CA2241724A1 - Vitronectin receptor antagonists - Google Patents

Vitronectin receptor antagonists Download PDF

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CA2241724A1
CA2241724A1 CA002241724A CA2241724A CA2241724A1 CA 2241724 A1 CA2241724 A1 CA 2241724A1 CA 002241724 A CA002241724 A CA 002241724A CA 2241724 A CA2241724 A CA 2241724A CA 2241724 A1 CA2241724 A1 CA 2241724A1
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amino
methyl
pyridinyl
acid
compound
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William H. Miller
Thomas Wen Fu Ku
Fadia E. Ali
William E. Bondinell
Richard M. Keenan
James Martin Samanen
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SmithKline Beecham Corp
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • A—HUMAN NECESSITIES
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

Compounds of formula (I) are disclosed which are vitronectin receptor antagonists useful in the treatment of osteoporosis.

Description

W O 97/24122 ' PCTrUS96/20744 TITLE
Vitronectin Receptor Antagonists S FIl~;LD OF THE INVENTION
This invention relates to phzlrm~relltic~lly active compounds which inhibit the vitronectin receptor and are useful for the tre~tm~nt of rli~e~seS wherein ihibition of the vitronectin receptor is in~ te-l, such as infl~mm~tion, cancer, angiogenesis, atherosclerosis, restenosis, and fli~e~.~e~ wherein bone resorption is a factor.1~) BACKGROUND OF THE INVENI ION
Integrins are a ~.u~e~ ily of cell a&esion receptors, which are transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include gpIIb /IIIa, the fibrinogen receptor, and av~3~ t~he vitronectin receptor. The 15 fibrinogen l~ce~ulor gpIIb mIa is expressed on the platelet surface and it n~e~ tes platelet aggregation and the formation of a h~most~tic clot at the site of a bleeding wound.
Philips, et al., ~lood., 1988, 71, 831.
The vitronectin receptor avB3 is expressed on a number of cells, in~ ing çnclothçli~l, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety OI
20 functions. The av~3 receptor expressed on the membrane of osteoclast cells is believed to play a role in the bone resportion process and contribute to the development of osteoporosis. Ross, et al., J. Biol. Chem., 1987, 262, 7703; Fisher, et al., Endocrinology 1993, 132, 1411; Bertolini et al., J. Bone Min. Res., 6, Sup. 1, S146, 252; EP 528 587 and 528 586. The av~3 receptor expressed on human aortic smooth muscle cells stimnl~tes 25 their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brown, et al., Cardiovascular Res., 1994, 28,18 15.
Additionally, a recent study has shown that a av~3 antagonist is able to promote tumor regression by in-lnting apoptosis of angiogenic blood vessels. Brooks, et al., Cell, 1994, 79, 1157. Thus, agents that would block the vitronectin receptor would be useful in 30 treating ~lice~ec m~ t~d by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer.

W O 97/24122 PCTrUS96120744 Alig et al., EP 0 381 033, Hartman, et al., EP 0 540,334, Blackburn, et al., WO
93/08174, Bondinell, et al., WO 95/18619, Bondinell, et al., WO 94/14776, Blackburn, et al. WO 95/04057, ~gbertson, et al, EP 0 478 328, Sugihara, et al. EP 529,8~8, Porter, et al., EP 0 542 363, and Fisher, et al., EP 0 635 492, and many others disclose certain ~-5 compounds that are useful for selectively inhibiting the fibrinogen receptor.
PCT/US95/08306, filed June 29, 1995 (Smithl~line Ree.ch~3m Corp.) and PCT/US95/08146 filed June 29, 19951995 (SmithKlin~ Beecham Corp.) disclose vitronectin receptor selective antagonists. However, there are few reports of compounds which are potent vitronectin receptor antagonists. It has now been discovered that certain 10 ~plop-iately substituted amino pyridine compounds are potent inhibitors of the vitronectin receptor. In particular, it has been discovered that the amino pyridine moiety may be combined with a fibrinogen atagonist t~mpl~te to prepare compounds which are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.
SUMMARY OF THE IN~ENTION
This invention comprises com~oullds of the formula (I) as described hereinafter,which have ph~rm~-~ological activity for the inhibition of the vitronection receptor and are useful in the tre~tmPnt of infl~-nm~tion, cancer, cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as 20 osteoporosis.
This invention is also a ph~rm~(~eutical composition compri~ing a compound according to formula (I) and a ph~rm~ eutically acceptable carrier.
This invention is also a method of treating (1i~e~ which are m~ t~rl by the vitronectin receptor. In a particular aspect, the compounds of this invention are useful for 2~ treating atherosclerosis, restenosis, infl~mm~tion, cancer and 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 30 invention comprise a fibrinogen receptor antagonist template that is linked to an optionally substituted o-amino pyridine moiety according to formula (I):

