N-(Benzyloxycarbonyl)-N-methylamino]methyl]-4-azabenzimidazole 2-Amino-3-[[N-(benzyloxycarbonyl)sarcosyl]amino]pyndine (513 mg, 1 63 10 mmol) was taken up in glacial AcOH (25 mL) and the reaction was heated in an oil bath set at 100-105°C After 24 h, the reaction was evaporated under vacuum and the residue was concentrated from toluene Silica gel chromatography (CHC13, then 2% MeOH/CHCl3 , then 4% MeOH/CHCl3) gave the title compound (385 mg, 80%) »H NMR (250 MHz, CDCI3) 8 3 07 (s 3H), 4 83 (s, 2H), 5 17 (s, 2H), 7 1-15 7 4 (m, 6H), 8 03 (d, IH), 8 46 (d, IH), MS (ES) m/e 297 2 (M+H)+ c) 2-(Methylamino)methyl-4-azabenzimidazole 2-[[N-(Benzyloxycarbonyl)-N-methylanuno]methyl]-4-azabenzimidazole (385 5 mg, 1 30 mmol) was dissolved m MeOH, and 10% Pd/C was added The 20 mixture was stirred at RT under H2 (balloon pressure) for 4 h, then the catalyst was removed by filtration through a bed of Celite® The clear, colorless filtrate was evaporated under vacuum to afford the title compound (237 0 mg, 100%) 'H NMR (250 MHz, CDCI3/CD3OD) 5 2 48 (s, 3H), 4 06 (s, 2H), 5 38 (br s, IH), 7 15-8 35 (m, 4H) d) Methyl (±)-7-[[[N-[2-(4-azabenzimidazolyl)]methyl-N-methyl]ammo]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate EDC (263 1 mg, 1 37 mmol) was added to a suspension of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine-2-acetate (392 2 30 mg, 1 34 mmol) and HOBT H20 (195 5 mg, 1 45 mmol) in DMF in a dned 100 mL round-bottomed flask The white suspension slowly dissolved to afford a clear, colorless solution A solution of 2-(methylamino)methyl-4-azabenzimidazole (237 0 mg, 1 3 mmol) m DMF and added, followed by dnsopropylethylamine (0 3 mL, 1 72 mmol) The reaction was stirred at RT for 4 d, then was evaporated under high 35 vacuum The residue was concentrated from toluene and was chromatographed on sdica gel (CHC13, then 5% MeOH/CHCl3, then 10% MeOH/CHCl3) to afford the 100 tide compound (183 3 mg, 32%) 'H NMR (250 MHz, CDCI3/CD3OD) 8 3 04 (s, 3H), 3 17 (s, 3H), 3 72 (s, 3H), 4 13 (s, 2H), 5 13 (dd, IH), 5 49 (d, IH), 6.54 (d, IH), 7 2-7 5 (m, 5H), 8 37 (br s , IH); MS(ES) m/e 437 2 (M+H)+ e) (±)-7-[[[N-[2-(4-azabenzimidazolyl)]methyl-N-melhyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid Methyl (±)-7-[[[N-[2-(4-azabenzimidazolyl)]methyl-N-methyl]anuno]carbonyl]-4-methyI-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate (183 mg, 0 42 mmol) was dissolved in MeOH, and IN sodium hydroxide 10 (15 mL, 1.5 mmol) was added The reaction was stirred at RT until complete by TLC, then was neutralized with IN HCl (1 5 mL, 1 5 mmol) The reaction was evaporated under vacuum, and the residue was partially dissolved in MeOH and precipitated with H2O The mixture was evaporated under vacuum to remove most of the MeOH, and the resulting aqueous suspension was allowed to stand at RT for 15 about 1 h before being filtered on a sintered glass funnel The isolated material was dned in a vacuum dessicator under high vacuum to afford the title compound (154.5 mg) MS(ES) m/e 423 2 (M+H)+ Anal Calcd for C21H22N6O4 2 75 H20 C, 53 44, H, 5 87; N, 17 81 Found C, 53 52, H, 5 62, N, 17 23 Example 22 Preparation of (±V7-[TrN-r2-(5(6VAzabenzimidazolvP]methvl-N-methvnamino1 carbonvll-4-niethvl-3-oxo-2.3.4,5-tetrahvdro-1H-1,4-benzodiazepine-2-acetic acid a) 2-[[N-(Benzyloxycarbonyl)-N-methylamino]methyl]-5(6)-azabenzimidazole N-(Benzyloxycarbonyl)sarcosine (4 07 g, 18 24 mmol) was dissolved in dry 25 THF, and tnethylamine (3 0 mL, 21 57 mmol) was added, followed by isobutylchloroformate (2 5 mL, 19 27 mmol) The white mixture was cooled in an acetone/dry ice bath to about -20 °C After 20 minutes, a solution of 3,4-diaminopyndine (2 0319 g, 18 62 mmol) m THF was added The yellow solution was kept stimng at -10 to -20°C for 15 mm, then was allowed to warm slowly to 30 RT After 3 d, the reaction was evaporated under vacuum, and the residue was partitioned between EtOAc ana 1 0 N NaHC03 The combined EtOAc layers were dned (MgS04) and concentrated The clear, slightly tan colored residue was dissolved in glacial AcOH, and the solution was stirred in an oil bath at 70°C After 24 h, the reaction was allowed to cool to RT and was concentrated The residue was 35 concentrated from toluene, then was chromatographed on silica gel (CHCI3, then 2% MeOH/CHCl3, then 4% MeOH/CHCl3) Two fractions were collected Fraction 1 101 PCTAJS95/08306 (530 mg, 5 5%) appeared to be the diacylated material (MS(ES) m/e 520 2 (M+H)+) Fraction 2 contained the title compound (761 mg, 14%) !H NMR (250 MHz, CDCI3) 5 3 07 (s, 3H), 4 77 (s 2H), 5 07 (s, 2H), 7 2-7.3 (m, 5H), 7 44 (d, IH), 8.34 (d, IH), 8 95 (s, IH), MS (ES) m/e 297.2 (M+H)+ b) 2-(Methylaimno)methyl-5(6)-azabenzimidazole 2-[[N-(Benzyloxycarbonyl)-N-methylanuno]methyl]-5(6)-azabenzimidazole (685 5 mg, 2 31 mmol) was dissolved m MeOH, and 10% Pd/C was added The mixture was stirred briskly at RT under H2 (balloon pressure) for 4 h, then was 10 filtered through Celite® to remove the catalyst A clear, colorless filtrate was evaporated under vacuum to leave the title product (381 mg, 100%) c) Methyl (±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]methyl-N-methyl]amino] carbonyl]-4-methyI-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetate EDC (263.1 mg, 1 37 mmol) was added to a suspension of methyl (±)-7- carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetate (697 3 mg, 2 39 mmol) and HOBT H2O (345 5 mg, 2 56 mmol) in DMF in a dned 100 mL round-bottomed flask. The white suspension began to dissolve After about 15 minutes, a solution of 2-(methylamino)methyl-5(6)-azabenzimidazole (380 6 mg, 20 2.35 mmol) in DMF was added The reaction was stirred at RT for 20 h, then was concentrated under vacuum. Sihca gel chromatography (CHCI3, then 5% MeOH/CHCls, then 10% MeOH/CHCl3) gave the title compound (679 mg, 66%) »H NMR (250 MHz, CDC13) S 3 00 (s, 3H), 3 12 (s, 3H), 3 48 (s, 3H), 3 66 (s, 3H), 5 07 (m, IH), 5 40 (d, IH), 6 35 (br s , IH), 7 05 (br s , IH), 7 12 (s, IH), 7 47 (d, 25, IH), 8 36 (d, IH), 8 94 (s, IH). d) (±)-7-[[[N-[2-(5(6)-Azabenzimidazolyl)]methyl-N-methyl]amino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid Methyl (±)-7-[[[N-[2-(5(6)-azabenzimidazolyl)]methyl-N-methyl]amino] 30 carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate (679 0 mg, 1 56 mmol) was dissolved in MeOH, and IN NaOH (3 0 mL, 3 0 mmol) was added A clear, yellow solution formed almost immediately The reaction was stirred at RT for 24 h, then was neutralized with IN aqueous HCl (3 0 mL, 3 0 mmol) The reaction was concentrated and the residue was suspended in H20 The 35 mixture was sonicated, and the colorless precipitate was collected and dned m a vacuum dessicator to leave the title compound (471 mg, 71 %) MS (ES) m/e 423 2 102 WO 96/00730 PCT/US95/08306 (M+H)+ Anal Calcd for C21H22N6O4 2 25 H20 C, 54 48, H, 5 77, N, 18 15 Found C, 54 67, H, 5 58, N, 17.64 Example 23 Preparation of (±V7-riT(2-imidazolvPmethvnamino1carbonvn-4-methvI-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetate a) Methyl (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate A mixture of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-10 1,4-benzodiazepine-2-acetate (584 mg, 2 0 mmol), 2-(aminomethyl)imidazole (2 2 mmol, prepared according to Annalen 1968, 718,249), HOBT H2O (270 mg, 2 mmol), tnethylamine (10 mL, 7 2 mmol), and EDC (383 mg, 2 mmol) in anhydrous DMF (40 mL) was stirred at RT overnight The reaction was concentrated in vacuum, and the resulting residue was diluted with 5% K2CO3 CH2CI2 extraction, 15 drying (MgS04), and concentration gave the title compound (0 76 g, 86%) MS (ES) m/e 372 (M+H)+ b) (±)-7-[[[(2-Imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid The compound of Example 23(a) (0 7 g, 1 6 mmol) was suspended in MeOH (10 mL) and THF (5 mL), and 10N NaOH (6 mL) was added The reaction was stirred at RT for 2 d, then was concentrated in vacuum The residue was diluted with H20, and the pH was adjusted to 5 to 6 with 1.5 N HCl Lyophilization gave the title compound* MS (ES) m/e 358 (M+H)+ Anal Calcd for C17H19N5O4 1 75 25 CF3CO2H C, 44 21, H, 3 75, N, 12 57 Found C, 44 21, H, 3 96, N, 12 54 Example 24 Preparation of (±)-7-nT2-(benzimidazolvDmethvnmethvlaminolcarbonvn-4-f2-methoxvethvl)-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid 30 a) Methyl (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate EDC (138 mg, 0 72 mmol) was added to a solution of methyl (±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (202 mg, 0 6 mmol), 2-(methylaminomethyl)benzimidazole dihydrochlonde (0 72 mmol), 35 HOBt H2O (97 mg, 0 72 mmol), and dnsopropylethylamine (0 42 mL, 2 4 mmol) m anhydrous DMF (3 mL) at RT The reaction was stirred at RT for 22 5 h, then 103 was concentrated on the rotavap The residue was reconcentrated from xylenes (to remove DMF), then was diluted with H2O (2 mL) CHCI3 extraction, drying (MgSC>4), concentration, and chromatography on silica gel (5% MeOH/CHCl3) gave the title compound (265 7 mg, 92%) as an off-white solid TLC Rf (5% 5 MeOH/CHCl3) 0 39, ^H NMR (400 MHz, CDCI3) 8 7 68-7 82 (m, J H)v 7 37-7 51 (m, IH), 7 15-7 35 (m, 4H), 6 45-6 57 (m, IH), 5 38 (d, J=16 5 Hz, IH), 5 04-5 14 (m, IH), 4 82 (1/2 AB, J=14 6 Hz, IH), 4 74 (1/2 AB, J=14 6 Hz, IH), 4 53 (d, J=5 0 iJz, IH), 3 99 (d, J=16 5 Hz, IH), 3 74 (s, 3H), 3 65-3 83 (m, IH), 3 37-3 61 (m, 3H), X22 (s, 3H), 3 15 (s, 3H), 2 98 (dd, J=16 0, 6 2 Hz, IH), 2 68 (dd, J=16 0, 10 6 7 Hz, IH), MS (ES) m/e 480 2 (M+H)+, 319.0 (M+H -161)+ b) (±)-7-[[[2-(Benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid 10N LiOH (0 66 mL, 0 66 mmol) was added to a solution of methyl (±)-7-15 [[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3.4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate (265 7 mg, 0 55 mmol) in THF (2 8 mL) and H2O (2 1 mL) at RT The hght yellow solution was stirred at RT for 17 h, then was concentrated to dryness on the rotavap. The residue was dissolved in H2O (2 mL), and the solution was neutralized with 1 0 N HCl (0 66 mL) The sohd 20 precipitate was collected by suction filtration and recrystallized from H2O/CH3CN to afford the title compound (147.0 mg, 55%) HPLC (PRP-l®, 15% CH3CN/H20-0 1% TFA) K'=4 3, !H NMR (400 MHz, DMSO-d^) 5 7 59 (d, J=7 6 Hz, IH), 7 47 (d, J=7 1 Hz, IH), 7 08-7 25 (m, 4H), 6 53 (d, J=8 2 Hz, IH), 6 13-6 26 (m, IH), 5 42 (d, J=16 3 Hz, IH), 5 00-5 12 (m, IH), 4 70-4 86 (m, 2H), 3 88-4 03 (m, IH), 25 3 44-3 60 (m, 2H), 3 22-3 '0 (m, 2H), 3 33 (s, 3H), 3 08 (s, 3H), 2 76 (dd, J=16 7, 8 8 Hz, IH), 2 53 (dd, J=16 7, 5 1 Hz, 1 H, partially obscured by residual solvent signal), MS (ES) 466 2 (M+HH, 305 0 (M+H -161)+ Anal Calcd for C24H27N5O5 H20 C, 59 62, H, 6 04, N, 14 48 Found C, 59 62, H, 6 18, N, 1446 Example 25 Preparation of (±)-7-nT2-(4-Azabenzimidazolvl)methvnmethvlaminolcarbonvn-4- (2-methoxvethvlV 3-OXO-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetic acid WO 96/00730 PCT/US95/08306 a) Methyl (±)-7-[[[2-(4-azabenzimidazolyl)methyl]metbylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate EDC (115 mg, 0 60 mmol) was added to a solution of methyl (±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate 5 (168 2 mg, 0.50 mmol), 4-aza-2-(methylaminomethyl)benzimidazole (0 62 mmol), HOBt H2O (81 mg, 0 60 mmol), and dusopropylethylamine (017 mL, 1.0 mmol) in anhydrous DMF (2 5 mL) at RT The reaction was stined at RT for 20 h, then was concentrated on the rotavap, and the residue was diluted with H2O (2 mL) CHCI3 extraction (3x5 mL), drying (MgS04), concentration, and reconcentration 10 from xylenes (to remove DMF) left a light yellow oil Chromatography on silica gel (10% MeOH/CHCl3) gave the tide compound (225 4 mg, 94%) as a colorless foam TLC Rf (10% MeOH/CHCl3) 0 39, >H NMR (400 MHz, CDC13; two components, data for the major component only 8 8 37-8 47 (m, IH), 7 98-8 06 (m, IH), 7 17-7 37 (m, 3H), 6 43-6 57 (m, IH), 5 38 (d, J=16 6 Hz, IH), 5 04-5 13 (m, IH), 4.85 15 (1/2 AB, J=14 7 Hz, IH), 4 78 (1/2 AB, J=14 7 Hz, IH), 4 53 (d, J=4 9 Hz, IH), 4 00 (d, J=16 6 Hz, IH), 3 74 (s, 3H), 3 65-3 81 (m, IH), 3 35-3 61 (m, 3H), 3 23 (s, 3H), 3 16 (s, 3H), 2 98 (dd, J=15 9,6 2 Hz, IH), 2 68 (dd, J=15 9, 6 7 Hz, IH), MS (ES) m/e 503 2 (M+Na)+, 481 2 (M+H)+, 319 0 (M+H - 162)+ b) (±)-7-[[[2-(4-Azabenzimidazolyl)methyl]methylamino]carbonyl]-4-(2-rnethoxyethyl)-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetic acid 1 0 N LiOH (0 56 mL, 0 56 mmol) was added to a solution of methyl (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxy(>thyl)-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (225 4 mg, 0 47 mmol) in 25 THF (2 4 mL) and H2O (18 mL) at RT The solution was stined at RT for 16.5 h, then was acidified with TFA (0 11 mL) and concentrated to dryness on the rotavap ODS chromatography (step gradient 12% CH3CN/H2O-O 1% TFA, then 20% CH3CN/H2O-O 1 % TFA), concentration to a small volume, and lyophilization gave the title compound (167.2 mg, 55%) as a light yellow powder HPLC (PRP-1®, 30 12% CH3CN/H2O-O 1% TFA) K'=2 7, *H NMR (400 MHz, DMSO-d6) 8 8 48 (d, J=4 9 Hz, IH), 8 22 (d, J=8 0 Hz, IH), 7 38-7 50 (m, IH), 7 15-7 30 (m, 2H), 6 54 (d, J=8.1 Hz, IH), 6 10-6 45 (m, IH), 5 43 (d, J=16.5 Hz, IH), 5 02-5 14 (m, IH), 4 82-4 99 (m, 2H), 3 95 (br d, J=16 5 Hz, IH), 3 44-3 63 (m, 2H), 3 23-3 40 (m, 2H), 3 13 (br s, 3H), 3 08 (s, 3H), 2 76 (dd, J=16 7, 8 8 Hz, IH), 2 53 (dd, J=16 7, 35 5 0 Hz, 1 H, partially obscured by residual solvent signal), MS (ES) m/e 467.2 105 / WO 96/00730 PCT/US95/08306 (M+H)+, 305 0 (M+H-162)+ Anal Calcd for C23H26N6O5 I5CF3CO2H 0 5 H20- C, 48 30, H, 4 44, N, 13 00 Found C, 48 09, H, 4 38, N, 12 95 Example 26 Preparation of (±V7-rfr2-f l-methvhndolvDmethvHmethvlaminolcarbonvH-4-methvl-3-oxo-2-3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetic acid a) Ethyl l-methylindole-2-carboxylate Iodomethane (4 98 mL, 80 mmol) was added dropwise to a mixture containing ethyl indole-2-carboxylate (1 89 g, 10 mmol) and sodium hydride (1.2 g, 10 60% dispersion, prewashed by hexane) in anhydrous THF (60 mL) in a flame dned flask under argon at 0°C. After 4 h at RT the reaction was concentrated on the rotavap The residue was taken into EtOAc and washed sequentially with H2O and saturated NaCl Drying (MgS04) and concentration gave the title compound (101 g, 50%) as a pale yellow sohd b) 1 -Methyl-2-(methylaminocarbonyl)indole A mixture of ethyl l-methylindole-2-carboxylate (4 06 g, 20 mmol) and methylanune (50 mL) was heated at 80°C in a sealed glass vessel overnight The reaction was cooled and the tide compound (2 4 g, 64%) was collected by filtration 20 as a colorless sohd MS (ES) m/e 189 0 (M+H)+ c) 1 -Methyl-2-(methylamino)methyhndole LAH (50 mL, 1M solution in THF) was added dropwise through a synnge to a solution of l-methyl-2-(methylaminocarbonyl)indole (2 33 g, 12 4 mmol) in 25 anhydrous THF (10 mL) with cooling, and the resulting solution was stirred at RT under argon overnight H2O was added dropwise with cooling to destroy excess LAH, and the colorless precipitate was removed by filtration and washed with THF The filtrate was dned (K2CO3), concentrated, and punfied by silica gel flash chromatography to afford the title compound (430 mg, 20% yield) as a yellow sohd 30 MS (ES) m/e 175 (M+H)+ d) Methyl (±)-7-[[[2-( 1 -methyhndolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate EDC (508 mg, 2 65 mmol) was added to a solution of methyl (±)-7-carboxy-35 4-methyl-3-oxo-2,3,4,5-. .ahydro-1H-1,4-benzodiazepine-2-acetate (774 mg, 2 65 mmol), l-methyl-2-(methylamino)methylindole (420 mg, 2 41 mmol), HOBT H2O 106 (358 mg, 2 65 mmol) and diisopropylethylamme (0 54 mL, 2 89 mmol) in anhydrous DMF (10 mL) at RT After 20 h the reaction was concentrated on the rotavap (high vacuum) The residue was taken up in EtOAc and washed sequentially with H2O (3 x 30 mL) and 10% Na2C03 (2 x 30 mL) Drying (MgS04), concentration, and silica 5 gel chromatography (1% MeOH/CH2Cl2) gave the title compound (809 mg, 75%) as a white solid MS(ES) m/e 449 2 (M+H)+ e) i±)-7-[[[2-(l-Methylindolyl)methyl]methylaimno]carbonyl]~4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetic acid 10 1.0 N NaOH (2 mL, 2 mmol) was added dropwise to a solution of methyl (±)-7-[[[2-(l-methylindolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetate (600 mg, 1 34 mmol) in MeOH (10 mL) at RT The resulting mixture was stirred for 20 h then was concentrated The residue was dissolved in H2O (10 mL) and acidified with 10N HCl with cooling 15 The precipitated solid was collected by filtration to give the title compound (400 mg, 69%) as a white solid MS (ES) m/e 435 2 (M+H)+ Anal Calcd for C24H26N4O4 0 75 H20 C, 64 34, H, 6 19, N, 12 51 Found C, 64 16, H, 6 13, N, 12 50 Example 27 Preparation of (±)-7-rfT2-(l-methvlindolvl)methvllamino1carbonvn-4-methvl-3-oxo-2.3 4.5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) l-Methyhndole-2-carboxamide A mixture of ethyl l-methylmdole-2-carboxylate (5.9 g, 29 mmol) and ammonium hydroxide (50 mL) was heated at 80°C in a sealed glass vessel overnight 25 The reaction was cooled and the title compound (2 2 g, 44%) was collected by filtrauon as a colorless solid MS (ES) m/e 175 0 (M+H)+ b) 1-Methyl- 2-(aminomethyl)indole Following the procedure of Example 26(c), except substituting 1-30 methylindole-2-carboxamide for l-methyl-2-(methylaminocarbonyl)mdole, the title compound (86%) was obtained as a yellow brownish sohd MS (ES) m/e 161 0 (M-i-H)+ 