WO1996000730A1

WO1996000730A1 - Vitronectin receptor antagonists

Info

Publication number: WO1996000730A1
Application number: PCT/US1995/008306
Authority: WO
Inventors: Fadia Ali; William Bondinell; William Francis Huffman; M. Amparo Lago; Richard Mcculloch Keenan; Chet Kwon; William Henry Miller; Thomas Nguyen; Dennis T. Takata
Original assignee: Smithkline Beecham Corporation
Priority date: 1994-06-29
Filing date: 1995-06-29
Publication date: 1996-01-11
Also published as: NO965608D0; PL318199A1; AU702661B2; NZ290008A; HUT76344A; AU3001095A; BR9508178A; NO965608L; MX9700041A; CA2193966A1; CN1156995A; EP0767792A1; HU9603525D0; NZ329656A; NZ329822A; EP0767792A4; CZ382496A3; JPH10504808A

Abstract

Compounds are disclosed which are vitronectin receptor antagonists useful in the treatment of osteoporosis. These compounds comprise a fibrinogen receptor antagonist template linked to a heterocyclic moiety.

Description

TITLE

Vitronectin Receptor Antagonists

FIELD OF THE INVENTION

This invention relates to pharmaceutically 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 Integrins are 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 oc_vB₃, the vitronectin receptor. The fibrinogen receptor gpllb /Ula 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, et al, Blood., 1988, 71, 831. The vitronectin receptor α_vB₃ is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions. The o_v6₃ 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. Chem., 1987, 262, 7703. The α_vβ₃ receptor expressed on human aortic smooth muscle cells stimulates their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brown, et al, Cardiovascular Res., 1994, 28, 1815. Additionally, a recent study has shown that a α_v6₃ antagonist 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. The vitronectin receptor is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton, et al, Exp. Cell Res. 1991, 195, 368, disclose that RGD-containing peptides and an anti-vitronectin receptor antibody (23 C6) inhibit dentine resoφtion 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 in tissue culture, and inhibits attachment of osteoclasts to bone. Fisher, et al, Endocrinology 1993, 132, 1411, has further shown that echistatin inhibits bone resoφtion in vivo in the rat. Bertolini et al, J. Bone Min. Res., 6, Sup. 1, SI 46, 252 have shown that cylco-S,S-N^α-acetyl-cysteinyl-N^α-methyl-argininyl-glycyl- aspartyl-penicillamine inhibits osteoclast attachment to bone. EP 528 587 and 528 586 report substituted phenyl derivatives which inhibit osteoclast mediated bone resoφtion. Alig et al., EP 0 381 033, Hartman, et al., EP 0 540,334, Blackburn, et al.,

WO 93/08174, Bondinell, et al., WO 93/00095, Blackburn, et al. WO 95/04057, Egbertson, et al, EP 0478 328, Sugihara, et al. EP 529,858, Porter, et al., EP 0 542 363, and Fisher, et al., EP 0635492 disclose certain compounds that are useful for inhibiting 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 vitronection receptor and are useful in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resoφtion is a factor, such as osteoporosis. This invention is also a pharmaceutical composition comprising a compound according to formula (I)-(V) and a pharmaceutically carrier.

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 useful for treating atherosclerosis, restenosis, inflammation, cancer and diseases wherein bone resoφtion is a factor, such as osteoporosis.

DETAILED DESCRIPTION

This invention comprises novel compounds which are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor. The compounds of the instant invention comprise a fibrinogen receptor antagonist template that is linked to a nitrogen-containing five-membered ring, which is optionally fused to an aromatic six-membered ring. The fibrinogen receptor antagonist template is substituted by an aliphatic substituent which contains an acidic moiety. It is preferred that about fourteen intervening covalent bonds via the shortest intramolecular path will exist between the acidic group of the fibrinogen receptor antagonist template and the nitrogen of the optionally fused five-membered ring.

As used herein, the term "fibrinogen receptor antagonist template" means the core structure of a fibrinogen receptor antagonist, said core being substituted by an acidic group and said core being linked to an organic group substituted with a basic nitrogen moiety. A fibrinogen receptor antagonist is an agent that inhibits the binding of fibrinogen to the platelet-bound fibrinogen receptor GPϋb-IIIa. It is an object of this invention that a fibrinogen receptor antagonist is converted to a vitronectin receptor antagonist by replacing the organic group substituted with a basic nitrogen moiety in a fibrinogen receptor antagonist with an optionally fused nitrogen-containing five-membered ring, preferably an imidazole ring and, most preferably, a benzimidazole ring. This invention comprises compounds of formula (I)-(V)

(I) or (II) or (III) or

(IV) or (V) wherein:

W is CHRSa-U- CHRgb-V- or

V

I

N— (CH )_q _J .

A is a fibrinogen receptor antagonist template;

U and V are absent or CO, CR⁸2, C(=CR⁸2), S(O)k, O, NR⁸, CROR⁸,

CR⁸(OR^k)CR⁸2, CR⁸2CR⁸(OR^k), C(O)CR⁸2, CR⁸2C(O), CON , NRCO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR⁸, NR⁸C(S), S(O)2NR⁸, NR^gS(O)2

N=N, NR⁸NR , NR^gCR⁸2, NR^gCR⁸ ₂, CR⁸2O, OCR⁸2, C≡C or CR⁸=CR^ε; G is NR^e, S or O; R^f is H, Cι_6alkyl, Het-C()-6alkyl, C3-7cycloalkyl-C()-6alkyl or Ar- CQ-6alkyl; R^k is R⁸, -C(O)R⁸, or -C(O)OR^f;

R' is is H, Cι_6alkyl, Het-Cθ-6alkyl_> C3-7cycloalkyl-Co_6alkyl, Ar- Cθ-6alkyl, or

Ci-6alkyl substituted by one to three groups chosed from halogen, CN, NR⁸ ₂, OR⁸, SR⁸, CO₂R⁸, and CON(R⁸)₂;

- A - R^f is H, C,_.6alkyl or Ar-C_walkyl;

R^e is H, Ci-6alkyl, Ar-Ci-6alkyl, Het-Ci-6alkyl, C3-7cycloalkyl-Ci-6alkyl, or (CH₂)_kCO₂R⁸; k is 0, 1 or 2; q is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; R° and R^c are independently selected from H, Cι_6alkyl, Ar-Cθ-6alkyl Het-

Co-6alkyl, or C3_6cycloalkyl-Cθ-6alkyl, halogen, CF3, OR^f, S(O)_kR^f, COR^f, NO2, N(R^f)2, CO(NR^f)2, CH2N(R^f)2, or R^b and R^c 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, Ci-4alkyl, OR^f, S(O)kR^f, COR^f, CO₂R^f OH, NO2,

N(R^f)2, CO(NR^f)2, and CH2N(R^f)2; or methylenedioxy; or a pharmaceutically acceptable salt thereof, with the proviso that:

(i) when A is 1 ,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)- 1 H- 1 ,4- benzodiazepine-2-acetic acid, then W is not -(CH₂)₂₃NHCO- attached at the 1- position of an imidazole ring; and (ii) when A is 1 ,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)- 1 H- 1 ,4- benzodiazepine-2-acetic acid, then W is not -(CH₂)₂ NHCO- attached at the 4(5)- position of an imidazole ring.

Also included in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo. In cases wherein the compounds of this invention may have one or more chiral centers, unless specified, this invention includes each unique nonracemic 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. In cases wherein compounds may exist in tautomeric forms, such as

O OR' keto-enol tautomers, such as ^^- and -^^r . 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-containing peptides to the vitronectin (αvβ3) receptor. Inhibition of the vitronectin receptor on osteoclasts inhibits osteoclastic bone resoφtion and is useful in the treatment of diseases wherein bone resoφtion 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 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 (II), wherein R and R are joined to form an aromatic ring containing up to b c two nitrogen atoms. In a preferred embodiment R and R are joined to form an optionally substituted phenyl ring according to formula (Ha):

Suitably W is -(CHRS)_aNR-CO- or , or, when G is CH, W is

-CH2CH2NR'CO-wherein R' is a methylene group attached to G. Preferably W is -CHRgNR-CO-.

Suitably R is H, Chalky!, C3-7cycloalkyl, Ar or Ci.βalkyl substituted by one to three groups chosen from halogen, CN, NR*₂, OR⁸, SR⁸, CO2R⁸, and CON(R⁸)₂, Ar, Het or Cs.γcycloalkyl. In particular, R' is H, methyl, butyl, cyanomethyl, carboxymethyl, phenylethyl or benzimidazolylmethyl.

Suitably R^x, R and R^z are independently chosen from Cι_6alkyl, methoxy, nitro, trifiuoromethyl, fluoro, chloro, amino or R^x and Ry are adjacent to one another and are joined to form a methylenedioxy group.

Preferably G is NR^e.

Suitably R^e is H, Cι.4alkyl, Ar, Het or C-^alkyl substituted by Ar or Het. More suitably, R^e is H, methyl or benzimidazolylmethyl.

In another specific embodiment, R^b and R^c form a six membered aromatic ring containing one or two nitrogen atoms according to formulas (Ilb-d):

wherein G, R^x and R^y are as above for formula (Ha).

In another aspect this invention is an intermediate compound of formula XXX:

wherein Pr¹ is a nitrogen protecting group, R is H, C^alkyl or ArC_{1 6}alkyl, a' is 1-3, and R", R^y and R^z are independently chosen from H, halogen, SR^f, OR^f, CF₃, N(R^f)₂, NO₂ and C,_.6alkyl. Preferred nitrogen protecting groups are alkyl and aryl carboxylic acid groups, and alkyloxycarbonyl or arylmethyloxycarbonyl groups, such as the acetyl, BOC and Cbz group. Typically Rg is H or methyl.

Specifically, the compounds of this invention are comprised of a nitrogen- containing optionally fused five-membered ring, a linking group W, and a fibrinogen receptor antagonist template A. In particular, the fibrinogen receptor antagonist template A is as defined in Bondinell, et al., WO 93/00095, published January 7,

1993, of the sub-formula (VI):

A¹ to A⁵ form an accessible substituted seven-membered ring, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosen 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-Cι_4alkyl,

Q-C2-₄alkenyl, Q-C2-4alkynyl, optionally substituted by one or more of =O, R¹¹ or

R⁷;

R* is H, Q-Cι_6alkyl, Q-Ci-6θxoalkyl, Q-C2-6alkenyl, Q-C3-₄θxoalkenyl, Q-C3.₄θxoalkynyl, Q-C₂-₄alkynyl, C3_6cycloalkyl, Ar or Het, optionally substituted by one or more of R¹¹ ;

Q is H, C3_6cycloalkyl, Het or Ar;

R⁷ is -COR8, -COCR'₂R⁹, -C(S)R8, -S(O)_rnOR', -S(O)_mNR'R", -PO(OR'), -PO(OR')₂, -B(OR')₂₎ -NO₂ and Tet;

R⁸ is -OR, -NR'R", -NR'SO₂R', -NR'OR, -OCR'₂C(O)OR', -OCR₂OC(O)- R', -OCR'₂C(O)NR₂, CF₃ or AA¹;

R⁹ is -OR, -CN, -S(O)_rR, S(O)_mNR'₂₎ -C(O)R' C(O)NR₂ or -CO₂R'; R^{1 1} is H, halo, -OR¹², -CN, -NR'R¹², -NO₂, -CF₃, CF₃S(O)_r, -CO₂R', -CONR*₂₎ Q-C₀-6alkyl-, Q-Cμ₆oxoalkyl-, Q-C₂-6alkenyl-, Q-C₂-6alkynyl-, Q-Co-6alkyloxy-, Q-Co-6alkylamino- or Q-Co-6alkyl-S(O) ;

R12 is R', -C(O)R, -C(O)NR'₂, -C(O)OR¹⁵, -S(O)_mR or S(O)_mNR'₂; R^ is R^ -CFs. -SR'. or -OR';

R¹⁴ is R', C(O)R, CN, NO₂, SO₂R or C(O)OR¹⁵;

R¹⁵ is H, Cι.6alkyl or Ar-Co-4alkyl.

R' is H, Ci-6alkyl, C3_7cycloalkyl-Co-₄alkyl or Ar-Co-4alkyl;

R" is R', -C(O)R" or -C(O)OR¹⁵; R"Js R" or AA2;

AA1 is an amino acid attached through its amino group and having its carboxyl group optionally protected, and AA2 is an amino acid attached through its carboxyl group, and having its amino group optionally protected; m is 1 or 2; n is 0 to 3; p is 0 or 1 ; and t is 0 to 2; or pharmaceutically 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 -(CH₂)₂ -NHCO- attached at the 1- position of an imidazole ring; and

(ii) when A is 1 ,2,4,5-tetrahydro-3-oxo-4-(2-phenylethyl)- 1 H- 1 ,4- benzodiazepine-2-acetic acid, then W is not -(CH₂)₂ NHCO- attached at the 4(5)- position of an imidazole ring.

With reference to formula (VI), suitably, Al is CRϊR^1', CR¹, NR¹, N, O or S(O)_x; A² is CR²R^2', CR², NR²; A3 is CR3R3', CR3, NR3, N, O or S(O)_x; A⁴ is CR⁴R^4', CR⁴, NR⁴, or N;

A⁵ is CR⁵R^5', CR⁵, NR⁵, N, O or S(O)_x;

D¹-D⁴ are CR^{1 1}, CR⁶ or N;

R¹ and R^1' are R* or R, or together are =O; R² and R^2' are R*, R or =O;

R³ and R^3' are R*, R or =O;

R⁴ and R^4' are R*, R or =O;

R⁵ and R^5' are R*, R or =O; and x is 0 to 2. More suitably, A¹ is CRiR^1', CR¹, NR¹, N, O or S; A² is CR²R^2', NR² or

CR²; A³ is CR3R3^'; A⁴ is CR⁴R⁴', CR⁴, NR⁴, or N; A⁵ is CR⁵R⁵', CR⁵, NR⁵, N, O; D¹ - D⁴ are CH; R² or R⁴ are R; R3,R ^' and R ,R^5' are =O or R*,H.

Preferably, A¹ is CHR¹, CR¹, NR", N or S; A² is CR² or CR²R^2'; A³ is CR³R^3'; A⁴ is CR R^4' or NR⁴; A⁵ is CR R^5', and D¹ - D⁴ are CH. In one embodiment, A¹ is CR¹, A² is CR², A³ is C=O, A⁴ is NR⁴ and A⁵ are CHR⁵.

In another embodiment, A¹ is NR¹, A² is CHCR², A³ is CR³R^3', A⁴ is NR⁴, and A⁵ are C=O.

In yet another embodiment, A¹ and A⁴ are C=O, A² is NR², A³ is CHR^3' and A⁵ is NR⁵.

In a preferred embodiment, A¹ is NR¹, A² is CHR², A³ is C=O, A⁴ is NR' and A⁵ is CHR⁵.

Representative sub-formulas of (VI) are given by each of formulas (Vla)- (Vli) below:

(Via) (VIb) (Vic)

Specific embodiments of this invention wherein the fibrinogen receptor antagonist template A is of the sub-formula (VI) are named in Examples 1-75.

Preferred compounds of this invention are: (2S )-7- [ [ [N-(2-benzimidazolyl)methyl-N-methy 1] amino] carbonyl]-4-methyl-3-oxo-

2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; -7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7- [ [ [2-(4- Azabenzimidazolyl)methyl]methy lamino] carbony 1] -4-(2- methoxyethyl)-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; -7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid;

(2S)-7-[[[N-butyl-N-benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-4-methyl-

2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; -7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl)-

2,3 ,4,5-tetrahydro- 1 H- 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-lH-l,4-benzodiazepine-2-acetic acid;

(±)-7-[[[2-(benzimidazolyl)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-methyI]amino]carbonyl]-3-oxo-4-(2- phenylethyl)-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid.

The most prefeπed fibrinogen receptor antagonist template is of the sub- formula (Via), wherein CR²R is CHCH₂CO₂H, CR³R³ is C=O, and CR⁵R^5' is CH₂. 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-benzodiazepine ring system. (±)-8-[[[(2-Benzimidazolyl)methyl]amino]- carbonyl]-4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid has a Ki of greater than 50 micromolar in the in vitro vitronectin binding assay described hereinbelow. In the formula below the definitions for the substituents are as defined in formulas (I)-(IV), unless specified otherwise.

Another embodiment of a prefeπed fibrinogen receptor template A is represented by the 1,4-benzodiazepine 2,5-dione of sub- formula (VII);

wherein:

Y is H, C^alkyl, C^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f, S(O)_kRf, COR^f, NO₂, N(R^f)₂, CO(NR^f)₂, CH₂N(Rf)₂, methylenedioxy, CN, CO₂R^f, OC(O)R^f, or NHC(O)R^f; and R^h is (CH₂)_qCO₂Rf. The preparation and the use of this sub-structure in preparing fibrinogen 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 April 29, 1993.

Table I, below, summaries other prefeπed fibrinogen receptor templates that are included within the scope of the present invention. Such templates are:

Table I mm

wherein:

R ¹ and R²² independently are H or -Z-CO2Ror Z-CON(R^f)2 with the proviso that one of A¹ or A² is -Z-CO2R^f or Z-CON(R^f)2;

Z is -CH2-, -O(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, CMalkyl, Cι_4alkoxy, Ci-4alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f,

S(O)kR^f, CORf NO2, N(R^f)2, CO(NR^f)2, CH2N(Rf)2, methylenedioxy or Z-CO-

R^f. in Alig, et al., EP 0 381 033, published August 8, 1990.

The prefeπed fibrinogen receptor template A in formula (VDI) is

Specific embodiments of this aspect of the invention are:

4- [2-[ [ [ 1 - [(B enzimidazol-2-yl)methyl]benzimidazol-2- yl]methyl]methylamino]acetyl] phenoxyacetic acid;

(±)-4- [ [2- [(Benzimidazol-2-yl)methy 1] methylamino] - 1 -hy droxyethy 1] - 1 ,2- phenylene dioxydiacetic acid;

4-[2-[[(Benzimidazol-2-yl)methyl]methylamino]acetyl]- 1 ,2- phenylenedioxydiacetic acid; or

3-[[4-[[[(Benzimidazol-2-yl)methy]amino]carbonyl]phenyl]amino]propionic acid.

⁽IX⁾

wherein:

R6 is aryl,

C3_6cycloalkyl, C4_ιoaralkyl, C ioalkoxyalkyl, C\-i oalkaryl, C \ _ \ øalkylthioalkyl, C \ _ j oalkoxythioalkyl, C \ _ \ oalkylamino,

C4_ιoaralkylamino, Cι_ιoalkanoylamino, C4_ιoaralkanoylamino, Cι_ιoalkanoyl, C4_ιoaτa kanoyl, or C ιo^car'^:-^,oxyalkyl; and

Y is H, CMalkyl, Cj^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f, S(O)_kRf, CORf NO₂, N(R^f)₂, CO(NRf)2, CH₂N(Rf)₂, methylenedioxy, CN, CO₂R^f, OC(O)R^f, or NHC(O)R^f, in Egbertson, et al., EP 0478 328, published April 1, 1992. The prefeπed compounds of formula (IX) are those wherein R-*-- is aryl, C . løalkyl, C3_6cycloalkyl, or C4__j.oaralkyl. A specific embodiment of this aspect of the invention is (S)-(2-butylsulfonyl-amino)-3-[4-(3-benzimidazo-2- yl)propyloxy)]phenylpropionic.

IX)

wherein:

M¹ is CH or N;

M² is CH or N, with the proviso that when M¹ is CH, M² is N; and GJs N or N^θR", in Eldred, et al., EP 0542 363, published May 19, 1993.

Prefeπed embodiments of the vitronectin receptor antagonists containing the substructure of formula (X) are those wherein GJs N an M¹ is N. A compound containing this substructure, namely 4-[4-[l-(2-methylbenzimidazolyl)piperidinyl]]- piperidineacetic acid, has a Ki of greater than 50 micromolar in the in vitro vitronectin binding assay described hereinbelow.

{XI)

wherein:

M¹ is CH or N; and

M² is CH or N, with the proviso that when M¹ is CH, M² is N, in Porter, et al., EP 0 537 980, published April 21, 1993.

wherein:

M¹ is CH or N;

Y is H, CMalkyl, C^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR-\

S(O)_kRf, COR^f, NO₂, N(Rf)₂, CO(NR^f)₂, CH N(R^f)₂, methylenedioxy, CN,

CO₂R^f, OC(O)R^f, or NHC(O)R^f;

D³ is CH₂ or C=O; and

R^h is (CH₂)_qCO₂R^f, in Klinnick, et al., EP 0 635,492, published January 25, 1995.

{xmi

wherein:

Y is H, CMalkyl, C^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f, S(O)_kR^f, COR^f, NO₂, N(R^f)₂, CO(NR^f)2, CH₂N(R^f)₂, methylenedioxy, CN, CO₂R^f, OC(O)R^f, or NHC(O)Rf;

R^h is (CH₂)_nCO₂R^f; and

in Blackburn, et al., WO 95/04057, published February 9, 1995. ι^χ

wherein:

L* is -C(O)NR⁸-(CH₂)-, -C(O)-(CH₂)_q-, NR⁸-(CH₂)_q-, -O-(CH₂)_q-, or S(O)_k-(CH₂)_q-, in Hartman, et al., EP 0 540 331, published May 5, 1993.

£XY)

in Sugihara, et al., EP 0 529,858, published March 3, 1993. (XVI)

wherein:

Y is H, CMalkyl, C^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f,

S(0)_kR^f, CORfl, NO₂, N(Rf)₂, CO(NRf)₂, CH₂N(R^f)₂, methylenedioxy, CN, C0₂R^f, OC(O)R^f , or NHC(O)R^f, in Himmeisbach, et al., EP 0483 667, published May 6, 1992.

QTVII)

in Linz, et al., EP 0567 968, published November 3, 1993. (XVIII)

wherein:

R^d is Het-C^alkyl; and

Z", Z'" independently are hydrogen, C_Malkyl, halo, OR^f, CN, S(O)_kR^f, CO₂R^f, or OH, in Bovy, et al., EP 0 539 343, published April 28, 1993.

The above descriptions of fibrinogen receptor templates for use in the present invention were taken from pending published patent applications. Reference should be made to such patent applications for their full disclosures, including the methods of preparing said templates and specific compounds using said templates, the entire disclosure of such patent applications being incoφorated herein by reference.

Table II, below, describes other fibrinogen receptor antagonists, whose core structures would be useful in carrying out the instant invention. Reference should be made to the patent applications and other publications for their full disclosures, including the methods of preparing said templates and specific compounds using said templates, the entire disclosure of the noted patent applications and other publications being incoφorated herein by reference. Since it is contemplated that any fibrinogen receptor antagonist that is linked to an optionally fused nitrogen- containing five-membered ring will possess the novel utility described herein, the list below does not limit the scope of the present invention.

Table II Adir et Compagnie

FR 928004, June 30, 1992, Fauchere, J. L., et al.

EP 0578535, June 29, 1993, Fauchere, J-L, et al.: Describes 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. JP 05239030, Sep. 17, 1993, aminomethyltetrahydroisoquinolines.

Asahi Glass

WO 90/02751, Ohba, M. et al.: Sept. 8, 1989: Describes cyclic RGD-containing peptides.

WO 90/115950, Mar. 22, 1990, Ohba, M., et al. EP 0406428, 1/9/91: Describes cyclic RGD-containing peptides WO 92/09627, Isoai, A. et al.: Nov. 29, 1991: Describes cyclic RGD-containing peptides.

Cassella AG

DE 4207254, (Der 93-289298/37) Mar. 7, 1992, Zoller, G., et al.: Describes guanidinopropyl-4-oxo-2-thioimidazolidin-3-yl-Asp-X analogs EP 93904010, Feb. 24, 1993, Zoller, G., 4-oxo-2-Thioxoimidazolidine Derivatives. EP 0565896, Mar. 18, 1993, Klinger, O, et al.: Describes guanidinoethylphenyloxyacetyl-Asp-X analogs. EP 0566919, (Der 93-338002/43) Apr. 3, 1993, Zoller, G., et al.: Describes guanidinopropyl-4-oxo-2-thioimidazolidin-3-yl-Asp-X analogs. EP 580008, (Der 94-027663/04) July 6, 1993, Zoller, G., et al.: Describes 5-m- guanidinophenyl-2,4-dioxoimidazolidin-3yl)acetyl-Asp-Phg.

DE 224414, July 6, 1993, Zoller, G., et al.: Describes 5-m-guanidinopheny 1-2,4- dioxoimidazolidin-3yl)acetyl-Asp-Phg. EP 584694, (Der 94-067259/09) Apr. 2, 1994, Zoller, G., et al.: Describes 5-m- guanidinophenyl-2,4-dioxoimidazolidin-3yl)acetyl-Asp-Phg. DE 4301747, (Der 94-235891/29) Jul. 28, 1994, Zoller, G., et al.: Describes 5-m- guanidinophenyl-2,4-dioxoimidazolidin-3yl)acetyl-Asp-Phg analogs. DE 4308034, (Der 94-286666/36) Sept. 15, 1994, Klinger, O. et al.: Describes 5-m- guanidinophenyl-2,4-dioxoimidazolidin-3yl)acetyl-Asp-Phg analogs. DE 4309867, Sept. 29, 1994, Klingler, O, et al.: Describes 5-m-guanidinophenyl- 2,4-dioxoimidazolidin-3yl)acetyl-Asp-Phg. Chiron

WO 93/07169, (Der 93-134382/16), Mar. 15, 1993, Devlin, J. J., et al.: Describes RGD peptides.

Ciba Geigy

EP 0452210, (Der 91-305246/42) Apr, 5, 1990, describes aminoalkanoyl-GDF analogs. EP 0452257, Mar. 26, 1991, Allen, M. C, et al.: Describes aminoalkanoylAsp-Phe analogs.

COR Therapeutics

WO 90/15620, June 15, 1990: Describes cyclic RGD-containing peptides.

EP 0477295, Apr. 1, 1992: Scarborough, R. M. et al.

WO 92/08472, May 29, 1992, Scarborough, R. M. et al. WO 93/223356, April 27, 1993, Swift, R. L., et al.: Describes cyclic RGD- containing peptides.

EP 0557442, Sept. 1, 1993, Scarborough, R. M., et al.

Scarborough, R. M.; Rose, J. W.; Hsu, M. A.; Phillips, D. R.; Fried, V. A.;

Campbell, A. M.; Nunnizzi, L.; Charo, I. F., Barbourin, A GPϋb-IIIa- Specific Integrin Antagonist from the Venom of Sistrurus M. Barbouri, J.

Biol Chem. , 266, 9359, 1991.

Daiichi Pharm Co Ltd.

JP 05078344-A, (Der 93-140339/17) Mar. 30, 1993: Describes Bis- amidinoheterocycles, eg. benzofurans.

DuPont Merck

WO 93/07170, Apr. 15, 1993: Describes cyclic-RGD-containing peptides. WO 94/11398, May 26, 1994: Wells, G. J. et al. Describes cyclic RGD containing peptides.

IL 109237, Jul. 31, 1994. WO 94/22909 , (Der 94-333113/41) Oct. 13, 1994: DeGrado W. F., et al.

WO 94/22910 , (Der 94-333114/41 Oct. 13, 1994: DeGrado W. F., et al. Prodrugs.

WO 94/22494 , (Der 94-332838/41) Oct. 13, 1994: DeGrado W. F., et al. Cyclic peptides EP 625164, Nov. 23, 1994: Degrado, W. F., et al. Cyclic peptides.

Mousa, S. A.; Bozarth, J. M.; Forsythe, M. S.; Jackson, S. M.; Leamy, A.; Diemer, M. M.; Kapil, R. P.; Knabb, R. M.; Mayo, M. C; Pierce, S. K.; al., e., Antiplatelet and Antithrombotic Efficacy of DMP 728, a Novel Platelet GPIIb/IIIa Receptor Antagonist, Circulation , 89, 3, 1994. Jackson, S.; DeGrado, W.; Dwivedi, A.; Parthasarathy, A.; Higley, A.; Krywko, J.; Rockwell, A.; Markwalder, J.; Wells, G.; Wexler, R.; Mousa, S.; Harlow, R., Template-Constrained Cyclic Peptides: Design of High- Affinity Ligands for GPHb/πia, J. Amer. Chem. Soc. , 116, 3220, 1994.

Ellem Ind Farma Spa

GB 2207922, Aug, 3, 1988, describes linear RGD analogs.

Farmitalia Erba SRL Carlo

EP 611765 (Der 94-265375/33) , Aug 24, 1994: Cozzi, P., et al. Describes 5-(2- pyrazinylmethyl-2-imidazol- 1 -yl)- 1 -cyclohexylethylidene)aminoxypentanoic acid.

Fuji Photo Film

JP 04208296-A (Der. 92-303598/38), Nov. 30, 1990, Describes RGD peptides. JP 04213311-A (Der. 92-305482/38), Nov. 27, 1990, Describes multimeric RGD peptides. JP 04217693-A, (Der 92-312284/38), Oct. 23, 1990, Descirbes multimeric RGD peptides. JP 04221394-A (Der. 92-313678/38), Oct. 26, 1990, Describes multimeric RGD peptides. JP 04221395-A (Der. 92-313679/38), Oct. 26, 1990, Describes multimeric RGD peptides. JP 04221396-A (Der. 92-313680/38), Oct. 26, 1990, Describes multimeric RGD peptides. JP 04221397-A (Der. 92-313681/38), Dec. 20, 1990, Describes multimeric RGD peptides. EP 0482649 A2, April 29, 1992, Kojima, M. et al.: Describes RGD peptides. EP 0488258A2, June 3, 1992, Komazawa, H., et al: Describes RGD peptides. EP 503301-A2, Feb. 14, 1991, Kitaguchi, H. et al.: Describes RGD peptides. JP 05222092, May 21, 1993, Nishikawa, N., et al.: DescribesLinear X-RGDS. JP 06239885, (Der 94-313705/39) , Aug 30, 1993, Nishikawa, N. et al.: Describes multimeric RGD peptides. WO 9324448, (Der 93-405663/50), Dec. 9, 1993, Nishikawa, N., et al.: Describes multimeric retro-inverseo RGD peptides. JP 06228189, (Der 94-299801/37), Aug. 16, 1994. Describes RGD peptides. EP 619118, (Der 94-311647/39) , Oct. 12, 1994, Nishikawa, N. et al.: Describes linear RGD peptides.

Fujisawa EP 0513675, May 8, 1992, N. Umekita, et al.: Describes amidinopheny loxy alkanoyl- Asp- Val-OH analogs . WO 9409030-A1, Apr. 28, 1994, Takasugi, H., et al.: Describes

Amidinophenoycbutanoyl-Asp- Val-OH analogs. EP 0513675, (Der 92-383589/47): Describes Amidinophenyloxybutyrl-Asp-Val analogs.

WO 9500502, Jan, 5, 1995, Oku, T., et al.,: Describes "aminopiperazine derivatives." FR 144633: Thromb Haem. 69, 706, 1993.

Cox, D.; Aoki, T.; Seki, J.; Motoyama, Y.; Yoshida, K., Pentamidine: A Specific Nonpeptide GPIIb/Tfla Antagonist, Thromb. Haem. , 69, 707, 1993. Genentech

WO 90/15072 (Der 91007159): Describes RGD-containing peptides:

WO 91/01331 (Der 91058116), July 5, 1990, P. L. Barker, et al.: Describes cyclic

RGD-containing peptides WO 91/04247, Sept. 24, 1990, T. R. Webb: Describes (guanidinoalkyl)Pro-GD analogs. WO 91/11458 (Der 91252610), Jan. 28, 1991, P. L. Barker, et al.: Describes cyclic

RGD-containing peptides WO 92/07870, Oct. 24, 1991 J. P. Burnier, et al.: Describes cyclic RGD- containing peptides.

WO 92/17492, Oct. 15, 1992, Burnier, J. P. et al.: Describes cyclic RGD-containing peptides. CA 2106314, Oct. 6, 1992, Burnier, J. P. et al.