W O97124122 PCT~US96/20744 R'~ (I)u ,N~,N~ (CR'2)v- W - A
Q ;~ 2-Q
F,Y Q
(I) wherein S A is a ~lbrinogen antagonist template;
W is a linking moiety of the form -(CHRg)a-U-(CHRg)b-V-;
Q 1, Q2 and Q3 are independently N or C-RY, provided that no more than one Of Ql, Q2 and Q3 is N;
R' is is H or Cl 6alkyl, C3 7cycloaLkyl-Co 6alkyl or Ar-Co 6alkyl 10 R" is R', -C(O)R' or-C(O)OR';
Rg is H or Cl 6alKyl, Het-Co 6alkyl, C3 7cycloalkyl-Co 6alkyl or Ar-Co 6alkyl;
Rk iS Rg, -C(O)Rg or-C(O)ORg Ri is H, Cl 6alkyl, Het-Co 6alkyl, C3 7cycloalkyl-Co 6alkyl, Ar-Co 6alkyl, Het-Co 6alkyl-U'-Cl 6alkyl, C3 7cycloalkyl-Co 6alkyl-U'-CI 6aLkyl or Ar-Co 6alkyl-U'-Cl ~alkyl;
15 RY is H, halo, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S(O)~, -C02Rg, -CORg or -CONRg2;
U and V are absent or CO, CRg2, C(=CRg2), S(O)c, O, NRg, CRgORg, CRg(ORk)CRg2, CR82CRg(ORk), C(O)CRg2, CRg2C(O), CONRi, NRiCO, OC(O), C(O)O, C(S)O, OC(S), C(S)NRg, NRgC(S), S(0)2NRg, NRgS(0)2 N=N, NRgNRg, NRgCRg2, NRgCRg2, CRg2O, OCRg2, CRg-CRg, C_ C, Ar or Het;
a is 0, 1 or 2;
bisO, 1 or2;
cisO, l or2;
uisOor l;
25 visOorl;
and ph~rm~re~lti~ ~lly acceptable salts thereof;
provided that:
(i) when v is 0, and R', R" and RY are H, and Ql-Q3 are CH, W-A is not 7-aminocarbonyl-2,3,4,5-tetrahydro-3-oxo-4-methyl-lH-1,4-benzodiazepine-2-acetic acid, 7-aminocarbonyl-1-acetyl-2,3,4,5-tetrahydro-3-oxo-4-methyl- lH- 1 ,4-benzodiazepine-2-acetic acid, or 7-aminocarbonyl-2,3,4,5-W O 97/24122 PCTrUS961207~4 tetrahydro-3-oxo~-methyl- 1 H- 1 -benzazepine-2-acetic acid, or the methyl esters thereof;
(ii) when v is 0 or 1 and ~', R" and RY are H, and Ql-Q3 are CH, W-A is not 3-propanoyl-glycyl-aspartyl-pheny~ ninp~ or o ~0 ~CO 2H