107 c) Methyl (±)-7-[[[2-(l-methyhndolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate Following the procedure of Example 26(d), except substituting l-methyl-2-(aminomethyl)indole for the l-methyl-2-(methylamino)methylindole, the title 5 compound (50%) was prepared MS (ES) m/e 435 2 (M+H)+ d) (±)-7-[[[2-(l-Methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahy dro-1H-1,4-benzodiazepine-2-acetic acid Following the procedure of Example 26(e), methyl (±)-7-[[[2-(l-10 methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l ,4-benzodiazepine-2-acetate was saponified to give the title compound as a colorless sohd MS (ES) m/e 358 (M+H)+ Anal. Calcd for C23H24N4O4 3 HCl 0 875 H20 C, 50 63, H, 5 31, N, 10 26 Found C, 51 00, H, 5 02, N, 9 89 Example 28 Preparation of 7-rrr(2RS-indohnvl')methvnaminolcarbonvll-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2S-acetic acid a) Methyl (±)-indoline-2-carboxylate Thionyl chlonde (2 86 mL, 39 mmol) was added to a solution of (±)-indohne-2-20 carboxyhc acid (4.26 g, 26 mmol) in methanol (30 mL) at 0°C The resulting mixture was stirred at RT for 18 h The solvent was removed in vacuo and the residue was taken into CH2CI2 and washed sequentially with H2O and saturated NaCl Drying (MgSC>4) and concentration gave the title compound (4 31 g, 94% ) as a pale yellow oil b) (±)-Indohne-2-carboxamide Gaseous NH3 was bubbled into a solution of methyl (±)-mdolme-2-carboxylate (4 3 g, 24 2 mmol) in methanol (50 mL) at RT for 30 nun The reaction was stirred for 18 h, then was filtered to afford the title compound (3 35 g 85%) as a 30 colorless sohd MS (ES) m/e 163 0 (M+H)+ c) (±)-2-(Aminomethyl)indohne LAH (20 mL, 1M solution in THF) was added dropwise through a synnge to a solution of (±)-indohne-2-carboxamide (2 2 g, 13 6 mmol) in anhydrous THF (20 35 mL) with cooling, and the resulting solution was refluxed under argon for 5 h More LAH (20 mL) was added, and reflux was continued for another 6 h 10% aqueous 108 THF was added dropwise with cooling to destroy excess LAH, and then Et20 was added After stirring for 10 min, the colorless precipitate was removed by filtration and washed with THF The filtrate was dned (K2CO3), concentrated, and punfied by silica gel flash chromatography (90 10 0 2 C^C^/MeOH/^N). The title 5 compound (1.02 g, 51 %) was obtained as an amber oil MS" (ES) m/e 149 0 (M+H)+ d) Methyl 7-[[[(2RS-indolinyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2S-acetate Following the procedure of Example 26(d), except substituting (±)-2- (aminomethyl)indoline for the l-methyl-2-(methylamino)methylindole, the title compound (44%) was prepared MS (ES) m/e 423 0 (M+H)+ e) 7-[[[(2RS-Indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-15 1H-1,4-benzodiazepme-2S-acetic acid Following the procedure of Example 26(e), methyl 7-[[[(2RS-indolinyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2S-acetate was saponified to give the title compound as a colorless sohd MS (ES) m/e 409 2 (M+H)+. Anal Calcd for C22H24N4O4 1 HCl 0.5 H20 20 C, 58 21, H, 5 77, N, 12.34 Found C, 58 36, H, 5 56, N, 12 26 Example 29 Preparation of (±1-7-rrr(2-imidazolvl')methvnanunolcarbonvll-3-oxo-4-(2-phenvlethvlV2.3.4.5-tetrahvdro-lH-l.4-benzodiazepme-2-acetic acid 25 a) Methyl (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate Methyl (±)-7-carboxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (400 mg, 1 04 mmol) was suspended in anhydrous toluene (5 mL), then thionyl chlonde (3 mL) was added and the reaction mixture was heated 30 to reflux for 1 5 h The solvent was then eliminated and more toluene was added (2 x 5 mL) and then distilled off The acid chlonde thus obtained was dissolved in dry DMF (8 mL) and diisopropylethylamme (506 mg, 3 9 mmol), DMAP (12 2,0 1 mmol) and 2-(aminomethyl)imidazole dihydrochlonde (222 mg, 1 3 mmol) were added The reaction mixture was allowed to stir at RT overnight, then the solvent 35 was removed under vacuum The residue was punfied by silica gel flash column chromatography (95% CH2Cl2/5% methanol) to produce the title compound (120 109 mg, 26%) *H NMR (CDCI3,400 MHz) 6 2 62 (dd, J=16 2, 6 2 Hz, IH), 2 76 (m, 2H), 2 94 (dd, J=16 2, 7 4 Hz, IH), 3 6-3 71 (m, 3H), 3 70 (s, 3H), 4 45 (s, 2H), 5 02 (dd, J=7.2, 6 4 Hz, IH), 5 27 (d, J=16 6 Hz, IH), 6 47 (d, J=8 5 IH), 6 89 (s, 2H), 7 06-7 16 (m, 5H), 7 31 (br s, IH), 7 49 (d, J=8 5 Hz, IH) b) (±)-7-[[[(2-Imidazolyl)methyl]aimno]carbonyl]-3-oxo-4-(2-phenyIethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid LiOH (16 mg, 0 38 mmol) was added at RT to a solution of methyl (±)-7-[[[(2-imidazolyl)methyl]anuno]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-10 tetrahydro-lH-l,4-benzodiazepine-2-acetate (98 mg, 0 21 mmol) in dioxane (3 mL) and H2O (3 mL) The reaction mixture was heated at 65°C for 3 h then the organic solvent was removed in vacuo The aqueous residue was acidified with 1M HCl solution (0 38 mL) to obtain a white sohd which was filtered, dissolved in hot methanol, and precipitated with ether The thus obtained white solid was collected 15 to yield the title compound (72 mg, 78%) *H NMR (DMSO-dg, 400 MHz) 5 2.59 (dd, J=16 2,5 0 Hz, IH), 2 77 (dd, J=7 7, 6 8 Hz, 2H), 2 92 (dd, J=16 5, 8 8 Hz, IH), 3 63-3 75 (m, 2H), 3 79 (d, J =16 5 Hz, IH), 4 61 (s, 2H), 5 13 (dd, J=8 8,5 0 Hz, IH), 5 45 (d, J=16 5 Hz, IH), 6 57 (d, J=8.6 Hz, IH), 7 07 (s, 2H), 7 10-7 19 (m, 5H), 7 41 (s, IH), 7 54 (d, J=8 4 Hz, IH) MS (ES) m/e 448 (M+H)+ Anal 20 Calcd for C24H25N5O4 H2O C, 61 92, H, 5 85, N, 15 04 Found C, 61 69, H, 5 60, N, 14 86 Example 30 Preparation of (±V7-nT(2-benzimidazolvl')methvnamino'lmethvn-4-methvl-3-oxo-25 23.4.5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Methyl (±)-7-formyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (180 mg, 0 65 mmol) (prepared as in Example 14(b)) was 30 suspended in anhydrous methanol, then sodium acetate (160 mg, 1 95 mmol), 2-(amino methyl)benzimidazole dihydrochlonde (143 mg, 0 65 mmol) and 4 A molecular sieves were added After 30 min , sodium cyanoborohydnde (45 mg, 0 71 mmol) was added m 2 portions over a period of 30 mm The reaction mixture was allowed to stir at RT overnight, then the methanol was removed under vacuum 35 The residue was diluted with CH2CI2, and the solution was washed with saturated NaHCC>3 Drying (MgS04), concentration, and silica gel chromatography (90% 110 CH2Cl2/9% methanol/1% NEt3) gave the title compound (133 mg, 49%) *H NMR (CDCI3,400 MHz) 5 2 67 (dd, J=16 1, 6 1 Hz, IH), 2 96 (dd, J=16 1,6 8 Hz, IH), 3 05 (s, 3H), 3 68 (d, J=16 4 Hz), 3 72 (br s, 2H), 3 75 (s, 3H), 4 11 (br s, 2H), 4 97 (dd, J=6 8 Hz, 6 1, IH), 5 35 (d, J=16 4 Hz, IK), 6 54 (d, J=8 1 Hz, IH), 6 87 (s, 5 IH), 7 05 (d, J=8 2 Hz, IH), 7 20-7 26 (m, 2H), 7 57 (m, 2H), MS(ES) m/e 408 (M+H)+ b) (±)-7-[[[(2-Benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo-2,3,4,5-tetrahy dro-1H-1,4-benzodiazepine-2-acetic acid 10 LiOH (14 6 mg, 0 34 mmol) was added at RT to a solution of methyl (±)-7- [[[(2-benzimidazolyl)methyl]anuno]methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (133 mg, 0 31 mmol) in dioxane (3 mL) and H20(l mL) The reaction mixture was stirred at RT overnight then the organic solvent was removed in vacuo The aqueous residue was acidified with 1M HCl solution (0 38 15 mL) to obtain a white solid which was punfied by ODS chromatography (10% acetonitnle/H2O-0 1% TFA) to afford the title compound (65 mg, 51%) *H NMR (DMSO-d6,400 MHz) 5 2 51 (m, IH), 2 73 (m, IH), 2 91 (s, 3H), 3 69 (bs, 2H), 3 76 (d, J=16 6 Hz, IH), 3 97 (br s, 2H), 4 97 (m, IH), 4 45 (d, J=16 6 Hz, IH), 5 77 (m, IH), 6 52 (d, J=8 1 Hz, IH), 6 97 (s, IH), 7 02 (d, J=8 1 Hz, IH), 7.20 (m, 20 2H), 7 52 (m, 2H), MS (ES) m/e 394 (M+H)+ Anal Calcd for C2iH23N503 2 CF3CO2H H2O C, 46 95, H, 4 26, N, 10 95 Found C, 46 81, H, 4 00; N, 84 Example 31 Preparation of (±)-7-nT(2-benzimidazolvl)methvl]ammo1carbonvn-1.4-dimethvl-3-oxo-2.3.4.5-tetrahvdro-lH-l .4-benzodiazepme-2-acetic acid a) Methyl (±)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-l ,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1 H-l ,4-benzodiazepme-2-acetate Following the procedure of Example 2(a), except substituting methyl (±)-7-30 carboxy-1,4-dimethyI-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate for the methyl (±)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-lH-l,4~ benzodiazepme-2-acetate, the title compound was prepared (60%) MS (ES) m/e 435 (M+H)+, JH NMR (250 MHz, CDCI3) 5 9 82 (m, IH), 7 81 (d, J=7 9 Hz, IH), 7 62 (s, IH), 7 5 (m, 2H), 7 22 (m, 2H), 6 79 (d, J=7 9 Hz, IH), 5 09 (d, J=16 6 Hz, 35 IH), 4 76-5 01 (m, 3H), 3 61 (s, 3H), 3 59 (d, J=16 6 Hz, IH), 3 1 (m, IH), 2 90 (s, 3H), 2 81 (s,3H), 2 65 (m, IH) 111 FCT/US95/08306 b) (±)-7-[[[(2-Benzimidazolyl)methyl]anuno]carbonyI]-l,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid A solution of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-l,4-5 dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate (0 080 g, 0 18 mmol) m a mixture of methanol (10 mL), water (10 rnL) and 1 0 M NaOH (0 75 mL) was heated at 50°C for 2 h, cooled to RT, and evaporated to diyness The residue was dissolved in water (5 0 mL) and the solution acidified to pH 5 with 0 25 N HCl to precipitate the title compound (55%) MS (ES) m/e 422 (M+H)+, Anal 0 Calcd for C22H23N5O4 2 3H20 C, 57 09, H, 6 01, N, 15 13 Found C, 57 29, H, 5 79, N, 14 82 *H NMR (400 MHz, DMSO-d6) 5 8 93 (br t, J=5 6 Hz, IH), 7 78 (d, J=8 4 Hz, IH), 7 73 (s, IH), 7 49 (m, 2H), 7 12 (m, 2H), 6 98 (d, J=8 4 Hz, IH), 5 30 (d, J=16 6 Hz, IH), 4 85 (m, IH), 4 68 (d, J=5 4 Hz, 2H), 4 10 (d, J=16 6 Hz, IH), 2 98 (s, 3H), 2 92 (m, IH), 2 80 (s, 3H), 2 60 (dd, J=16 7, 8 9 Hz, IH) Example 32 Preparation of (±V7-rrr(2-benzimidazolvl')methvnmethvlaminolcarbonvll-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid a) Methyl (±)-7-[[[(2-benzimidazolyl)methyl]methyIamino]carbonyl]-3-oxo-0 2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate Following the procedure of Example 15(b), except substituting methyl 7-carboxy-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate for the methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate, the crude title compound was prepared Chromatography (silica gel, 7% 5 MeOH/CH2Cl2) yielded the title compound (35%) MS (ES) m/e 422 2 (M+H)+ !H NMR (400 MHz, CDCI3) 5 7 45 (m, IH), 7 38 (m, 4H), 7 15 (d, J=8 4 Hz, IH), 6 90 (s, IH), 6 50 (d, J=8 4 Hz, IH), 5 35 (s, 3H), 4 95 (m, IH), 4 65 (m, IH), 3 71 (s, 3H), 3 65 (m, IH), 3 48 (s, 3H), 3 07 (m, IH), 2 75 (dd, J=16 4, 8 4 Hz, IH) 3 b) (±)-7-[[[(2-Benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid A solution of methyl (±)-7-[[[(2-benzimidazolyl)methyI]methylamino]carbonyI]-3-oxo-2,3,4,5-tetrahydro-lH-l,4-5 benzodiazepine-2-acetate (0 040 g, 0 09 mmol) in a mixture of methanol (7 0 mL), water (0 7 mL), and 1 0 M NaOH (0 7 mL) was kept 16 h at RT Tnfluoroacetic 112 acid (0 5 mL) was added and the solvents were removed to give the crude product Purification by semi-preparative HPLC (YMC ODS-AQ, 15 85, acetonitnle water, 0 1% TFA) gave the title compound MS (ES) m/e 408 2 (M+H)+, *H NMR (250 MHz, DMSO-d6) 5 8 19 (br t, J=4 5 Hz, IH), 7 72 (m, 2H), 7 38 (m, 2H), 7.28 (d, 5 J=8 4 Hz, IH), 7 15 (s, IH), 6 62 (d, J=8 4 Hz, IH), 6 22 (br s, IH), 5 05 (m, IH), 4 95 (s, 2H), 3 74 (dd, 15 8, 7 4 Hz, IH), 3 15 (s, 3H), 2 75 (dd, J=16 4,8 5 Hz, IH), 2 50 (m, IH) Example 33 Preparation of (2S)-7-[TrN-butvl-N-benzimidazol-2-vI)methvnamino1carbonvll-3-oxo-4-methvl-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetic acid a) N-BOC-2-methylbenzimidazole To a stined mixture of 2-methylbenzimidazole (15 g, 113 5 mmol), tnethylamine (12 g, 119 2 mmol), and DMAP (cat) in dry CH2CI2 (150 mL) was 15 added (Boc)20 After 2i h, the mixture was concentrated The residue was taken up in H2O, stirred and filtered to give a white solid (26 3 g, 100%) mp 71-72°C, *H NMR (250 MHz, CDCI3) 6 1 71 (s, 9H), 2 83 (s, 3H), 7 29 (m, 2H), 7.65 (m, IH), 7 91 (m, IH) b) l-BOC-2-bromomethylbenzimidazoIe Following the procedure in Example 4(a), except substituting N-BOC-2-methylbenzimidazole for 2-methylbenzothiazole, the title compound was prepared as a yellow oil (12 88 g, 77%) JH NMR (250 MHz, CDCI3) 5 1 79 (s, 9H), 4 95 (s, 2H), 7 40 (m, 2H), 7 75 (m, IH), 8 01 (m, IH) c) 2-( 1 -Butylaraino)methylbenzimidazole To a stirred solution of l-BOC-2-bromomethylbenzimidazole (2 00 g, 6 4 mmol) in dry THF (20 mL) was added n-butylamine (1 2 g, 15 4 mmol) After stimng at RT overnight, the mixture was concentrated The residue was taken up m 30 H2O and extracted with CH2CI2- The organic extracts were dned over MgSC>4 and concentrated to give a brown residue, which was dissolved in CH2CI2 (15 mL) and treated with TFA (5 mL) The resulting mixture was stirred at RT overnight then was concentrated The residue was taken up in H2O, and the solution was neutralized with 2 5 N NaOH CH2CI2 extraction, drying (MgS04), concentration, 35 and silica gel chromatography (2% MeOH/CH2Cl2) gave the title compound as a yellow oil (0 91 g, 70%) »H NMR (250 MHz, CDCI3) 8 0 79 (t, J=7 2 Hz, 3H), 113 1 23 (m, 2H), 1 54 (m, 2H), 3 35 (t, J=7 2 Hz, 2H), 4 55 (s, 2H), 7 25 (m, 2H), 7 48 (m, IH), 7 75 (m, IH) d) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-(n-butyl)]amino]carbonyl]-4-5 methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate To a stirred mixture of 2-(l-butylamino)methylbenziixudazole (0 14 g, 0 6671 mmol), methyl (S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (0 15 g, 0 5132 mmol), HOBT H2O (0 083 g, 0 6158 mmol), and (i-Pr)2NEt (0 133 g, 1 0263 mmol) in dry MeCN (5 mL) was added 10 EDC (0 183 g, 0 6158 mmol) After stimng at RT overnight, the mixture was concentrated The residue was taken up in H2O and extracted with CH2CI2 The combined organic layers were washed sequentially with saturated NaHC03 and bnne, then were dned (MgS04) and concentrated to give the title compound as a yellow foam (0 232 g, 95%) >H NMR (250 MHz, CDCI3) 5 0 79 (t, J=7 2 Hz, 3H), 15 1 23 (m, 2H), 1 54 (m, 2H), 2 54 (dd, J=16 8 Hz, 5 0 Hz, IH), 2 75 (dd, J =16 8 Hz, 8 9 Hz, IH), 2 86 (s, 3H), 3 32 (t, J=7 2 Hz, 2H), 3 60 (s, 3H), 3 72 (d, J=16 1 Hz, IH), 4 75 (s, 2H), 5 05 (m, IH), 5 48 (d, J= 16 1 Hz, IH), 0 20 (d, J =3 6 Hz, IH), 6 55 (d, J=8 9 Hz, IH), 7 16 (m, 4H), 7 53 (m, 2H) e) (S)-7-[[[N-(2-Benzimidazolyl)methyl-N-(n-butyl)]amino]carbonyl]-4-u sthyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-aceUc acid Following the procedure in Example 11(b), methyl-(S)-7-[[[N-(2-benzimidazolyI)methyl-N-(n-butyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetate was saponified to give an off white 25 solid Trituration in hot EtOH gave the title compound as a white solid (0 15 g, 60%) mp 160-162°C (dec), lH NMR (400 MHz, DMSO-d6) 5 0 79 (t, J=7 2 Hz, 3H), 1 23 (m, 2H), 1 54 (m, 2H), 2 54 (dd, J=16 8 Hz, 5 0 Hz, IH), 2 75 (dd, J =16 8 Hz, 8 9 Hz, IH), 2 86 (s, 3H), 3.32 (t, J=7 2 Hz, 2H), 3 72 (d, J=16 1 Hz, IH), 4 75 (s, 2H), 5 05 (m, IH), 5 48 (d, J= 16 1 Hz, IH), 6 20 (d, J =3 6 Hz, IH), 6 55 (d, 30 J=8 9 Hz, IH), 7 16 (m, 4H), 7 53 (m, 2H), MS (ES) m/e 464 (M+H)+; IR (KBr) 3400,3000-3100,2800-3100,1712, 1671, 1655,1630, 1611, 1271, 828 cm-1 Anal Calcd for C25H29N5O4 0 75 H2O C, 62 95, H, 6 44, N, 14 68 Found C, 62 75, H, 6 40, N, 14 41 114 Example 34 Preparation of fS)-7-[TfN-f2-ben7'miHa7n1v0methvl-N-('2-phenvlethvD1aminolcarbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetic acid 5 a) 2-(2-Phenylethylamino)methylbenzimidazole Following the procedure of Example 33(c), except substituting 2-phenylethylamine for n-butylamine, the tide compound (0 100 g, 31%) was prepared as a brown oil following silica gel flash chromatography (5% MeOH/CH2Cl2) !H NMR (250 MHz, CDCI3) 5 2 82 (t, J=7 5 Hz, 2H), 2 97 (t, J=7.5 Hz, 2H), 4 10 (s, 10 2H), 7.21 (m, 5H), 7 35 (m, 2H), 7 52 (m, 2H) b) Methyl £S)-7-[[[N-(2-benzimidazoIyl)methyl-N-(2-phenylethyl)]ammo]carbonyl]-4-me±yl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate 15 Following the procedure of Example 33(d), except substituting 2-(2- phenylethylamino)methylbenzunidazole for 2-(l-butylamino)methylbenzimidazole, the title compound (0 195 g, 97%) was prepared as an off-white foam following silica gel flash chromatography (2-5% MeOH/CH2Cl2) *H NMR(250 MHz, DMSO-d6) 5 2 54 (dd, J= 16 5,5 0 Hz, IH), 2.75 (dd, J=16 5, 8.9 Hz, IH), 2 85 (s, 20 3H), 2 90 (t, J=7 5 Hz, 2H), 3 60 (t, J=7.5 Hz, 2H), 3 65 (s, 3H), 3 78 (d, J=16 3 Hz, IH), 4 78 (s, 2H), 5 05 (m, IH), 5 42 (d, J=16 3 Hz, IH), 6 18 (d, J=3 5 Hz, IH), 6 54 (d, J=8 9 Hz, IH), 7 10 (m, 7H), 7 26( m, 2H), 7 48 (m, IH), 7 60 (m, IH), 12 30 (s, IH) c) (S)-7-[[[N-(2-BenzimidazoIyl)methyl-N-(2-phenylethyl)]amino]carbonyl]~4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetic ac»d Following the procedure of Example 11(b), methyl (S)-7-[[[N-(2-benzimidazolyi)methyl-N-(2-phenylethyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate was saponified Recrystallization from 30 EtOH gave the title compound (0 070 g, 40%) as an off white sohd MS (ES) m/e 512 (M+H)+, IR (KBr) 3300-3500, 3000-3100, 2800-300, 1631, 1647,1652,1618, 1405,698 cm*1 Anal Calcd for C29H29N5O4 2 5 H2O C, 62 58, H, 6 16, N, 12 58 Found C, 62 92, H, 6 02, N, 12 28 115 Example 35 Preparation of (S V7- ITfN-f 2-benzimidazolvl') methvl-N-carfaoxvmethvnamino'!carbonvl]-4-methvl-3-oxo-2.3.4.5-tetrahvdro-lH-1.4-benzodiazepme-2-acetic acid a) N-[(2-Benzimizazolyl)methyl]glycine