WO 93/08174, Oct. 15, 1991, B. K. Blackburn, et al.: Describes 2,5-dioxo-l,4- benzodiazepines .

CA 2106314, Oct. 6, 1992, Burnier, J. P., et al.

EP 0555328, Aug. 18, 1993, J. P. Burnier, et al.

WO 95/04057, Feb. 9, 1995, Blackburn, B. K., et al.: Describes 1,4-benzodiazepines containing a heterocyclic at positions 1,2. Scarborough, R. M., Naughton, M. A., Teng, W., Rose, J. W., Phillips, D. R.,

Nannizzi, L, Arfsten, A., Campbell, A. M., and Charo, I. F., J. Biol. Chem.

268, 1066, 1993. Dennis, M. S.; Henzel, W. J.; Pitti, R. M.; T., L. M.; Napier, M. A.; Deisher, T. A.;

Bunting, S.; Lazarus, R., Platelet Glycoprotein ϋb-IIIa Protein Antagonists from Snake Venoms: Evidence for a Family of Platelet- Aggregation

Inhibitors, Proc. Natl. Acad. Sci. USA , 87, 2471, 1989. Barker, P. L.; Bullens, S.; Bunting, S.; Burdick, D. J.; Chan, K. S.; Deisher, T.;

Eigenbrot, C; Gadek, T. R.; Gantzos, R.; Lipari, M. T.; Muir, C. D.; Napier,

M. A.; Pitti, R. M.; Padua, A.; Quan, C; Stanley, M.; Struble, M.; Tom, J. Y. K.; Burnier, J., P., Cyclic RGD Peptide Analogues as Antiplatelet

Antithrombotics, J. Med. Chem. , 35, 2040, 1992. McDowell, R. S.; Gadek, T. R., Structural Studies of Potent Constrained RGD Peptides, J. Amer. Chem. Soc. , 114, 9245, 1992.

Glaxo EP 537980, Oct. 13, 1992, B. Porter, et al.: Describes six cis-4-[4-(4- amidinophenyl)- 1 -piperazinyl]- 1 -hydroxycyclohexaneacetic acid analogs. EO 0542363, Nov. 10, 1992, Porter, B., et al.: Describes 4-[-4-amidinophenyl- piperazinyl]-piperidine-l -acetic acid analogs. WO 93/22303, Jan. 11, 1993, Middlemiss, D., et al.: Describes amidinophenyl- aiylpiperazineacetic acid analogs.

WO 93/22303, Jan. 11, 1993, Middlemiss, D., et al.: Describes amidinophenyl- arylpiperazineacetic acid analogs. WO 93/14077, Jan. 15, 1993, B. Porter, et al.: Describes amidinophenyl-piperizinyl- piperidine-acetic acid analogs. EP 609282 Al, Aug. 10, 1994, Porter, B. et al.: Describes cyclohexane acetic acid derivatives. EP 612313, Aug. 31, 1994, Porter, B., et al. Describes alpha-alkylpiperidineacetic acid derivatives. EP 93911769, Apr. 20, 1994, Midlemiss, D., et al. EP 637304 Al, Feb. 8, 1995, Middlemiss, D., et al. Piperazine Acetic acid Derivatives. Hann, M. M.; Carter, B.; Kitchin, J.; Ward, P.; Pipe, A.; Broomhead, J.; Hornby, E.; Forster, M.; Perry, C, An Investigation of the Bioactive Conformation of ARG-GLY-ASP Containing Cyclic Peptides and Snake Venom Peptides Which Inhibit Human Platelet Aggregation, In Molecular Recognition:

Chemical and Biochemical Problems II", S. M. Roberts, Ed., The Royal Society of Chemistry, Cambridge, 1992. Ross, B. C. Nonpeptide Fibrinogen Receptor Antagonists", (SAR leading to the discovery of GR 144053), In Seventh RSC-SCI Medicinal Chemistry Symposium, The Royal Society of Chemistry Fine Chemicals and Medicinals Group and SCI Fine Chemicals Group, Churchill College, Cambridge, 1993, L20. Pike, N. B.; Foster, M. R.; Hornby, E. J.; Lumley, P., Effect of the Fibrinogen Receptor Antagonist GR 144053 Upon Platelet Aggregation Ex Vivo Following Intravenous and Oral Administration to the Marmoset and

Cynomologous Monkey, Thromb. Haem. , 69, 1071, 1993.

Hoechst

DE 4009506, Mar. 24, 1990, Konig, W., et al.: Describes Hydantoin-(Arg-Gly)- Asp-X analogs.

Hoffmann-La Roche

AU 9344935, (Der 94-118783/15), Mar. 10, 1994, : Describes Cyclic RGD analogs. EP 0592791, Apr. 20, 1994, Bannwarth. W. et al.: Describes Cyclic RGD analogs.

Kogyo Gijutsuin

JP 06179696, June 28, 1994, Maruyama, S., et al.: Describes Gly-Pro-Arg-Pro-Pro and analogs.

Kyowa Hakko Kogyo KK

JP 05078244- A, Mar. 30, 1993: Describes dibenzo(b,e)oxepine derivatives.

Laboratoire Chauvin

WO 9401456, Jan. 20, 1994, Regnouf, D. V. J. et al.: Describes Ac-Arg-Gly-Asp- NHBn analogs.

La Jolla Cancer Res. Fndn

WO 9500544, Jan. 5, 1994, Pierschbacher, M. D. et al. US 079441, Jan 5, 1994, Pierschbacher, M. D. et al.: Describes RGD Peptides. Lilly / COR

EP 0635492, Jan. 25, 1995, Fisher, M. J., Happ, A. M., Jakubowski, J. A., Kinnick, M. D., Kline, A. D., Morin, Jr., J. M., Sail, M. A., Vasileff, R. T.,: Describes compounds with 6,6-templates.

Medical University of South Carolina

EP 587770, Mar. 23, 1994 Halushka, P. V., Spicer, K. M.

Merck

EP 0368486 (Der 90-149427/20), Nov. 10, 1988: Describes X-R-Tyr-D-Y analogs. EP 0382451 (Der 90248531): Descirbes RGD-containing snake venom inhibitors. EP 0382538 (Der 90248420): Descirbes RGD-containing snake venom inhibitors. EP 0410537, July 23, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides.

EP 0410539, July 25, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides. EP 0410540, July 25, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides. EP 0410541, July 25, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides. EP 0410767, July 26, 1990, R. F. Nutt, et al.: Describes linear RGD-containing peptides. EP 0411833, July 26, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides.

EP 0422937, Oct. 11, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides. EP 0422938, Oct. 11, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides. EP 0487238, Octover 13, 1991, T. M. Connolly, et al.: Describes Linear RGD- containing. EP 0437367 (Der 91209968), M. Sato et al.: Describes cyclic RGD-containing peptides, as inhibitors of osteoclast-mediated bone resoφtion. EP 576898, Jan. 5, 1994, Jonczyk, A., et al.: Describes linear RGD peptide analogs for use in inhibition of cell adhesion. WO 9409029, Apr. 28, 1994, Nutt, R. F. and Veber, D. F., describes piperidinylethylpyrrolidinylacetyl-Asp-Tφ(tetrazoles). EP 618225, (Der 94-304404/38) Oct. 5, 1994, Describes RGD peptide analogs as antimetastatic compounds. DE 4310643, (Der 94-311172/39), Oct. 6, 1994, Jonczyk, A., et al.,: Describes cyclic RGD analogs as antimetastatic agents.

NO 9404093, Oct. 27, 1994, Jonczyk, A., et al. EP 0632053, Jan. 4, 1995, Jonczyk, A., et al.,: Describes cyclic RGD analogs as antimetastatic agents. EP 0479481, Sept. 25, 1991, M. E. Duggan et al.: Describes X-GlyAsp-Y linear semipeptides.

EP 0478328, Sept. 26, 1991, M. S. Egbertson, et al.: Describes tyrosine derivatives. EP 0478362, Sept. 27, 1991 M. E. Duggan et al. : Describes X-Gly-(3- phenethyl)βAla analogs. EP 0478363, Sept. 27, 1991, W. L. Laswell, et al.: Describes Tyrosine sulfonamides.

EP 0512829, May, 7, 1992, Duggan, M. E., et al.: Describes chiral 3-hydroxy-6-(4- piperidinyl)heptanoyl-β-X-β-Ala-OH analogs, with variations on X and the central alkanoyl chain. EP 0512831, May, 7, 1992, Duggan, M. E., et al.: Describes chiral 2-oxo-3- (Piperidinylethyl)piperidinylacetyl-β-X-β-Ala-OH analogs, with variations on X and the central piperidinyl ring. EP 0528586, August 5, 1992, M. S. Egbertson, et al.: Describes tyrosine sulfonamides as inhibitors of osteoclast-mediated bone resoφtion. EP 0528587, August 5, 1992, M. S. Egbertson, et al.: Describes tyrosine sulfonamides as inhibitors of osteoclast-mediated bone resoφtion.

EP 0540334, October 29, 1992, G. D. Hartman, et al.: Describes benzimidazoles. US 5227490, Feb. 21, 1992, G. D. Hartman, et al.: Describes Tyrosine sulfonamides. CA 2088518, Feb. 10, 1993, Egbertson, M. S., et la. aminoalkyl-phenyl derivs. as bone resoφtion inhibts. US 5206373-A, (Der 93-151790/18) Apr. 27, 1993, Chung, J. Y. L., et al.: Describes

MK-383-type compounds. WO 9316994, (Der 93-288324/36), Sep. 2, 1993, Chung, J. Y. L., et al.: Describes pyridinylbutyl-L-Tyrbutylsulfonamide. US 5264420-A, Nov. 23, 1993, Describes piperidinylalkyl-Gly-betaAla analogs. US 5272158, Dec. 21, 1993, Hartman, G. D. et al.,: Describes piperidinylethylisoinole analogs. US 5281585, Jan. 25, 1994, Ihle, N., et al.,: Describes 3-(piperidinylethyl)- piperidinone analogs. GB 945317 A, Mar. 17, 1994 (Priority US 34042A , Mar. 22, 1993). GB 2271567 A, Apr. 20, 1994, Hartman, G. D. et al.: Describes compounds replacing Tyr with beta-phenylsuccinate. US 5294616, (Der 94-091561/11) Mar. 15, 1994, Egbertson, M. S., et al. US 5292756, (Der 94-082364) Apr. 8, 1994, Hartman, G. D. et al. WO 9408577, Apr. 28, 1994, Hartman, G. D., et al. WO 9408962, Apr. 28, 1994, Hartman, G. D., et al.

WO 9409029, (Der 94-151241/18) Apr. 28, 1994, Hartman, G. D., et al. Describes piperidinylpyrrolinylacetyl-Asp-Tφ-tetrazoles. US 5312923, May 17, 1994, Chung, J. Y. L. et al.

HU 9400249, May 30, 1994, Gante, J. et al.,: Describes piperazine analogs. WO 9412181, (Der 94-199942/24), Jun. 9, 1994, Egbertson, M. S. et al.,: Describes piperidinylethyloxyphenyl acetic acid analogs US 5321034, June 14, 1994, Duggan, M. E., et al.: Describes Piperidinylalkyl- betaamino acids. US 5334596, Aug. 2, 1994, Hartman, G. D. et al. EP 0608759 A, Aug. 3, 1994, GAnte, J. P. et al.: Describes amidinopiperazinyl compounds. WO 9418981, (Der 94-293975/36) Sep. 1, 1994, Claremon, D. A., et al.: Describes Many different amine suπogate.

GB 2276384, (Der 94-287743/36) Sep. 28, 1994, Claremon, D. A.., Liverton, N..,: Describes piperidinylethylquinazoline analogs. WO 9422825, Oct. 13, 1994, Claremon, D. A.. Liverton, N. J.,: Describes piperidinylethyl-retro-benzodiazepine analogs.

EP 0623615 A, Nov. 9, 1994, Raddatz, P. et al: Describes amidinophenyloxazolidinylmethyl-piperidine-4-carboxylic acid and analogs.

WO 9504531, Feb. 16, 1995, Hartman, G D., et al.: Describes piperidinylalkylheterocycles.

Nutt, R. F.; Brady, S. F.; Colton, C. D.; Sisko, J. T.; Ciccarone, T. M.; Levy, M. R.; Duggan, M. E.; Imagire, I. S.; Gould, R. J.; Anderson, P. S.; Veber, D. F., Development of Novel, Highly Selective Fibrinogen Receptor Antagonists as Potentially Useful Antithrombotic Agents, In Peptides, Chemistry and Biology, Proc. 12th Amer. Peptide Symp., J. A. Smith and J. E. Rivier, Ed.,

ESCOM, Leiden, 1992; 914.

Hartman, G. D.; Egbertson, M. S.; Halszenko, W.; Laswell, W. L.; Duggan, M. E.; Smith, R. L.; Naylor, A. M.; Manno, P. D.; Lynch, R. J.; Zhang, G.; Chang, C. T. C; Gould, R. J., Non-peptide Fibrinogen Receptor Antagonists. 1. Discovery and Design of Exosite Inhibitors, J. Med. Chem. , 35, 4640, 1992.

Gould, R. J.; Baπett, S.; Ellis, J. D.; Holahan, M. A.; Stranieri, M. T.; Theoharides, A. D.; Lynch, J. J.; Friedman, P. A.; Duggan, M. E.; Ihle, N. C; Anderson, P. S.; Hartman, G. D., Characterization of L-703,014, A Novel Fibrinogen Receptor Antagonist, Following Oral Administration to Dogs, Thromb. Haem. , 69, 539, 1993.

Merrell Dow

WO 93/24520, May 14, 1993, Harbeson, S. L., et al.: Describes cyclic RGD peptides. WO 9324520, Dec. 9, 1993, Harbeson, BitontiJ., A.,: Describes cyclic RGD analogs as antimetastatic agents. WO 9429349, Dec. 22, 1994, Harbeson, BitontiJ., A.,: Describes cyclic RGD analogs as antimetastatic agents.

Nippon Steel Corp WO 9405696, Mar. 17, 1993, Sato, Y., et al,. EP 628571, Dec. 14, 1994, Sato, Y. et al. WO 9501371, Jan. 12, 1995, Sato, Y. et al.: Describes RWSRGDW analogs.

ONO Pharmaceuticals JP 05286922 (Der 93-383035/48), Describes guanidinophenol alkylbenzoic acid esters.

Roche

EP 038,362, Feb. 19, 1990, M. Muller, et al.: Describes X-NHCHYCO-Gly-Asp- NHCHZCO₂H analogs.

EP 0372486, June, 13, 1990, Allig, L., et al. EP 0381033, July, 8, 1990, Allig, L., et al.

EP 0384362, August 29, 1990, Allig, L. et al.: Describes amidinophenyl-linked Gly- Asp-X semipeptides. EP 0445796, Sept. 11, 1991, Allig, L. et al.: Describes amidinophenyl-linked Gly- Asp-X semipeptides. EP 0505868, Sept. 30, 1992, Allig, L. et al.: Describes N-acyl-alphaamino acid derivatives, ie. analogs from EP0381003 with variations in the phenyloxyacetic acid group. US 5273982-A, (Der 94-006713/01) Dec. 28, 1993 : Describes amidinophenyl-linked Gly-Asp-X semipeptides. Alig, L.; Edenhofer, A.; Hadvary, P.; Hurzeler, M.; Knopp, D.; Muller, M.; Steiner, B.; Trzeciak, A.; Weller, T., Low Molecular Weight, Non-peptide Fibrinogen Receptor Antagonists, J. Med. Chem. , 35, 4393, 1992. Rhone-Poulenc Rorer

US 4952562, Sept. 29, 1989, S. I. Klein et al.: Describes X-Gly-Asp-Val-OH analogs. US 5064814, (Der 91-353169/48) Apr. 5, 1990: Describes Piperidinyl-azetidinyl- Asp-X analogs.

WO 9104746, Sept. 25, 1990, S. I. Klein et al.: Describes X-Asp- Val-OH analogs. WO 91/05562, Oct. 10, 1989, S. I. Klein et al.: Describes X-Gly-Asp- Val-OH analogs. WO 91/07976, (Der 91-192965) Nov. 28, 1990, S. I. Klein et al.: Describes X- cycloAA- Asp- Val-OH analogs.

WO 91/04746, S. I. Klein et al.: Describes des-AminoArginine RGD analogs. WO 92/18117, Apr. 11, 1991, S. I. Klein et al.: Describes X-Asp-Val-OH analogs. US 5086069, (Der 92-064426/08) Apr. 2, 1992, : Describes X-Gly-Asp-Val-OH analogs. WO 92/17196, Mar. 30, 1992, S. I. Klein et al.: Describes X-Gly-Asp-Val-OH analogs. US 5328900, (Der 94-221950/27) Jul. 12, 1992, : Describes X-azetidinyl-Asp-Val-

OH analogs. US 5332726, (Der 94-241043/29) Jul. 26, 1994, : Describes guanidinoalkanoyl-(N- alkyl)Gly-Asp-Val-OH analogs.

WO 93/11759, Dec. 7, 1992, S. I. Klein et al.: Describes Bis-guanidinoaklanoic acid analogs. EP 0577775, Jan 12, 1994, Klein, S. I. et al. CA 2107088, Sept. 29, 1992, Klein, S.I. et al.

Sandoz

EP 0560730, Mar. 8, 1993 G. Kottirisch and R. Metternich: Describes amidinophenylalkanamid-S-α-acetic acid analogs. G. Kottirisch, et al. Biorg. Med. Chem. Lett 3, 1675-1680, 1993, Describes amidinophenylacetyl-(Gly-Asp--γJactam mimetic)analogs. Schering AG

E 530937, Mar. 10, 1993, Noeski-Jungblut, C, et al. "Collagen Induced Platelet Aggregation Inbitor."

Searle / Monsanto

EP 0319506, (Der 89-3195506) Dec. 2, 1988, S. P. Adams, et al.: Describes RGD-X analogs. EP 0462,960, June, 19.1991, Tjoeng, F. S., et al.: Describes guanidinooctanoyl- Asp-Phe analogs. US 4857508, S. P. Adams, et al.: Describes RGD analogs.

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EP 0454651 A2, Oct. 30, 1991, Tjoeng, F. S., et al: Describes amidinoalkanoyl-

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US, 5272162, Dec. 21, 1993, Tjoeng, F. S., et al.: Describes amidinophenyl-X-

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Sumitomo Pharm. Co. Ltd.

WO 9501336, June 6, 1994, Ikeda, Y., et at., Describes piperidinyloxyacetyl-Tyr- piperidinyloxy acetic acid derivatives.

Sumitomo Seiyaku KK JP 06025290, (Der 94-077374/10) Feb. 1, 1994. Describes multimeric RGDT.

Taisho Pharm. (Teijin, Ltd)

JP 05230009, (Der 93-317431/40, Feb. 24, 1992: Describes amidino-Cbz-meta- aminophenylpropionate.

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Telios / La Jolla Cancer Research

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Temple U.

WO 9409036, (Der 94-151248/18), Apr. 28, 1994, Describes disintegrin peptides.

Terumo KK JP 6279389, Oct. 4, 1994, Obama, H., et al.: Describes 3-(4- amidinophenyloxymethyl)phenylamidopropionic acid analogs (ala Roche I- 35).

Karl Thomae / Boehringer Ingelheim EP 0483667, May 6, 1992, Himmelsbach, F., et al.: Describes amidinobiphenyl- oxymethyl-2-pyrrolidinone-acetic acid. EP 0496378, Jan. 22, 1992, Himmelsbach, F., et al.: Describes amidinobiphenyl- aminocarbonylcyclohexylcarboxylic acid analogs. EP 0503548, Sep. 16, 1992, Himmelsbach, F., et al.: Describes amidinophenyl- pyrrolidinone-phenylpropionic acid analogs. AU A-86926/91, May 7, 1992, Himmelsbach, F. et al.: Describes amidinophenyl compounds. EP 0528369, Feb. 24, 1993, Austel, V., et al.: Describes amidinobiphenyl- oxymethyl-2-pyrrolidinone-acetic acid. EP 0537696, Apr. 21, 1993 Linz, G., et al.: Describes amidinophenyl-pyridazine analogs. DE 4124942, Jan. 28, 1993, Himmelsbach, F. et al.: Describes amidino- triarylproionic acid analogs. DE 4129603, Mar. 11, 1993, Pieper, H, et al.: Describes amidinobiphenyl- benzimidazole.

EP 0547517 Al, (Der 93-198544) June 23, 1993, Soyka, R., et al.: Describes pyridyl compounds. EP 0567966, Nov. 3, 1993, Himmelsbach, F., et al.: Describes amidinobiphenyl- oxymethyl-2-pyrrolidinone-acetic acid. EP 0567967, Nov. 3 1993, Weisenberger, J., et al.: Describes amidinobiphenyl- oxymethyl2-pyπolidinone-acetic acid. EP 0567968, Nov. 3, 1993, Linz, G., et al.: Describes amidinobiphenyl-lactam-acetic acid and amidinophenyllactamphenylpropionic acid analogs. EP 0574808, June 11, 1993, Pieper, H., et al.: Describes amidinobiphenyl-X-acetic acid ester analogs.

Der 93-406657/51, Austel, V.., et al.: Describes amidinobiphenyl analogs. EP 587134, (Der 94-085077/11) Mar. 16, 1994, Himmerlsbach, F. D. D., et al.,

Describes amidinophenyltriazolone analogs. EP 589874, Apr. 6, 1994, Grell, W., et al. (P534005), DE 4234295, Apr. 14, 1994, Pieper, H., et al., Describes heteroaryl- azacyclohexylcarboxylic acid analogs. EP 0592949, Apr. 20, 1994, Pieper, H. D., et al., Describes amidinophenyl-

4piperidinamido-4-cyclohexylcarboxylic acid analogs. EP 596326, May, 11, 1994, Maier, R. et al. DE 4241632, June 15, 1994, Himmelsbach, F., et al., Describes piperidinopheny lamido-phenylpropionyl analogs . EP 0604800 A, Jul. 6, 1994, Himmelsbach, F. et al., Describes piperidinophenylamido-phenylalanine derivatives. DE 4302051, (Der 94-235999/29) July, 28, 1994, describes compounds containing a

2H-pyrazol-5-one. EP 0608858 A, Aug, 3, 1994, Linz, G. D., et al., Describes amidino-biphenyl compounds. DE 4304650, (Der 94-256165/32), Aug, 18, 1994, Austel, V., et al., describes compounds with a 5,6 template. EP 611660, Aug, 24, 1994, Austel, V., et al., Describes tricyclic template. DE 4305388, (Der 94-264904/33), Aug. 25, 1994, Himmelsbach, F., et al.,

Describes 6,6 and 7,6 templates. (P5D4005), EP 612741, (Der 94-265886/33), Aug. 31, 1994, Himmelsbach, F., et al., Describes 6,6 and 7,6 templates. EP 0639575 A, Feb. 22, 1995, Linz, G., et al.: Describes tetrahydrothiazolo- [5,4,c]pyridine 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 Xllth Int. Symp. on Med. Chem. Basel, Book of Abstracts, 47, 1992.

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975, 1993.

Univ. California WO 94/14848, July, 7, 1994, Zanetti, M. RGD peptides from CDR. Univ. New York

WO 94/00144, June 29, 1993, Ojima, I. et al.: Describes RGD peptide multimers.

Yeda Res. and Dev. Co. WO 93/09795, (Der 93-182236/22), Lido, O. et al.: Describes Guanidinopentanoic acid analogs.

Zeneca

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WO 9422835, Oct. 13, 1994, Wayne, M. G., et al. Describes pyridinopiperidino- amidophenylacetic acids. EP 632016, Jan. 4, 1995, Brewster, A. G.., et al. Describes pyridinopropionylhydrazinylbenzoyl analogs . 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 unique nonracemic 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 occuπence is independent of its meaning, or any other substituent's meaning, at any other occuπence. Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of this invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).

Ci-4alkyl as applied herein means an optionally substituted alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Ci_6alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Cθ-4alkyl and Cθ-6alkyl additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).

Any Ci-4alkyl or C]-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or -6 oxoalkyl may be optionally substituted with the group R^x, which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques. Suitable groups for R^x are CMalkyl, OR-*, SR*, CMalkyl, Ci-4alkylsulfonyl, Ci-4alkylsulfoxyl, -CN, N(R¹)2, CH2N(R!)2, -NO2, -CF3,

-CO2R'³ -CON(R¹)2, -CORl, -NR¹C(O)R¹, OH, F, Cl, Br, I, or CF3S(O)_r,wherein 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 CMalkyl, Ci-4alkoxy, Ci-4alkthio, trifluoroalkyl, OH, F, Cl, Br or I. Het, or heterocycle, indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring 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, indoline, moφholine, piperidine, piperazine, pyrrole, pyπolidine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline 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. 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 ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.

When R^D and R^c are joined together to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to the ring to which R^D and R^c are attached, the ring 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 ring. Preferably Rb and Rc will be -D1=D2-D3=D4 wherein Dl - D4 are independently CH, N or C-R_x with the proviso that no more than two of Dl - D4 are N. Most preferably, when Rb and R^c are joined together they form the group - 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, CIZ 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 CMalkyl, 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 dicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEA refers to diisopropylethyl amine, EDC refers to l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, hydrochloride. HOBt refers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DIEA refers to diisopropylethylamine, DME refers to dimethoxyethane, DMF refers to dimethylformamide, NBS refers to N- bromosuccinimide, Pd/C refers to a palladium on carbon catalyst, PPA refers to 1- propanephosphonic acid cyclic anhydride, DPPA refers to diphenylphosphoryl azide, BOP refers to benzotriazol-l-yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate, HF refers to hydrofluoric acid, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, PCC refers to pyridinium 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 L¹ and L² are groups which may react to form a covalent bond in the moiety W, by methods generally known in the art.

(xπ) (XX) (I)

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-l and L² will contain an amino or hydroxy group and the other will contain a displaceable group, such as a chloro, bromo or iodo group. When W contains an amide bond, typically one of L and L² will contain an amino group, and the other will contain a carboxylic acid group. In another approach, L^ may be an aryl or heteroaryl bromide, iodide or trifluoromethylsulfonyloxy derivative and L² may contain an amino group and the amide linkage may be formed by palladium- catalyzed aminocarbonylation with carbon monoxide in 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 preparing the linkage -(CHR")_r-U-(CHR")_s-V- are described, for example, in EP-A 0 372486 and EP-A 0 381 033 and EP-A 0478 363, which are incoφorated herein by reference.

For instance, if V is CONH, L¹ may be -NH2, L² may be OH (as in an acid) or Cl (as in an acid chloride), and R^6" may be W-(CR^,2)q-Z-(CR^,R¹⁰)_r-U-(CR'₂)s- C(O), with any functional groups optionally protected. For example, R⁶" may be (benzyloxycarbonyl-amidino)benzoyl- or (N^α-Boc,NS^uan-Tos)arginyl-. 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 R^6" may be W-(CR'₂)q-Z-(CR'R¹⁰)_r-U-(CR'₂)s-. For example, R^6" may be (benzyloxycarbonyl-amidino)phenyl, (benzyloxycarbonylamino)methylbenzyl- or 6- (benzyloxycarbonylamino)hexyl- . Where V is NHSO2_. L¹ may be SO2CI, L² may be -NH and R^6" may be as above. Where V is SO2NH, L¹ may be -NH₂ and L² may be SO₂Cl. 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 R^6" may be W- (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-(CR'₂)_q-Z-(CR'R¹⁰)_r-U-(CR'2)s-i-CHO.

Where V is CH2CH2 may be obtained by reduction of a suitably protected compound wherein V is CH=CH.

Where V is CH2O, CH2N or C≡ C , L¹ may be -OH, -NH or -C= C H,respectively; L² may be -Br; and R^6" 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-piperidinyl)-ethyl.

Similarly where U or V is OCH2, NRCH2 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≡ C , L¹ may be Br, I or CF3SO3, L² may be C≡ C H 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 7et. Lett., 31, 231 (1990). Compounds of the formula (I)-(V), wherein the fibrinogen receptor antagonist template is of the formula (VI) are prepared by the general methods described in Schemes I-III.

Scheme I

a) EDC, HOBT, (i-Pr)2NEt, DMF, 2-aminomethylbenzimidazole; b) SOCh, reflux; c) 2-aminobenzimidazole, pyridine, CH2CI2; d) 1.0 N LiOH, aqueous THF; e) acidification.

Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetate (1-1), prepared as described by Bondinell, et al. (WO 93/00095), is converted to an activated form of the carboxylic acid using, for example, EDC and HOBT or SOCI₂, and the activated form is subsequently reacted with an appropriate amine to afford the coπesponding amide 1-2. Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - VI (published by Wiley-Interscience). The methyl ester of 1-2 is hydrolyzed using aqueous base, for example, aqueous LiOH in 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 carboxylic acid 1-3. Alternatively, the intermediate carboxylate salt can be isolated, if desired.

Scheme II

a) (BOC)₂O, DMAP, CH3CN; b) SOCl₂, toluene, 70°C; c) H₂, 10 % Pd/C, 2,6- lutidine, THF; d) 2-(aminomethyl)benzimidazole, NaBHsCN, MeOH; e) formaldehyde, NaBH₃CN, AcOH, CH3CN; f) LiOH, THF, H₂O; g) acidification.

Conversion of the carboxylic acid moiety of 1 -Scheme II to an aldehyde can be accomplished by standard methodology, as described in "Compendium of Organic Synthetic Methods" (published by Wiley-Interscience). For example, after protection of the aniline nitrogen as its tert-butyl carbamate, the carboxylic acid is converted to the corresponding acid chloride with a suitable reagent, such as thionyl chloride. The tert-butyl carbamate is lost under these conditions. The resulting acid chloride 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 sodium cyanoborohydride. Alternative methods for converting an aldehyde to an amine are described 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. et al, Tetrahedron Letters 1973, 261; Borsch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673). Thus, reaction of 4-Scheme II with formaldehyde in the presence of a suitable reducing agent, such as sodium cyanoborohydride, gives 5-Scheme II. Saponification of the methyl ester of 5-Scheme II by the methods described earlier gives 6-Scheme II. The methyl ester of 4-Scheme II can be cleaved similarly.

Scheme III

a) NCS, DMF, 80 °C; b) see Scheme 1.

Halogenation of the aromatic moiety of 1-Scheme III can be accomplished with an appropriate elctrophilic halogenating reagent, such as N-chlorosuccinimide. The resulting chlorinated derivative, 2-Scheme III, is then conveted to 3-Scheme III by the methods described in Scheme I.

The core 6-7 fused ring system is prepared of formula (VI) by methods well known in the art, e.g., Hynes, et al, J. Het. Chem., 1988, 25, 1173; Muller, et al, Helv. Chim. Ada., 1982, 65, 2118; Mori, et al, Heterocycles, 1981, 16, 1491. Similarly, methods for preparing benzazepines, 1,4-benzothiazepines, 1,4- 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 preparing the benzodiazepine nucleus is given by Schemes IV and V. A representative method for preparing a benzazepine nucleus is given by Scheme VI. A representative method for preparing a benzothiazepine is given by Scheme VII. An benzoxazepine nucleus may be prepared in the same manner as Scheme VII, except substituting a benzyl alcohol for a benzyl thiol. Scheme IV

couple

Scheme V

Scheme VI

Scheme VII

0

The simple tri-substituted benzene starting materials are commercially available or prepared by routine methods well known in the art.

Schemes VHI-XI are illustrative of the methods for preparing certain compounds of the instant invention. In schemes VIII - X, a covalent bond of the group W is prepared by a nucleophilic displacement reaction.

In Scheme VIE, 4-[2-(methylamino)acetyl]phenol hydrochloride (Reel Trav. Chim. Pays-Bas 1949, 68, 960) is N-protected with a suitable nitrogen protecting group, such as a tert-butoxycarbonyl (BOC) group, to provide the N-protected derivative 2-Scheme VIII. Scheme VIII

a) (BOC)2θ, NaOH, 1,4-dioxane, H2O; b) BrCH2CO2Bn, K2CO3, acetone; c) 4 M HCl in 1,4-dioxane; d) 2-(chloromethyl)benzimidazole, Et3N, CH3CN, CH2CI2; e) H2, 5% Pd/C, MeOH.