~ N~J
CH 3 - , and the benzyl esters thereof.
Preferably, Ql, Q2 and Q3 are all CH, and u is 0.
Suitably, R' is H and R" is H or Cl 4alkyl.
Preferably v is 1.
Suitably, W is -(CHRg)a-CONRi- or -(CHRg)a-NRiCO-Suitably U' is CONR' or NR'CO.
A fibrinogen receptor antagonist is an agent that inhibits the binding of fibrinogen to the platelet-bound fibrinogen lc;cel)lor GPIIb-IIIa. Many fibrinogen antagonists are known to the art. As used herein, the term "fibrinogen receptor antagonist template"
means the core structure of a fibrinogen receptor antagonist, said core cont;~ining an acidic group and being linked to an organic group eu~stit~t~l with a basic nitrogen moiety. Typically, the core structure adds some form of rigid spacing between the acidic moiety and the basic nitrogen moiety, and contains one or more ring structures or amide bonds to effect this. It is preferred that about twelve to fifteen, more preferably thirteen or fourteen, intervening covalent bonds via the shortest intramolecular path will exist between the acidic group of the fibrinogen receptor antagonist template and nitrogen of the pyridine moiety in formula ~I). It is an object of this invention that a fibrinogen receptor antagonist is converted to a vitronectin receptor antagonist by replacing the basic nitrogen group in a fibrinogen receptor antagonist with an optionally substituted o-amino pyridine group. In addition, the number of intervening covalent bonds between the acidic moiety and the nitrogen of the pyridine will be about two to five, preferably three or four, covalent bonds shorter than the number of intervening covalent bonds between the acidic moiety and the basic nitrogen group of the fIbrinogen antagonist. The identity of the linking moiety W may be chosen to obtain the proper spacing between the acidic moiety of the fibrinogen antagonist template and the nitrogen atom of the pyridine. Generally, a WO 97/24122 P ~ nusg6~a744 fibrinogen antagonist will have an intramolecular ~ t~n~e of about 16 angstroms between the acidic moiety (e.g., the atom which gives up the proton or accepts the electron pair) and the basic moiety (e.g., which accepts a proton or donates and electron pair), while the vitronectin antagonist will have about 14 angstroms between the respective acidic and 5 basic centers.
For purposes of illustration, using the 7-2,3,4,5-tetrahydro-3-oxo-4-methyl-benzodiazepine fibrinogen antagonist template disclosed in WO 93/08174 as a suitable fibrinogen antagonist template, the compound (R,S)-7-[[[4-(aminoiminomethyl)phenyl]
arnino]carbonyl]-4-(2-phenylethyl)- 1 ,3,4,5-tetrahydro-3-oxo-2H- 1 ,4-benzodiazepine-2-10 acetic acid, which is potent and selective fibrinogen antagonist, is converted to a potentand selective vitronectin receptor antagonist by replacing the 4-(arninoiminomethyl)phenyl moiety with the 6-amino-pyrid-2-yl moiety. As illustrated below in Figure 1, in the former case, there are sixteen intervening covalent bonds between the acidic moiety and the basic moiety; in the fibrinogent antagonist whereas, in 15 the latter case there are 13 intervening covalent bonds in the vitronectin antagonist of this invention.
Fi~ure 1 H

o H2N~ o 1 Ph In fact the 4-(aminoiminomethyl)phenyl moiety is a common substituent on fibrinogen antagonist templates known to the art, and simple replacement of this moiety d with an optionally ~ubctihlted (6-aminopyrid-2-yl)methyl moiety may serve as guide to W O 97/241Z2 PCT~US96/20744 converting compounds having known fibrinogen antagonist templates into vitronectin receptor antagonists.
Also inrl~l~e~l in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be S any covalently bonded carriers which release the active parent drug according to formula (I) in vivo. In cases whelcill the compounds of this invention may have one or more chiral centers, unless specified, this invention includes each unique nonracemiccompound which may be synth~ci~P~l and resolved by conventional techniques. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and 10 trans (E) isomers are within the scope of this invention. In cases wherein compounds may o OR' exist in tautomeric forms, such as keto-enol taul~ , such as ~~ and ~~, and each tautomeric form is contemplated as being included within this invention whether exi~ting in equilibrium or locked in one form by app~ )liate substitution with R'.

The compounds of formula (I) inhibit the binding of vitronectin and other RGD-c~-nt~ining peptides to the vitronectin (ocv~3) receptor. Inhibition of the vitronectin receptor on osteoclasts inhibits osteoclastic bone resorption and is useful in the tre~tm~nt of diseases wherein bone resorption is associated with pathology, such as osteoporosis.
Additionally, since the compounds of the instant invention inhibit vitronectin receptors on 20 a number of dirrt;~ t types of cells, said compounds would be useful in the treatment of infl~mm~tion and cardiovascular di~e~çs, such as atherosclerosis and restenosis, and would be useful as anti-metastatic and ~ntitllmor agents.