benzyl ester Following the procedure in Example 33(c), except substituting glycine benzyl ester HCl for n-butylamine, the title compound (1 00 g, 60%) was prepared as an off white sohd *H NMR (250 MHz, CDCI3) 5 3 86 (s, 2H), 4 31 (s, 2H), 5 23 (s, 2H), 7.23 (m, 5H), 7 35 (m, 2H), 7.55 (m, 2H) b) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyI-N- (benzyloxycarbonyl)methyl]ammo] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate Following the procedure in Example 33(d), except substituting N-[(2-15 benzimizazolyI)methyl]glycine benzyl ester for 2-( 1 - butylamino)methylbenzimidazole, the title compound (0 95 g, 81%) was prepared as a yellow foam. *H NMR (250 MHz, CDCI3) 5 2 54 (dd, J=16 5,3.5 Hz, IH), 2 75 (dd, J=16 5,8 9 Hz, IH), 2.87 (s, 3H), 3 65 (s, 3H), 3 78 (d, J=16 3 Hz, IH), 4.30 (s, 2H), 4 86 (s, 2H), 5.05 (m, IH), 5 23 (s, 2H), 5 45 (d, J=16.3 Hz, IH), 6 55 (d, 20 J=8 9 Hz, IH), 7 10 (m, 2H), 7 23 (m, 5H), 7 55 (m, 2H), 7.81 (m, 2H) c) Methyl-(S)-7-[[[N-(2-benzimidazolyI)methyl-N-carboxymethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-IH-1,4-benzodiazepme-2-acetate A solution of methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N- (benzyloxycarbonyl)methyI]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-l,4-benzodiazepme-2-acetate (0 185 g, 0 333 mmol) in methanol (5 mL) was hydrogenated over 10% Pd/C at RT overnight The catalyst was removed by filtration through Celite®, and the filtrate was concentrated to give a yellow foam 30 Trituration with acetone gave the title compound (0 140 g, 90%) as an off white sohd IH NMR (250 MHz, CDCI3) 5 2 54 (dd, J=16 5,3 5 Hz, IH), 2 75 (dd, J=16 5, 8.9 Hz, IH), 2 87 (s, 3H), 3 65 (s, 3H), 3 78 (d, J=16 3 Hz, IH), 4 86 (s, 2H), 5 05 (m, IH), 5.23 (s, 2H), 5 45 (d, J=16 3 Hz, IH), 6 55 (d, J=8.9 Hz, IH), 7.10 (m, 2H), 7 55 (m, 2H), 7 81 (m, 2H) 116 PCT/CS95/G8306 d) (S)-7-[f[N-(2-Benzimidazolyl)methyl-N-carboxymethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IK-1,4-benzodiazepine-2-acetic acid A solution of Example 35(b) in methanol (5 mL) was hydrogenated at RT m 10% Pd/C overnight The catalyst was filtered through Cehte The filtrate was 5 concentrated to give a yellow foam which was tnturated m acetone to give the utle compound as an off white sohd (0.140 g, 90%)- MS (ES) m/e 465 (M+H)+ Anal Calcd for C23H23N5O6 12H2O C, 56 92, H, 5 26, N, 14 38 Found C, 57.09, H, 5 33, N, 14 00 Example 36 Preparation of (SV7-rrrN-(2-benzimidazolvl)methvl-N-cvclohexvllaminolcarbonvn-4-methvI-3-oxo-2.3.4.5-tetrahvdro-lF-l .4-benzodiazepme-2-acetic acid a) 2-(Cyclohexylamino)methylbenzL udazole Following the procedure of Example 33(c^, except substituting 15 cyclohexylarmne for n-butylanune, the tide compound (0 191 g, 52%) was prepared as a brown oil !H NMR (250 MHz, CDCI3) 5 1.35 (m, 4H), 1 75 (m, 4H), 2 21 (m, 2H), 2.78 (m, IH), 4 31 (s, 2H), 7 21 (m, 2H), 7 51 (m, 2H). b) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-cyclohexyl]ammo]carbonyl]-4-20 methyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-ben^ .xhazcpine-2-acetate Following the procedure of Example 33(d), except substituting 2-(Cyclohexylamino)methylbenzimidazole for 2-(l-butylanuno)methylbenzimidazole, the title compound (0 174 g, 50%) was prepared as a yellow foam 'H NMR (250 MHz, CDCI3) 5 1 15 (m, 4H), 1.60 (m, 4H), 1 85 (m, 2H), 2 65 (dd, J=16.5, 3 5 Hz, 25 IH), 2 98 (dd, J=16 5, 8 9 Hz, IH), 3 07 (s, 3H), 3 71 (d, J=16 3 Hz, IH), 4 48 (d, J=3 5 Hz, IH), 4 67 (s, 2H), 5 10 (m, IH), 5 47 (d, J=16 3 Hz, IH), 6.51 (d, J=8 9 Hz, IH), 7 15 (m, 3H), 7 22 (m, 2H), 7 31 (m, IH), 7 65 (m, IH) c) (S)-7-[[[N-(2-Benzimidazolyl)methyl-N-cyclohexyl]amino]carbonyl]-4-methyl-30 3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetic acid Following the procedure of Example 4(d), methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-cyclohexyl]ammo]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate was saponified The utle compound (0 100 g, 60%) was obtained as an off white sohd 'H NMR (400 MHz, DMSO-d6) 35 5 1 15 (m, 4H), 1.55 (m, 4H), 1 93 (m, 2H), 2 54 (dd, J=16 5, 3 5 Hz, IH), 2 78 (dd, J=16 5, 8 9 Hz, IH), 2 91 (s, 3H), 3 83 (d, J=16 3 Hz, IH), 3 85 (m, IH), 4 97 (s, 117 2H), 5 07 (m, IH), 5.48 (d, J=16 3 Hz, IH), 6 56 (d, J=8 9 Hz, IH), 7.20 (s, IH), 7 25 (d, J=8 9 Hz, IH), 7.50 (m, 2H), 7 82 (m, 2H); MS (ES) m/e 489 (M+H)+ Anal Calcd for C27H31N5O4 H2O C, 63 90, H, 6.55, N, 13 80 Found C, 63 91, H, 6 27, N, 13.60 Example 37 Preparation of (±)-7-rrr2-(5-nitrobenzimidazolvnmethvllmethvlaminolcarbonvll-4-methvl-3-oxo-2.3.4.5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) 2-[[N-(tert-Butoxycarbonyl)-N-methyl]anunomethyl]-5-nitrobenzuiudazoIe 10 BOC sarcosme (2 555 g, 13 51 mmol) was weighed into a dry 250 mL roundbottom flask, purged with argon The matenal was dissolved m dry THF (20 mL) Et3N (3 mL, 216 mmol) was added, followed by isobutylchlorofonnate (18 mL, 13 88 mmol) The reaction was stirred at RT under argon for 30 minutes, then was cooled to -20°C, and 4-mtrophenylenediamine (2 0423 g, 13 34 mmol) was 15 added as a sohd After the addition was complete, the cooling bath was removed and the reaction was allowed to warm to RT After 20 h, the reaction was concentrated under vacuum The matenal was dissolved in EtOAc and extracted with 10N NaHCOs The organic phase was dned (MgS04), filtered and concentrated under vacuum The residue was dissolved in glacial AcOH and heated 20 to 75 °C in an oil bath After 24 h, the reaction was concentrated under vacuum The residue was reconcentrated from toluene The matenal was flash chromatographed (silica gel, 1 2 CH2Cl2/Et20, 1 1 CH2Cl2/Et20,5% MeOH/CH2Cl2) to give the title compound (2 05 g, 51%) Both fractions had identical mass spectral data MS(ES) m/e 307 0 (M+H)+,1H NMR (250 MHz, CDCI3) 5 8 61-7 46 (m, 5H), 4 65 (s, 2H), 3 04 (s, 3H), 1 50 (S, 9H) b) 2-(Methylanuno)methyl-5-nitrobenzimidazole 2-[N-(tert-Butoxycarbonyl)-N-methyl]aminomethyl-5-nitrobenzinudazole (904 8 mg, 2 96 mmol) was treated with 4 N HCl m dioxane The reaction was stirred at RT for 1 h, then was concentrated under vacuum The yellow slurry was reconcentrated from toluene The residue was dned under high vacuum, leaving tne title compound (830 5 mg) as a light yellow solid This matenal was used without further punfication 118 c) Methyl (±)-7-[[[2-(5-mtrobenzimidazolyl)methyl]methylamino]cart>onyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate (5118 mg, 1 75 mmol) was weighed into a dry 200 mL 5 roundbottom flask. Dry DMF was added, followed by HOBt H2O (258 1 mg, 191 mmol) and EDC (351.5 mg, 1 83 mmol) The mixture was stirred at RT until all solids had dissolved, then a solution of 2-(methylamino)methyl-5-mtrobenzimidazole (492 5 mg, 1 76 mmol) and dnsopropylethylamine (1.0 mL, 5.74 mmol) in DMF was added at RT The reacuon was stirred at RT for 24 h then was 10 concentrated under vacuum. The residue was reconcentrated from toluene, then was chromatographed on silica gel (CHCI3 (0 25 L), then 3% MeOH/CHCl3 (1L), then 5% MeOH/CHCl3 (1L)) to afford the title compound (847 5 mg, quantitative) MS (ES) m/e 4810 (M+H)+ d) (±)-7-[[[2-(5-NitrobenZxmidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l 4-benzodiazepine-2-aceuc acid Methyl (±)-7-[[[?-f>- -obenzimidazolyl)methyl]methylaimno]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrai yaro-1H-1,4-benzodiazepine-2-acetate (386 3 mg, 0 080 mmol) was suspended in MeOH, and 10N NaOH (2 5 mL, 2 5 mmol) was added 20 The reaction was stirred at RT for 18 h, then was wanned in an oil bath set at 70°C After 4 h, the reacuon was cooled to RT and neutralized with 1 0 N HCl (2 5 mL) The solution was concentrated under vacuum After most of the MeOH had evaporated, a yellow precipitate formed The precipitate was collected on a sintered glass funnel and dned in a desiccator under vacuum to afford the utle compound 25 (317.3 mg, 85%) >H NMR (250 MHz, CDCI3) 5 8.55-6 60 (m, 6H), 5 50 (d, IK) „ 5 15 (dd, IH), 4 91 (s, 2H), 3 20 (s, 3H), 3 09 (s, 3H), MS (ES) m/e 467 2 (M+H)+ Anal Calcd for C22H22N6O6 HCl C, 52.54, H, 4 61, N, 16 71 Found C, 52 63, H, 4 83, N, 16 53 Example 38 Preparation of (±)-7-nT2-(5-aminobenzimidazolvnmethvnmethvlaininolcarbonvn-4-methvl-3-oxo-2.3.4.5'tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid a) (±)-7-[[[2-(5-Aminobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid 35 Methyl (±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (367 4 mg, 0 76 119 WO 96/00730 PCT/US95/08306 mmol) was suspended in MeOH, and 10% Pd/C catalyst was added The mixture was stirred bnskly at RT under H2 (balloon) After 4.5 h, the catalyst was removed by filtration through Celite® The filtrate was concentrated under vacuum, and the residue was dissolved in MeOH ION NaOH (2 5 mL, 2.5 amol) and H20 (10 5 mL) were added The reaction was stirred at RT for 24 h, then was neutralized with 10N HCl (2.5 mL) Concentration in vacuum left a dark residue, which was dissolved in MeOH Activated carbon (Nont®) was added, and the mixture was heated at reflux on the steam bath The activated carbon was removed by filtration through Celite®, and the filtrate was concentrated tc -hout 50 mL The precipitate 10 was collected on a sintered glass funnel and dned in a vacuum desiccator to give the title compound (158 0 mg) as a red powder: HPLC (PRP-1®, 10% CH3CN/H20-0 1% TFA) tR=4.64; MS (ES) m/e 437 2 (M+H)+, lH NMR (250 MHz, CD3OD) 5 7 42-6.56 (m, 6H), 5 54 (d, IH), 5 15 (dd, IH), 4 80 (s, 2H), 3 13 (s, 3H), 3 05 (s, 3H) Anal Calcd for C22H24N604 0.75 HCl 1 75 H20 C, 53 35, H, 5 75; N, 15 16 97 Found. C, 53.91, H, 6 00, N, 16.36.
Example 39 Preparation of (±W7-r2-(1.2.3.4-tetrahvdro-9H-pvndor3.4-blindolvl)carbonvll-4-methvI-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acettc acid 20 a) Methyl (±)-7-[2-(l,2,3,4-tetrahydro-9H-pyndo[3,4-b]indolyl)carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetate (308 5 mg, 1 06 mmol) was weighed into a 250 mL roundbottom flask Dry DMF was added, followed by HOBt H20 (159 1 mg, 1 18 25 mmol) and EDC (248 3 mg, 1 30 mmol) Dusopropylethylamme (0 20 mL, 1.15 mmol) was added, followed by a solution of l,2,3,4-tetrahydro-9H-pyndo[3,4b]indole (187 6 mg, 1 09 mmol) in DMF The reaction was stirred at RT for 24 h, then was concentrated under vacuum Chromatography (silica gel, step gradient, 2% MeOH/CHCl3, 3% MeOH/CHCl3) gave the title compound as a clear, 30 colorless oil (484 7 mg) >H NMR (250 MHz, CDC13) 5 9 09 (br s, IH), 7 47-7.04 (m, 7H), 6 49 (d, IH), 5 37 (d, IH), 5 05 (dd, IH), 4.77 (s, 2H), 3 69 (s, 3H), 2.99 (s, 3H), MS (ES) m/e 447 2 (M+H)+ b) (±)-7-[2-( 1,2,3,4-tetrahydro9H-pyndo[3,4-b]indolyl)carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetic acid Methyl (=;)-7-[2-(l,2,3,4-tetrahydro-9H-pyndo[3,4-b]mdolyl)carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (484.7 mg, 1 09 5 mmol) was dissolved m MeOH, and ION NaOH (2 0 mL, 2 0 mmol) was added The reaction was stirred at RT for 24 h, then was heated in an oil bath set at 75°C After 4 h, the reaction was neutralized with ION HCl and concentrated under vacuum The resultant precipitate was collected and reprecipitated from methanol/water to afford the title compound (380 mg, 80%) as a colorless powder 10 MS (ES) m/e 433.2 (M+H)+. Anal Calcd for C24H24N4O4 • 1.5 H20 C, 62 73, H, 5 92, N, 12 19 Found C, 62.56, H, 5 55, N, 11 91 Example 40 Preparation of (S)-7-riT2-(5 6-methvlendioxvbenzimidazolvl')methvl1methvlanuno1 15 carbonvll-4-methvl-3-oxo-2.3.4.5-tetrahvdro-lH-1.4-benzodiazePine-2-acetic acid a) 2-[[N-(BenzyIoxycarbonyl)-N-methyl]aminomethyl]-5,6-methylenedioxybenzimidazole Cbz-sarcosine (310 0 mg, 1 39 mmol) was dissolved in dry THF (10 mL) in a 250 mL roundbottom flask under argon Isobutylchloroformate (0.2 mL, 1.54 mmol) 20 was added, followed by Et3N (0.25 mL, 1.80 mmol) The reaction was stirred at RT under argon for 30 min, then was cooled to -10°C to -20°C A solution of 1,2-diamino-4,5-methylrnedioxybenzene (0.2 g, 1 314 mmol) m dry THF was added, and the reacuon was allowed to warm to RT After 18 h, the reaction was concentrated under vacuum The white solid residue was dissolved m EtOAc, and 25 the solution was washed with 10N NaHC03 The organic layer was dned (MgS04), filtered, and concentrated under vacuum The residue was dissolved in glacial AcOH and heated an oil bath set at 70 °C After 24 h, the reaction was concentrated under vacuum The residue was reconcentrated firom toluene, then was chromatographed on silica gel (1 1 CHiChlEliO) The matenal obtained in this 30 way (two components co-eluted) was redissolved in glacial AcOH and heated to 100 °C TLC of the reaction after 24 h still showed two products Concentration and chromatography (silica gel, 1 1 CHCl3/Et20) gave the title compound (145 0 mg, 32 7%) MS (ES) m/e 340 0 (M+H)+, 'H NMR (250 MHz, CDCI3) 8 7 32 (s, 5H), 7 27 (s, IH), 7 11 (s, IH), 5 94 (s, 2H), 5 13 (s, 2H), 4 58 (s, 2H), 3 03 (s, 3H) PCT/DS95/0830S b) 2-(Methylamino)methyl-5,6-methylenedioxybenzimidazole 2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]-5,6-methylenedioxybenzimidazole (145 0 mg, 0 43 mmol) was dissolved in MeOH, and 10% Pd/C was added. The mixture was stirred briskly at RT under H2 (balloon) 5 After 4 h, the reaction was filtered through Celite®, and the filtrate was concentrated under vacuum to afford the title compound (70 8 mg, 80 2%). c) Methyl (S)-7-[[[2-(5,6-methylendioxybenzimidazolyl)methyl]methylamino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate EDC (76 2 mg, 0 40 mmol) was added to a solution of methyl (2S)-7- carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (0.35 mmol) and HOBt H20 (57 9 mg, 0 43 mmol) in dry DMF, and the reaction was stirred at RT. Dusopropylethylanune (0 150 mL, 0 86 mmol) was added, followed by a solution of 2-(methylamino)methyl- 5,6-methylenedioxybenzimidazole (70 8 15 mg, 0 35 mmol) in dry DMF The reaction was stirred at RT for 24 h, then was concentrated under vacuum. Chromatography (silica gel, step gradient, CHCI3, 1 1 MeOH/CHCl3) and rechromatography (2% MeOH/CHCl3, 10% MeOH/CHCI3) gave the title compound (102 5 mg, 61 1%)- 'H NMR (250 MHz, CDCI3) 6 7 18-7 13 (m, 3H), 6 82 (s, IH), 6 49 (s, IH), 5 97 (s, 2H), 5 40 (d, IH), 5 05 (dd, IH), 20 4 74-4 56 (m, 2H), 3.73 (s, 3H), 3 13 (s, 3H), 3 01 (s, 3H) d) (S)-7-[[[2-(5,6-Methylendioxybenzimidazolyl)methyl)methylamino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid Methyl (S)-7-[[[2-(5,6-methylendioxybenzimidazolyl)methyl]methylamino] 25 carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (102 5 mg, 0.21 mmol) was dissolved in MeOH, and 1 0 N NaOH (0 5 mL, 0 5 mmol) was added The reaction was stirred at RT for 48 h, then was neutralized with 10N HCl Concentration under vacuum left a residue which was diluted with water and allowed to stand at RT overnight The resultant precipitate was collected 30 by filtration and dned under high vacuum to yield the title compound (29 0 mg, 30%) HPLC Ir=1 1 67,(PRP-1®, gradient elution over 20 mm, 5-50% CH3CN/H20-0 1% TFA) MS (ES) m/e 466 2 (M+H)+ Example 41 Preparation of (S)-7-(Tf2-(4.6-diazabenzimidazolvl)methvl]methvlamino1carbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdfo-lH-l,4-benzodiazepine-2-acetic acid 122 a) 2-[[N-(tert-ButQxycarbonyl)-N-methyl]aminoniethyl]-4,6-diazabenzimidazole Boc-sarcosine (3 6 g, 19 1 mmoi) was dissolved in dry THF m a flame-dned 250 mL roundbottom flask, and Et3N (6 mL, 43.14 mmol) was added The solution was cooled to 0°C to -5°C, and lsobutylchloroformate (2 5 mL, 1 93 mmol) was 5 added The white mixture was stirred at - 5 °C for 15 min, then was cooled to -20 °C to -30 °C, and 4,5-diaminopynmidine (2 1 g, 19.15 mmol) was added as a sohd The cooling bath was removed and the reaction was allowed to warm to RT After 24 h, the reaction was concentrated under vacuum The residue was dissolved in EtOAc and washed with 1.0 NaHC03. The organic layer was dned (MgS04), 10 filtered, and concentrated under vacuum The residue was redissolved in glacial AcOH and heated in an oil bath set at 70°C. After 24 h, the reaction was cooled to RT, concentrated under vacuum, and reconcentrated from toluene Flash chromatography column (silica gel, step gradient, 5% MeOH/CHCI3, 10% MeOH/CHCl3) gave the utle compound (1 66 g, 33%) *H NMR (250 MHz, 15 CDCI3) 6 9 11 (s, IH), 9 09 (s, IH), 3.92 (s, 2H), 2.90-2 95 (m, 3H), 1 40-1 45 (m, 9H); MS (ES) m/e 264 (M+H)+. b) 2-(Methylamino)methyl-4,6-diazabenzimidazole 2-[[N-(tert-Butoxycarbonyl)-N methyl]aminomethyl]-4,6-20 diazabenzunidazole (1.13 g, 4.29 mmol) was treated with 4 N HCl in dioxane A suspension formed, and more 4 N HCl in dioxane was added The heterogeneous mixture was stirred at RT for 2 h, then was concentrated under vacuum The residue was dissolved in MeOH and the product was precipitated with Et20 The precipitate was collected on a sintered glass funnel and dned in a vacuum desiccator to yield the 25 utle compound (328 5 mg, 46 9%) as a white powder TLC Rf 0 36 (3 1:1 n- Bu0H/H0Ac/H20), »H NMR (250 MHz, CD3OD) 5 9 56 (s, IH), 9 33 (s, IH), 4 81 (s, 2H), 2 99 (s, 3H), MS (ES) m/e 164 0 (M+H)+ c) Methyl (S)-7-[[[2-(4,6-JiazabenzunidazolyIjmethyl]methylamino]carbonyl]-4-30 methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate Methyl (S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate (262 6 mg, 0 55 mmol) was suspended in CH3CN (10 mL), and HOBt H20 (86 7 mg, 0 64 mmol) was added, followed by EDC (115 5 mg, 0 60 mmol) Dusopropylethylamme (150 mL, 0 86 mmol) was added, affording 35 a homogeneous solution A solution of 2-(methyIamino)methyl-4,6- diazabenzimidazoie (99 0 mg, 0.61 mmol) and dusopropylethylamme (150 mL, 0 86 123 mmol) was added, and the reaction was stirred at RT After 3 d, the solvents were evaporated under vacuum, and the residue was reconcentrated from toluene. Chromatography (sihca gel, step gradient, 5% MeOH/CHCl3,10% MeOH/CHCl3) yielded the title compound (190 mg, 79 %) MS (ES) m/e 438.2 (M+H)+, 'H NMR 5 (250 MHz, CDC13) 6 9 06 (s, IH), 9.03 (s, IH), 7 90-7 15 (m, 3H), 6 45 (d, IH), 5 40 (d, IH), 4.93 (dd, IH), 3 71 (s, 3H), 3 16 (s, 3H), 2 98 (s, 3H) d) (S)-7-[[[2-(4,6-Diazabenzunidazolyl)methyl]methylaimno]carbonyIJ-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4~benzodiazepme-2-aceuc acid 10 10N NaOH (15 mL, 1.5 mmol) was added to a solution of methyl (S)-7- [[[2-(4,6-diazabenzimidazolyl)methyl]methylammo]carbonyl]-4-xnethyl-3-oxo~ 2,3,4,5-tetrahydro-lH-l,4-benzodiazepuie-2-acetate (190 3 mg, 0 44 mmol) in MeOH (5 mL) and H2O (5 mL) The reaction was stirred at RT for 24 h, then was \ neutralized with 1.0 N HCl (1.5 mL) The reacuon was concentrated to dryness 15 under vacuum, and the residue was punfied by chromatography (ODS, step gradient, 5% CH3CN/H2O-O 1% TFA, 10% CH3CN/H2O-O 1% TFA, 20% CH3CN/H2O-0 1% TFA) One fraction was collected and concentrated under vacuum The residue was reconcentrated from toluene and dned under vacuum, then was dissolved in MeOH and precipitated with EtjN The white precipitate was 20 collected on a sintered glass funnel and dned in a vacuum desiccator to afford the title compound as a white powder (126 5 mg, 67 9%) HPLC tR 0 41, (ODS, gradient elution over 20 mm, 5-50% CH3CN/H2O-O 1% TFA), MS (ES) m/e 424.2 (M+H)+ Anal. Calcd for C2oH2!N704 0 5CF3C02H C, 52 50, H, 4 51, N, 2041 Found C, 52 62, H, 4 88, N, 20 01 Example 42 Preparation of (SW7-rrr?.