-5 t Other standard nitrogen protecting groups, such as those described 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 molecule. Alkylation of the phenol moiety of compound 2-Scheme VIII to afford the aryloxyacetic acid derivative 3-Scheme VIII can be accomplished by reaction with a haloacetic acid ester, for instance benzyl bromoacetate, under basic conditions in a neutral solvent. Generally, K2CO3 in refluxing acetone or 2-butanone gives acceptable results, but other bases, such as Li2CO3 or CS2CO3, and other solvents, such as DMF, THF, or DME, might also be used. The nitrogen protecting group of 3-Scheme VIJJ is removed under conditions appropriate for selective deprotection of the specific protecting group employed. For example, the BOC group of 3-Scheme VUJ can be removed under acidic conditions, such as 4 M HCl in 1,4-dioxane or TFA in CH2CI2, to afford amine 4-Scheme VIII as the corresponding ammonium salt. Conversion of compound 4-Scheme VIII to the bis-benzimidazole derivative 5- Scheme VDI can be accomplished by alkylation with 2-

(chloromethyl)benzimidazole in a solvent mixture of CH3CN and CH2CI2 in the presence of Et3N. Subsequent removal of the ester group of compound 5-Scheme VIII under appropriate conditions gives compound 6-Scheme VIII. The conditions selected for ester removal must be appropriate for the specific ester present as well as compatible with the other functionality in the molecule. For instance, the benzyl ester of 5-Scheme VIII 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 VEQ. In Scheme IX, commercially available andrenolone hydrochloride (1 -Scheme

2) is N-protected as discussed in Scheme 1 to provide the Cbz derivative 2-Scheme 2. Scheme IX

a) CbzCl, NaOH, toluene, H2O; b) BrCH2CO2CH3, K2CO3, acetone; c) H2, 10% Pd/C, EtOAc, MeOH; d) 2-(chloromethyl)benzimidazole, Et3N, CH3CN, CH2CI2; e) 1.0 N LiOH, THF, H2θ.

Dialkylation of 2-Scheme IX by reaction with a haloacetic acid ester, for instance methyl bromoacetate, under basic conditions in a neutral solvent, provides the 1,2-phenylenedioxydiacetic acid derivative 3-Scheme IX. K2CO3 in refluxing acetone generally gives acceptable results, but other bases and solvents, such as 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 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 appropriate 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 in the 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 hydrochloride (1 -Scheme X) is N-protected as described in Scheme VIII to provide the BOC derivative 2- Scheme X. Scheme X

a) (BOC)2θ, NaOH, 1,4-dioxane, H2O; b) BrCH2CO2CH3, K2CO3, acetone; c) 4 M HCl 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 derivative 5-Scheme X. Subsequent removal of the BOC group of 5-Scheme X as discussed in Scheme VIH 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. Scheme XI

4

a) ethyl acrylate, HOAc; b) SOCI2; c) 2-(aminomethyl)benzimidazole, 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-(carboxy)aniline (1 -Scheme XI) to ethyl acrylate in acetic acid as described in Chem. Ber., 91, 2239, 1958. The carboxyl in compound 2-Scheme XI is converted to the acid chloride with thionyl chloride, and the acid chloride is condensed with 2-(aminomethyl)benzimidazole dihydrochloride hydrate with diisopropylethylamine in dichloromethane 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 carboxylic acid with other metal hydroxides or carbonates in a suitable solvent. Scheme XII

1d 3) HO Ac reflux 1f

ig

The starting material for the foπnula lg-Scheme XII compounds are prepared following the procedures in Egbertson et al., J. Med. Chem., 1994, 37, 2537- 3551 which discloses general methods to alkylate the phenol of an N-protected tyrosine derivative, remove the N-protecting group, and sulfonylate the amine. Using benzyl 4-bromobutyrate as the alkylating agent, intermediate Id-Scheme XII was prepared. Removal of the benzyl ester and reaction with ortho- phenylenediamine under standard conditions afforded the benzimidazole lf-Scheme Xπ. Finally, saponification of the methyl ester yielded the target compound lg- Scheme xπ.

Intermediate compounds of formula (XXX) may be prepared from suitably protected amino acids and phenyl- 1,2-diamines or 2-nitro-anilines which are commercially available or prepared by methods available to those skilled in the art according to the Scheme (XIII) and (XIV). Scheme XIII

Pr¹-NR'-(CH₂)_a-C0₂H Pr¹-NR'-(CH₂)_a-CO-0 -CO-O^'

a) isobutyl chloroformate, THF, NEt3; b) Δ, AcOH

Scheme XIV

Pr¹-NR'-(CH₂)_a-C0₂H Pr¹-NR'-(CH₂)_a-CO-CI

a) thionyl chloride; b) Fe, AcOH, Δ

Amide coupling reagents as used herein denote reagents which may be used to form peptide bonds. Typical coupling methods employ carbodiimides, activated anhydrides and esters and acyl halides. Reagents such as EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride 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 PRACTICE OF PEPTIDE SYNTHESIS, Springer- Veriag, Berlin, 1984, Ali et al. in J. Med. Chem., 29, 984 (1986) and J. Med. Chem., 30, 2291 (1987) are generally illustrative of the technique and are incoφorated herein by reference.

Typically, the amine or aniline is coupled via its free amino group to an appropriate carboxylic acid substrate using a suitable carbodiimide coupling agent, such as N,N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP). Other methods, such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a suitably protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine, optionally in 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 chloride or tetrahydrofuran(THF), in the presence of a base, such as N-methyl morpholine, DMAP or a trialkylamine, with isobutyl chloroformate to form the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino 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 in standard reference books, like the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, 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 preparing 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 suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions 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, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li⁺, Na⁺, K⁺, Ca^{"1" "}, Mg^"*^""*^" and NH4"^1" are specific examples of cations present in pharmaceutically acceptable salts.

This invention also provides a pharmaceutical composition which comprises a compound according to formula (I)-(V) and a pharmaceutically acceptable carrier. Accordingly, the compounds of formula (I)-(V) may be used in the manufacture of a 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 pharmaceutically acceptable carrier prior to use. The liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in 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 in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride 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 carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid caπiers include starch, lactose, calcium sulfate dihydrate, teπa alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid caπier 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. 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 described herein are antagonists of the vitronectin receptor, and are useful for treating diseases wherein the underlying pathology is attributable to ligand 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 sex hormone deficiency. The compounds of this invention are also believed to have utility as antitumor, anti-angiogenic, 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 resoφtion, or 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 prefeπed. An intravenous infusion of the peptide in 5% dextrose in water or normal saline, or a 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 0J 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 the compounds are administered is readily determined by one routinely skilled in the art 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 pharmacological effect.

Inhibition of vitronectin binding

Solid-Phase [3 HJ-SK&F- 107260 Binding to α_vβ3: Human placenta or human platelet α_vβ3 (0J-0.3 mg/mL) in buffer T (containing 2 mM CaCl2 and 1% 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 ELISA plates (Corning, New York, NY) at 0J mL per well. 0J - 0.2 μg of α_vβ3 was added per well. 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 0J 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 Tris-HCl (pH 7.4), 100 mM NaCl, 1 mM CaCl2, 1 mM MnCl2, 1 mM MgCl2) to a final compound concentration of

100 μM. This solution is then diluted to the required final compound concentration.

Various concentrations of unlabeled antagonists (0.001 - 100 μM) were added to the wells in triplicates, followed by the addition of 5.0 nM of [³H]-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 in a well-to-well fashion. The receptors were solubilized with 0.1 mL of 1% SDS and the bound [³H]-SK&F-107260 was determined by liquid scintillation counting with the addition of 3 mL Ready Safe in a Beckman LS Liquid Scintillation Counter, with 40% efficiency. Nonspecific binding of [³H]-SK&F- 107260 was determined in the presence of 2 μM 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. The Kj (dissociation constant of the antagonist) was calculated according to the equation: Kj = IC5θ/(l + 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. Compounds of this invention are also tested for in vitro and in vivo bone resoφtion 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, described 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 using a polycarbonate membrane with pores of 8 um (Costar). The lower surface of the filter was coated with vitronectin. Cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 2.5 - 5.0 x 10⁶ cells/mL, and were pretreated with test compound at various concentrations for 20 min at 20°C. The solvent alone was used as control. 0.2 mL of the cell suspension was placed in the upper compartment of the chamber. The lower compartment contained 0.6 mL of DMEM supplemented with 0.2% bovine serum albumin. Incubation was caπied 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 either by a) counting the number of cells that had migrated to the lower surface of the filter or by b) extracting the stained cells with 10% acetic acid followed by determining the absorbance at 600 nM.

PARATHYROIDECTOMIZED RAT MODEL

Each experimental group consists of 5-6 male Sprague-Dawley rats. The rats are parathyroidectomized (by the vendor, Taconic Farms) 7 days prior to use. Twenty four hours prior to use, circulating ionized calcium levels are measured in whole blood immediately after it has been withdrawn by tail venipuncture into heparinized tubes. Rats are included if ionized Ca level (measured with a Ciba-Corning model 634 calcium pH analyzer) is _ 1.2 mM/L. The rats are then put on a diet of calcium-free chow and deionized 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 immediately by a single subcutaneous injection of either human parathyroid hormone 1-34 peptide (hPTHl-34, dose 0.2mg/kg in saline/0J% 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 appropriate route as single or multiple daily doses for a period of seven days. Prior 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 forelimbs are removed at the elbow, the foot is removed at the ankle and the skin removed. The sample is frozen and mounted vertically on a microtome chuck. Cross sections of the midshaft region of the ulna are cut in the cryostat. The rate of bone resoφtion is measured moφhometrically in the medial-dorsal portion of the cortical bone. The measurement is done as follows: the amount of bone resorbed at the periosteal surface is equal to the distance by which the periosteal surface has advanced towards the fluorescent label which had been incoφorated at the endosteal bone formation surface on day zero; this distance is calculated by subtracting the width of bone between the label and the periosteal surface on day 7 from the width on day zero; the resoφtion rate in microns per day is calculated by dividing the result by 7.

HUMAN OSTEOCLAST RESORPTION ASSAY ("PIT ASSAY")

• Aliquots of osteoclastoma-derived cell suspensions are removed from liquid nitrogen strorage, warmed rapidly at 37°C and washed l in RPMI-1640 medium by centrifugation (lOOOφm, 5 mins at 4°C).

• Aspirate the medium and replace it with murine anti-HLA-DR antibody, diluted 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 centrifugation (lOOOφm, 5 mins at 4°C) and the cells are transferred to a sterile 15 ml centrifuge 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-rich fraction) are decanted into a sterile 50 ml centrifuge tube. • 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 centrifugation and the density of osteoclasts adjusted to l.SxMfl/πά in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate.

• 3ml aliquots of the cell suspension ( er treatment) are decanted into 15ml centrifuge tubes. The cells are pelleted by centrifugation.

• To each tube 3ml of the appropriate treatment are added (diluted to 50 uM in the EMEM medium). Also included are appropriate 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 mins.

• 0.5ml aliquots of the cells are seeded onto sterile dentine slices in 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 slices are washed in phosphate buffered saline and fixed in 2% gluteraldehyde (in 0.2M sodium cacodylate) for 5 mins. • 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 mins 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 Tris-HCl, pH 7.4, 140 mM NaCl, 2 mM CaCl2 at 4°C for 2 h. The lysate was centrifuged at 100,000g for 1 h. The supernatant obtained was applied to a 5 mL lentil lectin sepharose 4B column (E.Y. Labs) preequilibrated with 20 mM Tris-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 lectin-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose. All procedures were performed at 4°C. The GPIIb-IIIa obtained was >95% pure as shown by SDS polyacrylamide gel electrophoresis.

Incoφoration of GPIIb-IIIa in Liposomes.

A mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) were dried to the walls of a glass tube under a stream of nitrogen. Purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg/mL and mixed with the phospholipids in a protei 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 tubing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes). The GPIIb-IIIa-containing liposomes wee centrifuged at 12,000g for 15 min and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg/mL. The liposomes were stored at -70C until needed.

Competitive Binding to GPIIb-IIIa

The binding to the fibrinogen 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 (Millipore Coφoration, Bedford, MA) using 0.22 um hydrophilic durapore membranes. The wells were precoated with 0.2 mL of 10 μg/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at room temperature for 1 h to block nonspecific binding. Various concentrations of unlabeled benzadiazapines 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 μg of the purified platelet GPIIb-IIIa-containing liposomes. The mixtures were incubated for 1 h at room temperature. The GPHb-IIIa-bound [3HJ-SK&F-107260 was seperated from the unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (2 times, each 0.2 mL). Bound radioactivity remaining on the filters was counted in 1.5 mL Ready Solve (Beckman Instruments, Fullerton, CA) in a Beckman Liquid Scintillation Counter (Model LS6800), with 40% efficiency. Nonspecific binding was determined in the presence of 2 μM 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 equilibrium). The IC50 is related to the equilibrium dissociation constant (Ki) of the antagonist based on the Cheng and Prusoff equation: Ki = IC50/(l+L/Kd), where L is the concentration of [3H]-SK&F- 107260 used in the competitive binding assay (4.5 nM), and Kd is the dissociation constant of [3H]- SK&F-107260 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 for the fibrinogen receptor. Prefeπed compounds have a Ki at the vitronectin receptor that is thirty-fold greater than that at the fibrinogen receptor. The most prefeπed compounds have a Ki at the vitronectin receptor that is a hundred-fold greater than that at the fibrinogen receptor.

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 Bruker AM 250 or Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-dβ is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (6) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, 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 recorded on a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR 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 m, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical and preparative HPLC were carried out on Rainin or Beckman chromatographs. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5 μ Apex- ODS indicates an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 μ, 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 polymeric (styrene- divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada) Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Coφ., Denver, Colorado. Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4- benzodiazepine-2-acetate, methyl (2S)-7-carboxy-4-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate, methyl (2R)-7-carboxy-4-methyl-3- oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate, methyl (±)-7-carboxy-4- isopropyl-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate, methyl (±)-7- carboxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-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-(Aminomethyl)imidazole was prepared according to the procedure in Annalen 1968, 718, 249.

Preparation 1 Preparation of methyl (±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3 A5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetate a) tert-Butyl 3-[(2-methoxyethyl)amino]methyl-4-nitrobenzoate

A mixture of tert-butyl 3-methyl-4-nitrobenzoate (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 succinimide. The filtrate was concentrated to leave a yellow oil.

This yellow oil was dissolved in 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 min, then was concentrated to remove the THF. The residue was diluted with E12O (630 mL) and washed sequentially with 1.0 N NaOH (125 mL) and H2O (125 mL). The combined aqueous layers were back- extracted with Et2θ (300 mL), and the combined organic layers were washed with brine (125 mL) and dried (MgSO4). Concentration and silica gel chromatography (3:2 EtOAc/hexanes) gave the title compound (10.30 g, 53%) as a yellow oil: TLC R_f (1: 1 EtOAc/hexanes) 0.43; ^lH NMR (250 MHz, CDCI3) δ 8.22 (d, J=1.7 Hz, IH), 7.99 (dd, J=8.4, 1.7 Hz, IH), 7.92 (d, J=8.4 Hz, IH), 4.08 (s, 2H), 3.51 (t, J=5J Hz, IH), 3.36 (s, 3H), 2.82 (t, J=5J Hz, 2H), 1.61 (s, 9H); FTIR (CCI4) 1723, 1530, 1369, 1302, 1162, 1116, 842 cm"¹; MS (ES) m/e 311 (M+H)⁺, 255 (M+H - C₄H₈)⁺. b) tert-Butyl 3-[[N-(2-methoxyethyl)-N-(tert-butoxycarbonyl)]amino]methyl-4- nitrobenzoate

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, 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 R_f (20% EtOAc/hexanes) 0.49; *H NMR (250 MHz, CDCI3) 57.85-8J5 (m, 3H), 4.75-4.95 (m, 2H), 3.35-3.65 (m, 4H), 3.25 (bs s, 3H), 1.60 (s, 9H), 1J5-1.80 (m, 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 - CO₂)⁺.

c) tert-Butyl 4-amino-3-[[N-(2-methoxyethyl)-N-(tert- butoxycarbonyl)]amino]methyl benzoate

10% Pd C (3.42 g, 3.22 mmol) was added to a solution of tert-butyl 3-[[N-(2- methoxyethyl)-N-(tert-butoxycarbonyl)]amino]methyl-4-nitrobenzoate (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 filtrate was concentrated to afford the title compound (12.16 g, 99%) as a colorless foam: TLC R_f (20% EtOAc/hexanes) 0.34; **H NMR (250 MHz, CDCI3) δ 7.68- 7.77 (m, 2H), 6.56 (d, J=8.9 Hz, IH), 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 (M+Na)⁺, 381.2 (M+H)+, 325.2 (M+H - C₄H₈)+, 281 (M+H - C₄H₈ - CO₂)⁺, 269.0 (M+H - 2 x C₄H₈)⁺, 225.0 (M+H - 2 x C₄H₈ - CO₂)⁺.

d) t-Butyl (±)-4-[2-(l,4-dimethoxy-l,4-dioxobutyl)amino]-3-[[N-(2-methoxyethyl)- N-(tert-butoxycarbonyl)]amino]methylbenzoate A solution of tert-butyl 4-amino-3-[[N-(2-methoxyethyl)-N-(tert- butoxycarbonyl)]amino]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 min, 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 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 residue was reconcentrated from CHCI3 (to remove MeOH), then was chromatographed on silica gel (30% EtOAc/hexanes). The title compound (15.03 g, 90%) was obtained as a faintly yellow oil: TLC Rf (30% EtOAc/hexanes) 0.39; ^lH NMR (250 MHz, CDCI3) δ 7.82 (dd, J=8.6, 2.0 Hz, IH), 7.72 (d, J=2.0 Hz, IH), 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=15J Hz, IH), 4.40 (1/2 AB, J=15J 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, 6.1 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 (M+H)⁺, 469.2 (M+H - C₄H₈)+, 425.2 (M+H - H₈ - CO₂)⁺.

e) Methyl (±)-7-carboxy-4-(2-methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetic acid

TFA (140 mL) was added all at once to a solution of t-butyl (±)-4-[2-(l,4- dimethoxy- 1 ,4-dioxobutyl)amino]-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 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 H2O (720 mL), and acidified with glacial AcOH (8 mL). The solution was cooled to RT, then 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 Et2θ, 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 R_f (10% MeOH/CHCl₃) 0.51; -*H NMR (250 MHz, DMSO-d₆) δ 7.59 (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), 5J2-5.22 (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 (1.51 g, total=7.91 g, 82%) as a light yellow solid: mp 226-229.5°C. Preparation 2 Using the procedures of Preparation 1, except substituting 3,4- methylenedioxyphenethylamine 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. ^lR NMR (DMSO-d6) δ 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 (±)-7-carboxy-3-oxo-2-3 A5-tetrahydro-lH-l ,4- benzodiazepine-2-acetate a) tert-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) in 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 Na2SO₄. Removal of solvent gave the crude product which was purified on flash chromatography

(15:85; EtOAc:Hexane) to give the title compound (81.5%): MS (ES) m/e 453 (M+H)⁺; ^lK NMR (400 MHz, CDCI3) δ 7.97-8J0 (m, 3H), 5J6 (s, 2H), 1.62 (s, 9H), 1.49 (s, 18H).

b) tert-Butyl 4-amino-3-[[bis-(t-butoxycarbonyl)]amino]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)+; -*H NMR (400 MHz, CDCI3) δ 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). c) (E/Z) tert-Butyl 4-[2-(l,4-dimethoxy-l,4-dioxo-2-butenyl)amino]-3-[[bis-(t- butoxycarbonyl)]amino]methylbenzoate

A solution of tert-butyl 4-amino-3-[[bis-(t-butoxycarbonyl)]amino]methyl benzoate (3.9 g, 9.2 mmol) and dimethylacetylene dicarboxylate (1.34 g, 9.4 mmol) was refluxed 1 h and evaporated to dryness to give the title compound: MS (ES) m/e 565.2 (M+H)+; ^lU NMR (400 MHz, CDCI3) δ 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-(l,4-dimethoxy-l,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)amino]-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 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)+; Η NMR (400 MHz, CDCI3) δ 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-(trifluoroacetate)

A solution of tert-butyl 4-[2-(l,4-dimethoxy-l,4-dioxobutyl)amino]-3-[[bis- (t-butoxycarbonyl)]amino]methylbenzoate (4.0 g, 7J mmol) in a mixture of methylene chloride (100 mL) and trifluoroacetic 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 in essentially quantitative yield: MS (ES) m/e 310.2 (M+H)⁺; -Η NMR (400 MHz, DMSO-d₆) δ 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, 3H), 3.65 (s, 3H), 2.89-3.07 (m, 2H).

f) Methyl (±)-7-carboxy-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

A solution of sodium methoxide in methanol (25 wt%, 6.7 mL, 30 mmol) was added to a solution of 4-[2-(l,4-dimethoxy-l,4-dioxobutyl)amino]-3- (aminomethyl)benzoic acid, bis-(trifluo.roacetate) (4.0 g, 7.0 mmol) at -10°C under argon. After 30 minutes, the cold solution was quenched with acetic acid (1.5 mL). 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)+; ^!H NMR (400 MHz, DMSO-d₆) δ 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 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-(methylaminomethyl)benzimidazole dihydrochloride

a) 2-[(tert-Butoxycarbonyl)sarcosyl]aminoaniline

A solution of phenylenediamine (100 g, 0.924 mole) and Boc-sarcosine (175 g, 0.924 mole) in DMF (1750 mL) was cooled to -10°C under argon, and a solution of DCC (190.8 g, 0.924 mole) in CH₂C1₂ (1750 mL) was added in a slow stream 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 brine (1 L). The CH₂C1₂ 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) and brine (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-methyl)aminomethyl]benzimidazole

A solution of 2-[(tert-butoxycarbonyl)sarcosyl]aminoaniline (178.4 g, 0.639 mole) in 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 into stiπed ice water, and cone. NH OH (1150 mL) was added to adjust the pH to 10. An oil formed which crystallized on stirring overnight. The solid was filtered and dried at 50°C at 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%). c) 2-(Methylaminomethyl)benzimidazole dihydrochloride

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- butoxycarbonyl-N-methyl)aminomethyl]benzimidazole (161 g, 0.616 mole) in

CH₂C1₂ (800 mL) was added in a slow stream over 30 min. The temperature rose to 8°C during the addition, and a white precipitate began to form before the addition was complete. The reaction was stirred for 20 min, then the title compound (66.6 g, 46%) was collected by filtration: mp 250 - 255 °C (dec). Anal. Calcd for C₉HπN₃ • 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 Et₂O, 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 (±)-7-rrrr2-benzimidazolyl)methyllaminolcarbonyl]-4-methyl-3-oxo- 2.3.4.5-tetrahydro- 1 H- 1 -4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate A mixture of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2-acetate (0.57 g, 1.82 mmol) and thionyl chloride (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-(aminomethyl)benzimidazole dihydrochloride (1.2 g, 5.46 mmol), pyridine (0.72 g, 9J mmol), and triethylamine (0.55 g, 5.46 mmol) in

CH2CI2 (15 mL) at 0°C under argon. The reaction mixture was then stirred in RT under argon. After 25.5 h, CH2CI2 (200 mL) and 5% NaHCO3 (50 mL) were added to the reaction mixture to give a light yellow precipitate which was filtered and air- dried to give the title compound (0.11 g, 14%). The filtrate was separated and the organic layer was washed sequentially with 5% NaHCO3 (50 mL) and H2O (50 mL), then was concentrated on the rotavap. After trituration with CH2CI2 and air- drying, a yellowish solid was collected to yield more of the title compound (0.35 g, 45%): !H NMR (250 MHz, CDCl3/T>MSO-d6) δ 6.30-8.70 (m, 9H), 5.52 (d, J=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), 2.97 (s, 3H), 2.85 (dd, J=16, 9 Hz, IH), 2.64 (dd, 5=11, 5 Hz, IH); MS (ES) m/e 422.2 (M+H)+.

b) (±)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro-lH-l,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-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine-2-acetate (0J 1 g, 0.26 mmol) in THF (4 mL) and H2O (5 mL). The resulting light brownish-yellow solution was stiπed for 21.5 h, then was concentrated on the rotavap. The resulting residue was lyophilized to give the crude product (0J 1 g, 100%) as a yellowish powder. Preparative HPLC (PRP- 1® column, step gradient, 10-20% CH3CN/H2θ-0J% TFA) afforded the title compound: *H NMR (250 MHz, DMSO-d6) δ 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 (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 C₂ιH₂ιN₅O₄ • 4/3 CF₃CO₂H • H₂O: C, 49.22; H, 4.25; N, 12.13. Found: C, 49.24; H, 4.22; N, 12.11.

Example 2 Preparation of (±)-7-rrr(2-benzimidazolyl)methyl1aminolcarbonyl1-3-oxo-4-(2- phenylethyl)-2,3 ,4,5-tetrahvdro- 1 H- 1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2- phenylethyl)-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

EDC (230 mg, 1.2 mmol) was added to a stirred solution of methyl (±)-7- carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2- acetate (382.4 mg, 1.0 mmol), 2-(aminomethyl)benzimidazole dihydrochloride (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 H2O (5 mL) and EtOAc (20 mL). The layers were separated and the organic layer was washed with H2O (5 mL). Drying (MgSO₄), 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/CHCl₃) gave the title compound (414.9 mg, 81%) as an off-white solid: TLC (10% MeOH/EtOAc) R_f 0.62; ^lU NMR (250 MHz, DMSO-d₆) δ 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 (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- 1 H- 1 ,4-benzodiazepine-2-acetic acid

A mixture of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3- oxo-4-(2-pheny lethyl)-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate (413 J mg, 0.81 mmol), 1.0 N LiOH (0.97 mL, 0.97 mmol), THF (4 mL), and H₂O (3 mL) was stirred at 40-45°C for 20 min, and the resulting solution was stirred at RT for 17 h. Acidification with TFA (0J9 mL, 2.4 mmol) and concentration left an off-white solid. Recrystallization from CH3CN/H2O gave the title compound (343.2 mg, 69%) as a colorless powder: HPLC (PRP-1®, 30% CH₃CN/H₂O-0J % TFA) K=1.5; ^lU NMR (400 MHz, CD3OD) δ 7.68-7.75 (m, 2H), 7.60 (dd, J=8.6, 2.2 Hz, 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), 5J8 (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 C28H27N.₅O₄ • CF3CO2H • 0.25 H₂O: C, 58.49; H, 4.66; N, 11.37. Found: C, 58.52; H, 4.47; N, 11.04.

Example 3 Preparation of (±)-4-isopropyl-7-rrr(2-benzimidazolyl)methyl1aminolcarbonyl1-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 1 ,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-lH-l,4-benzodiazepine-2-acetate (240.3 mg, 0.75 mmol), 2-(aminomethyl)benzimidazole dihydrochloride (198 mg, 0.90 mmol), HOBT H2O (122 mg, 0.90 mmol), and diisopropylethylamine (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 stiπed briskly. 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 stiπed briskly at RT for several min, then was cooled in ice and filtered. The filter pad was washed with EtOAc and dried in high vacuum to leave the title compound (275J mg, 82%) as an off-white powder: Η NMR (250 MHz, 20% CD3OD/CDCI3) δ 7.45-7.70 (m, 4H), 7.15-7.35 (m, 2H), 6.56 (d, J=9J Hz, IH), 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, J=6.8 Hz, 3H); MS (ES) 450.2 (M+H)⁺.

b) (±)-4-Isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

A mixture of methyl (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino] carbonyl]-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (275J mg, 0.61 mmol), 1.0 N LiOH (0.73 mL, 0.73 mmol), THF (3 mL), and H₂O (2.3 mL) was stirred at 35°C for 45 min, and the resulting solution was stirred at RT. After 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 triturated with H2O to leave a nearly colorless solid, which was dissolved with warming in 1:1 CH3CN/H2O. The solution was cooled to RT and diluted with several volumes of H₂O/0.1 % TFA. ODS chromatography (20% CH₃CN/H₂O-0.1 % TFA), concentration, and lyophilization gave the title compound (293.4 mg, 80%) as a colorless powder: HPLC (PRP-1®, 20% CH₃CN/H₂O-0J% TFA) K'=2.5; ^*»H NMR (400 MHz, CD3OD) δ 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), 5.21 (dd, J=8.9, 5.2 Hz, IH), 4.97 (d, 3=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 C₂3H25N₅O₄ • 1.25 CF₃CO₂H • 1.25 H₂O: C, 51.00; H, 4.83; N, 11.66. Found: C, 51.12; H, 4.91; N, 11.37.

Example 4 Preparation of (±)-7-rrrN-(2-benzothiazolyl)methvI-N-methyl1aminolcarbonyl]-4- methyl-3-oxo-2.3.4.5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) 2-Bromomethylbenzothiazole A mixture of 2-methylbenzothiazole (2.0 g, 13.40 mmol), N- bromosuccinimide (2.39 g, 13.40 mmol), and ABN (0.5 g, 3.04 mmol) in CCLj (40 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: ^lH NMR (250 MHz, DMSO-d₆): δ 5J2 (s, 2H), 7.5 (m, 2H), 8.01 (dd, J=7.9, 1.8 Hz, IH), 8J5 (dd, J=7.9, 1.8 Hz, IH).

b) 2-[(Methylamino)methyl]benzothiazole

To a stiπed 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 was continued overnight, then the mixture was concentrated. The residue was taken up in H2O, neutralized with 2.5 N NaOH, and extracted with CH2CI2. The organic extracts were dried (MgSO₄) and concentrated to give the title compound (0.36 g, 80%) as a brown oil: ^lE NMR (250 MHz, DMSO-d₆): δ 2.70 (s, 3H), 4.71 (s, 2H), 7.55 (m, 2H), 8.0 (d, J=7.9 Hz, IH), 8J7 (d, J=7.9 Hz, IH).

c) 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

A mixture of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2-acetate (0.25 g, 0.855 mmol), 2- [(methylamino)methyl]benzothiazole (0.228 g, 1.283 mmol), EDC (0.31 g, 1.0026 mmol), HOBT • H2O (0J4 g, 1.026 mmol), and diisopropylethylamine (0.30 mL, 1.711 mmol) in dry DMF (5 mL) was stiπed at RT in 20 h. The reaction mixture was concentrated, and the residue was taken up in H2O and extracted with CH2CI2. The combined organic extracts were dried (MgSO ) and concentrated. Silica gel chromatography (5% MeOH/CH2Cl2) gave the title compound (0.289g, 75%) as a yellow oil: -*H NMR (400 MHz, DMSO-d₆): δ 2.65 (dd, J=16.8, 5.0 Hz, IH), 2.82 (dd, j=16.8, 8.9 Hz, IH), 2.90 (s, 3H), 3J5 (s, 3H), 3.62 (s, 3H), 3.90 (d, J=16J Hz, IH), 4.90 (s, 2H), 5J3 (m, IH), 5.45 (d, J=16J Hz, IH), 6.29 (d, j=3.6 Hz, IH), 6.57 (d, J=8.3 Hz, IH), 7J9 (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), 8J0 (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- 1 H- 1 ,4-benzodiazepine-2-acetic acid

2.5 N NaOH (3.0 mL) was added to a stiπed 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 solid was collected and triturated in Et2θ to give the title compound (0.250 g, 89%) as a colorless solid: -H NMR (400 MHz, DMSO-d₆) δ 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, 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 C₂2H₂2N₄O₄S 1.5 H₂O: C, 56.76; H, 5.41; N, 12.03. Found: C, 56.37; H, 5.23; N, 11.86.