Table I, below, describes certain fibrinogen receptor antagonists, whose core 2~ structures are useful in carrying out the instant invention. Reference should be made to the patent applications and other publications for their full disclosures, including the m~tho~ of plep~ g said templates and specific compounds embodying said templ~tes.
The entire disclosure of the noted patent applications and other publications isincorporated herein by reference as though fully set forth. The list following is not 30 int~n-l~d to limit the scope of the present invention, but only to illustrate certain known templates.

W O 97124122 PCT~US96/20744 Table I

Adir et Cl r~
Fl~ 928004, June 30, 1992, Fauchere, et al.
EP 0578535, June 29, 1993, Fauchere, et al.
CA 2128560, Jan. 24, l99S, Godfroid, et al.

Asah; Bre .. ~, ;cs, Ltd.
JP 05239030, Sep. 17, 1993.
Asahi Glass WO 90/02751, Ohba, et al., Sept. 8, 1989.
WO 90/115950, Mar. 22, 1990, Ohba, et al.
EP 0406428, Jan. 9, 1991.
WO 92/09627, Isoai, A. et al., Nov. 29, 1991.

C~c~lls AG
DE 4207254, (Der 93-289298/37) Mar. 7, 1992, Zoller, et al.
EP 93904010, Feb. 24, 1993.
EP 0565896, Mar. 18, 1993, Klinger, et al.
EP 0566919, (Der 93-338002/43) Apr. 3, 1993, Zoller, et al.
EP 580008, (Der 94-027663/04) July 6, 1993, Zoller, et al.
DE 224414, July 6, 1993, Zoller, et al.
EP 584694, (Der 94-067259/09) Apr. 2, 1994.
DE 4301747, (Der 94-235891/29) Jul. 28, 1994, Zoller, et al.
DE 4308034, (Der 94-286666/36) Sept. lS, 1994, Klinger, O. et al.
DE 4309867, Sept. 29, 1994, ~lingler, et al.

Chiron WO 93/07169, (Der 93-134382/16), Mar. lS, 1993, Devlin, et al.

Ciba Geigy EP 0452210, (Der 91-305246/42) Apr, 5, 1990, Describes arminoalkanoyl-GDF analogs.
EP 0452257, Mar. 26, 1991, Allen, et al.: Describes arninoalkanoylAsp-Phe analogs.
COR Therapelltics WO 90/15620, June lS, 1990.

EP 0477295, Apr. 1, 1992, Scarborough, et al.
WO 92/08472, May 29, 1992, Scarborough, et al.
WO 93/223356, April 27, 1993, Swift, et al.
EP 0557442, Sept. 1, 1993, Scarborough, et al.
Scarborough, et al., J. Biol. Chem., 266, 9359, 1991.

Daiichi Pharm Co Ltd.
JP 05078344-A, (Der 93-140339/17) Mar. 30, 1993.

DuPollt Merck WO 93/07170, Apr. 15, 1993.
WO 94/11398, May 26, 1994: Wells, et al.
IL 109237, Jul. 31, 1994.
WO 94/22909, (Der 94-333113/41) Oct. 13, 1994, DeGrado, et al.
WO 94/22910, (Der 94-333114/41 Oct. 13, 1994: DeGrado, et al.
WO 94/22494, (Der 94-332838/41) Oct. 13, 1994: DeGrado, et al.
EP 625164, Nov. 23, 1994, Degrado, et al.
Mousa, et al, Circulation, 89, 3, 1994.
~ackson, J.Amer. Chem.Soc, 116,3220, 1994 Ellem Ind Farma Spa GB 2207922, Aug, 3, 1988.

Farmitalia Erba SRL Carlo EP 611765 (Der 94-265375/33), Aug 24, 1994: Cozzi, et al.