-<4-a7ahflnzimidazolvl)mcthvI1mcthvlaminolcarbonvn-4-methvl-3-oxo-2.3 4.5-tetrahvdro-1H-1,4-benzodiazemne-2-acetic acid a) 2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]-4-azabenzimidazole 30 A solution of Cbz-sarcosine (5 g, 22 4 mmol) and Et3N (4 mL, 28 76 mmol) in dry THF was cooled to 0°C m an ice bath, and isobutylchloroformate (3 0 mL, 23 13 mmol) was added The reaction was stirred at RT for 15 mm, then was added to a solution of 2,3-diaminopyndine (2 5 g, 22 7 mmol) in dry THF at -25°C The reacuon was stirred at -20°C for 30 min, then was allowed to warm to RT After 24 35 h, the reaction was concentrated under vacuum The residue was taken up in EtOAc and washed with 10N NaHC03 The organic layer was dned (MgS04), filtered and 124 concentrated under vacuum The residue was dissolved in glacial AcOH (200 mL) and heated in an oil bath set ?t 109 °C After 20 h, the reaction was concentrated under vacuum, and the residue was reconcentrated from toluene Chromatography (Silica gel, step gradient, CHCI3,3% MeOH/CHCl3,5% MeOH/CHCl3) gave the 5 utle compound (2.2 g, 33%), which was recrystallized from H2O MS (ES) m/e 296 2 (M+H)+ b) 2-(Methylamino)methyl-4-azabenzinndazole 2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]-4-azabenzimidazole 10 (551.3 mg, 1 86 mmol) was dissolved in MeOH, and 10% Pd/C was added. The mixture was stirred bnskly at RT under H2 (balloon) After 4 h, the reaction was filtered through Celite®, and the filtrate was concentrated under vacuum to afford the utle compound (420 1 mg, quantitative) 'H NMR (250 MHz, CDCI3) 8 8 34-8 32 (m, IH), 7 98-7 14 (m, 4H), 5 18-5 12 (m, IH), 4 87 (s, 2H), 3 32 (s, 3H) c) Methyl (S)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyI]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate EDC (309 1 mg, 1.61 mmol) was added to a soluuon of methyl (S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (504 6 20 mg, 1.54 mmol), diisopropylethylamine (0 30 mL, 1.78 mmol), and HOBt H2O (228 2 mg, 1 69 mmol) in dry DMF at RT After 10 minutes, 2-(methylamino)methyl-4-azabenzimidazole (3 08 mmol) neutralized with diisopropylethylamine (0.600 mL) was added, and the reaction was stirred at RT After 20 h, the solvents were evaporated under vacuum, and the residue was reconcentrated from toluene Chromatography (silica gel, step gradient, CHCI3,5% MeOH/CHCl3, 10% MeOH/CHCl3) gave the utle compound (326 8 mg, 48 6%) MS (ES) m/e 437 2 (M+H)+; *H NMR (250 MHz, CDC13) 8 8 39 (d, IH), 8 00-7.20 (m, 5H), 5 50 (d, IH), 5.15-4 80 (m, 3H), 3 70 (s, 3H), 3 10 (s, 3H), 2 93 (s, 3H) d) (S)-7-[[[2-(4-Azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyI-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate 1 0 N NaOH (2 0 mL, 2 0 mmol) was added to a soluuon of methyl (S)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (326 8 mg, 0 75 mmol) in MeOH (10 mL) and H2O (10 mL) at RT After 26 h, the reaction was neutralized with 10N HCl (2 0 mL, 2 0 mmol) and concentrated under vacuum The residue was taken up 125 PCT/US95/083C6 m H2O and the resultant white precipitate was collected on a sintered glass funnel, washed with H2O and dried under vacuum to afford the tide compound (218 1 mg, 69%) as a white powder MS (ES) m/e 423 4 (M+H)+ Anal Calcd for C2iH22N604 2H20 C, 55 02, H, 5 72, N, 18 33 Found C, 55 07; H, 5.55, N, 5 17 81 Example 43 Preparation of 7-ri-r2R-(2-benzimidazolvl)pvrrohdinvncarbonvl1-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2S-acetic acid 10 a) l-tert-Butoxycarbonyl-2R-(2-benzimidazolyl)pyrrohdine A solution of BOC-D-proiine (3 0 g, 14 mmol) and Et3N (2 5 mL, 18 mmol) in dry THF was cooled to 0 °C in an ice bath, and isobutylchloroformate (2 0 mL, 15 mmol) was added The reaction was stirred at 0°C for 20 nun, then was removed from the cooling bath and allowed to warm to RT for 10 minutes The white slurry 15 was added to a solution of o-phenylenediamine (1.55 g, 4 3 mmol) in THr at -20 to -30°C After the addition was complete, the reaction was removed from the cooling bath and allowed to proceed at RT After 20 h, the reaction was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1 0 N NaHC03 The organic layer was dned (MgS04), filtered and concentrated under vacuum The 20 residue was dissolved m glacial AcOH and heated in an oil bath set at 70-75°C After 24 h, the AcOH was evaporated under vacuum, and the residue was reconcentrated from toluene Recrystallization from EtOAc ga\c the title compound (1 1 g) The mother liquors were concentrated and the residue taken into Et20 to afford additional title compound (1 47 g) b) 2R-(2-benzimidazolyl)pyrrolidine l-tert-Butoxycarbonyl-2R-(2-benzunidazolyl)pyrrolidine (1 0702 g, 3 72 mmol) was treated with 4 N HCl/dioxane After 2 h at RT, the reaction was concentrated under vacuum, and the residue was treated with Et20 The white 30 precipitate was collected and dned under vacuum to afford the title compound ( 958 1 mg, 99 1%) lH NMR (250 MHz, CDC13) 8 7 89-7 85 (m, 2H), 7 68-7 65 (m, 2H), 5 38-5.31 (m, IH), 3 67-3 61 (m, 2H), 3 33-3.31 (m, IH), 2 88-2 21 (m, 4H), [°0D -4 9__ (e 1 0, H20) 126 c) Methyl 7-[l-[2R-(?.-benzimidazolyl)pyrrohdinyI]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro 1H-1,4-benzodiazepine-2S-acetate EDC (74 4 mg, 0 39 mmol) was added to a solution of methyl (S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (104.2 mg, 0.32 5 mmol), diisopropylethylamine (0 06 mL, 0 34 mmol), and HOBt H20 (56 6 mg, 0 42 mmol) m dry DMF at RT The reaction was stirred at RT, and a soluuon of 2R-(2-benzimidazolyl)pyirolidine (89.7 mg, 0.35 mmol) and dusopropylethylamme (0 120 mL, 0 69 mmol) m DMF was added. After 20 h, the reacuon was concentrated under vacuum, and the residue was reconcentrated from toluene 10 Chromatography (silica gel, step gradient, CHCI3, 3% MeOH/CHCl3,5% MeOH/CHCl3) gave the Utle compound (136 9 mg, 92 5%): *H NMR (250 MHz, CDCI3) 5 7 77 (d, IH), 7.63 (d, IH), 7 34-7 22 (m, 4H), 7 06-7 05 (m, IH), 6 37 (d, IH), 5 55-5 49 (m, IH), 5 30 (d, IH), 5 08-5 00 (m, IH), 3.68 (s, 3H), 2.92 (s, 3H), 2 55-1 70 (m, 4H), 1.22 (t, 3H), MS (ES) m/e 462.2 (M+H)+ d) 7-[l-[2R-(2-Benzimidazolyl)pyrrohdinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetic acid 1 0 N NaOH (0 75 mL, 0 75 mmol) was added to a soluuon of methyl 7-[l-[2R-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-20 IH-1,4-benzodiazepme-2S-acetate (136 9 mg, 0.30 mmol) in MeOH (5 mL) and H20 (5 mL) at RT After 24 h, 10N HCl (0 75 mL, 0 75 mmol) was added and the reacuon mixture was concentrated under vacuum Chromatography (ODS, step gradient, 0 1% TFA/H20,20% CH3CN/H20-0 1% TFA), concentration, and reconcentration from toluene left a residue, which was redissolved in H20 Lyophilization gave the title compound (92 mg) HPLC tR=10 68 (ODS, gradient elution over 20 mm, 5-50% CH3CN/H20-0 1% TFA), MS (ES) m/e 448 2 (M+H)+ Example 44 Preparation of l-\ 1 -f2S-(2-benzimidazolvl)pvrrolidinvllcarbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdro-lH-l .4-benzodiazepine-2S-acetic acid a) l-tert-Butoxycarbonyl-2S-(2-benzirmdazolyl)pyrrohdine Following the procedure of Example 43(a), except substituting BOC-L-prohne for the BOC-D-prolme, the title compound (3.2 g, 74%) was prepared 'H NMR (250 MHz, CDC13) 6 7 53 (br s, IH), 7 19-7 16 (m, 4H), 5 14 (d, IH), 3 50 (s, 2H), 2 87 (br s, IH), 2 19-1 97 (m, 3H), 1 49 (s, 9H), 1 25 (br s, 2H), MS (ES) m/e 288 2 (M+H)+ 127 WO 96/00730 PCT/US95/08306 b) 2S-(2-benzimidazolyl)pyrrolidine Following the procedure of Example 43(b), except substituting 1-tert-butoxycarbonyl-2S-(2-benzumdazolyl)pyrrolidine for the l-tert-butoxycarbonyl-2R-5 (2-benzimidazolyl)pyrrohdine, the tide compound wes prepared( 1.7988 g, 98 4%) iH NMR (250 MHz, CDC13) 5 7 89-7 86 (m, 2H), 7 69-7 65 (m, 2H), 5 30-5 40 (m, IH), 3.68-3 63 (m, 2H), 3.33-3.32 (m, IH), 2.20-2 89 (m, 4H), [a]D +3 9- (c 1 0, H20) c) Methyl 7-[l-[2S-(2-benzimidazolyl)pyirolidinyl]carbonyl]-4-methyl-3-oxo-23.4,5-tetrahydro-lH-1,4-benzodiazepine-2S-acetate Following the procedure of Example 43(c), except substituting 2S-(2-benzimidazolyl)pyrrolidine for the 2R-(2-benzimidazolyl)pyrrolidme, the Utle compound (90 4 mg, 61 %) was prepared MS (ES) m/e 462 4 (M+H)+ d) 7-[l-[2S-(2-Benzinudazolyl)pyirolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodi azepine-2S-acetic acid Followmg the procedure of Example 43(d), except substituting methyl 7-[l-[2S-(2-benzimidazolyl)pyrrohdmyl]carbonyl]-4-methy l-3-oxo-2,3,4,5 -tetrahydro-20 1H-1,4-benzodiazepine-2S-acetate for the methyl 7-[ 1 -[2R-(2- benzimidazolyl)pyrrolidinyl] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2S-acetate, the title compound (65 8 mg, 75%) was prepared HPLC tR=10 63 (ODS, gradient elution over 20 nun, 5-50% CH3CN/H2O-O 1% TFA), MS (ES) m/e 448.2 (M+H)+ Example 45 Preparation of (±)-7-nT2-(4-azabenzimidazoIvPmethvnmcthvlaminolcarbonvll-4-isopropvI-3-oxo-2.3.4.5-tetrahvdro-lH-l .4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[2-(4-azabenziimdazolyl)methyl]methylamino]carbonyl]-4-30 isopropyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate Following the procedure of Example 42(c), except substituting methyl (±)-7-carboxy-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate for the methyl (S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-IH-1,4-benzodiazepme-2-acetate, the title compound (226 mg, 96%) was prepared TLC Rf 35 (5% MeOH/CHCl3) 0 28, 'H NMR (250 MHz, CDCI3) 5 8 45 (d, IH), 7 96-7 10 (m, 128 5H), 6 40 (br s, IH), 5 09-4 77 (m, 5H), 3 70 % 3H), 3 47 (s, 3H), 3.09 (s, 3H), 1.23 (t, IH), 1 09 (d, IH), 0 86 (br s, IH) b) {±)-7-[[[2-(4-Azabenzimidazolyl)methyl]methylamino]carbonyl]-4-isopropyl-3-5 oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-dcetic acid ION NaOH (15 mL, 1.5 mmol) was added to a solution of methyl (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]caibonyl]-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (226 2 mg, 0 49 mmol) in MeOH (5 mL) and H2O (5 mL) at RT. After 24 h, the reaction was neutralized with 10 10N HCl and the solvents were evaporated under vacuum ODS chomatography (0 1% TFA/H2O, followed by 20% CH3CN/H2O-O 1% TFA), concentration, and reconcentration from toluene left a residue, which was redissolved in H2O Lyophilization gave impure title compound (181.9 mg) as a white powder, which was repunfied by ODS chromatography (10% CH3CN/H2O-O 1% TFA, followed by 15 20% CH3CN/H2O-O 1% TFA) Concentration and reconcentration from toluene left a residue, which was dissolved m MeOH and precipitated with Et20 The precipitate was collected on a sintered glass funnel and died in a vacuum desiccator to afford the title compound (65 5 mg). HPLC (ODS, gradient elution over 20 mm, 5-50% CH3CN/H2O-O 1% TFA) tR=12.32, MS (ES) m/e 451.2 (M+H)+. Anal 20 Calcd for C23H26N6O4 0 5 CF3C02H 0 75 H20 C, 55.33, H, 5 42, N, 16 13 Found C, 55 43, H, 5 60, N, 16.01 Example 46 Preparation of (SV7-riT2-(4-aza-5-25 methvlbenzimidazolvnmethvllmethvlanunolcarbonvl1-4-methvl-3-oxo-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepme-2-acetic acid a) 2-Amino-6-methyl-3-mtropyndine 2-Amino-6-picohne (5 1 g, 47 1 mmol) was weighed into a 500 mL round bonom flask, and the flask was cooled to -30°C Concentrated H2SO4 (20 mL) was 30 added, which caused some fuming to occur Concentrated HNO3 (10 mL, 160 mmol) was then added dropwise slowly The reaction was allowed to warm to RT over 30 mm, then was heated in an oil bath set at 80°C After 90 mm, the reaction was removed from the heating bath, and ice was added 6 25 N NaOH (150 mL, 937 5 mmol) was added slowly, and the resulting yellow precipitate was collected on 35 a sintered glass funnel Drying in a vacuum desiccator gave the title compound (1 7 129 WO 96/00730 PCT/DS95/08306 g, 24%) TLC Rf (5% MeOH/CHCl3) 0 77, 'H NMR (250 MHz, CDC13) 8 8 31 (d, IH), 6.32 (d, IH), 2 46 (s, 3H), MS (ES) m/e 154 0 (M+H)+ b) 2,3-Diamino-6-methylpyridine 2-Amino-6-methyl-3-nitropyndine (754 mg, 4 92 mmol) was suspended in MeOH, and 10% Pd/C was added The mixture was stirred briskly at R.T under H2 (balloon) After 4 h, the reaction was filtered through Celite®, and the filtrate was concentrated under vacuum to afford the Utle compound (677 mg, quantitative) 'H NMR (250 MHz, CD3OD) 8 6 82 (d, IH), 6 36 (d, IH), 2 25 (s, 3H) c) 2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]-5-methyl-4-azabenzimidazole A solution of Cbz-sarcosine (1.8 g, 7 85 mmol) in dry THF at RT was treated with isobutylchloroformate (1.25 mL, 9 64 mmol), followed by Et3N (3 0 mL, 21 57 15 mmol) After 30 min, a solution of 2,3-diamino-6-methylpyndine (882 mg, 7.16 mmol) in dry THF was added, and the reaction was stirred at RT After 3 d, the reaction was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHC03 The organic layer was dned (MgS04), filtered, concentratcd under vacuum, and reconcentrated from toluene The residue was 20 dissolved in glacial AcOH (100 mL) and heated in an oil bath set at 110°C. After 24 h, the reaction was concentrated under vacuum, and the residue was reconcentrated from toluene Chromatography (silica gel, step gradient, CHCI3,2% MeOH/CHCl3, 3% MeOH/CHCl3) gave the title compound (1 0 g4 46 6%) 'H NMR (250 MHz, CDCI3) 8 7 29 (s, 5H), 7 17 (s, IH), 7 03 (d, IH), 5.09 (s, 2H), 4 74 (s, 2H), 3 05 (s, 25 3H), 2 61 (s, 3H); MS (ES) m/e 311 0 (M+H)+ d) 2-(Methylamino)methyl-5-methyl-4-azabenzinudazole 2-[[N-(BenzyloxycarbonyI)-N-methyl]aminomethyl]-5-methyl-4-azabenzimidazole (1.0347 g, .33 mmol) was dissolved m MeOH, and 10% Pd/C was 30 added The mixture was stirred bnskly at RT under H2 (balloon) After 20 h, the reaction was filtered through Celite®, and the light yellow filtrate was concentrated under vacuum to afford the title compound (678 9 mg, quantitative) as a reddish colored matenal 130 > PCT/USb 5/08306 e) Methyl (S)-7-[[[2-(4-aza-5- methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate EDC (212 7 mg, 1 11 mmol) was added to a solution of methyl (S)-7-5 carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (293 5 mg, 0 93 mmol), dusopropylethylamme (0 30 mL, 1.72 mmol), and HOBt • H20 (143 5 mg, 1 06 mmol) in diy DMF at RT After 30 minutes, a solution of 2-(methylamino)methyl-5-methyl-4-azabenzimidazole (190 7 mg, 1.08 mmol) m dry DMF was added. The reaction was stirred at RT for 24 h, then was concentrated 10 under vacuum, and the residue was reconcentrated from toluene. Chromatography (silica gel, step gradient, CHCI3,3% MeOH/CHCl3,5% MeOH/CHCl3) gave the tide compound (265 mg, 63%) >H NMR (250 MHz, CDC13) 5 8 51 (br s, IH), 7 86-7.05 (m, 5H), 5 34 (d, IH), 5 06 (t, IH), 3 69 (s, 3H), 3 08 (s, 3H), 2 62 (s, 3H), MS (ES) m/e 451.2 (M+H)+ f) (S)-7-[[[2-(4-Aza-5-methylbenzimidazolyI)methyl]methyIamino]carbonyl]-4-methy 1-3-qxo-2,3 ,4,5-tetrahydro- 1H-1,4-benzodiazepine-2-acetic acid 1.0 N NaOH (2 0 mL, 2 0 mmol) was added to a solution of methyl (S)-7-[[[2-(4-aza-5-methylbenzinudazolyl)methyl]methylamxno]carbonyl]-4-methyl-3-20 oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepme-2-acetate (264 7 mg, 0 59 mmol) in MeOH (10 mL) and H2O (10 mL) at RT After 20 h, the reaction was neutralized with 1.0 N HCl (2.0 mL) and the solvents were evaporated under vacuum The crude matenal was precipitated from water to give rhe title compound (49 8 mg) TLC Rf0.51 (3 1 1 n-Bu0H/H0Ac/H20); HPLC tR=8 35 mm (PRP-1®, gradient 25 eluuon over 20 nun, 5-50% CH3CN/H2O-O 1 % TFA), MS (ES) m/e 437.2 (M+H)+ Anal Calcd for C22H24N6O4 0 75 H20 1.2 HCl C, 42.56, H, 3 53, N, 11 03 ' Found C, 42.20, H, 3 02, N, 11.36.