Example 5 Preparation of (±)-7-rrrN-(2-benzoxazolyl)methyl-N-methyllamino1carbonvn-4- methyl-3-oxo-2.3.4.5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) 2-Bromomethylbenzoxazole

Following the procedure of Example 4(a), except using 2-methylbenzoxazole in place of 2-methylbenzothiazole, the title compound (2.22 g, 70%) was prepared as a yellow oil: ^lU NMR (250 MHz, DMSO-d₆) δ 5.17 (s, 2H), 7.55 (m, 2H), 8.01 (d, 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 in place of 2-bromomethylbenzothiazole, the title compound (0.250 g, 71 %) was prepared as a brown oil: ^lU NMR (400 MHz, DMSO-d₆) δ 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- methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetate Following the procedure of Example 4(c), except using 2-[(methylamino) methyl]benzoxazole in place of 2-[(methylamino)methyl]benzothiazole, the title compound (0.342 g, 91%) was prepared as a brown oil: ^!H NMR (DMSO-dβ) δ 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, 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-benzodiazepine-2-acetic acid

Methyl-(±)-7-[[[N-(2-benzoxazolyl)methyl-N-methyl]amino]carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-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: -Η NMR (400 MHz, DMSO-d₆) δ 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=16J Hz, IH), 4.90 (d, J=5.7 Hz, 2H), 5.07 (m, IH), 5.45 (d, J=16J 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 C₂2H₂2N O₅ 1.25 H₂O: C, 59.39; H, 5.45; N, 12.50. Found: C, 59.43; H, 5.23; N, 12.14.

Example 6 Preparation of (±)-7-rfrN-r2-(5(6)-chlorobenzimidazolyl)methyll-N-methyllamino1 carbonyll-4-methyl-3-oxo-2.3.4.5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) 2-[[(N-tert-butoxycarbonyl-N-methyl)amino]methyl]-5(6)-chlorobenzimidazole 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 isobutylchloroformate (1.51 g, 11.01 mmol). After 1 h, 4-chloro-l,2- phenylenediamine (1.43 g, 10.571 mmol) was added. Stirring was continued for 2 h, then acetic 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 (MgSO₄), concentration, and silica gel chromatography (1% MeOH/CH2Cl2) gave the title compound (2J0 g, 67%) as a brown foam: ^lU NMR (250 MHz, DMSO-d₆): δ 1.45 (s, 9H), 2.95 (s, 3H), 4.60 (s, 2H), 7J0 (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]- 5(6)-chlorobenzimidazole (2J0 g, 7J01 mmol) in anhydrous CH2CI2 (20 mL) was added TFA (2.2 mL, 28.404 mmol). After stiπing overnight, the mixture was concentrated, neutralized with 2.5 N NaOH, and extracted with CH2CI2. The combined organic extracts were washed with brine, dried (MgSO₄), and concentrated to give the title compound (1.25 g, 90%) as a brown oil: ^lU NMR (250 MHz, DMSO-d₆) δ 2.35 (s, 3H), 3.88 (s, 2H), 7J7 (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- 1 H- 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 silica gel chromatography (5% MeOH/CH₂Cl₂): ^!H NMR (250 MHz, DMSO-d₆) δ 2.65 (dd, j=16.8, 5.0 Hz, IH), 2.82 (dd, J=16.8, 8.9 Hz, IH), 2.91 (s, 3H), 3J5 (s, 3H), 3.61 (s, 3H), 3.91 (d, J=16J Hz, IH), 4.80 (d, J=5.7 Hz, 2H), 5J5 (m, IH), 5.47 (d, J=16J 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- IH- 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 saponified following the procedure of Example 4(d). Trituration with EtOH/Et2θ gave the title compound (0.100 g, 69%) as a colorless solid: ^lK NMR (400 MHz, DMSO-d₆) δ 2.55 (dd, J=16.8, 5.0 Hz, IH), 2.75 (dd, J=16.8, 8.9 Hz, IH), 2.91 (s, 3H), 3J0 (s, 3H), 3.90 (d, J=16J Hz, IH), 4.9 (s, 2H), 5J0 (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), 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 C₂2H₂2ClN₅O₄: C, 56.30; H, 5.05; N, 14.92. Found: C, 56.27; H, 5.30; N, 15.14.

Example 7 Preparation of (±)-7-rrr(2-indolyl)methyl1aminolcarbonyn-4-methyl-3-oxo-2.3.4.5- tetrahvdro- 1 H- 1.4-benzodiazepine-2-acetic acid a) Indole-2-carboxamide

A mixture of ethyl indole-2-carboxylate (5 g, 26.5 mmol) and ammonium hydroxide (30 mL) was heated at 80°C in a sealed glass vessel overnight. The reaction was cooled and the title compound (3.06g, 73%) was collected by filtration as a colorless solid: ^lH NMR (400 MHz, DMSO-d₆) δ 7.95 (br, IH), 7.61 (d, IH), 7.41 (d, IH), 7.36 (br, IH), 7J2, (t, IH), 7.01 (t, IH).

b) 2-Cyanoindole A solution of indole-2-carboxamide (3.02 g, 18.8 mmol) in dichlorophenylphosphine 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 in vacuo gave an off-white solid which was purified by silica gel chromatography ( 1 % MeOH/C^C ) to yield the title compound (2.41 g, 90%): ^lH NMR (400 MHz, DMSO-d₆) δ 7.68 (d, IH), 7.46 (d, IH), 7.36 (s, IH), 7.34 (t, IH), 7J4 (t, IH).

c) 2-Aminomethylindole LAH (42 mL, 1M solution in THF) was added drop wise through a syringe to a solution of 2-cyanoindole (2.0 g, 14J mmol) in anhydrous THF (20 mL) with cooling, and the resulting solution was stirred at RT under argon for 5 h. 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 dried (K2CO3) and concentrated to afford the title compound (2.11 g, quantitative) as a yellow solid: IH NMR (400 MHz, DMSO-d₆) δ 7.41 (d, IH), 7.29 (d, IH), 6.97 (t, IH), 6.91 (t, IH), 6.20 (s, IH), 3.82 (s, 2H), 2. 18 (br, IH).

d) Methyl (±)-7-[[[(2Jndolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,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 (2J3 g, 7.26 mmol), 2-aminomethylindole (1.06 g, 7.26 mmol), HOBT • H₂O (1.08 g, 7.99 mmol) and diisopropylethylamine (1.53 mL, 8.71 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 and 10% Na2CO3 (2 x 30 mL). Drying (MgSO ), concentration, and silica gel chromatography (2% MeOH/CH Cl₂) gave the title compound (1.8 g, 60%): lH NMR (400 MHz, DMSO-d₆) δ 8.56 (t, IH), 7.95 (s, IH), 7.59 (s, IH), 7.56 (d, IH), 7.43 (d, IH), 7.33 (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), 5J4 (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]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine-2-acetic acid

1.0 N 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- l,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 residue was dissolved in H2O (20 mL) and acidified with TFA. ODS chromatography (27% CH3CN/H2θ-0J% TFA), concentration and lyophilization gave the title compound (100 mg, 30%) as an off-white solid: HPLC (ODS, 5-60% CH₃CN/H₂O-0J% TFA gradient elution over 20 min) K'=10.2; ^lH NMR (400 MHz, DMSO-d₆) δ 8.55 (t, IH), 7.57 (s, IH), 7.56 (d, IH), 7.43 (d, IH), 7.33 (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), 5.08 (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 • H₂O: 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-rrr(2-Benzimldazolyl)methyllamino1carbonvn-4-methyl-3- oxo-2.3.4.5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (2S)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo- 2 ,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate EDC ( 1 J 5 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 (2J 1 g, 5.02 mmol), 2-aminomethylbenzimidazole dihydrochloride (1J5 g, 6.02 mmol), HOBTΗ2O (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 rotavap (high vacuum), and the residue was taken up in CH2CI2 (240 mL) and washed with H2O. The organic layer was dried (Na2SO₄), dissolved in xylenes, and reconcentrated to remove residual DMF. The crude product was chromatographed on silica gel (MeOH/CHCl3) to give the title compound (1J g, 52%). b) (2S)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

1 N NaOH (4.75 mL, 4.75 mmol) was added to a cold solution of methyl (2S)-7- [[[(2-benzimidazolyl) methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine-2-acetate (1.0 g, 2.38 mmol), MeOH (10 mL) and H2O (5 mL). The solution was stiπed at room temperature for 18 hr and concentrated. ODS chromatography (CH3CN/H2O-OJ % TFA) gave the title compound (0.91 g, 94%): HPLC (5 Altex Ultrasphere ODS, 4.5 mm x 25 cm, 5%-60% CH₃CN/H₂O-0J% TFA gradient over 20 min) K'=5.7; ^lU NMR (400 MHz, DMSO-d₆) δ 8.7-8.9 (t, IH), 6.3-7.6 (m, 8H), 5.4-5.6 (d, IH), 5.0-5J (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 C2iH₂ιN₅O₄ • 3.5 H₂O: C, 53.61; H, 6.00; N, 14.89. Found: C, 53.38; H, 6.00; N, 14.55. [α]^D -237° (c 0.1).

Example 9

Preparation of (2R)-7-rrr(2-Benzimidazolyl)methyl1amino1carbonyn-4-methyl-3- oxo-2.3.4.5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (2R)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2,3,4,5-tetrahydro- 4-methyl-3-oxo- 1 H- 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 title compound (0.37 g, 86%) was prepared.

b) (2R)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Following the procedure of Example 8(b), the compound of Example 9(a) is saponified to yield the title compound (0.20 g, 57%): HPLC (5 Altex Ultrasphere ODS, 4.5 mm x 25 cm, 12% CH3CN/ H₂O-0J% TFA) K^*=4.7; **H NMR (400 MHz, DMSO-d₆) δ 8.7-8.9 (t, IH), 6.3-7.6 (m, 8H), 5.4-5.6 (d, IH), 5.0-5J (q, IH), 4.5- 4.1 (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 C2iH₂ιN₅O₄* 3.75 H₂O: C, 53.10; H, 6.05; N, 14.74. Found: C, 52.86; H, 6.03; N, 14.39. [α]^D= +205° (c 0.1).

Example 10 Preparation of (±)-7-rrr(2-benzimidazolyl)methyllamino1carbonvn-9-chloro-4- methyl-3-oxo-2,3A5-tetrahydro-lH-1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-carboxy-9-chloro-4-methyl-3-oxo-2,3,4,5 -tetrahydro- 1 H- 1 ,4- benzodiazepine-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 solid was triturated with C^Ch/MeOH (9: 1; 20 mL) for 1 h. Filtration and drying in vacuo gave the title compound (0.61 g, 55%): ^!H NMR (400 MHz, DMSO-d₆) δ 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-lH-l,4-benzodiazepine-2-acetate

Following the procedure of Example 8(a), substituting methyl (±)-7-carboxy- 9-chloro-4-methyl-3-oxo-2,3 ,4,5 -tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate for methyl (2S)-7-carboxy-4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2- acetate, and substituting 2-aminomethylbenzimidazole dihydrochloride for 4-(l- piperidinyl)piperidine, the title compound (0.68 g, 81%) was prepared.

c) (±)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-9-chloro-4-methyl-3-oxo- 2,3,4,5-tetrahydro-lH-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-benzodiazepine-2-acetate was saponified and purified to give the title compound (0.53 g, 84%): HPLC (5 Altex Ultrasphere ODS, 4.5 mm x 25 cm, 5%-60% CH₃CN/H₂O-0J% TFA gradient over 20 min) K'=6.5; ^!H NMR (400

MHz, DMSO-d₆) δ 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 C₂ιH2θClN₅O ^• 1.25 H2O: C, 54.31; H, 4.88; N, 15.08. Found: C, 54.77; H, 4.73; N, 14.68.

Example 11

Preparation of (±)-8-rrr(2-Benzimidazolyl)methyl1aminolcarbonyl1-2-methvI-3-oxo-

2.3.4.5-tetrahvdro- lH-2-benzazepine-4-acetic acid a) Methyl (±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate To a solution stiπed 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 mmol), 2-aminomethylbenzimidazole dihydrochloride (0.27 g, 1.2 mmol), HOBT ^• H2O (0J7 g, 1.2 mmol), diisopropylethylamine (0.53 g, 4 mmol), and DMF (5 mL) was added EDC (0.24 g, 1.2 mmol). The resulting mixture was stiπed for 18 h, then was concentrated to dryness, and the residue was partitioned between EtOAc and H2O. The organic phase was washed twice with H2O and once with brine, dried (MgSO₄), and concentrated. The residue was recrystallized from boiling EtOAc to give the title compound (0J6 g, 37%) as a colorless solid: *H NMR (CDCI3) δ 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=8J Hz, IH), 5.16 (d, J=16.4 Hz, IH), 4.82 (m, 2H), 3.78 (m, IH), 3.69 (s, 3H), 3.65 (d, J=16.6 Hz, IH), 3J0-2.90 (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- 1 H-2-benzazepine~4-acetic acid A solution of methyl (±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2- methyl-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetate (0J0 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 in H2O, and the solution was brought to pH 4-5 with 3N HCl. The resulting precipitate was collected by filtration and dried. Recrystallization from boiling isopropanol gave the title compound (0.035 g, 36%) as a colorless solid: ^!H NMR (DMSO-dβ) δ 9J3 (t, J=5.7 Hz, IH), 7.79 (m, IH), 7.48 (m, 2H), 7.23 (d, J=7.9 Hz, IH), 7J4 (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), 3J4 (dd, J=18, 2 Hz, IH), 2.90 (s, 3H), 2.70 (m, 2H), 2.38 (dd, J=l 1.4, 3 Hz, IH); MS (ES) m/e 407 (M+H)+. Anal. Calcd for C₂2H₂2N₄O₄ • 1.5 H₂O • 0.5 C₃H₈O: C, 60.90; H, 6.31; N, 12.09. Found: C, 60.68; H, 6.05; N, 12.05.

Example 12 Preparation of (±)-8-rrrN-(2-benzimidazolyl)methyl-N-methynamino1carbonvn-2- methyl-3-oxo-2.3.4.5-tetrahvdro-lH-2-benzazepine-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: ^lK NMR (CDCI3) δ 7.62 (m, 2H), 7.30 (m, 4H), 7J6 (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), 3J6 (s, 3H), 3J5-2.90 (m, 3H), 2.43 (dd, j=16.9, 5.3 Hz, IH).

b) (±)-8-[[[N-(2-Benzimidazolyl)methyl-N-methyl]amino]carbonyl]-2-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H-2-benzazepine-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, concentration, and drying gave the title compound (52%) as a colorless solid: -Η NMR (DMSO-d₆) δ 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), 3J0 (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 C₂₃H₂ N₄O₄ • HCl • 1.2 CH₂C1₂ - H₂O: C, 50.82; H, 5J8; N, 9.79. Found: C, 50.96; H, 5.48; N, 9.55.

Example 13 Preparation of (±)-7-rrrN-(2-benzimidazolyl)memyl-N-methyl]aminolcarbonyll-3- oxo-4-(2-phenylethyl)-2,3,4,5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-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-lH-l,4-benzodiazepine acetate and 2- (methylamino)methylbenzimidazole were coupled. Chromatography on silica gel ( 1 %-5% MeOH/CH2Cl₂) gave the title compound (57%) as a colorless solid: ^!H NMR (CDCI3) δ 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), 3J7 (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-lH-l,4-benzodiazepine-2-acetic acid

Methyl (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3- oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified according to the procedure of Example 11(b). Recrystallization from boiling isopropanol gave the title compound (57%) as a colorless solid: ^!H NMR (DMSO-d₆) δ 7.58 (m, IH), 7.47 (m, IH), 7.35-7J0 (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, 63.33; H, 6J8; N, 12.58.

Example 14 Preparation of (±)-7-rrrN-(2-benzimidazolyl)methyl-N-methynaminolmethvn- 1.4- dimethyl-3-oxo-2,3.4.5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (±)-l-(tert-butoxycarbonyl)-7-carboxy-4-methyl-3-oxo-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetate

A mixture of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- 1 ,4-benzodiazepine-2-acetate (1 g, 3.42 mmol), di-tert-butyl dicarbonate (1.48 g, 6.8 mmol) and 4-dimethylaminopyridine (42 mg, 0.3 mmol) in anhydrous CH3CN (30 mL) was stiπed 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 in vacuo, and the residue was extracted with EtOAc. The organic layers were washed sequentially with saturated NE^Cl and H2O, then were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography (7/3 hexane/EtOAc-1%

AcOH) gave the title compound (1.05 g, 78%) as a white solid: ^lE NMR (CDC13, 400 MHz) δ 1.55 (s, 9H), 2.69 (dd, J=16, 5 Hz, IH), 2.98 (dd, J=16, 5 Hz, IH), 3J0 (s, 3H), 3.65-3.68 (m, IH), 3.72 (s, 3H), 5J6 (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 Hz, IH).

b) Methyl (±)-7-formyl-4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,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 SOCI2 (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 chloride thus obtained was then suspended in 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 washed sequentially with 5% HCl and H2O. Drying (MgSO4) and concentration gave the title compound (139 mg, 60%) as a pale yellow solid, which was used in the next step without further purification: ^lH NMR (CDC13, 400 MHz) δ 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), 3.76 (s, 3H), 5J7 (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]amino]methyl]- 1 ,4- dimethyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate Methyl (±)-7-formyl-4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,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 dihydrochloride (100 mg, 0.45 mmol) and 4 A molecular sieves were added. After 30 min., sodium cyanoborohydride (32 mg, 0.49 mmol) was added in 2 portions over a period of 30 min. 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 cyanoborohydride (34 mg, 0.49 mmol). After 40 min. the reaction was concentrated under reduced pressure. The residue was diluted with CH2CI₂, and the solution was washed with saturated NaHCO3. Drying (MgSO4), concentration, and silica gel chromatography (55% CH2Cl₂/20% EtOAc/20% hexane/5% MeOH) gave the title compound (55 mg, 29%): -1H NMR (CDCI3, 400 MHz) δ 2.33 (s, 3H), 2.63 (dd, J=16.0, 5.0 Hz, IH), 2.74 (s, 3H), 3.03 (dd, 5=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 (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]amino]methyl]- 1 ,4-dimethyl-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid LiOH (5.8 mg, 0J7 mmol) was added at RT to a solution of methyl (±)-7-

[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]methyl]-l,4-dimethyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (50 mg, 0J 15 mmol) in THF (2 mL) and H2θ(3 mL). The reaction mixture was heated at 50°C for 30 min, then was concentrated in vacuo. The resulting residue was lyophilized to afford a pale yellow solid which was purified by preparative HPLC (11% CH3CN/H2O-0.1 % TFA) to afford the title compound (30 mg, 31%): 1H NMR (CD3OD, 400 MHz) δ 2.57 (m, 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, 7.0 Hz, IH), 5J8 (d, J=16.3 Hz, IH), 6.91 (d, J=8.4 Hz, IH), 7J2 (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 • 3.5 CF3CO₂H: 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-(2-benzimidazolyl)methyl-N-methyl1amino1carbonvn-4- methyl-3-oxo-2,3.4,5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) 2-(Methylaminomethyl)benzimidazole dihydrochloride

Methylamine (5.0 g, 0J6 mole) was dissolved in a solution of Et2θ (100 mL) and EtOH (5 mL) at 0°C, and 2-chloromethylbenzimidazole (13.4 g, 0.08 mole) was added in small portions. The reaction mixture was stirred at RT for 3 h, then was allowed to stand at RT overnight. More Et₂O (200 mL) was added, and the reaction was cooled in an ice bath for 3 h before filtering off the precipitate. The filtrate was saturated with HCl and filtered, and the filtrate was concentrated. Silica gel chromatography (step gradient, 10-25% MeOH/CH2θ2) yielded the title compound (2.5 g, 13%): *H NMR (250 MHz, 5:1 DMSO-d6/CDCl₃) δ 7J3-7.54 (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- 1 H- 1 ,4-benzodiazepine-2-acetate

Following the procedure of Example 1(a), except substituting 2- (methylamino methyl)benzimidazole dihydrochloride ( 1.2 g, 5J 3 mmol) for the 2- (aminomethyl) benzimidazole dihydrochloride, the crude title compound was prepared. Silica gel chromatography (10% MeOH/CH2Cl₂) yielded the title compound (0.29 g, 39%) as an off-white solid: ^]H NMR (250 MHz, CDCI3) δ 6.44- 7.62 (m, 9H), 5.41 (d, j=16.2 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=17J, 6.5 Hz, IH), 2.67 (dd, J=17J, 6.3 Hz, IH); MS (ES) m/e 436.2 (M+H)+.

c) (±)-7-[[[N-(2-Benzimidazolyl)methyl-N-methyl]amijo]carbonyl]-4-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid Following the procedure of Example 1(b), the compound of Example 15(b) was saponified and purified to give the title compound (0.21 g, 80%): MS (ES) m/e 422.2 (M+H)+. Anal. Calcd for C₂₂H₂3N5θ₄ • 4/3 CF₃CO₂H • H₂O: C, 47.93; H, 4.22; N, 10.96. Found: C, 47.88; H, 4.35; N, 10.96.

Example 16 Preparation of (±)-7-rrr2-(2-benzimidazolyl)ethyl1aminolca bonyl1-4-methyl-3-oxo- 2.3.4.5-tetrahvdro- IH- 1 ,4-benzodiazepine-2-acetic acid a) 2-Aminoethylbenzimidazole diacetate

A mixture containing 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 in a Pan apparatus. The reaction mixture was filtered through a bed of Celite® and concentrated to give the title compound (3.4 g, 95%): -Η NMR (250 MHz, CDCI3) δ 7.04-8J3 (m, 7H), 3J7-3.39 (m, 4H); MS (ES) m/e 162.0 (M+H)+.

b) Methyl (±)-7-[[[2-(2-benzimidazolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo- 2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

Following the procedure of Example 1(a), except substituting 2-aminoethyl benzimidazole diacetate (1.44 g, 5J3 mmol) for the 2-(aminomethyl)benzimidazole dihydrochloride, the crude tide compound was prepared. Silica gel chromatography (9% MeOH/CH2Cl2) yielded the title compound (0.64 g, 86%) as an off-white solid: ^!H NMR (250 MHz, CDCI3) δ 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]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Following the procedure of Example 1(b), the compound of Example 16(b) was saponified and purified to give the title compound (7.8 mg, 10%): MS (ES) m/e 422.0 (M+H)+. Anal. Calcd for C₂2H₂3N₅O₄ • 2 CF₃CO₂H • 2.5 H₂O: C, 44.96; H, 4.35; N, 10.08. Found: C, 44.79; H, 4.21; N, 10.08.

Example 17 Preparation of (±)-7-rr(2-benzimidazolyl)aminolcarbonyl1-4-methyl-3-oxo-2.3.4.5- tetrahvdro- 1 H- 1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[(2-benzimidazolyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

Following the procedure of Example 1(a), except substituting 2-amino benzimidazole (0.68 g, 5J3 mmol) for the 2-(aminomethyl)benzimidazole dihydrochloride, the crude title compound was prepared. Silica gel chromatography (7% MeOH/CH₂Cl₂) yielded the title compound (0.48 g, 69%) as an off-white solid: •*H NMR (250 MHz, CDC1₃) δ 6.50-8J6 (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- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Following the procedure of Example 1(b), the compound of Example 32(a) was saponified and purified to give the title compound (50 mg, 55%): MS (ES) m/e 394.2 (M+H)+. Anal. Calcd for C₂oHι₉N₅O₄ • 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 (2S)-7-rrrN-(2-benzimidazolyl)methyl-N-methyl1amino1carbonyl1-4- methyl-3-oxo-2.3.4.5-tetrahvdro-lH-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-benzodiazepine-2-acetate

Diisopropylethylamine (0.29 g, 2.25 mmol) was added in one portion to a stiπed mixture of 2-(methylaminomethyl)benzimidazole bis(trifluoroacetate) (1.8 mmol), methyl (2S)-7-carboxy-4-methyl-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% NaHCO3 (10 mL). The resulting precipitate was filtered and air-dried. Flash chromatography (silica gel, MeOH/CH₂Cl₂) yielded the title compound (79%): ^!H NMR (400 MHz,

CDCI3) δ 6.51-7.60 (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), 3J5 (s, 3H), 2.96 (s, 3H), 2.93 (dd, J=17J, 6.5 Hz, IH), 2.67 (dd, J=16J 6.5 Hz, IH); MS (ES) m/e 436.2 (M+H)+. b) (2S)-7-[[[N-(2-Benzimidazolyl)methyl-N-methyl]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 18(a) was saponified and purified to give the title compound (0J 1 g, 91%): MS (ESMS) m/e 422.2 (M+H)⁺. Anal. Calcd for C₂2H₂3N₅O₄ • 3 H₂O: C, 55.57; H, 6J5; N, 14.73. Found: C, 55.30; H, 6.13; N, 14.39.

Example 19 Preparation of (±')-4-Methyl-7-rffN-(2-( 1 -methyDbenzimidazolyl)methyl-N- methyllaminol carbonvn-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 (1J2 g, 5J3 mmol) was added dropwise at 0°C to a mixture containing 2-(methylaminomethyl)benzimidazole dihydrochoride (1.0 g, 4.27 mmol), dioxane (25 mL), H₂O (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 NaHSO₄. The mixture was extracted with CH2CI2 (2x80 mL), and the combined organic layers were washed with brine (30 mL) and dried (MgSO₄). Concentration gave the title product (0.7 g, 64%): *H NMR (400 MHz, CDCI3) δ 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) l-Methyl-2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl]benzimidazole

A mixture of 2-[[N-(tert-butoxycarbonyl)-N- methyl]aminomethyl]benzimidazole (0.51 g, 1.95 mmol), NaH (0J2 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 min, then was concentrated on the rotavap. The residue was diluted with CH2CI2 (100 mL), and the mixture was washed sequentially with H O (30 mL), 5% NaHCO3 (30 mL), and brine (30 mL). Drying (Na SO₄) and concentration gave the title compound (0.51, 94%): »H NMR (250 MHz, CDCI3) δ 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-(methylaminomethyl)benzimidazole bis(trifluoroacetate) A mixture of l-methyl-2-[[N-(tert-butoxycarbonyl)-N-methyl]aminomethyl] benzimidazole (0.51 g, 1.85 mmol) in 25% TFA/CH2CI2 (20 mL) was stirred at RT under argon for 20 min. The solvent was removed on the rotavap and the residue was recrystallized from Et₂O/CH₂Cl₂ to give title compound (0.69 g, 92%): ^lH NMR (250 MHz, 5:1 CDCl₃:DMSO-d₆) δ 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-( 1 -methyl)benzimidazolyl)methyl-N- methyl]amino] carbonyl]-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

Following the procedure of Example 18(a), except substituting l-Methyl-2- (methylaminomethyl)benzimidazole bis(trifluoroacetate) for 2,6-diaminopyridine, the title compound (0.53 g, 77%) was prepared: Η NMR (250 MHz, CDC1₃) δ 6.50-7.80 (m, 9H), 5.43 (d, J=16.4 Hz, IH), 5.03-5J0 (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), 3J3 (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-lH-l,4-benzodiazepine-2-acetic acid

Following the procedure of Example 1(b), the compound of Example 19(d) was saponified and purified to give the title compound (0J3 g, 60%): MS (ES) m/e 436.2 (M+H)+. Anal. Calcd for C₂3H₂5N₅O₄ • 1.5 H₂O: C, 59.73; H, 6J0; N, 15.14. Found: C, 59.39; H, 6.05; N, 14.96.

Example 20 Preparation of (±)-7-rrr(2-(5(6)-methoxy)benzimidazolyl)methynamino1carbonvn-4- methyl -3-QXQ-2.3.4.5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) N-[N-(Benzyloxycarbonyl)glycyl]-4-methoxy-2-nitroaniline

N-(Benzyloxycarbonyl)glycine (2.72 g, 13.13 mmol) was dissolved in CH2CI2 and an excess of thionyl chloride at room temperature. After 2 h, the reaction was evaporated under vacuum and the residue was stripped with toluene twice and dried under vacuum. The white solid was taken into CH2CI2 and 4- methoxy-2-nitroaniline (2J819 g, 12.98 mmol) was added as a solid, followed by triethylamine (2.0 mL, 1.455 g, 14.38 mmol). The reaction was stiπed at RT for 24 h, then was evaporated under vacuum. The residue was dissolved in EtOAc and washed with aqueous IN NaHCO3. The EtOAc layer was dried (MgSO₄) and concentrated under vacuum. Thin layer chromatography analysis (1:1:1 hexanes/Et2θ/CH2Cl2) showed good conversion to the acylated material. The crude material was dissolved in 2:1:1 hexanes/Et2O/CH2Cl2 initially, with the addition of enough Et2O/CH2Cl2 and sonication/heating to dissolve all the solid material. Silica gel chromatography (2:1:1 hexanes/Et₂O/CH2Cl2 (2 L), then 1:1: 1 hexanes/Et₂O/CH₂Cl2 (1.5 L), then Et₂O/CH2Cl₂) gave the title compound (3.3387 g, 72%): -H NMR (250 MHz, CDC1₃) δ 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- [(Benzyloxycarbonyl)amino] methyl]-5 (6)-methoxybenzimidazole

N-[N-(Benzyloxycarbonyl)glycyl]-4-methoxy-2-nitroaniline (1.0 g, 2.87 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, dried under vacuum, and adsorbed onto silica gel. Chromatography on a dry silica gel column (1:1 Et₂O/CH₂Cl2 (1.5 L) followed by 5% MeOH/CH₂Cl₂) gave the title compound (1.0063 g, 94% ): -H NMR (250 MHz, CDC1₃) δ 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)-methoxybenzimidazole

2-[N-[(Benzyloxycarbonyl)amino]methyl]-5(6)-methoxybenzimidazole (1.0063 g, 3.23 mmol) was dissolved in 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 (411.7 mg, 72%) as an oil: Η NMR (250 MHz, CDC1₃) δ 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- 1 H- 1 ,4-benzodiazepine-2-acetate

Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4- benzodiazepine-2-acetate (245.4 mg, 0.84 mmol) was dissolved in DMF. A solution of EDC (169.3 mg, 0.88 mmol) in DMF was added, followed by HOBT • H₂O (112J mg, 0.83 mmol). A solution of 2-(Aminomethyl)-5(6)- methoxybenzimidazole (1.434 mg, 0.81 mmol) in DMF was then added, followed by diisopropylethylamine (0.2 mL, 1.44 mmol). The reaction was stiπed at RT for 5 d, then was concentrated under vacuum. The residue was evaporated once with toluene. The crude material was partitioned between H2O and EtOAc. The aqueous phase was back-extracted with EtOAc, and the combined organic layers were dried (MgSO₄) and concentrated. TLC (10% MeOH/CHC^) 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) δ 3.06 (s, 3H), 3.70 (s, 3H), 3.80 (s, 3H), 4.74 (s, 2H), 5.28 (t, IH), 5.51 (d, 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-lH-l,4-benzodiazepine-2-acetic acid Methyl (±)-7-[[[(2-(5(6)-methoxy)benzimidazolyl)methyl]amino]carbonyl]-

4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-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 in an oil bath at about 65 °C. The solution was concentrated and the residue was redissolved in 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 dried under high vacuum to afford the title compound (103J mg, 94%): TLC (3:1:1 n-BuOH/AcOH/H₂O) Rf= 0.62; MS (ES) m/e 438.2 (M+H)+. Anal Calcd for C₂₂H₂₃N₅O₅ • 2 H₂O: C, 55.81 ; H, 5.75; N, 14.70. Found: C, 55.69; H, 5.59; N, 14.41.