Fuji Photo Film JP 04208296-A ~Der. 92-303598/38), Nov. 30, 1990.
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W O 97/24122 PCTrUS96/20744 ONO Phar ~- ~ff~~~~
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~ AG
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CA 0224l724 l998-06-26 W O 97/24122 PCTrUS96/20744 Searle / Monsanto EP 0319506, (Der 89-3195506) Dec. 2, 1988, Adams, et al.
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W O 97/24122 PCT~US96~0744 WO 9420457, (Der 94-302907/37) Sep. 15, 1994, Tjoeng, et al.
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Smi~h~lin~ Beerhsm EP 341 915, Ali, et al.
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S~rniton~o Seiyaku KK
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Taisho Pharm. (TeUin, Ltd) JP 05230009, (Der 93-317431/40, Feb. 24, 1992.
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WO 94/17804, Aug. 18, 1994, ~i~l~chi~
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PCTrUS96/20744 Takeda EP 0529858, Apr. 3, 1993, H. Sugihara, et al.
EP 606881, Jul. 20, 1994.
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Terumo KK
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Karl Thomae / Boehl h.~. Ingelheim EP 0483667, May 6, 1992, Himrnelsbach, et al.
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CA 02241i24 1998-06-26 W O 97/24122 PCT~US96/~0744 DE 4129603, Mar. 11, 1993, Pieper, et al.
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Univ. California WO 94/14848, July, 7, 1994, 7~netti 35 Univ. New York WO 94/00144, June 29, 1993, Oiima, et al.

W O 97/24122 PCT~US96/20744 Yeda Res. and Dev. Co.
WO 93/09795, (Der 93-182236/22), Lido, et al.

Zeneca WO 9422834, Oct. 13, 1994, Wayne, et al.
WO 9422835, Oct. 13, 1994, Wayne, et al.
EP 632016, Jan. 4, 1995, Brewster, et al.
EP 632019, Jan. 4, 1995, Brown, et al.
EP 632020, Jan. 4, 1995, Brown, et al.
In one particular embodiment, the fibrinogen receptor antagonist template A is the fused 6/7 ring bicyclic ring defined in Bondinell, et al., WO 93/00095, published January 7, 1993, as defined by sub-formula (VI):
~ D ~ A57~A4 ~D4~\Al _A~R (II) 1 5 wl~
Al to As form an ~< cec~ihle substituted seven-membered ring, which may be saturated or unsaturated, optionally Con~ining up to two heteroatoms chosen from the group of O, S and N wherein S and N may be optionally oxidized;
Dl to D4 form an ~rces~ihle substituted six membered ring, optionally Cont~inin~20 up to two nitrogen atoms;
R is at least one substituent chosen from the group of R7, or Q-C l 4alkyl, Q-C2 4alkenyl, Q-C2 4alkynyl, optionally substituted by one or more of =O, Rl l or R7;
R* is H, Q-Cl 6alkyl, Q-CI 6oxoalkyl~ Q-C2 6alkenyl, Q-C34oxoalkenyl, Q-C3 40xoalkynyl, Q-c2-4alkynyl~ C3 6cycloalkyl, Ar or Het, optionally substituted by 25 one or more of Rl l;
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', 30 -OCR'2C(O)NR'2, CF3 or AAl;
R9 is -OR', -CN, -S(O)rR', S(O)mNR'2, -C(O)R' C(O)NR'2 or -CO2R';
Rl l is H, halo, -ORl2, -CN, -NR'R12, -NO2, -CF3, CF3s(o)r~ -CO2R', -CONR'2, Q-Co 6alkyl-, Q-CI 6oxoalkyl-, Q-C2 6alkenyl-, Q-C2 6alkynyl-, Q-Co 6alkyloxy-, Q-Co 6alkylamino- or Q-Co 6alkyl-S(O)r-;