Example 47 Preparation of (S)-7-m2-(5.6- dimethoxvbenzimidazolvl)methvnmethvlaminolcarbonvn-4-methvl-3-oxo-2.3.4.5-tetrahvdro-lH-1.4-benzodiazeoine-2-acetic acid a) 2-[[N-(Benzyloxycarbonyl)-N-methyI]aminomethyI]-5,6-dimethoxybenzimidazole 35 Cbz-sarcosine (1.4 g, 6 1 mmol) was dissolved in dry THF in a 100 mL roundbottom flask, and Et3N (1.5 mL, 10.8 mmol) was added, followed by 131 isobutylchloroformate (0 80 mL, 6 17 mmol) The reaction was stirred at RT, then was added to a solution of 4,5-dimethoxyphenylenediamine (6 06 mmol) in diy THF at -25°C The Cbz-sarcosine, mixed-anhydnde solution was added to the cooled phenylenedianune solution. The reaction was stirred at -25°C for 10 min, then was 5 allowed to warm to RT After 20 h, the reaction was concentrated under vacuum The residue was taken up in EtOAc and washed with 1.0 N NaHCOs. The organic layer was dned (MgS04), filtered, concentrated under vacuum, and reconcentrated from toluene The residue was dissolved in glacial AcOH (100 mL) and heated m an oil bath heated set at 110 °C After 24 h, the reaction was concentrated under 10 vacuum. Flash chromatography (silica gel, step gradient, 2% MeOH/CHCl3,5% MeOH/CHCl3) gave the title compound (1 7 g, 81%) »H NMR (250 MHz, CDC13) 5 7 33 (s, 5H), 7 05 (s, 2H), 5.15 (s, 2H), 4 64 (s, 2H), 3.88 (s, 6H), 3.04 (s, 3H), MS (ES) m/e 3562 (M+H)+ b) 2-(Methylamino)methyl-5,6-dimethoxybenzimidazoie 2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]-5,6-dimethoxybenzimidazole (1 7454 g, 4 91 mmol) was dissolved m MeOH, and 10% Pd/C was added The mixture was stirred bnskly at RT under H2 (balloon). After 4 h, the reaction was filtered through Celite®, and the filtrate was concentrated under 20 vacuum to afford the title compound \ ) c) Methyl (S)-7-[[[2-(5,6- dimethoxybenzimidazolyl)meihyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetate EDC (139.9 mg, 0 73 mmol) was added to a suspension of methyl (S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate (198.5 mg, 0 68 mmol), and HOBt • H20 (98 8 mg, 0 73 mmol) in CH3CN at RT. After 15 minutes, dusopropylethylamme (0 200 mL, 115 mmol) was added, followed by a solution of 2-(methylamino)methyl-5,6-dimethoxybenzimidazoIe (147.3 mg, 0 67 mmol) m CH3CN The reaction was stirred at RT for 24 h, then the solvents were evaporated under vacuum The residue was reconcentrated from toluene, then was chromatographed (silica gel, step gradient, CHCI3,3% MeOH/CHCl3, 5% MeOH/CHCl3) to afford the utle compound (227 mg, 68%) 1H NMR (250 MHz, CDCI3) 8 7.29-7 16 (m, 5H), 5 37 (d, IH), 5 09 -5 03 (m, IH), 4 86-4 72 (m, 3H), 3 90 (s, 6H), 3 71 (s, 3H), 3 12 (s, 3H), MS (ES) m/e 496 (M+H)+ 132 d) (S)-7-[[[2-(5,6-dimethoxybenzimidazolyl)methyl]methylamino]cait>onyl]-4-methy l-3-oxo-23,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetic acid 1 0 N NaOH (1.5 mL, 1.5 mmol) was added to a soluuon of methyl (S)-7-[[[2-(5,6-dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-5 2,3.4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (227.1 mg, 0 46 mmol) in MeOH (10 mL) and H2O (10 mL) at RT After 24 h, the reaction was neutralized with 10N HCl (15 mL, 1 5 mmol). After 30 mm, a white precipitate had formed, which was collected on a sintered glass funnel and washed with water The matenal was dned in a vacuum desiccator to afford the title compovmd (144 3 mg, 65%) MS 10 (ES) m/e 482.2 (M+H)+. Anal Calcd for C24H27N5O6 1 75 H20 0 4 HCl* C, 54 64, H, 5 90, N, 13.27 Found C, 54.69, H, 5 92, N, 12 67 Example 48 Preparation of (±)-8-rr2-(2-benzimidazolvDacetvnamino1-2-methvl-3-oxo-2.3.4.5-15 tetrahydro-lH-2-benzazepme-4-acetic acid a) Methyl (±)-8-[[2-(2-benzimidazolyl)acetyl]ammo]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-2-benzazepine-4-acetate Methyl (±)-8-amino-2-methyl-3-oxo-2,3,4,5-tetrahydro-1 H-2-benzazepwe-4-acetate was coupled with 2-benzimidazloylacetic acid according to the procedure of example 11(a) Punfication by chromatography (silica gel, 2%-5% CH3OH/CH2CI2) gave the title compound as a colorless foam (31%)- *H NMR (CDCI3) 7.55 (m, IH), 7.44 (d, J=2 Hz, IH), 7 38 (dd, J=8 3 Hz, J=2 Hz, IH), 7 30 (m, 2H), 5 18 (d, J=16 3 Hz, IH), 4 24 (s, 2H), 3 71 (m, IH), 3 68 (s, 3H), 3 65 (d, J=16 3 Hz, IH), 3 03 (m, IH), 2 95 (s, 3H), 2 85 (m, IH), 2 40 (dd, J=16.9, 6.3 Hz, IH) b) (±)-8-[[2-(2-Benzimidazolyl)acetyl]amino]-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepme-4-acetic acid Methyl (±)-8-[[2-(2-benzimidazolYl)acetyl]amino]-2-methyl-3-oxo-23,4,5-tetrahydro-lH-2-benzazepine-4-acetate was saponified according to the procedure of Example 24(b) to give the Utle compound as a white sohd (47%) *H NMR (DMSO-d6) 5 10 38 (s, IH), 7.49 (m, 3H), 7 42 (d, J=8 4 Hz, IH), 7 15 (m, 2H), 7 06 (d, J=8 4 Hz, IH), 5 24 (d, J=16 5 Hz, IH), 3 96 (s, 2H), 2 35 (m, IH); MS (ES) m/e 407 2 (M+H)+ Anal Calcd for C22H22N4O4 1 75 H2O C, 60 33, H, 5 87, N, 12 79 Found C, 60 57, H, 5 49, N, 12 41. 133 Example 49 Preparation of (±)-8-rfr(2-benzimidazoIvDmethvI1methvlaminolcarbonvn-4-methvl-3-oxo-2,3,4,5-tetrahvdro-1 H-2-benzazepme-4-acetic acid a) Methyl (±)-8-[[[(2-benzimidazolyl)methyl]methylamino]caibonyl]-4-methyl-3-5 oxo-2,3,4,5-tetrahydro-1 H-2-benzazepine-4-acetate Methyl (±)-8-carboxy-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate was coupled with 2-(methylamino)methylbenzimidazole according to the procedure of Example 2(a). Purification by chromatography (silica gel, l%-6% CH3OH/CH2CI2) gave the title compound as a white foam (76%) NMR 10 (CDCI3) 5 7.62 (m, 2H), 7 43 (m, IH), 7.30 (m, 2H), 7 13 (m, 2H), 5 06 (d, J=14 6 Hz, IH), 4 86 (d, J=14.6 Hz, IH), 4 77 (dd, J=16 6 Hz, J=4 Hz), 3 91 (dd, J=16 6, 6 Hz, IH), 3 72 (s, 3H), 3 08 (s, 3H), 3 05 (m, 2H), 2 52 (dd, J=16 9,5 7 Hz, IH) b) (±)-8-[[[(2-Benzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-15 2,3,4,5-tetrahydro-1 H-2-benzazepine-4-acetic acid Methyl (±)-8-[[[(2-benzunidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate was saponified according to the procedure of Example 11(b) to give the title compound as a white sohd (90%) >H NMR (DMSO-dg) 5 7.88 (m, IH), 7 54 (m, 2H), 7 34 (d, J=7 9 Hz, IH), 7 30 (s>, 20 IH), 7 16 (m, 2H), 6.98 (m, IH), 4.87 (m, IH), 4 67 (m, 2H), 4.00 (m, IH), 3.87 (m, IH), 3 10 (m, IH), 3.02 (s, 3H), 2 76 (m, IH), 2 43 (m, IH), 1 97 (m, IH), MS (ES) m/e 407 (M+H)+ Anal. Calcd for C22H21N4O4L1 2 375 H2O C, 58 05, H, 5 70 N, 12 31 Found: C, 57 85; H, 5 41, N, 12 66 Example 50 Preparation of (S)-7-rff(2-benzimidazolv0methvnmethvlamino1carbonvn-3-oxo-4-(2-phenvlethvD-2.3.4.5-tetrahvdro-1H-1.4-benzodiazepine-2-acetic acid a) Methyl (S)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate To a solution stirred under argon at RT of methyl (±)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (9 0 g, 23 mmol) in CH3CN (100 mL) was added diazabicycloundecene (4 6 g, 30 mmol), followed by benzyl bromide (20 g, 116 mmol) The resulting solution was stirred for 1 h, then was concentrated The residue was partitioned between 1 0 N HCl and EtOAc, and the layers were separated The organic layer was washed with bnne, dned (MgS04), and concentrated The residue was punfied by chromatography (silica gel, CH2CI2) 134 to give a pale yellow oil (7 g) Preparative HPLC (Whelk O-l, 50 50 1 hexane CHCI3.CH3OH) gave an oil which was 97% of the desired (S)-enantiomer Removal of racemate by crystallization (EtOAc) gave a colorless oil (3 2 g, 98% ee) This matenal was placed in a 500 mL Pan: hydrogenation vessel with CH3OH (30 5 mL) and 10% Pd/C (0 45 g), and the mixture was shaken under H2 (50 psi) for 6 h The reaction mixture was then filtered and the filtrate was concentrated to give the title compound as a colorless foam (2 1 g, 47%) *H NMR (CDCI3) 8 7 78 (dd, J=8 5, 1.9 Hz, IH), 7 55 (d, J=1.9 Hz, IH), 7.30-7 10 (m, 5H), 6 51 (d, J=8 5 Hz, IH), 5 30 (d, J=16.6 Hz, IH), 5.10 (t, 5=6.5 Hz, IH), 3 77 (s, 3H), 3 74 (m, 3H), 10 3 67 (d, J=16 6 Hz, IH), 3 02 (dd, J=16,6 8 Hz, IH), 2.83 (t, J=7 1 Hz, 2H) 2 69 (dd, J=16, 6 5 Hz, IH) b) Methyl (S)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyI]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetate 15 Methyl (S)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetate was coupled with 2-(methylamino)methylbenzimidazole according to the procedure of Example 2(a) Purification by chromatography on silica gel (l%-5% CH3OH/CH2CI2) gave the title compound (2.85 g, 99%) as a colorless foam !H NMR (CDCI3) 8 7.63 (m, 2H), 7 33 (m, 2H), 7 25-7.10 (m, 7H), 20 6 59 (d, J=8 3 Hz, IH), 5 24 (d, J=16.7 Hz, IH), 5 03 (m, IH), 4 94 (d, J=14 6 Hz, IH), 4 85 (d, J=14 6 Hz, IH), 4 50 (d, J=4 7 Hz, IH), 3 77 (m, IH), 3 76 (s, 3H), 3 59 (d, J=16.7 Hz, IH), 3 57 (m, IH), 3 19 S, 3H), 2 99 (dd, J=16,6 5 Hz, IH), 2 81 (m, 2H), 2 67 (dd, J=16,6 4 Hz, IH) c) (S)~7-[[[(2-Benzinudazolyl)methyl]methylammo]carbonyl]-3-oxo-4-(2-pheny lethy l)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid Methyl (S)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyI)-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified according to the procedure of Example 11(b) to give the title compound (1 8 g, 66%) as (a white solid *H NMR (DMSO-d6) 8 7 54 (m, 2H), 7 30-7.10 (m, 9H), 6 54 (d, J=8i3 Hz, IH), 6 30 (br s, IH), 5 37 (d, J=16 2 Hz, IH), 5 05 (m, IH), 4 77 (s, 2H), 3 97 (br s, IH), 3 51 (m, 3H), 3 05 (s, 3H), 2 65 (m, 3H), 2 49 (m, IH) Anal Calcd for C29H29N5O4 H2O C, 65 77, H, 5 90, N, 13 22 Found C, 65 51, H, 5 84, N, 13 19 135 Example 51 Preparation of (±)-7-rrr2-fbenzimirfa7n1vnmethvllamino1carbonvl-4-r2-(3.4-methvlenedioxvphenvl')ethvll-3-oxo-2.3.4.5-tetrahvdro-1H-1,4-benzodiazepme-2-acetic acid a) Methyl (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(3,4- methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro- 1H-1,4-benzodiazepme-2-acetate Methyl (±)-7-carboxy-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate was coupled with 2-10 (aminomethyl)benzimidazole dihydrochlonde hydrate according to the procedure of Example 2(a) Purification by chromatography (silica gel, l%-5% CH3OH/CH2CI2) followed by recrystallization (CH30H/Et0Ac) gave the title compound as a tan solid (59%) *H NMR (DMSO-d6) 8 8 72 (t, J=5 Hz, IH), 7 61 (s, IH), 7 56 (m, 2H), 7 43 (m, IH), 7.13 (m, 2H), 6 76 (m, 2H), 6 57 (m, 2H), 6 37 (d, J=3 6 Hz, IH), 15 5 95 (s, 2H), 5.42 (d, J=16 5 Hz, IH), 5 13 (m, IH), 4.64 (m, 2H), 3 92 (d, J=16 5 Hz, IH), 3.61 (s, 3H), 3.58 (m, 2H), 2.83 (dd, J=16 6,7 6 Hz, IH), 2 65 (m, 3H) b) (±)-7-[[[2-(Benzunidazolyl)methyI]aimno]carbonyl-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-20 acetic acid Methyl (±)-7-[[[2-(benzimidazolyl)methyl]aminoJcarbonyl-4-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodia7epine-2-acetate was saponified accordmg to the procedure of Example 11(b) to give the title 25 compound (84%) as a white sohd !H NMR (DMSO-d6) 8 8 76 (t, J=5 Hz, IH), 7.58 (m, 2H), 7 48 (m, 2H), 7.13 (m, 2H), 6 76 (m, 2H), 6.58 (m, 2H), 5 94 (s, 2H), 5 40 (d, J=16.5 Hz, IH), 5 06 (m, IH), 4 64 (m, 2H), 3 91 (d, J=16.5 Hz, IH), 3 54 (m, 2H), 2 72 (m, IH), 2 60 (t, J=8 Hz, 2H), 2 50 (m, 1), MS (ES) m/e 542 (M+H)+ Anal Calcd for C29H27N5O6 1 5 H2O. C, 61 26, H, 5 32, N, 12.32 Found C, 30 61 42, H, 5 22, N, 12.25 Example 52 Preparation of (±)-7-rfrf4(5)-imidazolvl)methvl]amino1carfeonvll-4-methvl-3-oxo-2 3.4.5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid 136 a) Methyl (±)-7-[[[(4(5)-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate Following the procedure of Example 23(a), except substituting 4(5)-(aminomethyl)imidazole (prepared according to J Pharm. Sci 1973,403) tor the 2-5 (aminomethyl)imidazole, and heating the reacuon at 90-100°C for 24 h, the utle compound (21%) was prepared* MS (ES) m/e 372 (M+H)+ b) (±>7-[[[(4(5)-Imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid Following the procedure of Example 23(b), methyl (±)-7-[[[(4(5)- imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified to give the title compound MS (ES) m/e 358 (M+H)+ Anal Calcd for C17H19N5O4 I.I5CF3CO2H 0 05 H20 C, 47.37, H, 4.17, N, 14.31. Found C, 47 70, H, 3.91, N, 13 92 Example 53 Preparation of (±)-rrr4-(2-phenvhmidazolvl)methvnaminolcarbonvll-4-methvI-3-oxo-2.3.4.5-tetrahvdro-lH-l ,4-benzodiazepine-2-acetic acid a) 4-Anunomethyl-2-phenylimidazole dihydrochlonde 20 Hydroxylamine hydrochlonde (229 mg, 3 3 mmol) was added to a suspension of 2-phenyhmidazole-4-carboxaldehyde (516 mg, 3 mmol, prepared according toJ Chem Soc Perkin Trans 11974,1527) and sodium acetate (541 mg, 6 6 mmol) in absolute EtOH (5 mL) and H20 (5 mL) at RT A yellow, homogeneous solution was produced After 15 nun, the reacuon was concentrated 25 on the rotavap to remove the EtOH, and the oily, aqueous mixture was extracted with 20% MeOH/CHCl3 (10 mL) then with CHCI3 (10 mL) The combmed organic layers were dned (MgS04) and concentrated to leave a yellow foam.
The yellow foam was dissolved in absolute EtOH (9 mL), and 10N HCl (6 mL, 6 mmol) and 10% Pd/C (0 32 g, 0 3 mmol) were added The mixture was 30 shaken on a Parr apparatus at RT under H2 (50 psi) for 4 h, then was filtered through Celite® The filtrate was concentrated on the rotavap to leave a light yellow sohd Recrystallization fron absolute Et0H/H20 gave the title compound as a light pink sohd (465 mg, 63%) mp 273-275°C (dec), *H NMR (250 MHzJ CD3OD) 87 93-8 12 (m, 2H), 7 80 (s, IH), 7 50-7 76 (m, 3H), 4 40 (s, 2H), MS (ES) m/e 347 2 (2M 35 +H)+ 174 0 (M+H)+, 157 0 (M+H-NH3)+ 137 d) Methyl (±)-[[[4-(2-phenylimidazolyl)methyl]aimno]carbonyI]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate EDC (138 mg, 0 72 mmol) was added to a soluuon of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (175 4 mg, 0 6 5 mmol), 4-ammomethyl-2-phenylimidazole dihydrochlonde (177.2 mg, 0 72 mmol), H0BT-H20 (97 3 mg, 0 72 mmol), and dusopropylethylamme (0 52 mL, 3 0 mmol) m anhydrous DMF (3 mL) at RT After 22 h, the reaction was concentrated on the rotavap (high vacuum), and the residue was partitioned between H2O and EtOAc The layers were separated, and the aqueous was extracted with CHCI3 The organic 10 layers were combined, which caused an oil to separate This was dissolved by addition of MeOH. Drying (MgS04), concentration, and reconcentration from xylenes (to remove DMF) left a yellow semisolid residue Chromatography (silica gel, 10% MeOH/CHCl3) gave the tide compound (230 mg, 86%) as an oily foam which sohdified to an off-white sohd on treatment with EtOAc TLC Rf 0.42 (10% 15 MeOH/CHCl3), *H NMR (400 MHz, 10% CD3OD/CDCI3) 6 7 82 (d, J=7 3 Hz, 2H), 7 28-7 57 (m, 5H), 7 03 (s, IH), 6.54 (d, J=8 5 Hz, IH), 5 48 (d, J=16.6 Hz, IH), 5.12 (t, 3=6 8 Hz, IH), 4 52 (s, 2H), 3 79 (d, J=16 6 Hz, IH), 3.73 (s, 3H), 3.06 (s, 3H), 2 98 (dd, J=16 2,7 6 Hz, IH), 2 66 (dd, J=16 2, 6 0 Hz, IH), MS (ES) m/e 470.2 (M+Na)+, 448.2 (M+H)+ c) (±M[[4-(2-Pbenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid A suspension of methyl (±)-[[[4-(2-phenylimidazolyl)methyl]amino]carbonyl]-4-methy l-3-oxo-2,3,4,5-tetrahydro-1H-25 l,4-benzodiazepine-2-acetate (229 6 mg, 0.51 mmol), 1 0 N LiOH (0 61 mL, 0 61 mmol), THF (2.6 mL), and H2O (2 mL) was stirred at RT A homogeneous solution had formed within 15 mm After 2.5 h, the reaction was concentrated to about 1 mL and filtered An extra portion of H2O (2 mL) was used in the filtration The filtrate was neutralized with 10N HCl (061 mL), and the solid was collected and washed 30 with H2O The resulting solid was tnturated with hot 1 1 CH3CN/H2O, filtrered, and washed sequentially with CH3CN and H2O Drying in high vacuum gave the title compound (187 4 mg, 82%) as a colorless powder HPLC k' 1 6 (PRP-1®, 20% CH3CN/H2O-O 1% TFA), JH NMR (400 MHz, DMSO-d6) 8 8 32-8 47 (m, IH), 7 90 (d, 3=7 5 Hz, 2H), 7 51-7 61 (m, 2H), 7 38-7 48 (m, 2H), 7.26-7 36 (m, IH), 35 7 01 (br s, IH), 6 54 (d, J=8 3 Hz, IH), 6 30 (s, IH), 5 48 (d, J=16 5 Hz, IH), 5 02-5 12 (m, IH), 4 38 (br s, 2H), 3 81 (d, J=16 