Example 21 Preparation of (±)-7-fTrN-r2-(4-azabenzimidazolyl)lmethyl-N- methyl1aminolcarbonvn-4-methyl-3-oxo-2.3.4.5-tetrahvdro-lH-1.4-benzodiazepine- 2-acetic acid a) 2-Amino-3-[[N-(benzyloxycarbonyl)sarcosyl]amino]pyridine

N-(Benzyloxycarbonyl)sarcosine (4J g, 18.5 mmol) was dissolved in dry THF, and triethylamine (3 mL, 21.6 mmol) was added, followed by isobutylchloroformate (2.5 mL, 19.27 mmol). The solution was cooled to about - 20°C for 15 minutes, then a solution of 2,3-diaminopyridine (2.0767 g, 19.03 mmol) in dry THF was added slowly. The reaction was kept stirring between -10°C to -20°C for 15 minutes, then was allowed to warm to RT. After 3 d, the reaction was evaporated under vacuum, and the residue was partitioned between EtOAc and IN NaHCO3. The EtOAc phase was dried (MgSO₄) and evaporated under vacuum. The residue was dissolved in glacial AcOH and was stiπed in a oil bath at 70 °C. 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, CDC1₃) δ 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]pyridine (513 mg, 1.63 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 (CHCI3, then 2% MeOH/CHCl₃ , then 4% MeOH/CHCl₃) gave the title compound (385 mg, 80%): -H NMR (250 MHz, CDC1₃) δ 3.07 (s. 3H), 4.83 (s, 2H), 5J7 (s, 2H), 7.1- 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-methylamino]methyl]-4-azabenzimidazole (385.5 mg, 1.30 mmol) was dissolved in MeOH, and 10% Pd/C was added. The 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, CDCl₃/CD₃OD) δ 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]amino]carbonyl]- 4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

EDC (263 J mg, 1.37 mmol) was added to a suspension of methyl (±)-7- carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetate (392.2 mg, 1.34 mmol) and HOBT • H₂O (195.5 mg, 1.45 mmol) in DMF in a dried 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) in DMF and added, followed by diisopropylethylamine (0.3 mL, 1.72 mmol). The reaction was stirred at RT for 4 d, then was evaporated under high vacuum. The residue was concentrated from toluene and was chromatographed on silica gel (CHCI3, then 5% MeOH/CHCl₃, then 10% MeOH/CHCl₃) to afford the title compound (183.3 mg, 32%): -H NMR (250 MHz, CDCl₃/CD₃OD) δ 3.04 (s, 3H), 3J7 (s, 3H), 3.72 (s, 3H), 4J3 (s, 2H), 5J3 (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-methyl]amino]carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid

Methyl (±)-7-[[[N-[2-(4-azabenzimidazolyl)]methyl-N- methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine- 2-acetate (183 mg, 0.42 mmol) was dissolved in MeOH, and IN sodium hydroxide (1.5 mL, 1.5 mmol) was added. The reaction was stiπed 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 about 1 h before being filtered on a sintered glass funnel. The isolated material was dried 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 C₂iH₂₂N₆O₄ • 2.75 H₂O: C, 53.44; H, 5.87; N, 17.81. Found: C, 53.52; H, 5.62; N, 17.23.

Example 22

Preparation of (±)-7-rrrN-r2-(5(6)-Azabenzimidazolyl)1methyl-N-methvIlamino1 carbonyl]-4-methvI-3-oxo-2.3 ,4,5-tetrahvdro- 1 H- 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 THF, and triethylamine (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- diaminopyridine (2.0319 g, 18.62 mmol) in THF was added. The yellow solution was kept stirring at -10 to -20°C for 15 min, then was allowed to warm slowly to RT. After 3 d, the reaction was evaporated under vacuum, and the residue was partitioned between EtOAc and 1.0 N NaHCO3. The combined EtOAc layers were dried (MgSO₄) and concentrated. The clear, slightly tan colored residue was dissolved in glacial AcOH, and the solution was stiπed in an oil bath at 70°C. After 24 h, the reaction was allowed to cool to RT and was concentrated. The residue was concentrated from toluene, then was chromatographed on silica gel (CHCI3, then 2% MeOH/CHCl3, then 4% MeOH/CHCl3). Two fractions were collected. Fraction 1 (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, CDC1₃) δ 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-(Methylamino)methyl-5(6)-azabenzimidazole

2-[[N-(Benzyloxycarbonyl)-N-methylamino]methyl]-5(6)-azabenzimidazole (685.5 mg, 2.31 mmol) was dissolved in MeOH, and 10% Pd/C was added. The mixture was stiπed briskly at RT under H2 (balloon pressure) for 4 h, then was 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-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate EDC (263 J 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 (697.3 mg, 2.39 mmol) and HOBT • H2O (345.5 mg, 2.56 mmol) in DMF in a dried 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, 2.35 mmol) in DMF was added. The reaction was stirred at RT for 20 h, then was concentrated under vacuum. Silica gel chromatography (CHCI3, then 5% MeOH/CHCl3, then 10% MeOWCRCls) gave the title compound (679 mg, 66%): -H NMR (250 MHz, CDC1₃) δ 3.00 (s, 3H), 3J2 (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), 7J2 (s, IH), 7.47 (d, 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] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- 1 H- 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 stiπed 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 H2O. The mixture was sonicated, and the colorless precipitate was collected and dried in a vacuum dessicator to leave the title compound (471 mg, 71%): MS (ES) m/e 423.2 (M+H)+. Anal. Calcd for C₂ιH₂₂N₆O₄ • 2.25 H₂O: C, 54.48; H, 5.77; N, 18.15. Found: C, 54.67; H, 5.58; N, 17.64.

Example 23 Preparation of (±)-7-rrr(2-imidazolyl)methyllamino1carbonyn-4-methyl-3-oxo- 2.3.4.5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetate a) Methyl (±)-7- [ [ [(2-imidazolyl)methyl] aminojcarbonyl] -4-methy l-3-oxo-2,3 ,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

A mixture of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- 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), triethylamine (1.0 mL, 7.2 mmol), and EDC (383 mg, 2 mmol) in anhydrous DMF (40 mL) was stiπed at RT overnight. The reaction was concentrated in vacuum, and the resulting residue was diluted with 5% K₂CO3. CH2CI2 extraction, drying (MgSO₄), 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- 1 H- 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 1.0 N NaOH (6 mL) was added. The reaction was stiπed at RT for 2 d, then was concentrated in vacuum. The residue was diluted with H₂O, 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 Ci₇Hι₉N₅O₄ • 1.75 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-rrr2-(benzimidazolyl)methyl1methylamino]carbonyll-4-(2- methoxyethyl)-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2- methoxyethyl)-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,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- IH- 1 ,4-benzodiazepine-2-acetate (202 mg, 0.6 mmol), 2-(methylaminomethyl)benzimidazole dihydrochloride (0.72 mmol), HOBt • H2O (97 mg, 0.72 mmol), and diisopropylethylamine (0.42 mL, 2.4 mmol) in anhydrous DMF (3 mL) at RT. The reaction was stirred at RT for 22.5 h, then was concentrated on the rotavap. The residue was reconcentrated from xylenes (to remove DMF), then was diluted with H₂O (2 mL). CHCI3 extraction, drying (MgSO₄), concentration, and chromatography on silica gel (5% MeOE/CHCl^) gave the title compound (265.7 mg, 92%) as an off-white solid: TLC Rf (5% MeOH/CHCl₃) 0.39; ^JH NMR (400 MHz, CDCI3) δ 7.68-7:82 (m, IH), 7.37-7.51 (m, IH), 7J5-7.35 (m, 4H), 6.45-6.57 (m, IH), 5.38 (d, J=16.5 Hz, IH), 5.04-5J4 (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 Hz, 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), 3.22 (s, 3H), 3J5 (s, 3H), 2.98 (dd, J=16.0, 6.2 Hz, IH), 2.68 (dd, J=16.0, 6.1 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-lH-l,4-benzodiazepine-2-acetic acid

1.0 N LiOH (0.66 mL, 0.66 mmol) was added to a solution of methyl (±)-7- [[[2-(benzimidazolyl)methyl]methylamino]carbonyl]-4-(2-methoxyethyl)-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (265.7 mg, 0.55 mmol) in THF (2.8 mL) and H2O (2.1 mL) at RT. The light yellow solution was stiπed 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 solid precipitate was collected by suction filtration and recrystallized from H2O/CH3CN to afford the title compound (147.0 mg, 55%): HPLC (PRP-1®, 15% CH₃CN/H₂O- 0.1% TFA) K'=4.3; IH NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J=7.6 Hz, IH), 7.47 (d, J=7J Hz, IH), 7.08-7.25 (m, 4H), 6.53 (d, J=8.2 Hz, IH), 6J3-6.26 (m, IH), 5.42 (d, J=16.3 Hz, IH), 5.00-5J2 (m, IH), 4.70-4.86 (m, 2H), 3.88-4.03 (m, IH), 3.44-3.60 (m, 2H), 3.22-3.40 (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, 5J Hz, 1 H, partially obscured by residual solvent signal); MS (ES) 466.2 (M+H)+, 305.0 (M+H - 161)+. Anal. Calcd for C₂₄H27N5O5 • H₂O: C, 59.62; H, 6.04; N, 14.48. Found: C, 59.62; H, 6J8; N, 14.46.

Example 25 Preparation of (±)-7-rrr2-(4-AzabenzimidazoIyl)methyl1methylamino1carbonvn-4- (2-methoxyethyl)-3-oxo-2,3,4.5-tetrahydro-lH- 1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-(2- methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-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- 1 H- 1 ,4-benzodiazepine-2-acetate (168.2 mg, 0.50 mmol), 4-aza-2-(methylaminomethyl)benzimidazole (0.62 mmol), HOBt • H2O (81 mg, 0.60 mmol), and diisopropylethylamine (0J7 mL, 1.0 mmol) in anhydrous DMF (2.5 mL) at RT. The reaction was stiπed at RT for 20 h, then was concentrated on the rotavap, and the residue was diluted with H2O (2 mL). CHCI3 extraction (3 x 5 mL), drying (MgSO4), concentration, and reconcentration from xylenes (to remove DMF) left a light yellow oil. Chromatography on silica gel (10% MeOH/CHCl3) gave the title compound (225.4 mg, 94%) as a colorless foam: TLC R_f (10% MeOH/CHCl₃) 0.39; ^lH NMR (400 MHz, CDCI3) two components; data for the major component only, δ 8.37-8.47 (m, IH), 7.98-8.06 (m, IH), 7J7- 7.37 (m, 3H), 6.43-6.57 (m, IH), 5.38 (d, J=16.6 Hz, IH), 5.04-5J3 (m, IH), 4.85 (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), 3J6 (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- methoxyethyl)-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-methoxyethyl)-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (225.4 mg, 0.47 mmol) in THF (2.4 mL) and H₂O (1.8 mL) at RT. The solution was stiπed 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-0J% TFA, then 20% CH3CN/H2θ-0J% TFA), concentration to a small volume, and lyophilization gave the title compound (167.2 mg, 55%) as a light yellow powder: HPLC (PRP-1®, 12% CH₃CN/H₂O-0J% TFA) K'=2.7; ⁱH NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=4.9 Hz, IH), 8.22 (d, j=8.0 Hz, IH), 7.38-7.50 (m, IH), 7J5-7.30 (m, 2H), 6.54 (d, J=8J Hz, IH), 6J0-6.45 (m, IH), 5.43 (d, J=16.5 Hz, IH), 5.02-5J4 (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), 3J3 (br s, 3H), 3.08 (s, 3H), 2.76 (dd, J=16.7, 8.8 Hz, IH), 2.53 (dd, j=16.7, 5.0 Hz, 1 H, partially obscured by residual solvent signal); MS (ES) m/e 467.2 (M+H)+, 305.0 (M+H- 162)+. Anal. Calcd for C23H26N6O5 • 1.5 CF₃CO₂H • 0.5 H₂O: C, 48.30; H, 4.44; N, 13.00. Found: C, 48.09; H, 4.38; N, 12.95.

Example 26 Preparation of (±)-7-l^"IT2-( l-methylindolyl)methyl1methylaminolcarbonyl1-4-methyl- 3-oxo-2,3,4.5-tetrahvdro-lH-l,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, 60% dispersion, prewashed by hexane) in anhydrous THF (60 mL) in a flame dried 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 (MgSO4) and concentration gave the title compound (1.01 g, 50%) as a pale yellow solid.

b) 1 -Methyl-2-(methylaminocarbonyl)indole

A mixture of ethyl l-methylindole-2-carboxylate (4.06 g, 20 mmol) and methylamine (50 mL) was heated at 80°C in a sealed glass vessel overnight. The reaction was cooled and the title compound (2.4 g, 64%) was collected by filtration as a colorless solid. MS (ES) m/e 189.0 (M+H)+.

c) 1 -Methyl-2-(methylamino)methylindole

LAH (50 mL, 1M solution in THF) was added dropwise through a syringe to a solution of l-methyl-2-(methylaminocarbonyl)indole (2.33 g, 12.4 mmol) in 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 dried (K2CO3), concentrated, and purified by silica gel flash chromatography to afford the title compound (430 mg, 20% yield) as a yellow solid. MS (ES) m/e 175 (M+H)+.

d) Methyl (±)-7-[[[2-(l-methylindolyl)methyl]methylamino]carbonyl]-4-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

EDC (508 mg, 2.65 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 (774 mg, 2.65 mmol), l-methyl-2-(methylamino)methylindole (420 mg, 2.41 mmol), HOBT • H2O (358 mg, 2.65 mmol) and diisopropylethylamine (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% Na2CO3 (2 x 30 mL). Drying (MgSO₄), concentration, and silica 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) (±)-7-[[[2-( 1 -Methylindolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid 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-benzodiazepine-2-acetate (600 mg, 1.34 mmol) in MeOH (10 mL) at RT. The resulting mixture was stiπed for 20 h then was concentrated. The residue was dissolved in H2O (10 mL) and acidified with 1.0 N HCl with cooling. 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 H₂O: C, 64.34; H, 6J9; N, 12.51. Found: C, 64.16; H, 6J3; N, 12.50.

Example 27 Preparation of (±)-7~ΓΓΓ2-(1 -methylindolyl)methynaminolcarbonyll-4-methyl-3-oxo- 2.3 ,4.5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) l-Methylindole-2-carboxamide

A mixture of ethyl l-methylindole-2-carboxylate (5.9 g, 29 mmol) and ammonium hydroxide (50 mL) was heated at 80°C in a sealed glass vessel overnight. The reaction was cooled and the title compound (2.2 g, 44%) was collected by filtration 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- methylindole-2-carboxamide for l-methyl-2-(methylaminocarbonyl)indole, the title compound (86%) was obtained as a yellow brownish solid. MS (ES) m/e 161.0 (M+H)+. c) Methyl (±)-7-[[[2-(l-methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 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 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- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Following the procedure of Example 26(e), methyl (±)-7-[[[2-(l- methylindolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4- benzodiazepine-2-acetate was saponified to give the title compound as a colorless solid: MS (ES) m/e 358 (M+H)+. Anal. Calcd for C23H24N4O4 • 3 HCl • 0.875 H₂O: 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-indolinyl)methvnamino1carbonyl1-4-methyl-3-oxo-2.3.4.5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2S-acetic acid a) Methyl (±)-indoline-2-carboxylate

Thionyl chloride (2.86 mL, 39 mmol) was added to a solution of (±)-indoline-2- carboxylic 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 (MgSO4) and concentration gave the title compound (4.31 g, 94% ) as a pale yellow oil.

b) (±)-Indoline-2-carboxamide

Gaseous NH3 was bubbled into a solution of methyl (±)-indoline-2- carboxylate (4.3 g, 24.2 mmol) in methanol (50 mL) at RT for 30 min. The reaction was stirred for 18 h, then was filtered to afford the title compound (3.35 g 85%) as a colorless solid: MS (ES) m/e 163.0 (M+H)⁺.

c) (±)-2-(Aminomethyl)indoline

LAH (20 mL, 1M solution in THF) was added dropwise through a syringe to a solution of (±)-indoline-2-carboxamide (2.2 g, 13.6 mmol) in anhydrous THF (20 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 THF was added dropwise with cooling to destroy excess LAH, and then Et2θ was added. After stiπing for 10 min, the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K2CO3), concentrated, and purified by silica gel flash chromatography (90: 10:0.2 CH2Cl₂/MeOH/Et₃N). The title 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- 1 H- 1 ,4-benzodiazepine-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- 1 H- 1 ,4-benzodiazepine-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- benzodiazepine-2S-acetate was saponified to give the title compound as a colorless solid. MS (ES) m/e 409.2 (M+H)+. Anal. Calcd for C22H24N4O₄ J HCl • 0.5 H₂O: C, 58.21; H, 5.77; N, 12.34. Found: C, 58.36; H, 5.56; N, 12.26.

Example 29 Preparation of (±)-7-rrr(2-imidazolyl)methyl]amino]carbonyl1-3-oxo-4-(2- phenylethyl)-2,3,4,5-tetrahvdro- IH- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)- 2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

Methyl (±)-7-carboxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro- IH- 1 ,4- benzodiazepine-2-acetate (400 mg, 1.04 mmol) was suspended in anhydrous toluene (5 mL), then thionyl chloride (3 mL) was added and the reaction mixture was heated 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 chloride thus obtained was dissolved in dry DMF (8 mL) and diisopropylethylamine (506 mg, 3.9 mmol), DMAP (12.2, 0J mmol) and 2-(aminomethyl)imidazole dihydrochloride (222 mg, 1.3 mmol) were added. The reaction mixture was allowed to stir at RT overnight, then the solvent was removed under vacuum. The residue was purified by silica gel flash column chromatography (95% C i_C 2l5% methanol) to produce the title compound (120 mg, 26%). ^ NMR (CDCI3, 400 MHz) δ 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), 7.06-7J6 (m, 5H), 7.31 (br s, IH), 7.49 (d, J=8.5 Hz, IH).

b) (±)-7-[[[(2-Imidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5- tetrahydro- 1 H- 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]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5- 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 solid which was filtered, dissolved in hot methanol, and precipitated with ether. The thus obtained white solid was collected to yield the title compound (72 mg, 78%). *H NMR (DMSO-d6, 400 MHz) δ 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), 5J3 (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), 7J0-7J9 (m, 5H), 7.41 (s, IH), 7.54 (d, J=8.4 Hz, IH). MS (ES) m/e 448 (M+H)+. Anal. 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 (±)-7-rrr(2-benzimidazolyl)methyllaminolmethvn-4-methyl-3-oxo- 2.3.4,5-tetrahvdro- 1 H- 1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

Methyl (±)-7-formyl-4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4- benzodiazepine-2-acetate (180 mg, 0.65 mmol) (prepared as in Example 14(b)) was suspended in anhydrous methanol, then sodium acetate (160 mg, 1.95 mmol), 2- (amino methyl)benzimidazole dihydrochloride (143 mg, 0.65 mmol) and 4 A molecular sieves were added. After 30 min., sodium cyanoborohydride (45 mg, 0.71 mmol) was added in 2 portions over a period of 30 min. The reaction mixture was allowed to stir at RT overnight, then the methanol was removed under vacuum. The residue was diluted with CH2CI2, and the solution was washed with saturated NaHCO3. Drying (MgSO4), concentration, and silica gel chromatography (90% CH₂Cl₂/9% methanol/1% NEt3) gave the title compound (133 mg, 49%): ^lH NMR (CDC13, 400 MHz) δ 2.67 (dd, J=16J, 6J Hz, IH), 2.96 (dd, J=16J, 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, 6J, IH), 5.35 (d, J=16.4 Hz, IH), 6.54 (d, J=8J Hz, IH), 6.87 (s, 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- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid LiOH ( 14.6 mg, 0.34 mmol) was added at RT to a solution of methyl (±)-7-

[[[(2-benzimidazolyl)methyl]amino]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 H2OO 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 mL) to obtain a white solid which was purified by ODS chromatography (10% acetonitrile/H2θ-0J% TFA) to afford the title compound (65 mg, 51%): *H NMR (DMSO-d6, 400 MHz) δ 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=8J Hz, IH), 6.97 (s, IH), 7.02 (d, J=8J Hz, IH), 7.20 (m, 2H), 7.52 (m, 2H); MS (ES) m e 394 (M+H)+. Anal. Calcd. for C21H23N5O3 • 2

CF₃CO₂H - H2θ: C, 46.95; H, 4.26; N, 10.95. Found: C, 46.81; H, 4.00; N, 10.84.

Example 31 Preparation of (±)-7-HT (2-benzimidazolyl)methyllamino1carbonyl1- 1 ,4-dimethyl-3- oxo-2.3 ,4.5-tetrahvdro- 1 H- 1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]- 1 ,4-dimethyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

Following the procedure of Example 2(a), except substituting methyl (±)-7- carboxy- 1 ,4-dimethyl-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate for the methyl (±)-7-carboxy-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetate, the title compound was prepared (60%): MS (ES) m/e 435 (M+H)+; -*H NMR (250 MHz, CDCI3) δ 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, IH), 4.76-5.01 (m, 3H), 3.61 (s, 3H), 3.59 (d, J=16.6 Hz, IH), 3J (m, IH), 2.90 (s, 3H), 2.81 (s, 3H), 2.65 (m, IH).

I l l b) (±)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-l,4-dimethyl-3-oxo-2,3,4,5- tetrahy dro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

A solution of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-l,4- dimethyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate (0.080 g, 0J 8 mmol) in a mixture of methanol (10 mL), water (1.0 mL) and 1.0 M NaOH (0.75 mL) was heated at 50°C for 2 h, cooled to RT, and evaporated to dryness. 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. Calcd for C22H23N5O4 • 2.3 H₂O: 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) δ 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), 7J2 (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 (±)-7-rrr(2-benzimidazolyl)methvnmethylamino1carbonvn-3-oxo- 2.3.4.5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-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% MeOH/CH₂Cl₂) yielded the title compound (35%): MS (ES) m/e 422.2 (M+H)⁺. ^lH NMR (400 MHz, CDCI3) δ

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).

b) (±)-7-[[[(2-Benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

A solution of methyl (±)-7-[[[(2- benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-lH-l,4- 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. Trifluoroacetic 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; acetonitrile:water, 0.1% TFA) gave the title compound: MS (ES) m/e 408.2 (M+H)⁺; 'H NMR (250 MHz, DMSO-d₆) δ 8J9 (br t, j=4.5 Hz, IH), 7.72 (m, 2H), 7.38 (m, 2H), 7.28 (d, j=8.4 Hz, IH), 7J5 (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), 3J5 (s, 3H), 2.75 (dd, J=16.4, 8.5 Hz, IH), 2.50 (m, IH).

Example 33 Preparation of (2S)-7-rrrN-butyl-N-benzimidazol-2-yl)methyl1amino1carbonyl]-3- oxo-4-methyl-2.3.4.5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) N-BOC-2-methylbenzimidazole

To a stiπed mixture of 2-methylbenzimidazole (15 g, 113.5 mmol), triethylamine (12 g, 119.2 mmol), and DMAP (cat.) in dry CH2CI2 (150 mL) was added (Boc)2θ. After 24 h, the mixture was concentrated. The residue was taken up in H2O, stiπed and filtered to give a white solid (26.3 g, 100%): mp 71-72°C;

-1H NMR (250 MHz, CDCI3) δ 1.71 (s, 9H), 2.83 (s, 3H), 7.29 (m, 2H), 7.65 (m, lH), 7.91 (m, IH).

b) l-BOC-2-bromomethylbenzimidazole

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%): ^!H NMR (250 MHz, CDCI3): δ 1.79 (s, 9H), 4.95 (s, 2H), 7.40 (m, 2H), 7.75 (m, IH), 8.01 (m, IH).

c) 2-( 1 -Butylamino)methylbenzimidazole

To a stiπed 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 stirring at RT overnight, the mixture was concentrated. The residue was taken up in H2O and extracted with CH2CI2. The organic extracts were dried over MgSO4 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 (MgSO4), concentration, and silica gel chromatography (2% MeOH/CH2θ2) gave the title compound as a yellow oil (0.91 g, 70%): ^lU NMR (250 MHz, CDCI3) δ 0.79 (t, j=7.2 Hz, 3H), 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- methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

To a stiπed mixture of 2-(l-butylamino)methylbenzimidazole (0J4 g, 0.6671 mmol), methyl (S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetate (0J5 g, 0.5132 mmol), HOBT ^• H2O (0.083 g, 0.6158 mmol), and (i-Pr)2NEt (0J33 g, 1.0263 mmol) in dry MeCN (5 mL) was added EDC (0J83 g, 0.6158 mmol). After stirring 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 NaHCO3 and brine, then were dried (MgSO4) and concentrated to give the title compound as a yellow foam (0.232 g, 95%): ^lH NMR (250 MHz, CDCI3) δ 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), 3.60 (s, 3H), 3.72 (d, J=16J Hz, IH), 4.75 (s, 2H), 5.05 (m, IH), 5.48 (d, 5= 16.1 Hz, IH), 6.20 (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-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Following the procedure in Example 11(b), methyl-(S)-7-[[[N-(2- benzimidazolyl)methyl-N-(n-butyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified to give an off white solid. Trituration in hot EtOH gave the title compound as a white solid (0J5 g, 60%): mp 160-162°C (dec); ^lR NMR (400 MHz, DMSO-d6) δ 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=16J Hz, IH), 4.75 (s, 2H), 5.05 (m, IH), 5.48 (d, J= 16J Hz, IH), 6.20 (d, J =3.6 Hz, IH), 6.55 (d, J=8.9 Hz, IH), 7J6 (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. Example 34 Preparation of (S)-7-rrrN-f2-benzimidazolvnmethyl-N-(2- phenylethyI)1amino1carbonvn-4-methyl-3-oxo-2.3.4.5-tetrahvdro-lH-1.4- benzodiazepine-2-acetic acid a) 2-(2-Phenylethylamino)methylbenzimidazole

Following the procedure of Example 33(c), except substituting 2- phenylethylamine for n-butylamine, the title compound (0J00 g, 31%) was prepared as a brown oil following silica gel flash chromatography (5% MeOH/CH2θ2): --H NMR (250 MHz, CDCI3) δ 2.82 (t, J=7.5 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 4.10 (s, 2H), 7.21 (m, 5H), 7.35 (m, 2H), 7.52 (m, 2H).

b) Methyl {S)-7-[[[N-(2-benzimidazolyl)methyl-N-(2- phenylethyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4- benzodiazepine-2-acetate Following the procedure of Example 33(d), except substituting 2-(2- phenylethylamino)methylbenzimidazole for 2-( 1 -butylamino)methylbenzimidazole, the title compound (0J95 g, 97%) was prepared as an off-white foam following silica gel flash chromatography (2-5% MeOH/CH2Cl2): ^!H NMR(250 MHz, DMSO-d6) δ 2.54 (dd, J= 16.5, 5.0 Hz, IH), 2.75 (dd, J=16.5, 8.9 Hz, IH), 2.85 (s, 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), 6J8 (d, J=3.5 Hz, IH), 6.54 (d, J=8.9 Hz, IH), 7J0 (m, 7H), 7.26( m, 2H), 7.48 (m, IH), 7.60 (m, IH), 12.30 (s, IH).

c) (S)-7-[[[N-(2-Benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid

Following the procedure of Example 11(b), methyl (S)-7-[[[N-(2- benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified. Recrystallization from EtOH gave the title compound (0.070 g, 40%) as an off white solid: 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, 6J6; N, 12.58. Found: C, 62.92, H, 6.02, N, 12.28. Example 35 Preparation of (S)-7-rfTN-(2-benzimidazolyl)methyl-N- carboxymethyl1amino1carbonvn-4-methyl-3-oxo-2.3.4.5-tetrahydro- 1 H- 1.4- benzodiazepine-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 solid: -*H NMR (250 MHz, CDCI3) δ 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)methyl-N-

(benzyloxycarbonyl)methyl]amino] carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

Following the procedure in Example 33(d), except substituting N-[(2- benzimizazolyl)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) δ 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, J=8.9 Hz, IH), 7J0 (m, 2H), 7.23 (m, 5H), 7.55 (m, 2H), 7.81 ( m, 2H).

c) Methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N- carboxymethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4- benzodiazepine-2-acetate A solution of methyl-(S)-7-[[[N-(2-benzimidazolyl)methyl-N-

(benzyloxycarbonyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2-acetate (0J85 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. Trituration with acetone gave the title compound (0.140 g, 90%) as an off white solid. IH NMR (250 MHz, CDCI3) δ 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), 7J0 (m, 2H), 7.55 (m, 2H), 7.81 (m, 2H). d) (S)-7-[[[N-(2-Benzimidazolyl)methyl-N-carboxymethyl]amino]carbonyl]-4- methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazeρine-2-acetic acid

A solution of Example 35(b) in methanol (5 mL) was hydrogenated at RT in 10% Pd/C overnight. The catalyst was filtered through Celite. The filtrate was concentrated to give a yellow foam which was triturated in acetone to give the title compound as an off white solid (0J40 g, 90%): MS (ES) m/e 465 (M+H)+: Anal. Calcd for C23H23N5O6 • 1.2 H2O: C, 56.92; H, 5.26; N, 14.38. Found: C, 57.09; H, 5.33; N, 14.00.

Example 36

Preparation of (S)-7-rrrN-(2-benzimidazolyl)methyl-N-cyclohexyl]amino1carbonyll- 4-methyl-3-oxo-2,3A5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid a) 2-(Cyclohexylamino)methylbenzimidazole

Following the procedure of Example 33(c), except substituting cyclohexylamine for n-butylamine, the title compound (0J91 g, 52%) was prepared as a brown oil: ^!H NMR (250 MHz, CDCI3) δ 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]amino]carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

Following the procedure of Example 33(d), except substituting 2- (Cyclohexylamino)methylbenzimidazole for 2-( 1 -butylamino)methylbenzimidazole, the title compound (0J74 g, 50%) was prepared as a yellow foam: 'H NMR (250 MHz, CDCI3) δ 1J5 (m, 4H), 1.60 (m, 4H), 1.85 (m, 2H), 2.65 (dd, J=16.5, 3.5 Hz, 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), 5J0 (m, IH), 5.47 (d, J=16.3 Hz, IH), 6.51 (d, j=8.9 Hz, IH), 7J5 (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- 3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Following the procedure of Example 4(d), methyl-(S)-7-[[[N-(2- benzimidazolyl)methyl-N-cyclohexyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified. The title compound (0J00 g, 60%) was obtained as an off white solid: ^JH NMR (400 MHz, DMSO-d6) δ 1J5 (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, 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-nitrobenzimidazolyl)methyl1methylaminolcarbonvn-4- methyl-3-oxo-2.3A5-tetrahvdro- IH- 1 Abenzodiazepine-2-acetic acid a) 2-[[N-(tert-Butoxycarbonyl)-N-methyl]aminomethyl]-5-nitrobenzimidazole BOC sarcosine (2.555 g, 13.51 mmol) was weighed into a dry 250 mL roundbottom flask, purged with argon. The material was dissolved in dry THF (20 mL). Et3N (3 mL, 21.6 mmol) was added, followed by isobutylchloroformate (1.8 mL, 13.88 mmol). The reaction was stiπed at RT under argon for 30 minutes, then was cooled to -20°C, and 4-nitrophenylenediamine (2.0423 g, 13.34 mmol) was added as a solid. 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 material was dissolved in EtOAc and extracted with 1.0 N NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated under vacuum. The residue was dissolved in glacial AcOH and heated to 75 °C in an oil bath. After 24 h, the reaction was concentrated under vacuum. The residue was reconcentrated from toluene. The material was flash chromatographed (silica gel, 1:2 CH2Cl₂/Et₂O, 1:1 CH2Cl2/Εt2θ, 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)+; -H NMR (250 MHz, CDC1₃) δ 8.61-7.46 (m, 5H), 4.65 (s, 2H), 3.04 (s, 3H), 1.50 (S, 9H).

b) 2-(Methylamino)methyl-5-nitrobenzimidazole

2-[N-(tert-Butoxycarbonyl)-N-methyl]aminomethyl-5-nitrobenzimidazole (904.8 mg, 2.96 mmol) was treated with 4 N HCl in dioxane. The reaction was stiπed at RT for 1 h, then was concentrated under vacuum. The yellow slurry was reconcentrated from toluene. The residue was dried under high vacuum, leaving the title compound (830.5 mg) as a light yellow solid. This material was used without further purification. c) Methyl (±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]A- methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

Methyl (±)-7-carboxy A-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4- benzodiazepine-2-acetate (511.8 mg, 1.75 mmol) was weighed into a dry 200 mL roundbottom flask. Dry DMF was added, followed by HOBt • H₂O (258.1 mg, 1.91 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- nitrobenzimidazole (492.5 mg, 1.76 mmol) and diisopropylethylamine (1.0 mL, 5.74 mmol) in DMF was added at RT. The reaction was stirred at RT for 24 h then was concentrated under vacuum. The residue was reconcentrated from toluene, then was chromatographed on silica gel (CHC1 (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 481.0 (M+H)+.

d) (±)-7-[[[2-(5-Nitrobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Metiiyl (±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]A- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (386.3 mg, 0.080 mmol) was suspended in MeOH, and 1.0 N NaOH (2.5 mL, 2.5 mmol) was added. The reaction was stirred at RT for 18 h, then was warmed in an oil bath set at 70°C.