WO 97/24122 PCT~US96/20744 Rl2 is R', -C(O)R', -C(O)NR'2, -C(o)oRI5, -S(O)r"R' or S(O)mNR'2;
R13 is R', -CF3, -SR', or -OR';
R14 is R', C(O)R', CN, NO2, SO2R' o} C(o)oR15;
Rl5 is H, C1 6alkyl or Ar-Co 4alkyl;
S R' is H, Cl 6alkyl, C3 7cycloalkyl-Co 4alkyl or Ar-C~4alkyl;
R" is R', -C(O)R' or-C(O)ORI5;
R"' is R" or AA2;
AAl 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;
mis 1 or2;
nisOto3;
pisOor l;and tisOto2;or rh~ elltically acceptable salts thereof.
With reference to formula (II), suitably, Al is CRIRl, CR1, NR1, N, O or S(O)x;
A2 is CR2R2r~ CR2, NR2;
A3 is CR3R3, CR3, NR3, N, O or S(O)x;
A4 is CR4R4, CR4, NR4, or N;
As is CR5R5, CR5, NR5, N, O or S(O)x;
D1-D4 are CR1 1, CR6 or N;
R1 and R1 are R* or R, or together are =O;
R2 and R2 are R*, R or =O;
R3 and R3 are R*, R or =O;
R4 and R4 are R*, R or =O;
Rs and Rs are R*, R or =O; and xisOto2.
More suitably, Al is CR1Rl, CRl, NR1, N, O or S; A2 is CR2R2, NR2 or CR2;
A3 is CR3R3'; A4 is CR4R4, CR4, NR4, or N; As is CR5R5, CR5, NRs, N, O; Dl - D4 are CH; R2 or R4 are R; R3,R3 and R5,R5 are =0 or R*,H.
Preferably, A1 is CHR1, CRl, NR", N or S; A2 is CR2 or CR2R2; A3 is CR3R3;
A4 is CR4R4 or NR4; As is CRsRs, and Dl - D4 are CH.
In one embodiment, Al is CR1, A2 is CR2, A3 is C=O, A4 is NR4 and A5 are CHR5.
In another embodiment, Al is NRl, A2 is CHCR2, A3 is CR3R3, A4 is NR4, and A5 are C=O.

W O 97/24122 PCTrUS96/20744 In yet another embodiment, Al and A4 are C=0, A2 is NR2, A3 is CHR3 and A5 is NRs.
In a pl~rell~ed embollim~ t, Al is NRI, A2 is CHR2, A3 is C=0, A4 is NR' and A5 is CHR5.
Representative sub-formulas of (II) are given by each of form~ (IIa)-(IIi) below:

(IIa) ~IIb) (IIc) 10(IId) (IIe) (l~f) R5~R ' R5 R5' R 5 R5~

~' ~o~RR.3 ~ )~R3 Rl R~' R2 R2 or R1 R1 (IIg) (IIh) (~i) A preferred template is given by formula (III) ~Al--- AZ

~III) ~ wherein Al-A2 is NR1-CH, NC(o)R3-CH, N=C, CRI=C, CHRI-CH, 0-CH or S-CH;
Rl is H, C1 6 alkyl or benzyl;
20R2 is (CH2)qC02H;
R4 is H, Cl 6alkyl, Ar-Co 6alkyl, Het-Co 6alkyl, or C3 6cycloalkyl-Co 6aLkyl; and qis 1,20r3.

WO 97/24122 PCT/US96nO744 Preferably Al-A2 is NH-CH and R2 is CH2CO2H. Suitably, R3 is methyl and W
(as defined in formula (I)) is ~CH2)aNR'CO. Suitably Ri is ~ub~LiLuLed by NHR', CN, C02H, biotin, ben7imicl~7ole or optionally substituted phenyl.
Specific examples of vitronectin antagonists employing this template are:
S (S)-7-[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonylI- 2,3,4,5-tetrahydro-4-methyl-3-oxo- lH- 1 ,4-benzodiazepine-2-acetic;
(S)-7-[[[(6-Arnino-2-pyridinyl)methyl]amino]carbonyl]-2,3 ,4,5-tetrahydro4-methyl-3-oxo- lH- 1 ,4-benzodiazepine-2-acetic acid;
(S)-7-[[[(6-Ethylamino-2-pyridinyl)methyl]arnino]carbonyl]- 2,3,4,5-tetrahydro-4-methyl-3-oxo-lH-1,4-benzodiazepine-2-acetic acid; and (:t)-7-[[[(2-Arnino-4-pyrimidinyl)methyl]methylamino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo- lH- 1 ,4-benzodiazepine-2-acetic acid.
A preferred compound is (S)-7-[[[(6-Ethylamino-2-pyridinyl)methyl]amino]carbonyl]-2 ,3 ,4 ,5 -tetrahydro-4-methyl-3-oxo- I H- 1 ,4-benzodiazepine-2-acetic acid Another embodiment of a benzodiazepine fibrinogen receptor template A is represented by the 1,4-benzodiazepine 2,5-dione of sub-formula (IV);
~ Rh R~ ~ (IV) WllGlGill Y is H, Cl ,lalkyl, Cl 4alkoxy, Cl 4alkoxycarbonyl, F, Cl, Br, I, CF3, oRf, S(O)kRf, CORf, NO2, N(Rf)2, Co(NRf)2, CH2N(Rf)2, methylenedioxy, CN, CO2Rf, OC(O)Rf, or NHC(O)Rf; and Rh iS (CH2)qC02Rf.
Suitably Rh is CH2CH2CO2H.
Entries (V)-(XV) in Table II summarize other illustrative fibrinogen receptor 25 templates that are included within the scope of the present invention:

W O 97/24122 PCT~US96/20744 Table II

nl) A is J~R , J~RZZ, J~R2Z, ~RZZ
S or ,~R21 / S R22;
wherein:
R2 1 and R22 independently are H or -zco2Rfor Z-CoN(Rf)2 with the proviso that one of R21 or R22 is -z-co2Rf or Z-coN(Rf)2, 10 Zis-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, C1 4alkyl, Cl 4alkoxy, Cl 4alkoxycarbonyl, F, Cl, Br, I, CF3, ORf, S(o)kRf, CoRf, NO2, N(Rf)2, Co(NRf)2~ CH2N(Rf)2, methylenedioxy or Z-CORf, disclosed in Alig, et al., EP 0 381 033, published August 8, 1990.
I) R6SO2NH CO2R~
wher~
R6 is aryl, Cl loalkyl, C3 6cycloalkyl, C4 loaraLkyl, Cl loalkoxyaIkyl, 20 Cl loalkaryl, Cl loalkylthioalkyl, Cl loalkoxythioalkyl, Cl loalkylamino, C4 1oaralkylamino, C1-loalkanoylamino, C4 loaralkanoylarnino, C1-Ioalkanoyl, C4 l0aralkanoyl, or Cl locarboxyalkyl; and Y is H, C1~alkyl, Cl 4alkoxy, Cl 4alkoxycarbonyl, F, Cl, Br, I, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2~ Co(NRf)2~ CH2N(Rf)2, methylenedioxy, CN, CO2Rf, 25 OC(O)Rf, or NHC(O)Rf, disclosed in Egbertson, et al., EP 0 478 328, published April 1, 1992.

PCT~US9C/20744 (VII) ~ ~G' CHCO2Rf wherein:
M1 is CH or N;
M2 is CH or N, with the proviso that when Ml is CH, M2 is N; and G' is N or NfflR", disclosed in Eldred, et al., EP 0542 363, published May 19, 1993.

(VIII) --M~\M2_O<OH
\--/ CH2C~2Rf wherein:
Ml is CH or N; and M2 is CH or N, w;th the proviso that when Ml is CH, M2 is N, lS disclosed in Porter, et al., EP 0 537 980, published April 21, 1993.

X~

~M3 M~Rh wherein:
M1 is CH or N;
Y is H, Cl 4alkyl, Cl 4alkoxy, Cl 4alkoxycarbonyl, F, Cl, Br, I, CF3, oRf, S(O)kRf, CORf, NO2, N(Rf)2, CO(NRf)2, CH2N(Rf)2, methylenedioxy, CN, Co2Rf, OC(O)Rf, or NHC(o)Rf;
D3 is CH2 or C=O; and Rh is (CH2)qCO2Rf, disclosed in Klirmick, et al., EP 0 635,492, published January 25, 1995.

W O 97/24122 PCTrUS96/20744 E~
wherem:
Y is H, C1 4alkyl, Cl 4alkoxy, Cl 4alkoxycarbonyl, F, Cl, Br, I, CF3, ORf, S(O)kRf, CoRf, NO2, N(Rf)2, CO(NRf)2, CH2N(Rf)2~ methylenedioxy, CN, CO2Rf, 5 oC(O)Rf, or NHC(O)Rf;
Rh is (CH2)nCo2Rf; and C)~N~ N~ ~ ~, or ~J
disclosed in Blackburn, et al., WO 95/04057, published February 9, 1995.