5 Hz, IH), 2 91 (s, 3H), 2 76 (dd, 138 J=16 7,9.1 Hz, IH), 2 54 (dd, J=16.7,4 9 Hz, 1 H, partially obscured by residual solvent signal), MS (ES) m/e 434 2 (M+H)+. Anal Calcd for C23H23N5O4 0 75 H20 C, 61 81; H, 5.52, N, 15 67 Found* C, 62 05, H, 5 44, N, 15 59 Example 54 Preparation of C±')-7-nT2-('3-indolvDethvnarruno'lcarbonvl~l-4-methvl-3-oxo-2.3-4.5-tetrahydro-1H-1.4-benzodiazepme-2-acetic acid a) Methyl (±)-7-[[[2-(3-Indolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate 10 Followmg the procedure of Example 26(d), except substituting 3-(2- aminoethyl)indole for the l-methyl-2-(methylamino)methylindole, the tide compound was prepared (50%). MS (ES) m/e 435 2 (M+H)+ b) (±)-7-[[[2-(3-Indolyl)ethyl]amino]carbonyI]-4-rnethyl-3-oxo-2,3,4,5-15 tetrahydro-1H-1,4-benzodiazepine-2-acetic acid Following the procedure of Example 26(e), methyl (±)-7-[[[2-(3-Indolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-1,4-benzodiazepme-2-acetate was saponified to give the title compound as a colorless sohd MS (ES) m/e 421.0 (M+H)+. Anal Calcd for C23H24N4O4 1 3 H20 C, 20 62 24, H, 6 04, N, 12 24 Found C, 62.31, H, 5 61, N, 12 04 Example 55 Preparation of (S)-7-frf2-(4-phenvhmidazolvl)methvIlaminolcarbonvll-4-methvl-3-oxo-2.3.4.5-tetrahvdro-lH-l .4-benzodiazepme-2-acetic acid a) Methyl (S)-7-[[[2-(4-phenyliinidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepme-2-acetate Followmg the procedure of Example 23(a) except substituting 2-(aminomethyl)-4-phenyl imidazole (Aust J Chem., 1971,24,2389) for 2-(aminomethyl)imidazole, the utle compound was prepared* MS (ES) m/e 448 (M+H)+ b) (S)-7-[[[2-(4-Phenylimidazolyl)methyljamino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid Followmg the procedure of Example 23(b) methyl (S)-7-[[[2-(4-phenyhmidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-1,4-benzodiazepine-2-acetate was saponified to give the title compound MS (ES) 139 WO 96/00730 PCT/US95/08306 m/e434(M+H)+ Anal Calcd for C23H23N5O4 • 0 5 CF3CO2H 0 5 HCl 1.75 H20 C, 47 01; H, 4 80, N 11.42 Found C, 47 14; H, 4.17, N, 11 51 Examples 56-75 Followmg the general procedures of Examples 1-55, the following compounds were prepared 56 (+/-)-2,3,4,5-Tetrahydro-7-[[[benzimidazol-2-yl)methyl3methylammo]carbonyl]-4-(3,3-dimethylbutyl)-3-oxo- IH-1,4-benzodiazepine-2-acetic acid, 10 57 (-)-7-[[[6-TnfluoromethylbenzimidazoyI-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-benzodiazepine-2-acetic acid, 58 (-)-7-[[[4,7-Dimethoxybenzimidazoyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-benzodiazepine-2-acetic acid, 59 (+/-)-2,3,4,5-Tetrahydro-7-[[[(benzimidazol-2-yl)methylanuno]carbonyl]-4-15 (3,3-dimethylbutyl)-3-oxo-1H-1,4-benzodiazepine-2-acetic acid, 60 (-)-7-[[[7-Methylbenzimidazol-2-ylmethyl]methylamino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-l ,4-benzodiazepme-2-acetic acid, 61 (2S)-[[[N-ammobutyl-N-(benzimidazlo-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl-2,3,4,5-tetrahydro- IH-1,4-benzodiazepine-2-acetic acidbis(tnfluoroacetate)salt, 62 (2S)-[[[N-cyanomethyl-N-(benzimidazlo-2-yl)methyI]amino]carbonyl]-3-oxcn4-methy 1-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid dihydrochlonde salt, 63 (S)-2,3,4,5-Tetrahydro-7-[[[(benzimidazol-2-yl)]methyl]anuno]carbonyl]-4-25 (4-phthalimidobutyl)-3-oxo-l,4-benzodiazepme-2-acetic acid, 64 (-)-7-[[[Imidazo[4,5B]-4,6-dimethylpyndyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-benzodiazepme-2-acetic acid tnfluoroacetate salt; 65 (+/-)-7-[[(2-Benzimidazol-2-ylmethyl)-N-methylammo]carbonyl]-2,3,4,5-30 tetrahydro-3-oxo-4-[2-(3',4'-methy lenedioxyphenyl)ethyl]- IH-1,4-benzodiazepine-2- acetic acid, 66 (+/-)-2,3,4,5-Tetrahydro-7-[[[(Ben2imidazol-2-yI)methyl]amino]carbonyl]-4-(2-methoxyethyl)-3-oxo-1H-1,4-benzodiazepme-2-aceac acid, 67 (S)-7-[[2-[ 1 -Methylbenzimidazolyl]benzimidazolylmethylamino]carbonyl]-35 2,3,4,5-tetrahydro-4-methyl-3-oxo-lH-l,4-benzodiazepine-2-acetic acid, 140 WO 96/00730 PCT/DS95/08306 68 (S)-7-[[[N-Cyclohexyl-N-(benzimidazol-2-yI)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetic acid, 69 (S)-7-[[[2-Bis-(Benzimidazolylmethyl)aminocarbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepme-2-acetic acid, 70 (+/-)-2,3,4,5-Tetrahydro-7-[[[imidazo[4,5-B]pynd-2- yl]methyl]methylamino]carbonyl]-4-(3,3-dimethylbutyl)-3-oxo-lH-l,4-benzodiazepine-2-acetic acid, 71 (+/-)-7-[[(2-Benzimidazol-2-ylmethyl)-N-methylamino]carbonyl-2,3,4,5-tetrahydro-3-oxo-4-(2',2',2'-tnfluoroethyl)-1H-1,4-benzodaizepme-2-acetic acid, 10 72 (+/-)-7-[[(2-Benzimidazolyl)acetyl]amino]-5-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid, 73 (+/-)-7-[[(2-Benzimidazol-2-ylmethyl)ammo]carbonyl]-23.4,5-tetrahydro-3-oxo-4-(2',2',2,-tnfluorbethyl)-1H-1,4-benzodiazepine-2-acetic acid, 74 (-)-7-[[[5,6-Difluorobenzimidazoyl-2-ylmethyl]aminornethyl]carbonyl]-15 2,3,4,5-tetrahydro-4-methyl-3-oxo-1,4-benzodiazepine-2-acetic acid; and 75 (+/-)-7-[[Bis-(Benzimidazol-2-ylmethyl)aimno]cart>onyl]-2,3,4,5-tetrahydro-4-phenylethyl-3-oxo~ 1H-1,4-benzodiazepme-2-acetic acidtns(tnfluoroacetate)salt Example 76 Preparation of 4-r2-fTn-r(Tten7.imidazol-2-vl)methvllben2imidazol-2-vllmethvllmethvlaminolacetvnphenoxvaceucacid a) 4-[2-(BOC-methylanuno)acetyl]phenol A solution of di-tert-butyl dicarbonate (5 96 g, 273 mmol) in 1,4-dioxane (25 mL) was added dropwise at 0°C to a mixture of 4-[2-25 (methylamino)acetyl]phenol hydrochloride (5 0 g, 24 8 mmol), 1,4-dioxane (30 mL), H2O (25 mL) and 1.0 N NaOH (25 mL, 25 mmol) After 24 h, the reaction was warmed to RT and stirred for 1 5 hr More 1.0 N NaOH (25 mL, 25 mmol) was added, and the reaction was stirred for an additional 0 5 h at RT, then was evaporated on the rotavap The residue was diluted with EtOAc (80 mL), and the 30 mixture was acidified to pH 2 using 1 0 M NaHS04 The resulting mixture was extracted with EtOAc, and the combmed organic layers were washed with H2O and dned (Na2S04) Filtration and concentration gave the title compound (6 49 g, 99%) iH NMR (250 MHz, CDCI3) 8 6 70-8 05 (m, 4 H), 4.53 (s, 2H), 2 98 (s, 3H), 1 50 (s, 9H) 141 b) Benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate A mixture of 4-[2-(BOC-methylamino)acetyl]phenol (5 04 g, 19 0 mmol) and K2CO3 (2 63 g, 19 0 mmol) in acetone (100 mL) was stirred at reflux under argon for lh The mixture was cooled to RT and benzyl bromoacetate (5.23 g, 22 8 5 mmol) was added The reaction was heated at reflux for 18 h, then was cooled and filtered The filter cake was washed with acetone, and the filtrate was concentrated on the rotavap The residue was dissolved in CH2CI2 (300 mL) and washed sequentially with H2O (50 mL) and bnne (50 mL) Drying (Na2S04), concentration, and flash chromatography ( silica gel, 1.3 EtOAc/hexanes) yielded the 10 Utle compound (7 28 g, 93%) *H NMR (250 MHz, CDCI3) 5 6 85-7 95 (m, 9 H), 5.23 (s, 2H), 4 71 (s, 2H), 4 55 (d, 2H), 2 95 (d, 3H), 1 45 (d, 9H) c) Benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochlonde A mixture of benzyl 4-[2-(BOC-methylammo)acetyl]phenoxyacetate (7.26 g, 15 17 57 mmol) and 4 M HCl in 1,4-dioxane (150 mL) was stirred for 1 h at RT Evaporation on the rotavap and trituration with Et20 afforded the title compound as a white powder (5 93 g, 97%) *H NMR (250 MHz, CD3OD) 5 7.05-8 00 (m, 9 H), 5 23 (s, 2H), 4 88 (s, 2H), 4 65 (s, 2H), 2 80 (s, 3H) d) Benzyl 4-[2-[[[l-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylammo]acetyl]phenoxyacetate Et3N (0 28 g, 2 78 mmol) was added slowly to a mixture of benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochlonde (0 39 g, 1 11 mmol), 2-(chloromethyl)benzimidazole (0.24 g, 1 45 mmol), CH3CN (20 mL), and CH2CI2 (5 25 mL) at RT under argon After 5 h, the reaction mixture was concentrated on the rotavap The residue was dissolved in CH2CI2 and washed sequentially with 5% NaHC03 and bnne. Drying (MgS04), concentration, and flash chromatography ( silica gel, step gradient, 7-15% MeOH/CH2Cl2) yielded the tide compound as an off-white powder (0.08 g, 12%) MS (ES) m/e 574 2 [M + H]+. e) 4-[2-[[[ 1 -[(Benzimidazol-2-yl)methyl]benztmidazol-2-yl]methyl]methylamino]acetyl] phenoxyacetic acid A mixture of benzyl 4-[2- [[ [ 1 -[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylammo]acetyl]phenoxyacetate (0 08 g, 0 18 mmol) and 5% Pd/C 35 (0 11 g) in MeOH (15 m L) was shaken on a Pan- apparatus under H2 (41 psi) for 1 h The mixture was filtered through a bed of Celite®, and the filter pad was washed 142 with glacial AcOH and MeOH. The filtrate was concentrated to give the crude product (0 07 g) Preparative HPLC (Hamilton PRP-1® column, step gradient, 10-30% CH3CN/H2O-O 1% TFA) afforded the tide compound MS (ES) m/e 484 2 [M + H]+ Anal Calcd for C27H25N5O4 3 C2HF3O2 C, 48 01, H, 3 42 N, 8 48 5 Found. C, 48 40, H, 3.72, N, 8.77 Example 77 (±)-4-rr2-r(Ben2imidazoI-2-vl')methvllmethvlaminol-1 -hydroxvethvll-1.2-phenvlenedioxvdiacetic acid 10 a) N-Cbz-Adrenalone Adrenalone hydrochlonde (28 6 g, 0 121 mole) was added to 2 0 N NaOH (200 mL, 0 2 mol) which was first cooled to 5°C in an ice bath 2.0 N NaOH (60 mL, 0 06 mole) in one addition funnel and a solution of benzyl chloroformate (17 3 mL, 0 121 mol) in toluene (18 mL) in another addition funnel were added at rates 15 such that the reaction temperature remained between 5-10°C and that addition of both solutions was completed simultaneously. The resulting brown solution was stirred at 5°C for 75 min, then was diluted with H2O (230 mL) and acidified with 1.0 N HQ (536 mL) A gummy precipitate formed initially, but solidified on tnturation with a glass rod followed by stimng for 30 mm The pale green solid was filtered, 20 stirred bnefly with H2O, filtered, stirred bnefly with EtOH, and filtered The resulting sohd was ground in a mortar with more EtOH, then was filtered and dned in vacuum to afford the title compound (28 6 g, 75%)- mp 183-186°C b) Dimethyl 4-[2-(Cbz-methylamino)acetyl]-1,2-phenylenedioxydiacetate 25 A mixture of N-Cbz-adrenalone (23 6 g, 74 8 mmole), acetone (340 mL), and anhydrous K2CO3 (21 0 g, 152 mmole) was heated at reflux under argon After 70 nun, the beige suspension was cooled to RT, and methyl bromoacetate (17 9 mL, 189 mmole) was added The resulting suspension was stirred at RT under argon for 16 hr, then was heated to 50°C. After 6 h, the mixture was cooled to RT and 30 filtered, and the filtrate was concentrated to dryness The residue was dissolved m CH2CI2 and washed sequentially with H20 and 5% K2CO3 Drying (Na2S04) and concentration gave the title compound as an oil which sohdified on standing (26 35 g, 82%) mp 56 - 59°C 143 PCI7US95/08306 c) Dimethyl 4-[2-(methylamino)- 1-hydroxyethyl]-1,2-phenylenedioxydiacetate Following the procedure of Example 76(e), except substituting dimethyl 4-{2-(Cbz-methylamino)acetyl]-l ,2-phenylenedioxydiacetate (2 1 g, 4 57 mmol) for benzyl 4-[2-[[[ 1 -[(benzimidazol-2-yl)methyl]benzimidazol-2-5 yl]methyl]methylamino]acetyl] phenoxyacetate and using EtOAc (50 mL) and MeOH (20 mL) as solvents, the title compound (1 34 g, 90 %) was prepared MS (ES) m/e 328 0 [M + H]+. d) Dimethyl (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-l-hydroxyethyl]-10 1,2-phenylenedioxydiacetate Following the procedure of Example 76(d), except substituting dimethyl 4-[2-(methylamino)-1 -hydroxyethyl]-1 ,2-phenylenedioxydiacetate (1 37 g, 4 20 mmol) for benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride, the title compound was prepared (0 25g, 13 %) MS (ES) m/e 458 2 [M + H]+ e) (±)-4-[[2-[(Benzimidazol-2-yl)methyl]methylamino]-1 -hydroxyethyl]-1,2-phenylenedioxydiacetic acid A mixture of dimethyl (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-1-hydroxyethyl]-1,2-phenylenedioxydi acetate (0 23 g, 0 5 mmol), THF (10 mL), 20 H2O (10 mL), and 1.0 N LiOH (2 0 mL, 2.0 mmol) was stirred at RT for 26 h The reaction mixture was concentrated on the rotavap, and the aqueous residue was acidified with 10N AcOH (2 mL) with cooling m an ice bath The resulting mixture was lyophihzed to give the crude product (0 32 g) Preparative HPLC (Hamilton PRP-1® column, 10% CH3CN/H2O-0.1% TFA) afforded the title 25 compound MS (ES) m/e 430 2 [M + H]+ Anal Calcd for C21H23N3O7 7/2 C2HF3O2 C, 39 73, H, 3 39 N, 4 97 Found C, 39 47, H, 3 38, N, 4 86 Example 78 4-r2-H"(Benzimidazol-2-vl)methvnmethvlamino1acetvl1-1.2-phenvlenedioxvdiacetic 30 acid a) l-BOC-2-methylbenzimidazole A mixture of 2-methylbenzimidazole (1 5 g, 11.35 mmole), Et3N (1 66 mL, 11 92 mmole), DMAP (0 20 g, 1 6 mmole), and (BOQ2O (2.60 g, 11 92 mmole) m anhydrous CH2CI2 (15 mL) was stirred at RT for 24 hr, then was concentrated The 35 residue was taken up in H2O, stirred, and filtered to afford the title compound as a colorless sohd (2.63 g, 100%) mp 71-72°C 144 b) l-BOC-2-(bromomethyl)benzimidazole NBS (8 43 g, 47 4 mmol) and AIBN (2 1 g, 12 8 mmol) were added to a solution of l-BOC-2-methylbenzimidazole (10 0 g, 43 1 mmol) in CCI4 (120 mL) at 5 reflux After 21 h, the reaction was cooled and filtered Tne filtrate was concentrated, and the resulting brown oil was chromatographed (silica gel, 15% EtOAc/hexanes) to afford the title compound *H NMR (400 MHz, CDCI3) 8 7 94 -8 01 (m, 1 H), 7 70-7.75 (m, 1 H), 7 31 - 7 44 (m, 2 H), 4.96 (s, 2 H), 1 75 (s, 9 H) c) 4-[2-(BOC-methylamino)acetyl]-1,2-dihydroxybenzene Following the procedure of Example 76(a), except substituting adrenalone hydrochlonde (5 0 g, 23 0 mmol) for 4-[2-(methylamino)acetyI]phenol hydrochloride, the title compound (1 2 g, 19%) was prepared following flash chromatography (silica gel, 1.1 EtOAc/hexanes) MS (ES) m/e 282 2 [M+H]+ d) Dimethyl 4-[2-(BOC-methylamino)acetyl]-1,2-phenylenedioxydiacetate Following the procedure of Example 76(b), except substituting 4-[2-(BOC-methylamino)acetyl]-l,2-dihydroxybenzene (0 9 g, 3 2 mmol) for 4-[2-(BOC-methylamino)acetyl]phenol and methyl bromoacetate (1.23 g, 8 0 mmol) for benzyl 20 bromoacetate, the title compound (1 11 g, 81 %) was prepared MS (ES) m/e 426 2 [M+H]+. e) Dimethyl 4-[2-(methylamino)acetyl]-1,2-phenylenedioxydiacetate hydrochloride Following the procedure of Example 76(c), except substituting dimethyl 4-25 [2-(BOC-methylamino)acetyl]-l,2-phenylenedioxydiacetate (1 11 g, 2 6 mmol) for benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate, the title compound was prepared (1.1 g, quantitative) MS (ES) m/e 326 0 [M+H]+ f) Dimethyl 4-[2-[[(l-BOC-benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-30 phenylenedioxydiacetate Followmg the procedure of Example 76(d), except substituting dimethyl 4-[2-(methylamino)acetyl]-l ,2-phenylenedioxydiacetate hydrochlonde (0 24 g, 0 66 mmol) for benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochlonde, 1-BOC-2-(bromomethyl)benzimidazole (0 31 g, 0 99 mmol) foi2-35 (chloromethyl)benzimidazole, and using THF (5 mL) and CH2CI2 (5 mL) as 145 solvents, the title compound was prepared (0 14 g, 38%) MS (ES) m/e 556 2 [M+H]+ g) Dimethyl 4-[2-[[(benzimidazol-2-yl)methyl]methylanuno]acetyl]-1,2-5 phenylenedioxydiacetate bis(tnfluoroacetate) A mixture of dimethyl 4-[2-[[(l-BOC-benzimidazol-2-yl)methyl]methylamino]acetyl]-l,2-phenylenedioxydiacetate (0.13 g, 0.23 mmol) in TFA 4 mL) and CH2CI2 (12 mL) was stirred at RT under argon for 20 nun Removal of the solvents on the rotavap gave the title compound (0.18 g, 10 quantitative)- MS (ES) m/e 456.2 [M + H]+ h) 4-[2-[[(Benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetic acid Following the procedure of Example 77(e), except substituting dimethyl 4-15 [2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-lf2-phenylenedioxydiacetate bis(tnfluoroacetate) (0.16 g, 0.23 mmol) for dimethyl 0±)-4-[[2-[(benzuiudazol-2-yl)methyl]methylamino]-l-hydroxyethyl]-1,2-phenylenedioxydiacetate, the title compound was prepared (0.08 g, 80%) MS (ES) m/e 428 2 [M + H]+ Anal Calcd for C21H21N3O7 • 11/5 C2HF3O2 9/5 H2O C, 42 93, H, 3.80 N, 5 91. Found 20 C, 42.62, H, 3 52, N, 6.30.