After 4 h, the reaction 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 dried in a desiccator under vacuum to afford the title compound (317.3 mg, 85%). ^lH NMR (250 MHz, CDCI3) δ 8.55-6.60 (m, 6H), 5.50 (d, IH),

5J5 (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-rrr2-(5-aminobenzimidazolyl)methynmethylamino]carbonyl1-4- methyl-3-oxo-2.3 ,4.5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) (±)-7-[[[2-(5-Aminobenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid 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 mmol) was suspended in MeOH, and 10% Pd/C catalyst was added. The mixture was stiπed briskly 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. 1.0 N NaOH (2.5 mL, 2.5 mmol) and H₂O (10 mL) were added. The reaction was stirred at RT for 24 h, then was neutralized with 1.0 N HCl (2.5 mL). Concentration in vacuum left a dark residue, which was dissolved in MeOH. Activated carbon (Norit®) 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 to about 50 mL. The precipitate was collected on a sintered glass funnel and dried in a vacuum desiccator to give the title compound (158.0 mg) as a red powder: HPLC (PRP-1®, 10% CH3CN/H2O- 0.1% TFA) t_R=4.64; MS (ES) m/e 437.2 (M+H)+; IH NMR (250 MHz, CD3OD) δ 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 C22H24N6O4 • 0.75 HCl • 1.75 H₂O: C, 53.35; H, 5.75; N, 16.97. Found: C, 53.91; H, 6.00; N, 16.36.

Example 39 Preparation of (±)-7-r2-(1.2.3.4-tetrahydro-9H-pyridor3Ab1indolyl)carbonvn-4- methyl-3-oxo-2.3.4.5-tetrahvdro- 1 H- 1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[2-(l,2,3,4-tetrahydro-9H-ρyrido[3,4-b]indolyl)carbonyl]-4- methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

Methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4- benzodiazepine-2-acetate (308.5 mg, 1.06 mmol) was weighed into a 250 mL roundbottom flask. Dry DMF was added, followed by HOBt • H₂O (159.1 mg, 1.18 mmol) and EDC (248.3 mg, 1.30 mmol). Diisopropylethylamine (0.20 mL, 1.15 mmol) was added, followed by a solution of l,2,3,4-tetrahydro-9H- pyrido[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/CHC ) gave the title compound as a clear, colorless oil (484.7 mg): »H NMR (250 MHz, CDC1₃) δ 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-(l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)carbonyl]A-methyl-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Methyl (±)-7-[2-( 1 ,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (484.7 mg, 1.09 mmol) was dissolved in MeOH, and 1.0 N NaOH (2.0 mL, 2.0 mmol) was added. The reaction was stiπed at RT for 24 h, then was heated in an oil bath set at 75°C. After 4 h, the reaction was neutralized with 1.0 N 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: MS (ES) m/e 433.2 (M+H)+. Anal. Calcd for C₂₄H₂₄N₄O₄ • 1.5 H₂O: 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-rrr2-(5.6-methylendioxybenzimidazolyl)methyllmethylamino1 carbonyπ-4-methyl-3-oxo-2,3 ,4.5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) 2- [[N-(Benzyloxycarbonyl)-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) 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-methylenedioxybenzene (0.2 g, 1.314 mmol) in dry THF was added, and the reaction was allowed to warm to RT. After 18 h, the reaction was concentrated under vacuum. The white solid residue was dissolved in EtOAc, and the solution was washed with 1.0 N NaHCO3. The organic layer was dried

(MgSO4), 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 from toluene, then was chromatographed on silica gel (1:1 CH2θ2/Et2θ). The material obtained in this 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/Et2O) gave the title compound (145.0 mg, 32.7%): MS (ES) m/e 340.0 (M+H)+; -H NMR (250 MHz, CDC1₃) δ 7.32 (s, 5H), 7.27 (s, IH), 7.11 (s, IH), 5.94 (s, 2H), 5J3 (s, 2H), 4.58 (s, 2H), 3.03 (s, 3H). 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 stiπed briskly at RT under H2 (balloon). 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) Med yl (S)-7-[[[2-(5,6-methylendioxybenzimidazolyl)methyl]medιylamino] carbonyl]-4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 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- IH- 1 ,4-benzodiazepine-2-acetate (0.35 mmol) and HOBt • H2O (57.9 mg, 0.43 mmol) in dry DMF, and the reaction was stiπed at RT. Diisopropylethylamine (0J50 mL, 0.86 mmol) was added, followed by a solution of 2-(methylamino)methyl- 5,6-methylenedioxybenzimidazole (70.8 mg, 0.35 mmol) in dry DMF. The reaction was stiπed 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/CHCl₃) gave the title compound (102.5 mg, 61.1%): -H NMR (250 MHz, CDC1₃) δ 7.18- 7J3 (m, 3H), 6.82 (s, IH), 6.49 (s, IH), 5.97 (s, 2H), 5.40 (d, IH), 5.05 (dd, IH), 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- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Methyl (S)-7-[[[2-(5,6-methylendioxybenzimidazolyl)methyl]methylamino] carbonyl] -4-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 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 1.0 N HCl. Concentration under vacuum left a residue which was diluted with water and allowed to stand at RT overnight. The resultant precipitate was collected by filtration and dried under high vacuum to yield the title compound (29.0 mg, 30%): HPLC t_R=l 1.67;(PRP-1®, gradient elution over 20 min, 5-50% CH₃CN/H₂O-0J% TFA) MS (ES) m/e 466.2 (M+H)+.

Example 41 Preparation of (S)-7-rrr2-(4.6-diazabenzimidazolyl)methyllmethylamino]carbonyll- 4-methyl-3-oxo-2,3A5-tetrahydro-lH-1.4-benzodiazepine-2-acetic acid a) 2-[[N-(tert-Butoxycarbonyl)-N-methyl]aminomethyl]A,6-diazabenzimidazole

Boc-sarcosine (3.6 g, 19J mmol) was dissolved in dry THF in a flame-dried 250 mL roundbottom flask, and Et3N (6 mL, 43.14 mmol) was added. The solution was cooled to 0°C to -5°C, and isobutylchloroformate (2.5 mL, 1.93 mmol) was added. The white mixture was stirred at - 5 °C for 15 min, then was cooled to -20 °C to -30 °C, and 4,5-diaminopyrimidine (2J g, 19.15 mmol.) was added as a solid. 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 NaHCO3. The organic layer was dried (MgSO4), 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/CHCl3, 10% MeOH/CHCl₃) gave the title compound (1.66 g, 33%): -H NMR (250 MHz, CDC1₃) δ 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]A,6- diazabenzimidazole (1J3 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 Et2θ. The precipitate was collected on a sintered glass funnel and dried in a vacuum desiccator to yield the title compound (328.5 mg, 46.9%) as a white powder. TLC R_f 0.36 (3: 1 : 1 n-

BuOH/HOAc/H₂O); »H NMR (250 MHz, CD₃OD) δ 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-diazabenzimidazolyl)methyl]methylamino]carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

Methyl (S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4- benzodiazepine-2-acetate (262.6 mg, 0.55 mmol) was suspended in CH3CN (10 mL), and HOBt • H₂O (86.7 mg, 0.64 mmol) was added, followed by EDC (115.5 mg, 0.60 mmol). Diisopropylethylamine (150 mL, 0.86 mmol) was added, affording a homogeneous solution. A solution of.2-(methylamino)methy 1-4,6- diazabenzimidazole (99.0 mg, 0.61 mmol) and diisopropylethylamine (150 mL, 0.86 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 (silica 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 (250 MHz, CDC1₃) δ 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), 3J6 (s, 3H), 2.98 (s, 3H).

d) (S)-7-[[[2-(4,6-Diazabenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid 1.0 N NaOH ( 1.5 mL, 1.5 mmol) was added to a solution of methyl (S)-7-

[[[2-(4,6-diazabenzimidazolyl)methyl]medιylamino]carbonyl]-4-methyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-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 reaction was concentrated to dryness under vacuum, and the residue was purified by chromatography ( ODS, step gradient, 5% CH₃CN/H₂O-0J% TFA, 10% CH₃CN/H₂O-0J % TFA, 20% CH3CN/H2θ-0J% TFA). One fraction was collected and concentrated under vacuum. The residue was reconcentrated from toluene and dried under vacuum, then was dissolved in MeOH and precipitated with Et3N. The white precipitate was collected on a sintered glass funnel and dried in a vacuum desiccator to afford die title compound as a white powder (126.5 mg, 67.9%): HPLC tR 0.41; (ODS, gradient elution over 20 min, 5-50% CH₃CN/H₂O-0J% TFA); MS (ES) m e 424.2 (M+H)+. Anal. Calcd for C₂₀H₂₁N₇O₄ • 0.5 CF₃CO₂H: C, 52.50; H, 4.51; N, 20.41. Found: C, 52.62; H, 4.88; N, 20.01.

Example 42 Preparation of (S)-7-rrr2-(4-azabenzimidazolyl)methyl1methylamino]carbonyll-4- methyl-3-oxo-2.3.4.5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid a) 2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]A-azabenzimidazole 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 in an ice bath, and isobutylchloroformate (3.0 mL, 23.13 mmol) was added. The reaction was stiπed at RT for 15 min, then was added to a solution of 2,3-diaminopyridine (2.5 g, 22.7 mmol) in dry THF at -25°C. The reaction was stiπed at -20°C for 30 min, then was allowed to warm to RT. After 24 h, the reaction was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHCO3. The organic layer was dried (MgSU4), filtered and concentrated under vacuum. The residue was dissolved in glacial AcOH (200 mL) and heated in an oil bath set at 109 °C. After 20 h, the reaction was concentrated under vacuum, and the residue was reconcentrated from toluene. Chromatography (Silica gel, step gradient, CHC1₃, 3% MeOH/CHCl₃, 5% MeOH/CHCl₃) gave the title compound (2.2 g, 33%), which was recrystallized from Et2θ: MS (ES) m/e 296.2 (M+H)+.

b) 2-(Methylamino)methyl-4-azabenzimidazole

2-[ [N-(Benzyloxycarbonyl)-N-methyl] aminomethyl] A-azabenzimidazole (551.3 mg, 1.86 mmol) was dissolved in MeOH, and 10% Pd/C was added. The mixture was stirred briskly at RT under H2 (balloon). After 4 h, the reaction was filtered through Celite®, and the filtrate was concentrated under vacuum to afford the title compound (420J mg, quantitative): ^JH NMR (250 MHz, CDC1₃) δ 8.34- 8.32 (m, IH), 7.98-7J4 (m, 4H), 5J8-5J2 (m, IH), 4.87 (s, 2H), 3.32 (s, 3H).

c) Methyl (S)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]A- methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

EDC (309J mg, 1.61 mmol) was added to a solution of methyl (S)-7- carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetate (504.6 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 A-azabenzimidazole (3.08 mmol) neutralized with diisopropylethylamine (0.600 mL) was added, and the reaction was stiπed 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 title compound (326.8 mg, 48.6%): MS (ES) m/e 437.2 (M+H)+; Η NMR (250 MHz, CDC1₃) δ 8.39 (d, IH), 8.00-7.20 (m, 5H), 5.50 (d, IH), 5J5A.80 (m, 3H), 3.70 (s, 3H), 3J0 (s, 3H), 2.93 (s, 3H).

d) (S)-7-[[[2-(4-Azabenzimidazolyl)methyl]methylamino]carbonyl]-4-medιyl-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate

1.0 N NaOH (2.0 mL, 2.0 mmol) was added to a solution 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 1.0 N

HCl (2.0 mL, 2.0 mmol) and concentrated under vacuum. The residue was taken up in H2O and the resultant white precipitate was collected on a sintered glass funnel, washed with H2O and dried under vacuum to afford the title compound (218J mg, 69%) as a white powder: MS (ES) m/e 423.4 (M+H)+. Anal. Calcd for C₂ιH₂₂N₆O₄ • 2 H₂O: C, 55.02; H, 5.72; N, 18.33. Found: C, 55.07; H, 5.55; N, 17.81.

Example 43 Preparation of l-\ 1 -r2R-(2-benzimidazolyl)pyπolidinyl1carbonyl]-4-methyl-3-oxo- 2.3 ,4.5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2S-acetic acid a) l-tert-Butoxycarbonyl-2R-(2-benzimidazolyl)pyrrolidine

A solution of BOC-D-proline (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 stiπed at 0°C for 20 min, then was removed from the cooling bath and allowed to warm to RT for 10 minutes. The white slurry was added to a solution of ø-phenylenediamine (1.55 g, 4.3 mmol) in THF 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 NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated under vacuum. The residue was dissolved in 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 gave the title compound (1J g). The mother liquors were concentrated and the residue taken into Et₂θ to afford additional title compound (1.47 g).

b) 2R-(2-benzimidazolyl)pyrrolidine l-tert-Butoxycarbonyl-2R-(2-benzimidazolyl)pyπolidine (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 Et2θ. The white precipitate was collected and dried under vacuum to afford the title compound (

958J mg, 99J%): »H NMR (250 MHz, CDC1₃) δ 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); [α]_D .9_ (c l.0, H₂O). c) Methyl 7-[l -[2R-(2-benzimidazolyl)pyrrolidinyl]carbonyl]-4-methyl-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 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 mmol.), diisopropylethylamine (0.06 mL, 0.34 mmol), and HOBt ^• H2O (56.6 mg, 0.42 mmol) in dry DMF at RT. The reaction was stirred at RT, and a solution of 2R- (2-benzimidazolyl)pyπolidine (89.7 mg, 0.35 mmol) and diisopropylethylamine (0J20 mL, 0.69 mmol) in DMF was added. 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 title compound (136.9 mg, 92.5%): ^lU NMR (250 MHz, CDC1₃) δ 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)pyπolidinyl]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2S-acetic acid

1.0 N NaOH (0.75 mL, 0.75 mmol) was added to a solution of methyl 7-[l- [2R-(2-benzimidazolyl)pyπolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2S-acetate ( 136.9 mg, 0.30 mmol) in MeOH (5 mL) and

H₂O (5 mL) at RT. After 24 h, 1.0 N HCl (0.75 mL, 0.75 mmol) was added and the reaction mixture was concentrated under vacuum. Chromatography (ODS, step gradient, 0.1% TFA/H₂O, 20% CH₃CN/H2O-0J% TFA), concentration, and reconcentration from toluene left a residue, which was redissolved in H2O. Lyophilization gave the title compound (92 mg): HPLC tR=10.68 (ODS, gradient elution over 20 min, 5-50% CH₃CN/H₂O-0J % TFA); MS (ES) m/e 448.2 (M+H)+.

Example 44 Preparation of 7-ri-r2S-(2-benzimidazolyl)pyrrolidinyl1carbonyl1A-methyl-3-oxo- 2,3 A5-tetrahvdro-lH-l,4-benzodiazepine-2S-acetic acid a) 1 -tert-Butoxycarbonyl-2S-(2-benzimidazolyl)pyrrolidine

Following the procedure of Example 43(a), except substituting BOC-L- proline for the BOC-D-proline, the title compound (3.2 g, 74%) was prepared. -H NMR (250 MHz, CDC1₃) δ 7.53 (br s, IH), 7.19-7.16 (m, 4H), 5J4 (d, IH), 3.50 (s, 2H), 2.87 (br s, IH), 2J9-1.97 (m, 3H), 1.49 (s, 9H), 1.25 (br s, 2H); MS (ES) m/e 288.2 (M+H)+. b) 2S-(2-benzimidazolyl)pyπolidine

Following the procedure of Example 43(b), except substituting 1-tert- butoxycarbonyl-2S-(2-benzimidazolyl)pyπolidine for the l-tert-butoxycarbonyl-2R- (2-benzimidazolyl)pyrrolidine, the title compound was prepared( 1.7988 g, 98.4%): -H NMR (250 MHz, CDC1₃) δ 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), [α]_D +3.9- (c 1.0, H₂O).

c) Metiiyl 7-[l-[2S-(2-benzimidazolyl)pyπolidinyl]carbonyl]-4-methyl-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2S-acetate

Following the procedure of Example 43(c), except substituting 2S-(2- benzimidazolyl)pyrrolidine for the 2R-(2-benzimidazolyl)pyrrolidine, the title compound (90.4 mg, 61%) was prepared: MS (ES) m/e 462.4 (M+H)+.

d) 7-[ 1 -[2S-(2-Benzimidazolyl)pyrrolidinyl]carbonyl] A-methyl-3-oxo-2,3 ,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2S-acetic acid

Following the procedure of Example 43(d), except substituting methyl 7-[l- [2S-(2-benzimidazolyl)pyπolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine-2S-acetate for the methyl 7-[l-[2R-(2- benzimidazolyl)pyrrolidinyl] carbonyl] -methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4- benzodiazepine-2S-acetate, the title compound (65.8 mg, 75%) was prepared: HPLC t_R=10.63 (ODS, gradient elution over 20 min, 5-50% CH₃CN/H₂O-0J% TFA); MS (ES) m/e 448.2 (M+H)+.

Example 45 Preparation of (±)-7-rrr2-(4-azabenzimidazolyl^')methyllmethylamino1carbonyn-4- isopropyl-3-oxo-2,3A5-tetrahydro-lH-1.4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]A- 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 A-isopropyl-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate for the methyl (S)-7-carboxyA-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetate, the title compound (226 mg, 96%) was prepared: TLC Rf (5% MeOH/CHCl₃) 0.28; -H NMR (250 MHz, CDC1₃) δ 8.45 (d, IH), 7.96-7.10 (m, 5H), 6.40 (br s, IH), 5.09-4.77 (m, 5H), 3.70 (s, 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- oxo-2,3 ,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid

1.0 N NaOH (1.5 mL, 1.5 mmol) was added to a solution of methyl (±)-7- [[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]A-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 1.0 N HCl and the solvents were evaporated under vacuum. ODS chomatography (0.1% TFA/H₂O, followed by 20% CH₃CN/H₂O-0J % 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 repurified by ODS chromatography (10% CH₃CN/H₂O-0J% TFA, followed by 20% CH3CN/H2O-0.1 % TFA). Concentration and reconcentration from toluene left a residue, which was dissolved in MeOH and precipitated with Et2θ. The precipitate was collected on a sintered glass funnel and dried in a vacuum desiccator to afford the title compound (65.5 mg): HPLC (ODS, gradient elution over 20 min, 5-50% CH₃CN/H₂O-0J% TFA) t_R= 12.32; MS (ES) m/e 451.2 (M+H)+. Anal. Calcd for C₂₃H₂₆N₆O₄ • 0.5 CF₃CO₂H ■ 0.75 H₂O: C, 55.33; H, 5.42; N, 16.13. Found: C, 55.43; H, 5.60; N, 16.01.

Example 46 Preparation of (S)-7Jrf2J4-aza-5- methylbenzimidazolyl)methyl]methylamino1carbonyllA-methyl-3-oxo-2.3.4.5- tetrahvdro- 1 H- 1.4-benzodiazepine-2-acetic acid a) 2-Amino-6-methyl-3-nitropyridine

2-Amino-6-picoline (5J g, 47J mmol) was weighed into a 500 mL round bottom flask, and the flask was cooled to -30°C. Concentrated H2SO4 (20 mL) was 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 min, then was heated in an oil bath set at 80°C. After 90 min, 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 a sintered glass funnel. Drying in a vacuum desiccator gave the title compound (1.7 g, 24%): TLC R_f (5% MeOH/CHCl₃) 0.77; -H NMR (250 MHz, CDC1₃) δ 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-nitropyridine (754 mg, 4.92 mmol) was suspended in MeOH, and 10% Pd/C was added. The mixture was stiπed briskly at RT under H2 (balloon). After 4 h, the reaction was filtered through Celite®, and the filtrate was concentrated under vacuum to afford the title compound (677. mg, quantitative): ^JH NMR (250 MHz, CD₃OD) δ 6.82 (d, IH), 6.36 (d, IH), 2.25 (s, 3H).

c) 2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]-5-methylA- 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 mmol). After 30 min, a solution of 2,3-diamino-6-methylpyridine (882 mg, 7J6 mmol) in dry THF was added, and the reaction was stiπed at RT. After 3 d, die reaction was concentrated under vacuum. The residue was taken up in EtOAc and washed with 1.0 N NaHCO3. The organic layer was dried (MgSU4), filtered, concentrated under vacuum, and reconcentrated from toluene. The residue was 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 g, 46.6%): -H NMR (250 MHz, CDC1₃) δ 7.29 (s, 5H), 7.17 (s, IH), 7.03 (d, IH), 5.09 (s, 2H), 4.74 (s, 2H), 3.05 (s, 3H), 2.61 (s, 3H); MS (ES) m/e 311.0 (M+H)+.

d) 2-(Methylamino)methyl-5-methylA-azabenzimidazole

2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]-5-methylA- azabenzimidazole (1.0347 g, .33 mmol) was dissolved in MeOH, and 10% Pd/C was added. The mixture was stirred briskly 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 material. e) Methyl (S)-7-[[[2-(4-aza-5- memylbenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

EDC (212.7 mg, 1.11 mmol) was added to a solution of methyl (S)-7- carboxy A-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (293.5 mg, 0.93 mmol), diisopropylethylamine (0.30 mL, 1.72 mmol), and HOBt • H2O (143.5 mg, 1.06 mmol) in dry DMF at RT. After 30 minutes, a solution of 2- (methylamino)methyl-5-methylA-azabenzimidazole (190.7 mg, 1.08 mmol) in dry DMF was added. The reaction was stiπed at RT for 24 h, then 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 title compound (265 mg, 63%): Η NMR (250 MHz, CDC1₃) δ 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)+.

(S)-7-[[[2-(4-Aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]A- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,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-methylbenzimidazolyl)methyl]methylamino]carbonyl]-4-medιyl-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-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 material was precipitated from water to give the title compound (49.8 mg): TLC R_f 0.51 (3:1:1 n-BuOH/HOAc/H₂O) ; HPLC t_R=8.35 min (PRP-1®, gradient elution over 20 min, 5-50% CH3CN/H2O-0.1 % TFA); MS (ES) m/e 437.2 (M+H)+. Anal. Calcd for C₂₂H₂₄N₆O₄ • 0.75 H₂O • 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 (SV7-HT2J5.6- dimethoxybenzimidazolyl)methyllmethylaminolcarbonyll-4-methyl-3-oxo-2.3.4.5- tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) 2-[[N-(Benzyloxycarbonyl)-N-methyl]aminomethyl]-5,6- dimethoxybenzimidazole Cbz-sarcosine (1.4 g, 6J mmol) was dissolved in dry THF in a 100 mL roundbottom flask, and Et3N (1.5 mL, 10.8 mmol) was added, followed by isobutylchloroformate (0.80 mL, 6J7 mmol). The reaction was stiπed at RT, then was added to a solution of 4,5-dimethoxyphenylenediamine (6.06 mmol) in dry THF at -25°C. The Cbz-sarcosine, mixed-anhydride solution was added to the cooled phenylenediamine solution. The reaction was stirred at -25°C for 10 min, then was 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 NaHCO3. The organic layer was dried (MgSO4), filtered, concentrated under vacuum, and reconcentrated from toluene. The residue was dissolved in glacial AcOH (100 mL) and heated in an oil bath heated set at 110 °C. After 24 h, the reaction was concentrated under 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) δ 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 356.2 (M+H)+.

b) 2-(Methylamino)methyl-5,6-dimedιoxy benzimidazole

2-[ [N-(Benzyloxycarbonyl)-N-methyl] aminomethyl] -5,6- dimetiioxybenzimidazole (1.7454 g, 4.91 mmol) was dissolved in MeOH, and 10% Pd/C was added. The mixture was stirred briskly at RT under H2 (balloon). After 4 h, the reaction was filtered through Celite®, and the filtrate was concentrated under vacuum to afford the title compound.

c) Methyl (S)-7-[[[2-(5,6- dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate EDC (139.9 mg, 0.73 mmol) was added to a suspension of methyl (S)-7- carboxy A-methyl-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate ( 198.5 mg, 0.68 mmol), and HOBt • H₂O (98.8 mg, 0.73 mmol) in CH3CN at RT. After 15 minutes, diisopropylethylamine (0.200 mL, 1J5 mmol) was added, followed by a solution of 2-(methylamino)methyl-5,6-dimethoxybenzimidazole (147.3 mg, 0.67 mmol) in CH3CN. The reaction was stiπed 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 title compound (227 mg, 68%): ^!H NMR (250 MHz, CDC1₃) δ 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)+. d) (S)-7-[[[2-(5,6-dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]-4- methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

1.0 N NaOH (1.5 mL, 1.5 mmol) was added to a solution of methyl (S)-7- [[[2-(5,6-dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (227J mg, 0.46 mmol) in MeOH (10 mL) and H2O (10 mL) at RT. After 24 h, the reaction was neutralized with 1.0 N HCl (1.5 mL, 1.5 mmol). After 30 min, a white precipitate had formed, which was collected on a sintered glass funnel and washed with water. The material was dried in a vacuum desiccator to afford the title compound (144.3 mg, 65%): MS (ES) m/e 482.2 (M+H)⁺. Anal. Calcd for C₂₄H₂₇N₅O₆ • 1.75 H₂O • 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-benzimidazolyl)acetyl1amino^"l-2-methyl-3-oxo-2,3A5- tetrahydro- 1 H-2-benzazepine-4-acetic acid a) Methyl (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-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-benzazepine-4- acetate was coupled with 2-benzimidazloylacetic acid according to the procedure of example 11(a). Purification 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), 5J8 (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-benzazepineA-acetic acid

Methyl (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-methyl-3-oxo-2,3,4,5- tetrahydro- lH-2-benzazepineA-acetate was saponified according to the procedure of Example 24(b) to give the title compound as a white solid (47%): ^JH NMR (DMSO-d6) δ 10.38 (s, IH), 7.49 (m, 3H), 7.42 (d, J=8.4 Hz, IH), 7J5 (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. Example 49 Preparation of (±)-8-rrr(2-benzimidazolyl)methvnmethylaminolcarbonyl1-4-methyl- 3-0X0-2,3 A5-tetrahvdro- 1 H-2-benzazepine-4-acetic acid a) Methyl (±)-8-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H-2-benzazepine A-acetate

Methyl (±)-8-carboxy-3-oxo-2,3,4,5-tetrahydro-lH-2-benzazepineA-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%): ^!H NMR (CDCI3) δ 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]A-methyl-3-oxo- 2,3,4,5-tetrahydro-lH-2-benzazepine-4-acetic acid

Methyl (±)-8-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]A-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 solid (90%): »H NMR (DMSO-d6) δ 7.88 (m, IH), 7.54 (m, 2H), 7.34 (d, J=7.9 Hz, IH), 7.30 (s, IH), 7J6 (m, 2H), 6.98 (m, IH), 4.87 (m, IH), 4.67 (m, 2H), 4.00 (m, IH), 3.87 (m, IH), 3J0 (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 C22-H2lN4θ4Li • 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-rrr(2-benzimidazolyl)methyllmethylaminolcarbonvn-3-oxo-4-

(2-phenylethyl)-2,3A5-tetrahvdro-lH-1.4-benzodiazepine-2-acetic acid a) Methyl (S)-7-carboxy-3-oxoA-(2-phenylethyl)-2,3 ,4,5-tetrahydro- IH- 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 brine, dried (MgSO4), and concentrated. The residue was purified by chromatography (silica gel, CH2CI2) to give a pale yellow oil (7 g). Preparative HPLC (Whelk O-l, 50:50: 1 hexane:CHCl3: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 material was placed in a 500 mL Parr hydrogenation vessel with CH3OH (30 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 (2J g, 47%): *H NMR (CDCI3) δ 7.78 (dd, j=8.5, 1.9 Hz, IH), 7.55 (d, J=1.9 Hz, IH), 7.30-7J0 (m, 5H), 6.51 (d, J=8.5 Hz, IH), 5.30 (d, j=16.6 Hz, IH), 5J0 (t, j=6.5 Hz, IH), 3.77 (s, 3H), 3.74 (m, 3H), 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]carbonyl]-3-oxoA-(2- phenylethyl)-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate 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: ^JH NMR (CDCI3) δ 7.63 (m, 2H), 7.33 (m, 2H), 7.25-7J0 (m, 7H), 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), 3J9 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-Benzimidazolyl)methyl]methylamino]carbonyl]-3-oxoA-(2- phenylethyl)-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Methyl (S)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4- (2-phenylethyl)-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate was saponified according to die procedure of Example 11(b) to give the title compound (1.8 g, 66%) as a white solid: ^lH NMR (DMSO-d6) δ 7.54 (m, 2H), 7.30-7.10 (m, 9H), 6.54 (d, J=8.3 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. Example 51 Preparation of (±)-7-rrr2-(benzimidazolyl)methyl1aminolcarbonyl-4-r2-(3,4- methylenedioxyphenyl)ethyll-3-oxo-2,3.4.5-tetrahvdro- IH- 1 ,4-benzodiazepine-2- acetic acid a) Methyl (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(3,4- methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2- acetate

Methyl (±)-7-carboxyA-[2-(3,4-methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine-2-acetate was coupled with 2- (aminomethyl)benzimidazole dihydrochloride hydrate according to the procedure of Example 2(a). Purification by chromatography (silica gel, l%-5% CH3OH/CH2CI2) followed by recrystallization (CH3OH/EtOAc) gave the title compound as a tan solid (59%): ^lH NMR (DMSO-d6) δ 8.72 (t, J=5 Hz, IH), 7.61 (s, IH), 7.56 (m, 2H), 7.43 (m, IH), 7J3 (m, 2H), 6.76 (m, 2H), 6.57 (m, 2H), 6.37 (d, J=3.6 Hz, IH), 5.95 (s, 2H), 5.42 (d, J=16.5 Hz, IH), 5J3 (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-(BenzimidazolyI)methyl]amino]carbonylA-[2-(3,4- methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2- acetic acid

Methyl (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonylA-[2-(3,4- methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2- acetate was saponified according to the procedure of Example 11(b) to give the title compound (84%) as a white solid: ^**H NMR (DMSO-d6) δ 8.76 (t, J=5 Hz, IH), 7.58 (m, 2H), 7.48 (m, 2H), 7J3 (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, 61.42; H, 5.22; N, 12.25.

Example 52 Preparation of (±)-7-rrr(4(5)-imidazolyl)methyl1amino]carbonyπA-methyl-3-oxo- 2,3,4,5-tetrahvdro-lH-l,4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[(4(5)-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 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) for the 2- (aminomethyl)imidazole, and heating the reaction at 90-100°C for 24 h, the title 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- 1 H- 1 ,4-benzodiazepine-2-acetic acid Following the procedure of Example 23(b), methyl (±)-7-[[[(4(5)- imidazolyl)methyl]amino]carbonyl] A-methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4- benzodiazepine-2-acetate was saponified to give d e title compound: MS (ES) m/e 358 (M+H)⁺. Anal. Calcd for C17H19N5O₄ • 1J5 CF₃CO₂H • 0.05 H₂O: C, 47.37; H, 4J7; N, 14.31. Found: C, 47.70; H, 3.91; N, 13.92.

Example 53 Preparation of (±)-rrr4-(2-phenylimidazolyl)methyl1aminolcarbonyl1 A-methyl-3- oxo-2.3 ,4,5-tetrahvdro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) 4-Aminomethyl-2-phenylimidazole dihydrochloride Hydroxylamine hydrochloride (229 mg, 3.3 mmol) was added to a suspension of 2-phenylimidazoleA-carboxaldehyde (516 mg, 3 mmol; prepared according to7. Chem. Soc. Perkin Trans. 1197 '4, 1527) and sodium acetate (541 mg, 6.6 mmol) in absolute EtOH (5 mL) and H2O (5 mL) at RT. A yellow, homogeneous solution was produced. After 15 min, the reaction was concentrated 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 combined organic layers were dried (MgSO4) and concentrated to leave a yellow foam.