Example 79 Preparation of 3-IT4-ITffBenzimidazol-2-vDmethv1amino1carbonvllphenvllamino1 propionic Acid 25 a) ethyl 3-[4-(carboxy)phenylammo]propionate A solution of 4-aminobenzoic acid (6.85 g, 0 05 mol) and ethyl acrylate (15 g, 0.15 mol) in acetic acid (40 mL) was heated to 100°C for 15 h. The sohd which formed was filtered, washed with hexane and dned to give of the title compound (7 5 g, 63%) b) ethyl 3-[[4-[[[(benzimidazol-2-yl)methy]ammo]carbonyl]phenyl]amino]propionic acid The compound of Example 79(a)(0 3 g, 1 26 mmol) in thionyl chlonde (10 mL) was heated to reflux for 10 min, cooled, concentrated in vacuo, and residual 35 thionyl chlonde was removed by addition of methylene chlonde followed by concentration m vacuo The residual oil was dissolved in methylene chlonde and 146 treated with 2-(aminomethyl)benzimidazole dihydrochlonde hydrate (0 33 g, 1 5 mmol) and diisopropylethylamine (0.56 g, 4 3 mmol) The resulting mixture was surred overnight, washed with water and the organic phase was dned (sodium sulfate) and concentrated in vacuo The resulting pale yellow sohd was 5 chromatographed (silica gel, methanol-dichloromethane 3 97) and fractions containing the product were pooled and concentrated in vacuo to give the title compound MS(ES) m/e 367 [M+H]+ c) 3-[[4-[[[(benzimidazoI-2-yl)methylamino]carbonyl]phenyl]amino]propionic acid 10 A solution of the compound of Example 79(b)(0 4 g, 1 1 mmol) in methanol (20 mL), water (2 mL) and 0 95N aqueous sodium hydroxide (2.5 mL) was stirred and heated to 50°C for 2 h The mixture was treated with tnfluoroacetic acid (1 mL), concentrated in vacuo, and the residue was tnturated with dichloromethane (4 x 100 mL) The resulting white sohd was recrystaJlized from 20% 15 acetonitnle/water-0 1% tnfluoroacetic acid to give the title compound MS(ES) m/e 339 [M+H]+ Example 80 Preparation of 4-r4-ri-(2-Methvlbenzimida2ovl)pipendinvlll-pipendineacetic acid 20 sodium salt a) Methyl 4-[4-[l-(t-butyloxycarbonyl)pipendinyl]]pipendineacetate A mixture of t-butyi l-(4,4'-bipipendine)carboxylate (3 1 g, 10 mmol), prepared as descnbed by Bondinell, et al (WO 93/00095), methyl bromoacetate (1 7 g, 11 mmol), and tnethylamine (2 3 g, 22 mmol) in DMF (15 mL) was heated ar 85 °C for 25 4 h The reaction mixture was diluted with EtOAc (50 mL), partitioned between NaHC03 (5% soution, 100 mL) and extracted with EtOAc (2x50 mL) The combmed organic extracts were washed with H2O, saturated NaCl soution, dned over MgS04, and evaporated to give the titled compound (3.37 g, 99%) MS (ES) m/e 341 2 [m+H]+ b) Methyl 4-[4-(l-pipendmyl)]pipendineacetate 147 PCT/US95/G8306 A mixture of Example 1(a) (3 37 g, 10 mmol) and 4M HCl in dioxane (20 mL) in CH2CI2 (25 mL) was stirred at RT for 18 h The resulting white suspension was filtered to give the tided compounds as the dihydrocjlonde (3.1 g, 99%) c) Methyl 4-[4-[-1 -(2-Methylbenzimidazoyl)pipendinyl]]-piperidineacetate To a stirred solution of Example 1(b) (2 g, 6 4 mmol) and tnethylamine (3.6 mL, 25 6 mmol) in CH2CI2 (50 mL) was added m portions a suspension of 2-chloromethylbenzimidazole (1 1 g, 6 6 mmol) m CH2C12 (25 mL) at RT After stirring foi 4 h, the reaction mixture was diluted with CH2CI2 (50 mL), partitioned 10 between NaHCC>3 (5% soution, 100 mL) and extracted with CH2CI2 (2x50 mL). The combined organic extractswere washed with H2O, a saturated NaCl soution, dried over MgS04, and evaporated The tided compound was punfied by flash chromatograpy (S1O2/ 6% MeOH/CH2Cl2) to yield the tided compound (0.36 g, 16%) iH NMR (400MHz, CDCI3) 5 1 07 (m, 2H), 1 35 (m, 4H), 1 65 (t, J= 9 1, 15 4H), 2 09 (q, J= 10 9,4H), 2 93 (m, 4H), 3 20 (s, 2H), 3 71 (s, 3H), 3 79 (s, 2H), 7.22 (m, 2H), 7 56 (bs, 2H) MS (ES) m/e 471.2 [m+H]+. d) 4-[4-[l-(2-Methylbenzimidazoyl)pipendwyl]]-piperidineacetic acid sodium salt To a stirred solution of Example 1(c) (0 45 g, 1 2 mmol) in MeOH (15 mL) was 20 added IN NaOH solution (8 5 mL, 8 5 mmol) at RT After 18 h, the white suspension was filtered to white sohd (0 2 g, mp > 250 °C, 43%,) as the tifled compound. MS (ES) m/e 357 2 [m+H]+ *H NMR (400MHz, CD3OD) 5 1 10 (bm, 2H), 1 34 (bm, 4H), 1 73 (bm, 4H), 2 11 (bm, 4H), 3 05 (m, 6H)„ 3 77 (s, 2H), 7 21 (bm, 2H), 7 52 (bm,2H) Anal Calcd for C2o H27 N4 C^Na. 0 375 H20 C, 62 36, H, 7 26, N, 14 54 Found. C, 62.38, H, 7.20 N, 14.32 Example 81 la) Benzyl 4-bromobutyrate 30 To a stirred, cooled (O0C) mixture of benzyl alcohol (1 0 g, 5.392 mmol) and pyndine (0.47 g, 5 9312 mmol) in anhydrous methylene chlonde (10 mL) was added 148 4-bromobutyryl chlonde (0.58 g, 5 9312 mmol) After stimng in 1 h at room temperature, the mixture was concentrated, taken up m H2O, extracted with EtOAc, washed with bnne, dned over MgS04t filtered and concentrated to give a colorless oil (1.38 g, 100%) *H NMR (CDCI3, 300 MHz) 8 2 24 (m, 2H), 2 59 (t, J=5 7 Hz, 5 2H), 3 48 (t, J=5 7 Hz, 2H), 5.14 (s, 2H), 7 38 (m, 5H) lb) (S)-Benzyl 4-(N-t-Boc-tyrosme methyl ester)butyrate A mixture of Example la (1 57 g, 6 1177 mmol), N-t-Boc-tyrosine methyl ester (1 80 g, 6.1177 mmol), and CSCO3 in dned DMF (10 mL) was stirred at RT in 20 h 10 The mixture was concentrated, taken up in H2O, extracted with EtOAc The organic extracts were washed by bnne, dned over MgS04> filtered and concentrated to give 2 30 g brown oil of the tide compound (79%) *H NMR (300 MHz, CDCI3) 8 147 (s, 9H), 2.15 (m, 2H), 2.59 (t, J= 5 7 Hz, 2H), 3 03 (m, 2H), 3.70 (s, 3H), 3.97 (t, J=5.7 Hz, 2H), 4 55 (m, IH), 4.97 (d, 5 8 Hz, IH), 5 12 (s, 2H), 6 78 (d, J= 8 3 Hz, 15 2H), 7 05 (d, J=8 3 Hz, 2H), 7.41 (m, 5H) lc) (S)-Benzyl 4-(tyrosine methyl ester)butyrate To a stirred solution of Examplelb (2.30 g, 4 8778 mmol) in dned CH2CI2 (10 mL) was added 12 mL of TFA. After stimng at RT in 3 h, the mixture was concentrated, 20 taken up m H2O, neutralized by 2.5N NaOH, extracted with CH2CI2, dned over MgS04, filtered, and concentrated to give a brown oil (1 60 g, 88%) IH NMR (300 MHz, CDC13) 8 2 15 (m, 2H), 2 55 (t, J=5.7 Hz, 2H), 2 95 (dd, J=13 8 Hz, 7 3 Hz, IH), 3 13 (dd, J=13 8 Hz, 7.3 Hz, IH), 3 70 (s, 3H), 3.97 (t, J=5 7 Hz, IH), 4 95 (d, J=7 3 Hz, IH), 5 15 (s, 2H), 6 80 (d, J=8 3 Hz, 2H), 7 10 (d, J=8 3 Hz, 2H), 7.35 (m, 25 5H) Id) (S)-Benzyl 4-[(N-butylsulfonyl) tyrosme methyl ester]butyrate To a stirred mixture of Example lc (1 60 g, 4 3079 mmol) and pyndine (0 41 g, 5 1695 mmol) in dned CH2CI2 (15 mL) was added n-butylsulfonyl chionde (0 81 g, 30 5 1695 mmol) After stimng at RT m 2 h, the mixture was concentrated, taken up in H2O, extracted with EtOAc The organic extracts were washed by 2N HCl, saturated 149 NaHC03, bnne, dned over MgSO^ filtered, and concentrated to give a brown oil (2 01 g, 95%) IH NMR (300 MHz, CDC13) 8 0.89 (t, J=7.3 Hz, 3H), 1.37 (m, 2H), 1 65 (m, 2H), 2 20 (m, 2H), 2 60 (t, J=5 7 Hz, 2H), 2.72 (t, J=7.3 Hz, 2H), 2 95 (dd, J=13 8 Hz, 7 3 Hz, IH), 3.10 (dd, J=13.8 Hz, 7 3 Hz, IH), 3 77 (s, 3H), 3.93 (t, 5 J=5 7 Hz, 2H), 4.30 (in, IH), 4.70 (d, J=7 3 Hz, IH), 5 12 (s, 2H), 6.80 (d, J=8 3 Hz, 2H), 7 03 (d, J=8.3 Hz, 2H), 7 35 (m, 5H) le) (S)-4-[(N-butylsulfonyl)tyrosine methyl ester]butync acid A soluuon of Example Id (0.781 g, 1.589 mmol) in MeOH (10 mL) was 10 hydrogenated at 50 PSI in 10% Pd/C (0 50 g) in 3 h The catalyst was filtered through cehte. The filtrate was concentrated to give a white sohd (0 59 g, 93%). IH NMR (300 MHz, CDC13) 8 0.89 (t, J=7.3 Hz, 3H), 1 35 (m, 2H), 1 65 (m, 2H), 2 10 (m, 2H), 2 55 (t, J=5.7 Hz, 2H), 2 75 (t, J=7 3 Hz, 2H), 2 95 (dd, J=13 8 Hz, 7.3 Hz, IH), 3 05 (dd, J=13 8 Hz, 7.3 Hz, IH), 3 48 (s, 3H), 3 97 (t, J=5 7 Hz, 2H), 4 30 (m, 15 IH), 4 90 (d, J=7.3 Hz, IH), 6 90 (d, J=8 3 Hz, 2H), 7 10 (d, J=8.3 Hz, 2H).
If) (S)-N-butylsulfonyl-4-(3-(benzimidazol-2-yl)propyl)tyrosme methyl ester To a stirred, cooled (0^C) mixture of Example le (0.595 g, 1.4823 mmol) and Et3N (0.16 g, 1 5565 mmol) in dned THF (7 mL) was added isobutylchloroformate (0.212 20 g, 1 5565 mmol). After stimng at O^C in 1 h, o-phenylenediamme (0 16 g, 14823 mmol) and 1 mL of HO Ac was added The reacuon mixture was heated at reflux overnight The mixture was cooled, diluted with EtOAc, washed by H2O, saturated NaHC03, bnne, dned over MgS04, concentrated and punfied by flash column chromatograph (5% Me0H/CH2Cl2) to give a white foam (0.487 g, 69%) *H NMR (300 MHz, CDCI3) 8 0.89 (t, J=7 3 Hz, 3H), 1 35 (m, 2H), 1 65 (m, 2H), 2.30 (m, 2H), 2 80 (t, J=5 7 Hz, 2H), 2 95 (dd, J=13 8 Hz, 7 3 Hz, IH), 3.10 (m, 3H), 3.0 (s, 3H), 3 98 (t, J=5 7 Hz, 2H), 4 35 (m, IH), 4 90 (d, 7.3 Hz, IH), 6 77 (d, j=8 3 Hz, 2H), 7 03 (d, J=8.3 Hz, 2H), 7 26 (m, 2H), 7 58 (m, 2H) lg) (S)-N-Butylsulfonyl-p-[3-(2-benzimidazoyl)propyl]tyrosine To a stirred solution of Example If (0 487 g, 1 0285 mmol) in MeOH (5 mL) was added LiOH H2O (0.09 g, 2.0571 mmol) in 24 h The mixture was concentrated, diluted in H2O, neutralized with 2 ON HCl The off white solid was filtered, tnturated in hot EtOH to give the title compound as a white sohd (0 377 g, 80%, 5 Mp >230 °C) *H NMR (300 MHz, DMSO-d6) 5 0 75 (t, 7 3 Hz, 3H), 1 15 (m, 2H), 1.30 (m, 2H), 2.20 (m, 2H), 2 52 (m, 2H), 2 75 (dd, J=13 8 Hz, 7 3 Hz, IH), 2 97 (dd, J= 13.8Hz, 7 3 Hz, IH), 3 00 (t, J=5 7 Hz, 2H), 3 90 (m, IH), 4 10 (t, J=5.7 Hz, 2H), 6 85 (d, 8.3 Hz, 2H), 7 10 (m, 2H), 7 20 (d, J=8 3 Hz, 2H), 7 50 (m, 2H), 7 61 (d, J=7 3 Hz, IH) IR (cm"1, KBr) 3300-3400, 3244,3000-3100, 2800-300, 10 1634„ 1612,1512,1466,1384, 1245,1148, 1110 MS (ESI, M+H) 460 2 Anal Calc. for C23H29N305S C, 60 11, H, 6 36, N, 9 14, Found C,60 01, H, 6 34, N, 9 01 Example 82 Preparation of 4-f2-ffri-f(Benzimidazol-2-vl)methvllbenzimidazol-2-vllmethvllmethvlaminolacetvnphenoxvacetic acid a) 4-[2-(BOC-methylamino)acetyl]phenol A solution of di-tert-butyl dicarbonate (5 96 g, 27 3 mmol) in 1,4-dioxane (25 mL) was added dropwise at 0°C to a mixture of 4-[2-20 (methylamino)acetyl]phenol hydrochlonde (5 0 g, 24 8 mmol), 1,4-dioxane (30 mL), H2O (25 mL) and 10N NaOH (25 mL, 25 mmol) After 24 hr, the reaction was warmed to RT and stirred for 1 5 hr More 10N NaOH (25 mL, 25 mmol) was added, and the reaction was stirred for an additional 0 5 h at RT, then was evaporated on the rotavap The residue was diluted with EtOAc (80 mL), and the 25 mixture was acidified to pH 2 using 1 0 M NaHS04 The resulting mixture was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with H2O (30 mL) ana dned (Na2S04) Filtration and concentration gave the tide compound (6 49 g, 99%)- *H NMR (250 MHz, CDCI3) 5 6 70-8 05 (m, 4 H), 4 53 (s, 2H), 2 98 (s, 3H), 1 50 (s, 9H) 151 WO 96/00730 PCT/DS95/08306 b) Benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate A mixture of 4-[2-(BOC-methylamino)acetyl]phenol (5 04 g, 19 0 mmol) and K2CO3 (2 63 g, 19 0 mmol) in acetone (100 mL) was stirred at reflux under argon for lh The mixture was cooled to RT and benzyl bromoacetate (5 23 g, 22.8 5 mmol) was added The reaction was heated at reflux for 18 h, then was cooled and filtered The filter cake was washed with acetone, and the filtrate was concentrated on the rotavap The residue was dissolved in CH2CI2 (300 mL) and washed sequentially with H2O (50 mL) and bnne (50 mL) Drying (Na2S04), concentrauon, and silica gel flash chromatography (13 EtOAc/hexanes) yielded the 10 utle compound (7.28 g, 93%) *H NMR (250 MHz, CDCI3) 8 6 85-7.95 (m, 9 H), 5 23 (s, 2H), 4.71 (s, 2H), 4 55 (d, 2H), 2.95 (d, 3H), 1 45 (d, 9H) c) Benzyl 4-[2-(methylaimno)acetyl]phenoxyacetate hydrochlonde A mixture of benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate (7 26 g, 15 17 57 mmol) and 4 M HCl m 1,4-dioxane (150 mL) was stirred for 1 h at RT Evaporation on the rotavap and tnturaUon with Et20 afforded the title compound (5.93 g, 97%) as a white powder ill NMR (250 MHz, CD3OD) 8 7 05-8 00 (m, 9 H), 5.23 (s, 2H), 4 88 (s, 2H), 4 65 (s, 2H), 2 80 (s, 3H) d) Benzyl 4-[2-[[[l-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate Et3N (0 28 g, 2 78 mmol) was added slowly to a mixture of benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochlonde (0 39 g, 1 11 mmol), 2-(chloromethyl)benzimidazole (0 24 g, 1 45 mmol), CH3CN (20 mL), and CH2CI2 (5 25 mL) at RT under argon After 5 h, the reaction mixture was concentrated on the rotavap The residue was dissolved in CH2CI2 (100 mL) and washed sequenUally with 5% NaHC03 (2 x 20 mL) and bnne (20 mL) Drying (MgS04), concentration, and silica gel flash chromatography (step gradient, 7 - 15% MeOH/CH2Cl2) yielded the utle compound (0 08 g, 12%) as an off-white powder MS (ES) m/e 574.2 [M + 30 H]+ 152 WO 96/00730 PCT/US95/08306 e) 4-[2-[[[l-[(Benzimidazol-2-yl)methyl]benzimidazoI-2-yljmethyl]methylamino]acetyl] phenoxyacetic acid A mixture of benzyl 4-[2-[[[l-[(benzimidazol-2-yl)methyl]benzimidazol-2-yl]methyl]methylamino]acetyl]phenoxyacetate (0 08 g, 0 18 mmol) and 5% Pd/C 5 (0 11 g) m MeOH (15 m L) was shaken on a Pair apparatus under H2 (41 psi) for 1 h The mixture was filtered through a bed of celite®, and the filter pad was washed with glacial AcOH and MeOH The filtrate was concentrated to give the crude product (0 07 g) Preparative HPLC (Hamilton PRP-1® column, step gradient, 10 -30% CH3CN/H2O containmg 0 1% TFA) afforded the tide compound MS (ES) 10 m/e 484 2 [M + H]+ Anal Calcd for C27H25N5O4 3 C2HF3O2 C, 48 01, H, 3 42 N, 8 48 Found C, 48 40, H, 3 72, N, 8 77 Example 83 (±)-4-fT2-rfBenzimidazol-2-vl1methvPmethvlarmnol-1 -hvdroxvethvll-1.2-15 phenvlenedioxvdiacetic acid a) N-Cbz-Adrcnalone Adrenalone hydrochlonde (28 6 g, 0.121 mole) was added to 2 0 N NaOH (200 mL, 0 2 mole) which was first cooled to 5°C in an ice bath 2 0 N NaOH (60 mL, 0 06 mole) in one addition funnel and a solution of benzyl chloroformate (17.3 20 mL, 0.121 mole) m toluene (18 mL) in another addition funnel were added at rates such that the reacuon temperature remained between 5 - 10°C and that addition of both solutions was completed simultaneously. The resulting brown solution was stirred at 5°C for 75 min, then was diluted with H2O (230 mL) and acidified with 10N HCl (536 mL) A gummy precipitate formed initially, but solidified on trituration with a glass rod followed by stimng for 30 nun The pale green sohd was filtered, stirred bnefly with H2O (180 mL), filtered, stirred bnefly with EtOH (135 mL), and filtered The resulting sohd was ground m a mortar with more EtOH (135 mL), then was filtered and dned in vacuum to afford the title compound (28 6 g, 75%) mp 183 - 186°C 153 WO 96/00730 PCT/CS95/08306 b) Dimethyl 4- [2-(Cbz-methylamino)acetyl]-1,2-phenylenedioxydiacetate A mixture of N-Cbz-adrenalone (23 6 g, 74 8 mmole), acetone (340 mL), and anhydrous K2CO3 (21.0 g, 152 mmole) was heated at reflux under argon After 70 mm, the beige suspension was cooled to RT, and methyl bromoacetate (17.9 mL, 5 189 mmole) was added The resulting suspension was stirred at RT under argon for 16 hr, then was heated to 50°C After 6 hr, the mixture was cooled to RT and filtered, and the filtrate was concentrated to dryness The residue was dissolved in CH2CI2 (800 mL) and washed sequentially with H2O (160 mL) and 5% K2CO3 (2 x 100 mL) Drying (Na2SC>4) and concentration gave the title compound (26 35 g, 10 82%) as an oil which sohdified on standing- mp 56 - 59°C. c) Dimethyl 4-[2-(methylammo)-1 -hydroxyethyl]-1,2-phenylenedioxydiacetate Followmg the procedure of Example 82(e), except substituting dimethyl 4-[2-(Cbz-methylammo)acetyl]-l ,2-phenylenedioxydiacetate (2.1 g, 4.57 mmol) for 15 benzyl 4-[2-[[[ 1 -[(benzimidazol-2-yl)methyl]benzimidazol-2- yl]methyl]methyIamino]acetyl]-phenoxyacetate and using EtOAc (50 mL) and MeOH (20 mL) as solvents, the title compound (1 34 g, 90 %) was prepared MS (ES) m/e 328.0 [M + H]+ d) Dimethyl (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylamino]-I-hydroxyethyl]-1,2-phenylenedioxydiacetate Followmg the procedure of Example 82(d), except substituting dimethyl 4-[2-(methylamino)-1 -hydroxyethyl]-1,2-phenylenedioxydiacetate (1 37 g, 4 20 mmol) for benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochlonde, the title compound (0.25g, 13 %) was prepared: MS (ES) m/e 458.2 [M + H]+ e) (±)-4-[[2-[(Benzimidazol-2-yl)methyl]methylamino]-1 -hydroxyethyl]-1,2-phenylenedioxydiacetic acid A mixture of dimethyl (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylammo]-l-hydroxyethyl]-l,2-phenylenedioxydiacetate (0 23 g, 0 5 mmol), THF (10 mL), H2O (10 mL), and 1.0 N LiOH (2 0 mL, 2 0 mmol) was stirred at RT for 26 h The 154 reaction mixture was concentrated on the rotavap, and the aqueous residue was acidified with 1.0 N AcOH (2 mL) with cooling in an ice bath The resulting mixture was lyophihzed to give the crude product (0 32 g) Preparative HPLC (Hamilton PRP-1® column, 10% CH3CN/H2O containing 0 1% TFA) afforded the 5 title compound MS (ES) m/e 430 2 [M + H]+ Anal Calcd for C21H23N3O7 • 7/2 C2HF3O2 C, 39 73, H, 3 39 N, 4 97 Found C, 39 47, H, 3 38, N, 4 86 Example 84 4-r2-rr(Ben2imidazol-2-vl)methvllmethvlamino1acetvll-1.2-phenvlenedioxvdiacetic 10 acid a) l-BOC-2-methylbenzimidazole A mixture of 2-methylbenzimidazole (1 5 g, 11 35 mmole), Et3N (1 66 mL, 11 92 mmole), DMAP (0 20 g, 1 6 mmole), and (BOQ2O (2 60 g, 11 92 mmole) m anhydrous CH2CI2 (15 mL) was stirred at RT for 24 hr, then was concentrated The 15 residue was taken up m H2O, stirred, and filtered to afford the title compound (2.63 g, 100%) as a colorless sohd mp 71 - 72°C b) l-BOC-2-(bromomethyl)benzimidazole NBS (8 43 g, 47 4 mmole) and AIBN (2 1 g, 12 8 mmole) were added to a 20 solution of l-BOC-2-methyibenzimidazole (10 0 g, 43 1 mmole) in CCI4 (120 mL) at reflux After 21 hr, the reaction was cooled and filtered. The filtrate was concentrated, and the resulting brown oil was chromatographed on silica gel (15% EtOAc/hexanes) to afford the title product *H NMR (400 MHz, CDCI3) 8 7.94 -8 01 (m, 1 H), 7 70 - 7 75 (m, 1 H), 7 31 - 7 44 (m, 2 H), 4 96 (s, 2 H), 1.75 (s, 9 H) c) 4- [2-(BOC-methylamino)acetyl]-1,2-dihydroxybenzene Following the procedure of Example 82(a), except substituting adrenalcne hydrochlonde (5 0 g, 23 0 mmol) for 4-[2-(methylamino)acetyl]phenol hydrochlonde, the title compound (1.2 g, 19%) was prepared followmg silica gel 30 flash chromatography (1 1 EtOAc/hexanes) MS (ES) m/e 282.2 [M + H]+ 155 d) Dimethyl 4-[2-(BOC-methylammo)acetyl]-l,2-phenylenedioxydiacetate Followmg the procedure of Example 82(b), except substituting 4-[2-(BOC-methylamino)acetyl]-l,2-dihydroxybenzene (0 9 g, 3.2 mmol) for 4-[2-(BOC-methylamino)acetyi]phenol and methyl bromoacetate (1.23 g, 8.0 mmol) for benzyl 5 bromoacetate, the title compound (1 11 g, 81%) was prepared: MS (ES) m/e 426 2 [M + H]+ e) Dimethyl 4-[2-(methyIamino)acetyl]-l,2-phenylenedioxydiacetate hydrochlonde Following the procedure of Example 82(c), except substituting dimethyl 4-10 [2-(BOC-methylamino)acetyl]-l,2-phenylenedioxydiacetate (1 11 g, 2 6 mmol) for benzyl 4-[2-(BOC-methylammo)acetyI]phenoxyacetate, the title compound(l.l g, quantitative) was prepared MS (ES) m/e 326.0 [M + H]+ f) Dimethyl 4-[2-[[(l-BOC-benzimidazol-2-yl)methyl]methylamino]acetyl]-l,2-15 phenylenedioxydiacetate Followmg the procedure of Example 82(d), except substituting dimethyl 4-[2-(methylamino)acetyl]-1,2-phenylenedioxydiacetate hydrochlonde (0.24 g, 0 66 rnmol) for benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride, 1-BOC-2-(bromomethyl)benzimidazole (0 31 g, 0 99 mmol) for 2-20 (chloromethyl)benzimidazole, and using THF (5 mL) and CH2CI2 (5 mL) as solvents, the title compound (0 14 g, 38%) was prepared MS (ES) m/e 556 2 [M + H]+ g) Dimethyl 4-[2-[[(benzimidazol-2-yI)methyljmethyIaminojacetyl]-l,2-25 phenylenedioxydiacetate bis(tnfluoroacetate) A mixture of dimethyl 4-[2-[[(l-BOC-benzimidazol-2-yl)methyI]methyIammo]-acetyl]-l,2-phenylenedioxydiacetate (0 13 g, 0 23 mmol) m TFA 4 mL) and CH2CI2 (12 mL) was stirred at RT under argon for 20 min Removal of the solvents on the rotavap gave the title compound (0 18 g, 30 quantitative) MS (ES) m/e 456.2 [M + H]+ 156 h) 4-[2-[[(BenzimidazoI-2-yl)methyl]methylammo]acetyl]-1,2-phenylenedioxydiacetic acid Following the procedure of Example 82(e), except substituting dimethyl 4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]-1,2-phenylenedioxydiacetate 5 bis(tnfluoroacetate) (0 16 g, 0.23 mmol) for dimethyl (±)-4-[[2-[(benzimidazol-2-yl)methyl]methylammo]-1-hydroxyethyl]-1,2-phenylenedioxydiacetate, the title compound (0.08 g, 80%) was prepared MS (ES) m/e 428 2 [M + H]+ Anal Calcd forC2lH2lN3<>7 II/5C2HF3O2 9/5 H2O C, 42 93, H, 3 80 N, 5 91 Found. C, 42 62, H, 3.52, N, 6 30 Example 85 Preparation of 3-f r4-rrr(Benzimidazol-2-vl")methvlamino1carfaonvllphenvllamino1 propionic Acid a) ethyl 3-[4-(carboxy)phenylamino]propionate 15 A solution of 4-axmnobenzoic acid (6 85 g, 0 05 mol) and ethyl acrylate (15 g, 0 15 mol) m acetic acid (40 mL) was heated to 100°C for 15 h. The sohd which formed was filtered, washed with hexane and dned to give the title compound (7.5 g, 63%) b) ethyl 3-[[4-[[[(benzimidazol-2-yl)methy]amino]carbonyl]phenyl]aimno]propiomc acid The compound of Example 85(a)(0 3 g, 1.26 mmol) m thionyl chlonde (10 mL) was heated to reflux for 10 mm, cooled, concentrated m vacuo, and residual thionyl chlonde was removed by addition of methylene chlonde followed by 25 concentration ui vacuo The residual oil was dissolved in methylene chlonde and treated with 2-(aminomethyl)benzimidazole dihydrochlonde hydrate (0 33 g, 1.5 mmol) and diisopropylethylamine (0 56 g, 4 3 mmol) The resulting mixture was stirred overnight, washed with water and the organic phase was dried (sodium sulfate) and concentrated in vacuo The resulting pale yellow sohd was 30 chromatographed (silica gel, methanol-dichloromethane 3 97) and fractions 157 containing the product were pooled and concentrated m vacuo to give the title compound MS(ES) m/e 367 [M+H]+ c) 3-[[4-[[[(benzimidazol-2-yl)methy]amino]carbonyl]phenyl]amino]propionic acid (20 mL), water (2 mL) and 0 95N aqueous sodium hydroxide (2 5 mL) was stirred and heated to 50°C for 2 h The mixture was treated with tnfluoroacetic acid (1 mL), concentrated m vacuo, and the residue was tnturated with dichloromethane (4 x 100 mL). The resulting white sohd was recrystallized from 20% 10 acetonitnle/water-0 1% tnfluoroacetic acid to give the title compound. MS(ES) m/e 339 [M+H]+ Example 86-92 Followmg the general procedures of Examples 1-55, the following compounds 1 5 are parpared* A soluuon of the compound of Example 85(b)(0 4 g, 1.1 mmol) in methanol n n /"A \_y / v oh c02h h n h N\^C02H cojh 158 Example The above description fully discloses how to make and use the present invention However, the present invention is not limited to the particular 15 embodiments described hereinabove, but mcludes all modifications thereof within the scope of the followmg claims The vanous references to journals, patents and other publications which are cited herein compnses the state of the art and are incorporated herein by reference as though fully set forth 159 Example 93 Parenteral Dosage Unit Composition A preparation which contains 20 mg of the compound of Example 1 as a stenle dry powder is prepared as follows 20 mg of the compound is dissolved in 15 5 mL of distilled water The solution is filtered under stenle condiuons into a 25 mL multi-dose ampoule and lyophilized The powder is reconstituted by addition of 20 mL of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. Subsequent dilution may be made by addition of a metered volume of this dosage umt to another volume of D5W 10 for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV dnp infusion or other mjection-infusion system Example 94 Oral Dosage Unit Composition 15 A capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnesium stearate The resulting powder is screened and filled into a hard gelatin capsule.