The yellow foam was dissolved in absolute EtOH (9 mL), and 1.0 N HCl (6 mL, 6 mmol) and 10% Pd/C (0.32 g, 0.3 mmol) were added. The mixture was shaken on a Pan 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 solid. Recrystallization fron absolute EtOH/H2θ gave the title compound as a light pink solid (465 mg, 63%): mp 273-275°C (dec); Η NMR (250 MHz, CD3OD) δ 7.93- 8J2 (m, 2H), 7.80 (s, IH), 7.50-7.76 (m, 3H), 4.40 (s, 2H); MS (ES) m/e 347.2 (2M +H)+, 174.0 (M+H)+, 157.0 (M+H-NH₃)+. b) Methyl (±)- [[ [4-(2-phenylimidazolyl)methyl] amino]carbonyl] A-methyl-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-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetate (175.4 mg, 0.6 mmol), 4-aminomethyl-2-phenylimidazole dihydrochloride (177.2 mg, 0.72 mmol), HOBTΗ2O (97.3 mg, 0.72 mmol), and diisopropylethylamine (0.52 mL, 3.0 mmol) in 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 layers were combined, which caused an oil to separate. This was dissolved by addition of MeOH. Drying (MgSU4), concentration, and reconcentration from xylenes (to remove DMF) left a yellow semisolid residue. Chromatography (silica gel, 10% MeOH/CHC ) gave the title compound (230 mg, 86%) as an oily foam which solidified to an off-white solid on treatment with EtOAc: TLC Rf 0.42 (10% MeOH/CHCl ); ^lE NMR (400 MHz, 10% CD3OD/CDCI3) δ 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, J=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) (±)-[[[4-(2-Phenylimidazolyl)methyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

A suspension of methyl (±)-[[[4-(2- phenylimidazolyl)methyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5-tetrahydro-lH- 1 ,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 stiπed at RT. A homogeneous solution had formed within 15 min. 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 1.0 N HCl (0.61 mL), and the solid was collected and washed with H2O. The resulting solid was triturated 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-0J% TFA); *H NMR (400 MHz, DMSO-d₆) δ 8.32-8.47 (m, IH), 7.90 (d, J=7.5 Hz, 2H), 7.51-7.61 (m, 2H), 7.38-7.48 (m, 2H), 7.26-7.36 (m, IH), 7.01 (br s, IH), 6.54 (d, J=8.3 Hz, 1H),.6.30 (s, IH), 5.48 (d, j=16.5 Hz, IH), 5.02- 5J2 (m, IH), 4.38 (br s, 2H), 3.81 (d, J=16.5 Hz, IH), 2.91 (s, 3H), 2.76 (dd, 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 H₂O: C, 61.81; H, 5.52; N, 15.67. Found: C, 62.05; H, 5.44; N, 15.59.

Example 54

Preparation of (±)-7-rrr2-(3-indolyl)ethyllamino1carbonyll-4-methyl-3-oxo-2,3.4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid a) Methyl (±)-7-[[[2-(3-Indolyl)ethyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate Following the procedure of Example 26(d), except substituting 3-(2- aminoethyl)indole for the l-methyl-2-(methylamino)methylindole, the title compound was prepared (50%): MS (ES) m/e 435.2 (M+H)⁺.

b) (±)-7-[[[2-(3-Indolyl)ethyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Following die procedure of Example 26(e), methyl (±)-7-[[[2-(3- Indolyl)edιyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetate was saponified to give the title compound as a colorless solid. MS (ES) m/e 421.0 (M+H)+. Anal. Calcd for C23H24N4O4 • 1.3 H₂O: C, 62.24; H, 6.04; N, 12.24. Found: C, 62.31; H, 5.61; N, 12.04.

Example 55 Preparation of (S)-7-rrr2-(4-phenylimidazolyl)methynamino1carbonyl1A-methvI-3- oxo-2,3A5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid a) Methyl (S)-7-[[[2-(4-phenylimidazolyl)methyl]amino]carbonyl]A-methyl-3-oxo- 2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetate

Following the procedure of Example 23(a) except substituting 2-(aminomethyl)- 4-phenyl imidazole (Aust. J. Chem., 1971, 24, 2389) for 2-(aminomethyI)imidazole, the title compound was prepared: MS (ES) m/e 448 (M+H)⁺.

b) (S)-7-[[[2-(4-Phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid

Following the procedure of Example 23(b) methyl (S)-7-[[[2-(4- phenylimidazolyl)methyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2-acetate was saponified to give die title compound: MS (ES) m/e 434 (M+H)+. Anal. Calcd for C23H23N₅O₄ • 0.5 CF₃CO₂H • 0.5 HCl ^• 1.75 H₂O: C, 47.01; H, 4.80; N 11.42. Found: C, 47.14; H, 4J7; N, 11.51.

Examples 56-75 Following the general procedures of Examples 1-55, the following compounds were prepared:

56. (+/-)-2,3,4,5-Tetrahydro-7-[[[benzimidazol-2- yl)methyl]methylamino]carbonyl]-4-(3,3-dimethylbutyl)-3-oxo- IH- 1 ,4- benzodiazepine-2-acetic acid; 57. (-)-7-[[[6-Trifluoromethylbenzimidazoyl-2-ylmethyl]aminomethyl]carbonyl]-

2,3 A5-tetrahydroA-methyl-3-oxo-benzodiazepine-2-acetic acid;

58. (-)-7-[[[4,7-Dimethoxybenzimidazoyl-2-ylmethyl]aminomethyl]carbonyl]- 2,3 ,4,5-tetrahydro -methyl-3-oxo-benzodiazepine-2-acetic acid;

59. (+/-)-2,3,4,5-Tetrahydro-7-[[[(benzimidazol-2-yl)methylamino]carbonyl]A- (3 ,3-dimethylbutyl)-3-oxo- 1 H- 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-benzodiazepine-2-acetic acid;

61. (2S)-[[[N-aminobutyl-N-(benzimidazlo-2-yl)methyl]amino]carbonyl]-3-oxo- 4-methyl-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acidbis(trifluoroacetate)salt;

62. (2S)-[[[N-cyanomethyl-N-(benzimidazlo-2-yl)methyl]amino]carbonyl]-3- oxoA-methyl-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid dihydrochloride salt;

63. (S)-2,3,4,5-Tetrahydro-7-[[[(benzimidazol-2-yl)]methyl]amino]carbonyl]-4- (4-phthalimidobutyl)-3-oxo- 1 ,4-benzodiazepine-2-acetic acid;

64- (-)-7-[[[Imidazo[4,5B]A,6-dimethylpyridyl-2- ylmethyl]aminomethyl]carbonyl]-2,3,4,5-tetrahydroA-methyl-3-oxo- benzodiazepine-2-acetic acid trifluoroacetate salt;

65. (+/-)-7-[[(2-Benzimidazol-2-ylmethyl)-N-methylamino]carbonyl]-2,3,4,5- tetrahydro-3-oxo-4-[2-(3',4'-methylenedioxyphenyl)ethyl]-lH-l,4-benzodiazepine-2- acetic acid;

66. (+/-)-2,3,4,5-Tetrahydro-7-[[[(Benzimidazol-2-yl)methyl]amino]carbonyl]A- (2-methoxyethyl)-3-oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acid;

67. (S)-7-[[2-[ 1 -Methylbenzimidazolyl]benzimidazolylmethylamino]carbonyl]- 2,3,4,5-tetrahydroA-methyl-3-oxo- 1 H-l ,4-benzodiazepine-2-acetic acid; 68. (S)-7-[[[N-Cyclohexyl-N-(benzimidazol-2-yl)methyl]amino]carbonyl]-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid;

69. (S)-7-[[[2-Bis-(Benzimidazolylmethyl)aminocarbonyl]-2,3,4,5-tetrahydro-4- methyl-3-oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acid; 70 (+/-)-2,3,4,5-Tetrahydro-7-[[[imidazo[4,5-B]pyrid-2- yl]methyl]methylamino]carbonyl]A-(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'-trifluoroethyl)- 1 H- 1 ,4-benzodaizepine-2-acetic acid; 72. (+/-)-7-[[(2-Benzimidazolyl)acetyl]amino]-5-oxo-4-(2-ρhenylethyl)-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid;

73. (+/-)-7-[[(2-Benzimidazol-2-ylmethyl)amino]carbonyl]-2,3,4,5-tetrahydro-3- oxo -(2^l,2',2'-trifluoroethyl)- 1 H- 1 ,4-benzodiazepine-2-acetic acid;

74. (-)-7-[[[5,6-Difluorobenzimidazoyl-2-ylmethyl]aminomethyl]carbonyl]- 2,3,4,5-tetrahydroA-methyl-3-oxo-l,4-benzodiazepine-2-acetic acid; and

75. (+/-)-7-[[Bis-(Benzimidazol-2-ylmethyl)amino]carbonyl]-2,3,4,5-tetrahydro- 4-phenylethyl-3-oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acidtris(trifluoroacetate)salt.

Example 76 Preparation of 4-r2-rrri-r(Benzimidazol-2-yl)methyl1benzimidazol-2- yll methyll methylaminol acetyllphenoxy acetic 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- (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 stiπed 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 mixture was acidified to pH 2 using 1.0 M NaHSO4. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with H2O and dried (Na2SO4). Filtration and concentration gave the title compound (6.49 g, 99%): -1H NMR (250 MHz, CDCI3) δ 6.70-8.05 (m, 4 H), 4.53 (s, 2H), 2.98 (s, 3H), 1.50 (s, 9H). 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 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 die rotavap. The residue was dissolved in CH2CI2 (300 mL) and washed sequentially with H2O (50 mL) and brine (50 mL). Drying (Na2SO4), concentration, and flash chromatography ( silica gel, 1:3 EtOAc/hexanes) yielded the title compound (7.28 g, 93%): 1H NMR (250 MHz, CDCI3) δ 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 hydrochloride

A mixture of benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate (7.26 g, 17.57 mmol) and 4 M HCl in 1,4-dioxane (150 mL) was stiπed for 1 h at RT.

Evaporation on the rotavap and trituration with Et2θ afforded the title compound as a white powder (5.93 g, 97%): 1H NMR (250 MHz, CD3OD) δ 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 hydrochloride (0.39 g, 1.11 mmol), 2- (chloromethyl)benzimidazole (0.24 g, 1.45 mmol), CH3CN (20 mL), and CH2CI2 (5 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% NaHCO3 and brine. Drying (MgSO4), concentration, and flash chromatography ( silica gel, step gradient, 7 - 15% MeOH/CH2θ2) yielded the title compound as an off-white powder (0.08 g, 12%): MS (ES) m/e 574.2 [M + H]+.

e) 4-[2-[[[l-[(Benzimidazol-2-yl)methyl]benzimidazol-2- yl]methyl]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, 0J8 mmol) and 5% Pd/C (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 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-0J% TFA) afforded the title compound: MS (ES) 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 77 (±)-4-rr2-r(Benzimidazol-2-yl)methvnmethylamino1- 1 -hydroxyethyll- 1.2- phenylenedioxydiacetic acid a) N-Cbz-Adrenalone

Adrenalone hydrochloride (28.6 g, 0J21 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, 0J21 mol) in toluene (18 mL) in another addition funnel were added at rates such that the reaction temperature remained between 5-10°C and that addition of both solutions was completed simultaneously. The resulting brown solution was stiπed at 5°C for 75 min, then was diluted with H2O (230 mL) and acidified with 1.0 N HCl (536 mL). A gummy precipitate formed initially, but solidified on trituration with a glass rod followed by stirring for 30 min. The pale green solid was filtered, stiπed briefly with H2O, filtered, stiπed briefly with EtOH, and filtered. The resulting solid was ground in a mortar with more EtOH, then was filtered and dried 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 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 min, the beige suspension was cooled to RT, and methyl bromoacetate (17.9 mL, 189 mmole) was added. The resulting suspension was stiπed at RT under argon for 16 hr, then was heated to 50°C. After 6 h, the mixture was cooled to RT and filtered, and the filtrate was concentrated to dryness. The residue was dissolved in CH2CI2 and washed sequentially with H2O and 5% K2CO3. Drying (Na2SO4) and concentration gave the title compound as an oil which solidified on standing (26.35 g, 82%): mp 56 - 59°C. 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 (2J g, 4.57 mmol) for benzyl 4-[2-[[[ 1 -[(benzimidazol-2-yl)methyl]benzimidazol-2- 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) Dimediyl (±) -[[2-[(benzimidazol-2-yl)methyl]methylamino]- 1 -hydroxyethyl]- 1,2-phenylenedioxy diacetate

Following die procedure of Example 76(d), except substituting dimethyl 4- [2-(methylamino)-l-hydroxyethyl]-l,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) (±) A-[[2-[(Benzimidazol-2-yl)methyl]methylamino]- 1 -hydroxyethyl]- 1 ,2- phenylenedioxydiacetic acid

A mixture of dimethyl (±)A-[[2-[(benzimidazol-2-yl)methyl]methylamino]- 1 -hydroxyethyl]- 1,2-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 stined at RT for 26 h. The 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 lyophilized to give the crude product (0.32 g). Preparative HPLC (Hamilton PRP-1® column, 10% CH3CN/H2O-0J% TFA) afforded the 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 78 4-r2-rr(Benzimidazol-2-yl)methyl1methylaminolacetvn-l,2-phenylenedioxydiacetic 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 (BOC)₂O (2.60 g, 11.92 mmole) in anhydrous CH2CI2 (15 mL) was stined at RT for 24 hr, then was concentrated. The residue was taken up in H2O, stined, and filtered to afford the title compound as a colorless solid (2.63 g, 100%): mp 71-72°C. b) 1 -BOC-2-(bromomethyl)benzimidazole

NBS (8.43 g, 47.4 mmol) and ABN (2J g, 12.8 mmol) were added to a solution of l-BOC-2-methylbenzimidazole (10.0 g, 43J mmol) in CC1 (120 mL) at reflux. After 21 h, the reaction was cooled and filtered. The filtrate was concentrated, and the resulting brown oil was chromatographed (silica gel, 15% EtOAc/hexanes) to afford the title compound: -*H NMR (400 MHz, CDC1₃) δ 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]-l,2-dihydroxybenzene

Following the procedure of Example 76(a), except substituting adrenalone hydrochloride (5.0 g, 23.0 mmol) for 4-[2-(methylamino)acetyl]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) Dimed yl 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 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- [2-(BOC-methylamino)acetyl]- 1 ,2-phenylenedioxydiacetate ( 1 J 1 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-[[( 1 -BOC-benzimidazol-2-yl)methyl]methylamino]acetyl]- 1 ,2- phenylenedioxydiacetate

Following the procedure of Example 76(d), except substituting dimethyl 4- [2-(methylamino)acetyl]-l,2-phenylenedioxydiacetate hydrochloride (0.24 g, 0.66 mmol) for benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride, 1-BOC- 2-(bromomethyl)benzimidazole (0.31 g, 0.99 mmol) for 2- (chloromethyl)benzimidazole, and using THF (5 mL) and CH2CI2 (5 mL) as solvents, the title compound was prepared (0J4 g, 38%): MS (ES) m/e 556.2 [M+H]+.

g) Dimethyl 4-[2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]- 1 ,2- phenylenedioxydiacetate bis(trifluoroacetate)

A mixture of dimethyl 4-[2-[[(l-BOC-benzimidazol-2- yl)methyl]methylamino]acetyl]-l,2-phenylenedioxydiacetate (0J3 g, 0.23 mmol) in TFA 4 mL) and CH2CI2 (12 mL) was stined at RT under argon for 20 min. Removal of the solvents on the rotavap gave the title compound (0J8 g, 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- [2-[[(benzimidazol-2-yl)methyl]methylamino]acetyl]- 1 ,2-phenylenedioxydiacetate bis(trifluoroacetate) (0J6 g, 0.23 mmol) for dimethyl (±)A-[[2-[(benzimidazol-2- yl)methyl]methylamino]- 1 -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: C, 42.62; H, 3.52; N, 6.30.

Example 79

Preparation of 3-rr4-rr[(BenzimidazoI-2-yl)methv1aminolcarbonyl1phenvnamino] propionic Acid a) ethyl 3-[4-(carboxy)phenylamino]propionate

A solution of 4-aminobenzoic acid (6.85 g, 0.05 mol) and ethyl acrylate (15 g, 0J5 mol) in acetic acid (40 mL) was heated to 100°C for 15 h. The solid which formed was filtered, washed with hexane and dried to give of the title compound

(7.5 g, 63%).

b) ethyl 3-[[4-[[[(benzimidazol-2-yl)methy]amino]carbonyl]phenyl]amino]propionic acid

The compound of Example 79(a)(0.3 g, 1.26 mmol) in thionyl chloride (10 mL) was heated to reflux for 10 min, cooled, concentrated in vacuo, and residual thionyl chloride was removed by addition of methylene chloride followed by concentration in vacuo. The residual oil was dissolved in methylene chloride and treated with 2-(aminomethyl)benzimidazole dihydrochloride hydrate (0.33 g, 1.5 mmol) and diisopropylethylamine (0.56 g, 4.3 mmol). The resulting mixture was stiπed overnight, washed with water and the organic phase was dried (sodium sulfate) and concentrated in vacuo. The resulting pale yellow solid was 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-[[[(benzimidazol-2-yl)methy]amino]carbonyl]phenyl]amino]propionic acid A solution of the compound of Example 79(b)(0.4 g, 1 J mmol) in methanol

(20 mL), water (2 mL) and 0.95N aqueous sodium hydroxide (2.5 mL) was stined and heated to 50°C for 2 h. The mixture was treated with trifluoroacetic acid (1 mL), concentrated in vacuo, and the residue was triturated with dichloromethane (4 x 100 mL). The resulting white solid was recrystallized from 20% acetonitrile/water-0J% trifluoroacetic acid to give the title compound. MS(ES) m/e 339 [M+H]+.

Example 80 Preparation of 4-r4-ri-(2-Methylbenzimidazoyl)piperidinvn]-piperidineacetic acid sodium salt a) Methyl 4-[4-[l-(t-butyloxycarbonyl)piperidinyl]]piperidineacetate A mixture of t-butyl l-(4,4'-bipiperidine)carboxylate (3J g, 10 mmol), prepared as described by Bondinell, et al. (WO 93/00095), methyl bromoacetate (1.7 g, 11 mmol), and triethylamine (2.3 g, 22 mmol) in DMF (15 mL) was heated ar 85 °C for 4 h. The reaction mixture was diluted with EtOAc (50 mL), partitioned between NaHCO₃ (5% soution, 100 mL) and extracted with EtOAc (2x50 mL). The combined organic extracts were washed with H2O, saturated NaCl soution, dried over MgSU4, and evaporated to give the titled compound (3.37 g, 99%). MS (ES) m e 341.2 [m+H]+ .

b) Methyl 4-[4-(l-piperidinyl)]piperidineacetate A mixture of Example 1(a) (3.37 g, 10 mmol) and 4M HCl in dioxane (20 mL) in CH2CI2 (25 mL) was stined at RT for 18 h. The resulting white suspension was filtered to give the titled compounds as the dihydrocjloride (3J g, 99%).

c) Methyl 4-[4-[-l-(2-Methylbenzimidazoyl)piperidinyl]]-piperidineacetate

To a stined solution of Example 1(b) (2 g, 6.4 mmol) and triethylamine (3.6 mL, 25.6 mmol) in CH2CI2 (50 mL) was added in portions a suspension of 2- chloromethylbenzimidazole (1J g, 6.6 mmol) in CH2CI2 (25 mL) at RT. After stining for 4 h, the reaction mixture was diluted with CH2CI2 (50 mL), partitioned between NaHCO3 (5% soution, 100 mL) and extracted with CH2CI2 (2x50 mL). The combined organic extractswere washed with H2O, a saturated NaCl soution, dried over MgSO4, and evaporated. The titled compound was purified by flash chromatograpy (Siθ2 6% MeOH/C^C ) to yield the titled compound (0.36 g, 16%). !H NMR (400MHz, CDCI3) δ 1.07 (m, 2H), 1.35 (m, 4H), 1.65 (t, J= 9J, 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)piperidinyl]]-piperidineacetic acid sodium salt To a stiπed solution of Example 1(c) (0.45 g, 1.2 mmol) in MeOH (15 mL) was added IN NaOH solution (8.5 mL, 8.5 mmol) at RT. After 18 h, the white suspension was filtered to white solid (0.2 g, mp > 250 °C, 43%,) as the titled compound. MS (ES) m/e 357.2 [m+H]+. ^lE NMR (400MHz, CD3OD) δ 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 O₂Na. 0.375 H₂O: 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: To a stiπed, cooled (O°C) mixture of benzyl alcohol (1.0 g, 5.392 mmol) and pyridine (0.47 g, 5.9312 mmol) in anhydrous methylene chloride (10 mL) was added 4-bromobutyryl chloride (0.58 g, 5.9312 mmol). After stiπing in 1 h at room temperature, the mixture was concentrated, taken up in H2O, extracted with EtOAc, washed with brine, dried over MgSO4₅ filtered and concentrated to give a colorless oil (1.38 g, 100%). 1H NMR (CDCI3, 300 MHz): δ 2.24 (m, 2H), 2.59 (t, J=5.7 Hz, 5. 2H), 3.48 (t, J=5.7 Hz, 2H), 5J4 (s, 2H), 7.38 (m, 5H).

lb) (S)-Benzyl 4-(N-t-Boc-tyrosine methyl ester )butyrate:

A mixture of Example la (1.57 g, 6J 177 mmol), N-t-Boc-tyrosine methyl ester

(1.80 g, 6J 177 mmol), and CsCO3 in dried DMF (10 mL) was stined at RT in 20 h. 0 The mixture was concentrated, taken up in H2O, extracted with EtOAc. The organic extracts were washed by brine, dried over MgSO4_t filtered and concentrated to give 2.30 g brown oil of the tide compound (79%). --H NMR (300 MHz, CDCI3) δ 1.47 (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), 5J2 (s, 2H), 6.78 (d, J= 8.3 Hz, 5 2H), 7.05 (d, J=8.3 Hz, 2H), 7.41 (m, 5H).

lc) (S)-Benzyl 4-(tyrosine methyl ester)butyrate:

To a stined solution of Examplelb (2.30 g, 4.8778 mmol) in dried CH2CI2 (10 mL) was added 12 mL of TFA. After sthring at RT in 3 h, the mixture was concentrated, 0 taken up in H2O, neutralized by 2.5N NaOH, extracted with CH2CI2, dried over

MgSO4, filtered, and concentrated to give a brown oil (1.60 g, 88%). IH NMR (300 MHz, CDC13) δ 2J5 (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), 5J5 (s, 2H), 6.80 (d, J=8.3 Hz, 2H), 7.10 (d, j=8.3 Hz, 2H), 7.35 (m, 5 5H).

Id) (S)-Benzyl 4-[(N-butylsulfonyl) tyrosine methyl ester]butyrate: To a stined mixture of Example lc (1.60 g, 4.3079 mmol) and pyridine (0.41 g, 5J695 mmol) in dried CH2CI2 (15 mL) was added n-butylsulfonyl chloride (0.81 g, 0 5J695 mmol). After stirring at RT in 2-h, the mixture was concentrated, taken up in H2O, extracted with EtOAc. The organic extracts were washed by 2N HCl, saturated NaHCO3, brine, dried over MgSO4_. filtered, and concentrated to give a brown oil (2.01 g, 95%). IH NMR (300 MHz, CDC13) δ 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), 3J0 (dd, J=13.8 Hz, 7.3 Hz, IH), 3.77 (s, 3H), 3.93 (t, J=5.7 Hz, 2H), 4.30 (m, IH), 4.70 (d, J=7.3 Hz, IH), 5J2 (s, 2H), 6.80 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.35 (m, 5H).

le) (S)A-[(N-butylsulfonyl)tyrosine methyl ester]butyric acid:

A solution of Example Id (0.781 g, 1.589 mmol) in MeOH (10 mL) was hydrogenated at 50 PSI in 10% Pd/C (0.50 g) in 3 h. The catalyst was filtered through celite. The filtrate was concentrated to give a white solid (0.59 g, 93%). IH NMR (300 MHz, CDC13) δ 0.89 (t, J=7.3 Hz, 3H), 1.35 (m, 2H), 1.65 (m, 2H), 2J0 (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, IH), 4.90 (d, J=7.3 Hz, IH), 6.90 (d, J=8.3 Hz, 2H), 7J0 (d, J=8.3 Hz, 2H).

If) (S)-N-butylsulfonyl-4-(3-(benzimidazol-2-yl)propyl)tyrosine methyl ester:

To a stined, cooled (0°C) mixture of Example le (0.595 g, 1.4823 mmol) and Et3N

(0J6 g, 1.5565 mmol) in dried THF (7 mL) was added isobutylchloroformate (0.212 g, 1.5565 mmol). After stirring at O^C in 1 h, o-phenylenediamine (0J6 g, 14823 mmol) and 1 mL of HOAc was added. The reaction mixture was heated at reflux overnight. The mixture was cooled, diluted with EtOAc, washed by H2O, saturated NaHCO3, brine, dried over MgSO4, concentrated and purified by flash column chromatograph (5% MeOH/CH2Cl2) to give a white foam (0.487 g, 69%). 1H NMR (300 MHz, CDCI3) δ 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), 3J0 (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 stiπed solution of Example If (0.487 g, 1.0285 mmol) in MeOH (5 mL) was added LiOH.H2θ (0.09 g, 2.0571 mmol) in 24 h. The mixture was concentrated, diluted in H2O, neutralized with 2.0N HCl. The off white solid was filtered, triturated in hot EtOH to give the title compound as a white solid (0.377 g, 80%, Mp: >230 °C). ^lH NMR (300 MHz, DMSO-d6) δ 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), 4J0 (t, J=5.7 Hz, 2H), 6.85 (d, 8.3 Hz, 2H), 7J0 (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, 1634, 1612, 1512, 1466, 1384, 1245, 1148, 1110. MS (ESI, M+H) 460.2. Anal. Calc. for C23H29N3O5S: C, 60.11; H, 6.36; N, 9J4; Found: C.60.01; H, 6.34; N, 9.01.

Example 82 Preparation of 4-r2-rr[l-r(Benzimidazol-2-yl)methyl1benzimidazol-2- yllmethyllmethylaminolacetyllphenoxyacetic 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- (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 hr, the reaction was warmed to RT and stiπed for 1.5 hr. More 1.0 N NaOH (25 mL, 25 mmol) was added, and the reaction was stined for an additional 0.5 h at RT, then was evaporated on the rotavap. The residue was diluted with EtOAc (80 mL), and the mixture was acidified to pH 2 using 1.0 M NaHSO4. The resulting mixture was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with H2O (30 mL) and dried (Na2SO4). Filtration and concentration gave the title compound (6.49 g, 99%): ^lK NMR (250 MHz, CDCI3) δ 6.70-8.05 (m, 4 H), 4.53 (s, 2H), 2.98 (s, 3H), 1.50 (s, 9H). 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 stined at reflux under argon for lh. The mixture was cooled to RT and benzyl bromoacetate (5.23 g, 22.8 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 brine (50 mL). Drying (Na2SO4), concentration, and silica gel flash chromatography (1:3 EtOAc/hexanes) yielded the title compound (7.28 g, 93%): -1H NMR (250 MHz, CDCI3) δ 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 hydrochloride

A mixture of benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate (7.26 g, 17.57 mmol) and 4 M HCl in 1,4-dioxane (150 mL) was stined for 1 h at RT.

Evaporation on the rotavap and trituration with Et2θ afforded the title compound (5.93 g, 97%) as a white powder: 1H NMR (250 MHz, CD3OD) δ 7.05-8.00 (m, 9 H), 5.23 (s, 2H), 4.88 (s, 2H), 4.65 (s, 2H), 2.80 (s, 3H).

Et3N (0.28 g, 2.78 mmol) was added slowly to a mixture of benzyl 4-[2- (methylamino)acetyl]phenoxyacetate hydrochloride (0.39 g, 1.11 mmol), 2- (chloromethyl)benzimidazole (0.24 g, 1.45 mmol), CH3CN (20 mL), and CH2CI2 (5 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 sequentially with 5% NaHCO3 (2 x 20 mL) and brine (20 mL). Drying (MgSO4), concentration, and silica gel flash chromatography (step gradient, 7 - 15% MeOH/CH2θ2) yielded the title compound (0.08 g, 12%) as an off-white powder: MS (ES) m/e 574.2 [M + H]+. e) 4-[2-[[[l-[(Benzimidazol-2-yl)methyl]benzimidazol-2- yl]methyl]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, 0J8 mmol) and 5% Pd/C (0J 1 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 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 containing 0.1% TFA) afforded the title compound: MS (ES) 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 (±)A-rr2-r(Benzimidazol-2-yl)methyllmethylamino]-l-hydroxyethyl]-l,2- phenylenedioxydiacetic acid a) N-Cbz-Adrenalone

Adrenalone hydrochloride (28.6 g, 0J21 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 mL, 0J21 mole) in toluene (18 mL) in another addition funnel were added at rates such that the reaction temperature remained between 5 - 10°C and that addition of both solutions was completed simultaneously. The resulting brown solution was stiπed at 5°C for 75 min, then was diluted with H2O (230 mL) and acidified with 1.0 N HCl (536 mL). A gummy precipitate formed initially, but solidified on trituration with a glass rod followed by stining for 30 min. The pale green solid was filtered, stined briefly with H2O (180 mL), filtered, stined briefly with EtOH (135 mL), and filtered. The resulting solid was ground in a mortar with more EtOH (135 mL), then was filtered and dried in vacuum to afford the title compound (28.6 g, 75%): mp l83 - 186°C. 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 min, the beige suspension was cooled to RT, and methyl bromoacetate (17.9 mL, 189 mmole) was added. The resulting suspension was stined 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 (Na2SO4) and concentration gave the title compound (26.35 g, 82%) as an oil which solidified on standing: mp 56 - 59°C.

c) Dimethyl 4- [2-(methylamino)- 1 -hydroxyethyl] - 1 ,2-phenylenedioxydiacetate

Following the procedure of Example 82(e), except substituting dimethyl 4- [2-(Cbz-methylamino)acetyl]-l,2-phenylenedioxydiacetate (2J g, 4.57 mmol) for benzyl 4-[2-[[[l-[(benzimidazol-2-yl)methyl]benzimidazol-2- 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 (±)A-[[2-[(benzimidazol-2-yl)methyl]methylamino]-l-hydroxyethyl]- 1 ,2-phenylenedioxydiacetate

Following the procedure of Example 82(d), except substituting dimethyl 4- [2-(methylamino)-l -hydroxyethyl]- 1,2-phenylenedioxydiacetate (1.37 g, 4.20 mmol) for benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride, the title compound (0.25g, 13 %) was prepared: MS (ES) m/e 458.2 [M + H]+.

e) (±) -[[2-[(Benzimidazol-2-yl)methyl]methylamino]- 1 -hydroxyethyl]- 1 ,2- phenylenedioxydiacetic acid

A mixture of dimethyl (±)A-[[2-[(benzimidazol-2-yl)methyl]methylamino]- 1 -hydroxyethyl]- 1,2-ρhenylenedioxydiacetate (0.23 g, 0.5 mmol), THF (10 mL), H2O (10 mL), and 1.0 N LiOH (2.0 mL, 2.0 mmol) was stined at RT for 26 h. The 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 lyophilized to give the crude product (0.32 g). Preparative HPLC (Hamilton PRP-1® column, 10% CH3CN/H2O containing 0.1% TFA) afforded the 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(Benzimidazol-2-yl)methyllmethylaminolacetvn-l,2-phenylenedioxydiacetic add 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) in anhydrous CH2CI2 (15 mL) was stined at RT for 24 hr, then was concentrated. The residue was taken up in H2O, stined, and filtered to afford the title compound (2.63 g, 100%) as a colorless solid: mp 71 - 72°C.

b) 1 -BOC-2-(bromomethyl)benzimidazole

NBS (8.43 g, 47.4 mmole) and AIBN (2.1 g, 12.8 mmole) were added to a solution of l-BOC-2-methylbenzimidazole (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) δ 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 adrenalone hydrochloride (5.0 g, 23.0 mmol) for 4-[2-(methylamino)acetyl]phenol hydrochloride, the title compound (1.2 g, 19%) was prepared following silica gel flash chromatography (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 82(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 bromoacetate, the title compound (1.11 g, 81%) was prepared: MS (ES) m/e 426.2 [M + H]+.

Following the procedure of Example 82(c), except substituting dimethyl 4- [2-(BOC-methylamino)acetyl]-l,2-phenylenedioxydiacetate (1J 1 g, 2.6 mmol) for benzyl 4-[2-(BOC-methylamino)acetyl]phenoxyacetate, the title compound(l.l g, quantitative) was prepared: MS (ES) m/e 326.0 [M + H]+.

Following the procedure of Example 82(d), except substituting dimethyl 4- [2-(methylamino)acetyl]-l,2-phenylenedioxydiacetate hydrochloride (0.24 g, 0.66 mmol) for benzyl 4-[2-(methylamino)acetyl]phenoxyacetate hydrochloride, 1-BOC- 2-(bromomethyl)benzimidazole (0.31 g, 0.99 mmol) for 2- (chloromethyl)benzimidazole, and using THF (5 mL) and CH2CI2 (5 mL) as solvents, the title compound (0J4 g, 38%) was prepared: MS (ES) m/e 556.2 [M + H]+.

A mixture of dimethyl 4-[2-[[(l-BOC-benzimidazol-2- yl)methyl]methylamino]-acetyl]-l,2-phenylenedioxydiacetate (0J3 g, 0.23 mmol) in TFA 4 mL) and CH2CI2 (12 mL) was stiπed at RT under argon for 20 min. Removal of the solvents on the rotavap gave the title compound (0J8 g, 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 82(e), except substituting dimethyl 4- [2- [ [(benzimidazol-2-yl)methyl] methylamino] acety 1] - 1 ,2-pheny lenedioxy diacetate bis(trifluoroacetate) (0J6 g, 0.23 mmol) for dimethyl (±)A-[[2-[(benzimidazol-2- yl)methyl]methylamino]- 1 -hydroxyethyl]- 1 ,2-phenylenedioxydiacetate, the title compound (0.08 g, 80%) was prepared: 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: C, 42.62; H, 3.52; N, 6.30.

Example 85 Preparation of 3-rr4-rrr(Benzimidazol-2-yl)methv1amino1carbonyl]phenyllamino1 propionic Acid a) ethyl 3-[4-(carboxy)phenylamino]propionate A solution of 4-aminobenzoic acid (6.85 g, 0.05 mol) and ethyl acrylate (15 g, 0J5 mol) in acetic acid (40 mL) was heated to 100°C for 15 h. The solid which formed was filtered, washed with hexane and dried to give the title compound (7.5 g, 63%).

The compound of Example 85(a)(0.3 g, 1.26 mmol) in thionyl chloride (10 mL) was heated to reflux for 10 min, cooled, concentrated in vacuo, and residual thionyl chloride was removed by addition of methylene chloride followed by concentration in vacuo. The residual oil was dissolved in methylene chloride and treated with 2-(aminomethyl)benzimidazole dihydrochloride hydrate (0.33 g, 1.5 mmol) and diisopropylethylamine (0.56 g, 4.3 mmol). The resulting mixture was stiπed overnight, washed with water and the organic phase was dried (sodium sulfate) and concentrated in vacuo. The resulting pale yellow solid was 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-[[[(benzimidazol-2-yl)methy]amino]carbonyl]phenyl]amino]propionic acid A solution of the compound of Example 85(b)(0.4 g, 1 J mmol) in methanol (20 mL), water (2 mL) and 0.95N aqueous sodium hydroxide (2.5 mL) was stined and heated to 50°C for 2 h. The mixture was treated with trifluoroacetic acid (1 mL), concentrated in vacuo, and the residue was triturated with dichloromethane (4 x 100 mL). The resulting white solid was recrystallized from 20% acetonitrile/water-0J% trifluoroacetic acid to give the title compound. MS(ES) m e 339 [M+H]+.

Example 86-92 Following the general procedures of Examples 1-55, the following compounds are parpared:

Example

The above description fully discloses how to make and use the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprises the state of the art and are incoφorated herein by reference as though fully set forth. Example 93

Parenteral Dosage Unit Composition

A preparation which contains 20 mg of the compound of Example 1 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 mL of distilled water. The solution is filtered under sterile conditions 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 unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.

Example 94 Oral Dosage Unit Composition 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, dried, mixed witii 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 described herein, but encompasses all modifications within die scope of die claims which follow.

Claims

What is claimed is:

1. A compound according to formula (I) or (II) or (III) or (IV) or (V):

(I) or (II) or (III) or

(V)

A is a fibrinogen receptor antagonist template;

U and V are absent or CO, CR⁸2, C(=CR⁸2), S(O)k, O, NR⁸, CROR⁸,

CR^g(ORk)CR⁸2, CR^s2CR^J(OR ), C(O)CR⁸2, CR⁸2C(O), CONR, NRCO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR⁸, NR^SC(S), S(O)2NR⁸, NR⁸S(O)2

N=N, NR⁸NR⁸, NR'CR⁸2, NR⁸CR⁸ ₂, CR^E2θ, OCR⁸2, C≡C or CR⁸=CR⁸; G is NR^e, S or O;

R^E is H, Cι_6alkyl, Het-Cθ-6alky C3-7cycloalkyl-Cθ-6alkyl or Ar- Cθ-6alkyl;

R^k is R^g, -C(O)R⁸, or -C(O)OR^f; R is is H, Ci-6alkyl, Het-Q)-6alkyl, C3-7cycloalkyl- )-6alkyl, Ar- Cθ-6*dkyl, or

Ci-6alkyl substituted by one to three groups chosed from halogen, CN, NR^g ₂, OR⁸, SR⁸, CO₂R⁸, and CON(R⁸)₂;

R^f is H, C,_.6alkyl or Ar-C,_.6alkyl; R^e is H, C i -6alkyl, Ar-C i -6alkyl, Het-C i -6alkyl, C3-7cycloalkyl-C i -όalkyl, or (CH₂)_kCO₂R⁸; k is 0, 1 or 2; q is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2;

R^D and R^c are independently selected from H, Cι_6alkyl, Ar-Cθ-6-dkyl, Het-

Co-6alkyl, or C3-6cycloalkyl-Cθ-6alkyl, halogen, CF3, OR^f, S(O)_kR^f, COR^f,

NO2, N(R^f)2, CO(NR^f)2, CH2N(R^f)2, or R^b and R^c 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, CMalkyl, OR^f, S(O)kR^f, COR^f, CO₂R^f OH, NO2,

N(R^f)₂, CO(NR^f)2, and CH2N(R^f)2; or methylenedioxy; or a pharmaceutically acceptable salt thereof, with the proviso that: (i) when A is 1 ,2,4,5-tetrahydro-3-oxo -(2-phenylethyl)- 1 H- 1 ,4- benzodiazepine-2-acetic acid, then W is not -(CH₂)₂₃NHCO- attached at die 1- position of an imidazole ring; and

(ii) when A is 1 ,2 ,4,5-tetrahydro-3-oxo -(2-phenylethyl)- 1 H- 1 ,4- benzodiazepine-2-acetic acid, then W is not -(CH₂)₂ NHCO- attached at the 4(5)- position of an imidazole ring.

2. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein:

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-Cι_ alkyl, Q-C2-4alkenyl, Q-C2-₄alkynyl, optionally substituted by one or more of =O, R^{1 1} or R⁷;

R* is H, Q-Cι_6alkyl, Q-Ci.βoxoalkyl, Q-C2-6alkenyl, Q-C3-4θxoalkenyl, Q-C3_4θxoalkynyl, Q-C2-4alkynyl, C3_6cycloalkyl, Ar or Het, optionally substituted by one or more of R¹ -^■ ;

Q is H, C3-6cycloalkyl, Het or Ar; R⁷ is -COR⁸, -COCR'₂R⁹, -C(S)R⁸, -S(O)_mOR, -S(O)_mNR'R", -PO(OR'),

-PO(OR')2, -B(OR')2, -NO₂ and Tet;

R⁸ is -OR', -NR'R", -NR'SO₂R', -NR'OR', -OCR'₂C(O)OR', -OCR'₂OC(O)- R', -OCR'₂C(O)NR'2, CF₃ or AA;

R9 is -OR', -CN, -S(O)_rR\ S(O)_mNR'₂, -C(O)R' C(O)NR'₂ or -CO R'; R¹1 is H, halo, -OR¹², -CN, -NR'R¹², -NO₂, -CF3, CF₃S(O)_r, -CO₂R',

-CONR'2, Q-C₀-6alkyl-, Q-Cι_₆oxoalkyl-, Q-C₂-6alkenyl-, Q-C₂-6alkynyl-, Q-Co-6alkyloxy-, Q-Co-6alkylamino- or Q- )-6alkyl-S(O)_r-;

R¹² is R', -C(O)R, -C(O)NR'₂, -C(O)OR 5, -S(O)_mR' or S(O)_mNR'₂; R¹³ is R, -CF₃, -SR, or -OR'; R14 is R, C(O)R, CN, NO₂, SO₂R' or C(O)OR¹⁵;

R¹⁵ is H, Cι_6alkyl or Ar-Co-4alkyl; R' is H, Cj-βalkyl, C3.7cycloaIkyl-Co-₄alkyl or Ar-Co^alkyl;

R" is R', -C(O)R or -C(O)OR¹⁵;

R"Js R" or AA2;

AA1 is an amino acid attached through its amino group and having its carboxyl group optionally protected, and AA2 is an amino acid attached through its carboxyl group, and having its amino group optionally protected; m is 1 or 2; n is 0 to 3; p is 0 or 1 ; and t is 0 to 2; or pharmaceutically acceptable salts thereof, with the proviso that: (i) when A is 1 ,2 ,4,5-tetrahydro-3-oxo -(2-phenylethyl)- 1 H- 1 ,4- benzodiazepine-2-acetic acid, then W is not -(CH₂)₂₃NHCO- attached at the 1- position of an imidazole ring; and (ii) when A is l,2,4,5-tetrahydro-3-oxoA-(2-phenylethyl)-lH-l,4- benzodiazepine-2-acetic acid, then W is not -(CH₂)₂ NHCO- attached at die 4(5)- position of an imidazole ring.

3. A compound according to claim 2 wherein: A¹ is CRϊR^1', CR¹, NR¹, N, O or S(O)_x;

A² is CR²R^2', CR², NR²;

A³ is CR³R^3', CR³, NR³, N, O or S(O)_x;

A⁴ is CR⁴R^4', CR⁴, NR⁴, or N;

A5 is CR⁵R⁵', CR⁵, NR5, N, O or S(O)_x; Dϊ-I^ are CH or N;

R¹ and R^1' are R* or R, or together are =O;

R² and R^2' are R*, R or =O;

R³ and R^3' are R*, R or =O;

R⁴ and R^4' are R*, R or =O; R5 and R^5' are R*, R or =O; and x is 0, 1 or 2.

4. A compound according to claim 2 wherein:

A¹ is CRJR¹', CR¹, NR¹, N, O or S; A² is CR²R^2', NR² or CR²; A³ is CR³R^3'; A⁴ is CR⁴R^4', CR⁴, NR⁴, or N; A⁵ is CR⁵R^5', CR⁵, NR⁵, N, O; D¹ and D⁴ are CH; D² or D³ is CH⁶; R² or R⁴ are R; R³,R^3' and R⁵,R^5' are =O or R*,H.

5. A compound according to claim 2 wherein:

A¹ is CHR¹, CR¹, NR", N or S; A² is CR² or CR R^2'; A³ is CR³R³'; A⁴ is CR⁴R^4' or NR⁴; A⁵ is CR⁵R⁵' D¹- D⁴ are CH.

6. A compound according to claim 2 wherein:

A¹ is CR¹, A² is CR², A³ is C=O, A⁴ is NR⁴ and A⁵ are CHR⁵.

7. A compound according to claim 2 wherein:

A¹ is NR¹, A² is CHCR², A³ is CR³R^3', A⁴ is NR⁴, and A⁵ are C=O.

8. A compound according to claim 2 wherein:

A¹ and A⁴ are C=O, A² is NR², A³ is CHR^3' and A⁵ is NR⁵.

9. A compound according to claim 2 wherein:

A¹ is NR¹, A² is CHR², A³ is C=O, A⁴ is NR' and A⁵ is CHR⁵*

10. A compound according to claim 2 wherein:

11. A compound according to claim 2 wherein:

12. A compound according to claim 11 wherein:

R¹ is H or C_Malkyl; R²,R² are H,-CH,CO₂H; and R⁵R⁵ are H,H.

13. A compound according to claim 2 wherein:

(2S)-7-[[[N-(2-benzimidazolyl)medιyl-N-methyl]amino]carbonyl]-4-methyl-3-oxo- 2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid;

7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(4-Azabenzimidazolyl)methyl]methylamino]carbonyl]A-(2- methoxyethyl)-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]A-(2-methoxyethyl)-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid;

7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-methyl-3-oxo-

2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxoA-methyl-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; 7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl)-

2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; 7-[[[N-(2-benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]A-methyl-3- oxo-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonylA-[2-(3,4- methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4- benzodiazepine-2-acetic acid; and (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-3-oxoA-(2- phenylethyl)-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid. (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- lH-l,4-benzodiazepine-2-acetic acid;

(±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxoA-(2-phenylethyl)-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-(2-benzothiazolyl)methyl-N-methyl]amino]carbonyl]A-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-(2-benzoxazolyl)methyl-N-methyl]amino]carbonyl]A-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-[2-(5(6)-chlorobenzimidazolyl)methyl]-N-methyl]amino] carbonyl]A- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-indolyl)methyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2-acetic acid; (2S)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (2R)-7-[[[(2-Benzimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-9-chloroA-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5- tetrahydro- lH-2-benzazepineA-acetic acid;

(±)-8-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]-2-methyl-3-oxo-

2,3,4,5-tetrahydro- lH-2-benzazepine-4-acetic acid; (±)-7-[[[N-(2-benzimidazolyl)medιyl-N-methyl]amino]carbonyl]-3-oxoA-(2- phenylethyl)-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]methyl]- 1 ,4-dimethyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-(2-benzimidazolyl)methyl-N-methyl]amino]carbonyl]A-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(2-benzimidazolyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid;

(±)-7-[[(2-benzimidazolyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2-acetic acid; (2S)-7-[[[N-(2-benzimidazolyl)medιyl-N-methyl]amino]carbonyl]A-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)A-Methyl-7-[[[N-(2-(l-methyl)benzimidazolyl)methyl-N-methyl]amino] carbonyl]-3-oxo-2,3,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-(5(6)-methoxy)benzimidazolyl)methyl]amino]carbonyl]A-methyl-3-oxo-

2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-[2-(4-azabenzimidazolyl)]medιyl-N-methyl]amino]carbonyl]A-methyl-3- oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[N-[2-(5(6)-Azabenzimidazolyl)]methyl-N-methyl]amino] carbonyl]-4- methyl-3-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5-tetrahydro-

1 H- 1 ,4-benzodiazepine-2-acetate; (±)-7-[[[2-(benzimidazolyl)methyl]methylamino]carbonyl]A-(2-methoxyethyl)-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(4-Azabenzimidazolyl)methyl]methylamino]carbonyl]A-(2- methoxyethyl)-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(l-methylindolyl)methyl]methylamino]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(l-methylindolyl)methyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; [[[(2RS-indolinyl)methyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2S-acetic acid;

(±)-7-[[[(2-imidazolyl)medιyl]amino]carbonyl]-3-oxoA-(2-phenylethyl)-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]amino]medιyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]- 1 ,4-dimethyl-3-oxo-2,3 ,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (2S)-7-[[[N-butyl-N-benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxoA-methyl- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid;

7-[[[N-(2-benzimidazolyl)methyl-N-(2-phenylethyl)]amino]carbonyl]A-methyl-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; 7-[[[N-(2-benzimidazolyl)methyl-N-carboxymethyl]amino]carbonyl]-4-methyl-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; 7-[[[N-(2-benzimidazolyl)methyl-N-cyclohexyl]amino]carbonyl]A-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(5-nitrobenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(5-aminobenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[2-( 1 ,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl)carbonyl] A-methyl-3-oxo-

2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; 7-[[[2-(5,6-methylendioxybenzimidazolyl)methyl]methylamino] carbonyl]-4- methyl-3-oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; 7-[[[2-(4,6-diazabenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3-oxo- 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid;

7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3-oxo-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; [l-[2R-(2-benzimidazolyl)pynolidinyl]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-

1 H- 1 ,4-benzodiazepine-2S-acetic acid; [ 1 -[2S-(2-benzimidazolyl)pynolidinyl]carbonyl] A-methyl-3-oxo-2,3 ,4,5-tetrahydro-

1 H- 1 ,4-benzodiazepine-2S-acetic acid; (±)-7-[[[2-(4-azabenzimidazolyl)methyl]methylamino]carbonyl]-4-isopropyl-3-oxo-

2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; 7-[[[2-(4-aza-5-methylbenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3- oxo-2,3,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid;

7-[[[2-(5,6-dimethoxybenzimidazolyl)methyl]methylamino]carbonyl]A-methyl-3- oxo-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-8-[[2-(2-benzimidazolyl)acetyl]amino]-2-methyl-3-oxo-2,3,4,5-tetrahydro-lH-2- benzazepineA-acetic acid; (±)-8-[[[(2-benzimidazolyl)methyl]medιylamino]carbonyl]A-memyl-3-oxo-2,3,4,5- tetrahydro- 1 H-2-benzazepine A-acetic acid; 7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-4-(2-phenylethyl)-

2,3,4,5-tetrahydro-lH-l,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(benzimidazolyl)methyl]amino]carbonyl-4-[2-(3,4- methylenedioxyphenyl)ethyl]-3-oxo-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine-2-acetic acid; (±)-⁷-[[[(4(5)-imidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (±)-[[[4-(2-phenylimidazolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (±)-7-[[[2-(3-indolyl)ethyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5-tetrahydro-lH- l,4-benzodiazepine-2-acetic acid; 7-[[[2-(4-phenylimidazolyl)methyl]amino]carbonyl]A-methyl-3-oxo-2,3,4,5- tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid; (+/-)-2,3,4,5-Tetrahydro-7-[[[benzimidazol-2-yl)methyl]methylamino]carbonyl]-4- (3,3-dimethylbutyl)-3-oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acid;

(-)-7-[[[6-Trifluoromethylbenzimidazoyl-2-ylmethyl]aminomethyl]carbonyl]-

2,3,4,5-tetrahydroA-methyl-3-oxo-benzodiazepine-2-acetic acid; (-)-7-[[[4,7-Dimethoxybenzimidazoyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5- tetrahydro-4-methyl-3-oxo-benzodiazepine-2-acetic acid; (+/-)-2,3,4,5-Tetrahydro-7-[[[(benzimidazol-2-yl)methylamino]carbonyl]-4-(3,3- dimetiιylbutyl)-3-oxo-lH-l,4-benzodiazepine-2-acetic acid; (-)-7-[[[7-Methylbenzimidazol-2-ylmethyl]methylamino]carbonyl]-2,3,4,5- tetrahydro A-methyl-3-oxo- 1 ,4-benzodiazepine-2-acetic acid; (2S)-[[[N-aminobutyl-N-(benzimidazlo-2-yl)methyl]amino]carbonyl]-3-oxo-4- methyl-2,3 ,4,5-tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acidbis(trifluoroacetate)salt; (2S)-[[[N-cyanomethyl-N-(benzimidazlo-2-yl)methyl]amino]carbonyl]-3-oxo-4- methyl-2,3 ,4,5-tetrahydro- IH- 1 ,4-benzodiazepine-2-acetic acid dihydrochloride salt; 2,3,4,5-Tetrahydro-7-[[[(benzimidazol-2-yl)]methyl]amino]carbonyl]A-(4- phthalimidobutyl)-3-oxo- 1 ,4-benzodiazepine-2-acetic acid; (-)-7-[[[Imidazo[4,5B]A,6-dimethylpyridyl-2-ylmethyl]aminomethyl]carbonyl]-

2,3,4,5-tetrahydroA-methyl-3-oxo-benzodiazepine-2-acetic acid trifluoroacetate salt; (+/-)-7-[[(2-Benzimidazol-2-ylmethyl)-N-methylamino]carbonyl]-2,3,4,5- tetrahydro-3-oxoA-[2-(3',4'-methylenedioxyphenyl)ethyl]- 1 H- 1 ,4- benzodiazepine-2-acetic acid; (+/-)-2,3,4,5-Tetrahydro-7-[[[(Benzimidazol-2-yl)methyl]amino]carbonyl]A-(2- methoxyethyl)-3-oxo-lH-l,4-benzodiazepine-2-acetic acid;

7-[[2-[l-Methylbenzimidazolyl]benzimidazolylmethylamino]carbonyl]-2,3,4,5- tetrahydro A-methyl-3-oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acid; 7-[[[N-Cyclohexyl-N-(benzimidazol-2-yl)methyl]amino]carbonyl]-3-oxo-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; 7-[[[2-Bis-(Benzimidazolylmethyl)aminocarbonyl]-2,3,4,5-tetrahydro-4-methyl-3- oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (+/-)-2,3,4,5-Tetrahydro-7-[[[imidazo[4,5-B]pyrid-2- yl]methyl]methylamino]carbonyl]A-(3,3-dimethylbutyl)-3-oxo-lH-l,4- benzodiazepine-2-acetic acid; (+/-)-7-[[(2-Benzimidazol-2-ylmethyl)-N-methylamino]carbonyl-2,3,4,5-tetrahydro-

3-oxo A-(2',2',2'-trifluoroethyl)- 1 H- 1 ,4-benzodaizepine-2-acetic acid; (+/-)-7-[[(2-Benzimidazolyl)acetyl]amino]-5-oxoA-(2-phenyledιyl)-2,3,4,5- tetrahydro- 1 H- 1 ,4-benzodiazepine-2-acetic acid; (+/-)-7-[[(2-Benzimidazol-2-ylmethyl)amino]carbonyl]-2,3,4,5-tetrahydro-3-oxo-4- (2',2',2'-trifluoroethyl)- 1 H- 1 ,4-benzodiazepine-2-acetic acid;

(-)-7-[[[5,6-Difluorobenzimidazoyl-2-ylmethyl]aminomethyl]carbonyl]-2,3,4,5- tetrahydroA-methyl-3-oxo-l,4-benzodiazepine-2-acetic acid; and (+/-)-7-[[Bis-(Benzimidazol-2-ylmethyl)amino]carbonyl]-2,3,4,5-tetrahydroA- phenylethyl-3-oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acidtris(trifluoroacetate)salt.

14. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein:

R2 and R²2 independently are H or -Z-CO2Ror Z-CON(R^f)2 with the proviso that one of A 1 or A2 is -Z-CO2R^f or Z-CON(Rf)2;

Z is -CH2-, -O(CH2)q-, -NR^f(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, Cι_4alkyl, Cι_4alkoxy, Ci^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f, S(O)kR^f, COR^f, NO2, N(R^f)2, CO(NR^f)2, CH2N(R^f)2, methylenedioxy or Z-CO- Rf.

15. A compound according to claim 14 wherein A is

16. A compound according to claim 15 which is: 4-[2-[[[l-[(Benzinύdazol-2-yl)methyl]benzimidazol-2- yl]methyl]methylamino]acetyl] phenoxyacetic acid;

(±)A-[[2-[(Benzimidazol-2-yl)methyl]methylamino]-l-hydroxyethyl]-l,2-phenylene dioxydiacetic acid; 4-[2-[[(Benzimidazol-2-yl)methyl]methylamino]acetyl]-l,2-phenylenedioxydiacetic acid; or 3-[[4-[[[(Benzimidazol-2-yl)methy]amino]carbonyl]phenyl]amino]propionic acid.

17. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein:

R6 is aryl, Cj-ioalkyl, C3_6cycloalkyl, C4_ιoaralkyl, Cι_iQ- koxyalkyl, Cι_ιo- karyl,

Cι_ιoalkylamino,

C4_ιoa^ralkylamino, Cj.joalkanoylamino, C4_ιo^aralkanoylamino, Cι_ιo*-dkanoyl, C4_ιoaralkanoyl, or Cι_ιocarboxyalkyl; and

Y is H, CMalkyl, C^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f, S(O)_kR^f, CORf, NO₂, N(Rf)₂, CO(NRf)₂, CH₂N(R*^f)₂, methylenedioxy, CN, CO₂R^f , OC(O)R^f , or NHC(O)R^f .

18. A compound according to claim 17 wherein ϊtβ is aryl, Cι_ιoalkyl, C3_6cycloalkyl, or C4_ιo^ari-dkyl.

19. A compound according to claim 18 which is (S)-(2-butylsulfonyl-amino)-3-[4- (3-benzimidazo-2-yl)propyloxy)]phenylpropionic acid or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein: M' is CH or N;

M² is CH or N, with the proviso that when M¹ is CH, M² is N; and G' is N or N^®R".

21. A compound according to claim 20 wherein G is N and D¹ is N.

22. A compound according to claim 21 wherein the fibrinogen receptor antagonist template A is

wherein: M¹ is CH or N; and

M² is CH or N, with the proviso that when M¹ is CH, M² is N.

23. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein:

M' is CH or N;

Y is H, CMalkyl, C^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f,

S(O)_kR^f, COR^f, NO₂, N(R^f)₂, CO(NRf)₂, CH₂N(Rf)₂, methylenedioxy, CN, CO₂R^f, OC(O)Rf, or NHC(O)Rf ; D³ is CH₂ or C=O; and R^h is (CH₂)_qCO₂Rf.

24. A method according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein:

Y is H, CMalkyl, Cj^alkoxy, Cj^alkoxycarbonyl, F, Cl, Br, I, CF3, ORf,

S(O)_kR^f, COR^f, NO₂, N(Rf)₂, CO(NRf)₂, CH₂N(R^f)₂, methylenedioxy, CN, CO₂R^f, OC(O)R^f, or NHC(O)R^f; and

R^h is (CH₂)_qCO₂R^f.

25. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein:

Y is H, CMalkyl, C^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f, S(O)_kRf COR^f, NO₂, N(Rf)₂, CO(NR^f)₂, CH₂N(Rf)₂, methylenedioxy, CN, CO₂R^f, OC(O)R^f, or NHC(O)R^f; R^h is (CH₂)„CO.R^f; and

26. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein:

L* is -C(O)NR⁸-(CH₂)-, -C(O)-(CH₂) -, NR⁸-(CH₂) -, -O-(CH ^₂)'i -, or

S(O)ACHJ

27. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

ccy-t^o

28. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

wherein:

Y is H, CMalkyl, C^alkoxy, C^alkoxycarbonyl, F, Cl, Br, I, CF3, OR^f, S(O)_kRf, COR^f 1 , NO₂, N(R^f)₂, CO(NR )₂, CH₂N(R^f)₂, methylenedioxy, CN, CO₂R^f, OC(O)R^f, or NHC(O)R^f.

29. A compound according to claim 1 wherein the figbrinogen receptor template A

wherein:

R^d is Het-C_Malkyl; and

Z", Z'" independently are hydrogen, C alkyl, halo, OR^f, CN, S(O)_kR^f,

CO₂R^f, or OH.

30. A compound according to claim 1 wherein the fibrinogen receptor antagonist template A is

31. A compound according to claim 1 which is:

wherein : R^x, Ry and R^z are independendy Cι_6alkyl, methoxy, nitro, trifiuoromethyl, fluoro, chloro, or amino; or R^x and Ry are adjacent to one another and are joined to form a methylenedioxy group.

32. A compound according to claim 1 which is:

wherein;

R^x and R are independently methoxy, nitro, trifiuoromethyl, fluoro, chloro, or amino; or R^x and Ry are adjacent to one another and are joined to form a methylenedioxy group.

33. A pharmaceutical composition having vitronectin receptor inhibiting activity which comprises a pharmaceutically acceptable canier and a compound according to formula (I) or (II) or (III) or (IV) or (V).

34. A method of inhibiting a vitronectin receptor in a mammal which comprises administering an effective amount of a compound according to formula (I) or (II) or (UI) or (IV) or (V):

(IV) or (V) wherein: W is CHRε_a-U- CHRSb-V- or

V

N— (CH₂)_q <

A is a fibrinogen receptor antagonist template; U and V are absent or CO, CR⁸2, C(=CR⁸2), S(O)_k, O, NR⁸, CROR⁸,

CR⁸(OR-<)CR⁸2. CR^s2CR^e(ORk), C(O)CR⁸2, CR⁸2C(O), CONR, NRCO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR⁸, NR⁸C(S), S(O)2NR^E, NR⁸S(O)2

N=N, NR⁸NR⁸, NR⁸CR^E2, NR⁸CR⁸ ₂, CR⁸2O, OCR⁸2, C≡C or CR⁸=CR^E; G is NR^e, S or O;

R⁸ is H, Ci-6alkyl, Het-Cθ-6alkyl, C3-7cycloalkyl-Cθ-6-dkyl or Ar- Cθ-6alkyl;

R^k is R⁸, -C(O)R^E, or -C(O)OR^f;

R' is is H, Cι_6alkyl, Het-Cθ-6alkyl, C3-7cycloalkyl-Cθ-6- kyl, Ar- Cθ-6al yl, or

R^f is H, C,_.6alkyl or Ar-C,_.6alkyl;

R^e is H, Ci-6alkyl, Ar-Ci-6alkyl, Het-C l-6alkyl, C3-7cycloalkyl-Cι_6alkyl, or (CH₂)_kCO₂R⁸; 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 R^c are independently selected from H, Ci-6alkyl, Ar-Cθ-6-dkyl, Het-

Co-6alkyl, or C3-6cycloalkyl-Cθ-6alkyl, halogen, CF3, OR^f, S(O)_kR^f, COR^f, NO2, N(R^f)2, CO(NR^f)2, CH2N(R^f)2, or R^D and R^c 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, CMalkyl, OR^f, S(O)_kR^f, COR^f, CO₂R^f OH, NO2,

N(R^f) , CO(NR^f)₂, and CH2N(R^f) _; or methylenedioxy; or a pharmaceutically acceptable salt thereof.

35. A method according to claim 34 wherein the compound inhibits the vitronectin receptor at a concentration of less than 50 micromolar.

36. A method according to claim 34 wherein the compound inhibits the vitronectin receptor at a concentration of less than 1 micromolar.

37. A method according to claim 34 wherein the compound inhibits the vitronectin receptor with a Ki at the vitronectin receptor that is ten-fold greater than the Ki for said compound at the fibrinogen receptor.

38. A method according to claim 34 wherein the compound inhibits the vitronectin receptor with a Ki at the vitronectin receptor that is thirty-fold greater than the Ki for said compound at the fibrinogen receptor.

39. A method according to claim 34 wherein the compound inhibits the vitronectin receptor with a Ki at the vitronectin receptor that is a hundred-fold greater than the Ki for said compound at the fibrinogen receptor.

40. A method according to claim 34 for treating diseases wherein bone resoφtion is a factor.

41. A method according to claim 34 for treating osteoporosis.

42. A method according to claim 34 for treating inflammation.

43. A method according to claim 34 for treating restenosis.

44. A method according to claim 34 for treating atherosclerosis.

45. A compound according to formula (XXX): R^z

wherein Pr¹ is a nitrogen protecting group, R^f is H, Cj.galkyl or ArC_j.galkyl, a' is

1-3, and R\ R^y and R¹ are independently H, halogen, SR^f, OR^f, CF₃, N(R^f)₂, NO₂ and Ci.galkyl.