Example 95 Oral Dosage Unit Composition A tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 1 with a 10% gelatin solution The wet granules are screened, dned, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid, and compressed into a tablet The foregoing is illustrative of the making and using of this invention. This invention, however, is not limited to the precise embodiments descnbed herein, but encompasses all modifications within the scope of the claims which follow. 160

Claims (1)

  1. WHAT WE CLAIM IS: 1. A compound according to formula (HI): 5 (I'D wherern W is CHRga-U- CHRSb-V- or V I n—(cha, >< _J . J - A is a fibnnogen receptor antagonist template, 10 U and V are absent or CO, CRS2» C(=CRg2), S(0)k, O, NKS, CRSOR8, CRg(ORk)CRg2, CRgjCR^ORk), QOJCRg* CR^QO), CONR1, NR'CO, OC(O), C(0)0, C(S)0, OC(S), C(S)NRg, NRgC(S), S(0)2NRg, NRgS(0>2 N=N, NRgNRg, NRgCRg2, NRgCRg2, CRg20,0CRg2, C=C orCRg=CRg, Rg is H, Cj.gRlkyl, Het-Co_6alkyl, C3_7cycloalkyl~Co_6alkyl or Ar- C^galkyl, 15 Rk is Rg, -C(0)Rg, or -C(0)0Rf, Rl is is H, Ci^alkyl, Het-Co^alkyl, C3.7cycloalkyl-Co^alkyl, Ar- C^galkyl, or C^alkyl subsututed by one to three groups chosen firom halogen, CN, NR^, ORg, SRg, CC^Rg, and CON(Rg)2; Rf is H, Cj^alkyl or Ar-C^galkyl; 20 Re is H, Cj.galkyl, Ar-Cj.galkyl, Het-Cj^alkyl, C3_7cycloalkyl-Ci^alkyl, or (CH2)kC02Rg, kisO, 1 or 2, q is 1 or 2; 161 a is 0,1 or 2; b is 0, 1 or 2, and Rc arc independently selected from H, C^alkyl, Ar-C^galkyl, Het- Co-galkyl, or C3-6cycloalkyl-Co_6alkyl, halogen, CF3, ORf, S(0)j,Rf, CORf, NO2, N(R^2, CO(NRf)2, CH2N(R*)2, or R^ and Rc are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF3, C^alkyl, ORf, S(0)kRf, CORf, C02Rf OH, NO2, N(R^2, CO(NRf)2. and CH2N(Rf)2, or methylenedioxy. or a pharmaceutically acceptable salt thereof 2 A compound according to claim 1 wherern the fibnnogen receptor antagonist template A is wherern A1 to A5 form an accessible substituted seven-membered nng, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosep from the group of O, S and N wherein S and N may be optionally oxidized, D1 to D4 form an accessible substituted six membered ring, optionally containing up to two nitrogen atoms; R is at least one substituent chosen from the group of R7, or Q-C^alkyl, Q-C2-4alkenyl, Q-C2-4alkynyl, optionally substituted by one or more of =0, R11 or R7. R* is H, Q-C^alkyl, Q-Cj.goxoalkyl, Q-C2-6alkenyl, Q-C3^oxoalkenyl, Q-C3^oxoalkynyl, Q-C2-4alkynyl, C3_6cycloalkyl, Ar or Het, optionally substituted by one or more of R11, Q is H, C3.6cycloalkyl, Het or Ar, 162 R7 is -COR8, -COCR'2R9, -C(S)R8, -S(0)310R', -SCO^NRH", -PO(OR% -PO(OR02, -B(OR02, -N02 and Tet, R8 is -OR', -mCR", -NR502R', -NRt)R\ -0CR'2C(O)0R', -0CR'20C(0)-R\ -0CR'2C(0)NR'2, CF3 or AA*. R9 is -OR', -CN, -S(0)rR\ S(0)mNR'2, -C(0)R' C(0)NR'2 or -C02R*; R11 is H, halo, -OR12, -CN, -NR'R12, -N02, -CF3, CF3S(0)r, -C02R\ -CONR'2, Q-Co^alkyl-, Q-C^oxoalkyl-, Q-C^alkenyl-, Q-C2-6alkynyl-, Q-Cq. galkyloxy-, Q-C^galkylamino- or Q-Co_$alkyl-S(0)r-» R12 is R', -C(0)R', -C(0)NR'2, -C(0)0R15, -S(0)mR' or S(0)mNR'2, R15 is H, Cj.galkyl or Ar-Co^alkyl, R' is H, Cj.galkyl, C3_7cycloalkyl-Co-4alkyl or Ar-Co-4alkyl; R" is R\ -C(0)R' or -C(0)0R15; AAl is an amino acid attached through its amino group and having its carboxyl group optionally protected; m is 1 or 2, and r is 0 or 2, or pharmaceutical^ acceptable salts thereof 3 A compound according to claim 2 wherein: A1 is CRlRi; CR1, NR1, N, O or S(0)x, A2 is CR2R2', CR2, NR2; A3 is CR3R3', CR3, NR3, N, O or S(0)x, A4 is CR4R4', CR4, NR4, or N; A5 is CR5R5', CR5, NR5, N, O or S(0)x, D1-!)4 are CH orN; R1 and R1' are R* or R, or together are =0; R2 and R2' are R*, R or =0, R3 and R3' are R*, R or =0, R4 and R4' are R*, R or =0, 163 R5 and R5' are R*, R or =0, x is 0,1 or 2, and R and R* are as defined in claim 2 5 4 A compound according to claim 2 wherein A1 is CRlRl', CR1, NR1, N, O or S, A2 is CR2R2', NR2 or CR2, A3 is CR3R3', A4 is CR4R4', CR4, NR4, or N; A5 is CR5R5', CR5, NR5, N, or O, D1 and D4 are CH; one of D2 or D3 is CH and the other is CH or N, one of R2 or R4 are R and the other is H, R3,R3' and R5,R5' are =0 or R*JH, R1 and R1' are R* or R; and R2' and R4' are H. 10 5 A compound according to claim 2 wherern. A1 is CHR1, CR1, NR", N or S, A2 is CR2 or CR2R2', A3 is CR3R3', A4 is CR4R4' or NR4, A5 is CR5R5* and D1- D4 are CH in which R1 is R* or R, R2 and R2> are R*, R or together are =0; R3 and R3' are R*, R or together are =0; R4 and R4' are R*, R or 15 together are =0, R5 and R5' are R*, R or together are =0, and R, R* and R' are as defined in claim 2 6. A compound according to claim 2 wherern A1 is CR1, A2 is CR2, A3 is C=0, A4 is NR4 and a5 are CHR5 in which R1 is R* or 20 R, R2 is R* or R, R4 is R* or R, R5 is R* or R, and R and R* are as defined in claim 7. A compound according to claim 2 wherern* A1 is NR1, A2 is CHCR2, A3 is CR3R3', A4 is NR4, and A5 are C=0 m which R1 is 25 R* or R, R2 is R*, R, R3 and R3' are R*, R or together are =0, R4 is R* or R; and R and R* are as defined in claim 2 8 A compound according to claim 2 wherern A1 and A4 are C=0, A2 is NR2, A3 is CHR3' and A5 is NR5 in which R2 is R* or R; 30 R3'is R* or R, R5 is R* or R or =0, and R and R* are as defined in claim 2 164 9 A compound according to claim 2 wherein i A1 is NRl, A2 is CHR2, A3 is C=0, A4 is NR' and A5 is CHR5 in which R1 is R* R, R2 is R* or R, R5 is R* or R, R, R* and R* are as defined in claim 2 10. A compound according to claim 1 wherein A is m which R] and Rp are R* or R, or together are =0, R2 and R2» are R*, R or together are =0, R3 and R3< are R*, R or together are =0, R4 and R4» are R*, R or together are =0, R5 and R5' are R*, R or together are =0, and R and R* are as defined m claim 2 11 A compound according to claim 1 wherern A is- 165 \5 A R R *2 o a,' in which Rj is R* or R, R2 and R2« are R*, R or together are =0, 5 R4 is R* or R, R5 and R5' are R*, R or together are =0; and R and R* are as defined in claim 2 12 A compound accordmg to claim 11 wherern 10 Rj is H or CMalkyl, R2, R2' are H,-CH2C02H, R4 is R* or R, and R5R5' are HJH m which R and R* are as defined in claim 2 13 A compound accordmg to claim 2 which is (±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-15 l,4-benzodiazepme-2-acetic acid, (±)-7-[[[2-(l-methykndolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo- 2,3,4,5-tetrahydro- 1H-1,4-benzodiazepine-2-acetic acid, (±)-7-[[[2-(l-methylmdolyl)methyl]anuno]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- 1H-1,4-benzodiazepine-2-acetic acid, 20 [[[(2RS-mdohnyl)methyl]anuno]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-1,4-benzodiazepme-2S-acetic acid, (±)-7-[2-(l,2,3,4-tetrahydro-9H-pyndo[3,4-b]mdolyl)carbonyl]-4-methyl-3-oxo- 2,3,4,5-tetrahydro- IH-1,4-benzodiazepme-2-acetic acid, (±)-7-[[[2-(3-mdolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-25 l,4-benzodiazepme-2-acetic acid 166 / 14 A compound accordmg to claim 1 wherem the fibnnogen receptor antagonist template A is R6 is aryl, Cj.joalkyl, C^cycioalkyl, C^joaralkyl, Cj.ujalkoxyalkyl, C^ioalkaryl, Cj.10alkylthioalkyl, Ci_ioalkoxythioalkyl, Ci_ioalkylamino, C^ioaraU^yl31111110. Cj.iQalkanoylammo, C^ioaralkanoylamino, Cj.ioalkanoyl, C^iQaralkanoyl, or C^igcarboxyalkyl, Y is H, Cj^alkyl, C^alkoxy, C j^alkoxycarbonyl, F, CI, Br, I, CF3, ORf, S(0)kRf, CORf, N02, N(Rf)2, CO(NRf)2, CH2N(Rf)2, methylenedioxy, CN, C02Rf, 0C(0)Rf, orNHC(0)Rf, Rf is H, Cj.galkyl or Ar-Cj^alkyl, and k is 0,1 or 2 15 A compound accordmg to claim 14 wherem R^ is aryl, Ci.joalkyl, C^gcycloalkyl, or C^iparalkyl 16. A compound accordmg to claim 1 wherem the fibnnogen receptor antagonist template A is r6so2nh c02n wherem wherem M1 is CH or N, M2 is CH or N, with the proviso that when M1 is CH, M2 is N, 167 G'isN orN®R", Rf is H, Cj^alkyl or Ar-Q.galkyi, and Rg is H, C^alkyl, Het-Co^alkyl, C3_7cycloalkyl-Co_6alkyl or Ar- Co_6alkyl. 5 17 A compound according to claim 16 wherein G'isN and M1 is N 18- A compound accordmg to claim 1 wherem the fibnnogen receptor antagonist template A is -rv /~v°h n—/ \—/ ch2co2r{ 10 wherem M1 is CH or N, M2 is CH or N, with the proviso that when M1 is CH, M2 is N, and Rf is H, Ci.galkyl or Ar-C^galkyl 15 19 A compound accordmg to claim 1 wherem the fibnnogen receptor antagomst template A is 3-m1 . M3 XRh wherem: M1 is CH or N, 20 Y is H, Cj^alkyl, C^alkoxy, C^alkoxycarbonyl, F, CI, Br, I, CF3, ORf, S(0)kRf, CORf, N02, N(Rf)2, C0(NRf)2, CH2N(Rf)2, methylenedioxy, CN, C02Rf, 0C(0)Rf, or NHC(0)Rf, M3 is CH2 or C=0, Rhis(CH2)qC02Rf; 25 Rf is H, Ci_galkyl or Ar-C^galkyl, k is 0,1 or 2, and q is 1 or 2 168 20 A compound according to claim 1 wherein the fibrinogen receptor antagomst template A is wherein: Y is H, Cj^alkyl, C^alkoxy, C^alkoxycarbonyl, F, CI, Br, I, CF3, ORf, S(0)kRf, CORf, N02, N(Rf)2, CO(NRf)2, CH2N(Rf)2, methylenedioxy, CN, CO^f, 0C(0)Rf, or NHC(0)Rf, Rhis(CH2)qC02Rf; Re is H, Cj.galkyl, Ar-Cj.galkyl, Het-C^galkyl, C3_7cycloalkyl-Ci_6alkyl, or (CH2)kC02Rg, Rf is H, Cj.galkyl or Ar-C^galkyl, k is 0, 1 or 2, and q is 1 or 2 21 A compound according to claim 1 wherem the fibrmogen receptor antagomst template A is \ ✓ b wherein* Y is H, Cj^alkyl, C^alkoxy, C^alkoxycarbonyl, F, CI, Br, I, CF3, ORf, S(0)kRf, CORf, N02, N(Rf)2, CO(NRf)2, CH2N(Rf)2, methylenedioxy, CN, C02Rf, 0C(0)Rf, or NHC(0)Rf, R" is (CH2)nC02Rf; 169 0 BisHsc'r N , Ha~ , or Rf is H, Cj.galkyl or Ar-Cj^alkyl; k is 0,1 or 2; and n is 0 or 3. 5 22 A compound accordmg to claim 1 wherem the fibnnogen receptor antagomst template A is l-c02r0 10 wherem L* is -C(0)NRg-(CH2)". ■C(0)-(CH2)q-, NRg-(CH2)q-, -0-(CH2)q-. or S(0)k-(CH2)q-, R8 is H, C^galtyl, Het-C^galkyl, C3_7cycloalkyl-Co.6alkyl or Ar-Co_6alkyl, 15 k is 0,1 or 2, and q is 1 or 2 23 A compound accordmg to claim 1 wherem the fibnnogen receptor antagomst template A is h ^n—ch—coar° 20 co2r° xo wherem* Rg is H, Ci^alkyl, Het-C^galkyl, C3_7cycloalkyl-C0_6alkyl or Ar-C^galkyl. 170 24 A compound accordmg to claim 1 wherem the fibnnogen receptor antagomst template A is wherem Y is H, C^alkyl, C^alkoxy, Cj^alkoxycarbonyl, F, CI, Br, I, CF3, ORf, S(0)kRf, CORfl, NO2, N(Rf)2, CO(NRf)2, CH2N(Rf)2, methylenedioxy, CN, C02Rf, 0C(0)Rf, or NHC(0)Rf, R8 is H, C^alkyl, Het-Co_$alkyl, C3_7cycloalkyl-Co_6alkyl or Ar-C^galkyl, Rf is H, Cj^alkyl or Ar-Cj^alkyl; and k is 0,1 or 2 I A 25 A compound according to claim 1 wherem the fibnnogen receptor antagomst template A is wherem Rg is H, Cj.galkyl, Het-Co^alkyl, C3_7cycloalkyl-CQ.6alkyl or Ar-C^alkyl, and q is 1 or 2. 26 A pharmaceutical composition which compnses a pharmaceutical^ acceptable earner and a compound accordmg to any one of claims 1-25. 27. The use of a compound accordmg to any one of claims 1-25 in the manufacture of a medicament 28 The use of a compound accordmg to formula (HI): ,171 (iin wherein* W is CHRSa-U- CHRSb-V- or I V I M—(CHA JK ] 9 A is a fibnnogen receptor antagonist template, U and V are absent or CO, CRg^ Q^CRS^. SCO)^ O, NRS, CRSORS, CRg(ORk)CRS2. CRS2CRg(ORk), C(0)CRg2, CRg2C(0), CONRi, NR'CO, OC(O), C(0)0, C(S)0, OC(S), C(S)NRg, NRgC(S), S(0)2NRg, NRgS(0)2 N=N, NRgNRg, NRgCRg2, NRgCRg2, CRg20, OCRg2, CsC or CRg=CRg, Rg is H, Ci.galkyl, Het-Co_6alkyl, C3_7cycloalkyl-Co_6alkyl or Ar- Q^alkyl, Rk is Rg, -C(0)Rg, or -C(0)0Rf, R1 is is H. Cj.galkyl, Het-C^galkyl, C3_7cycloalkyl-Co_6alkyl, Ar- C^galkyl, or C^galkyl substituted by one to three groups chosed from halogen, CN, NR^, ORg, SRg, C02Rg, and CON(Rg)2, Rf is H, C^alkyl or Ar-Cj^alkyl; Re is H, Cj.galkyl, Ar-Cj.galkyl, Het-Cj.galkyl, C3_7cycloalkyl-C i^alkyl, or (CH^CO^g; k is 0,1 or 2, q is 1 or 2, a is 0,1 or 2, b is 0,1 or 2, 172 Rb and Rc are independently selected from H, Cj.galkyl, Ar-C^galkyl, Het- C^galkyl, or C3-6cycloalkyl-Co_6alkyl, halogen, CF3, ORf, SCO)^, CORf, N02, N(Rf)2, CO(NRf)2, CH^CR^, or R*5 and Rc are joined together to form a five or sm membered aromatic or non-aromatic carbocyclic or 5 heterocyclic nng, optionally substituted by up to three substituents chosen from halogen, CF3, CMalkyl, ORf, S(0)kRf, CORf, C02Rf OH, N02, N(Rf)2, CO(NRf)2, and CH2N(Rf)2> or methylenedioxy» or a pharmaceutical^ acceptable salt thereof, m the manufacture of a medicament for the inhibition of the vitronectm receptor in a mammal in need thereof. 10 29 The use according to claim2S wherem the compound inhibits the vitronectm receptor at a concentration of less than 50 micromolar 30 The use according to claim 28 wherem the compound inhibits the vitronectm 15 receptor with a Ki at the vitronectm receptor that is ten-fold greater than the Ki for said compound at the fibnnogen receptor 31. The use according to claim 28 wherem the compound inhibits the vitronectm receptor with a Ki at the vitronectm receptor that is thirty-fold greater than the Ki for 20 said compound at the fibnnogen receptor 32. The use accordmg to claim 28 wherem the compound inhibits the vitronectm receptor with a Ki at the vitronectin receptor that is a hundred-fold greater than the Ki for said compound at the fibnnogen receptor / 33. The use of a compound according to formula (111) as defined in claim 28 in the manufacture of a medicament for the treatment of diseases m which bone resorption is a factor 173 32982? 34. The use of a compound according to formula (IH) as defined in claim 28 in the manufacture of a medicament for the treatment of osteoporosis, inflammation, restenosis, or atherosclerosis iT-W ^ By the authorised agents A J PARK & SON ^&4JUsJ*=> END OF CLAIMS i RECEIVED Imciiectuul Property Office 7 ^ FEB 1998 of New Zealand 174
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