(XI) wherein:
L~ is -C(O)NRg-(CH2)-, -C(0)~(CH2)q~~ NRg-(CH2)q-, -O~(CH2)q~~ or S(O)k-(CH2)q~.
disclosed in Hartman, et al., EP 0 540 331, published May 5, 1993.

(XII) N N--CH2 Co2R9 CO~o disclosed in Sugihara, et al., EP 0 529,858, published March 3, 1993.
(~III~

~ "'--C0 R9 wherein:

Y is H, Cl 4alkyl, Cl 4alkoxy, Cl 4alkoxycarbonyl, F, Cl, Br, I, CF3, ORf, S(o)kRf, CORf, NO2, N(Rf)2, Co(NRf)2, CH2N(Rf32, methylenedioxy, CN, CO2Rf, OC(O)Rf, or NHC(O)Rf, disclosed in Himmeisbach, et al., EP 0 483 ~67, published May 6, 1992.
S
(XIV) ~ (CH2),,C02R~
--N
disclosed in ~inz, et al., EP 0 567 968, published November 3, 1993.
(XV) ~Rd ;<zco2Rg wherein:
Rd is Het-Co 6alkyl; and Z", Z"' independently are hydrogen, C~ 4alkyl, halo, ORf, CN, S(O)kRf, 15 CO2Rf, or OH, disclosed 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 variations 20 possible for such templates and methods of ~r~a~ g said templates, the entire disclosure of such patent applications being incorporated herein by reference.
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 synth~i7ed and resolved by conventional techniques. In cases in which 25 compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. The m~nin~ of any substituent at any one occurrence is independent of its m~ning, or any other substituent's m~nin~, at any other occurrence.
Abbreviations and symbols commonly used in the peptide and chemical arts are 30 used herein to describe the compounds of this invention. In general, the arnino acid abbreviations follow the IUPAC-IUB Joint Commi~ion on Biochemical Nomenclature as - described in Eur. J. Biochem., 158, 9 (1984).

W O 97/24122 PCT~US96/20744 Cl 4alkyl as applied herein means an optionally sulJ~iLul~d alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. C1 6alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Co 4alkyl and Co 6alkyl additionally indicates 5 that no alkyl group need be present (e.g., that a covalent bond is present).
Any Cl 4alkyl or Cl 6 alkyl, C2 6 alkenyl, C2 6 alkynyl or C1 6 oxoalkyl may be optionally sub~lilul~d with the group RX, which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques. Suitable groups for Rx are Cl 4alkyl, OR', SR', Cl 4alkyl, Cl 4alkylsulfonyl, Cl 4aLkylsulfoxyl, -CN, N(R')2~ CH2N~R~)2~ -NO2, -CF3, -CO2 R', -CON(R')2, -CO R', -N R'C(O) R', OH, F, Cl, Br, I, N3 or CF3S(O)r-,wherein r is O to 2 and ~' is as defined with respect to forrnula (II).
Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substit~lçnt~, such as those defined above for alkyl, especially Cl 4alkyL Cl 4alkoxy, Cl~alkthio, C02H, N3, trifluoroalkyl, OH, F, Cl, Br or I.
Het, or heterocycle, in~iic~te~ an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring cont~ining one to threeheteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by convention~l ch~mir~l synthesis. Illustrative heterocycles are benzofuryl, ben7imi(1~701e, benzopyran, benzothiophene, biotin, furan, im~idazole, indoline,morpholine, piperidine, pipe1~zille, pyrrole, pyrrolidine, tetrahydropyridine, pyridine, thiazole, thiophene, quin~-linl-, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. Any aecçssihle combination of up to three substituents on the Het ring, such as those defined above for alkyl that are available by eh~mi~l 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 chernical synthesis and is stable, is within the scope of this invention.
(T)u The ring represented by Q2 is a six-membered ring cont~ining at least t one nitrogen which is 2,6-disubstituted relative to such nitrogen. The ring may optionally have an additional nitrogen atom in the ring, and hence may be a pyrazine or a pyrimirline. The substituent ~Y may be in any position on Ql - Q3 which results in a W O 97/24122 PCTfiUS96~Z0744 stable structure. It will be a~a~ t that when the value of u is 1 the compound described will be an N-oxide; whereas, when the value of u is 0 there is no oxygen substituent on the nitrogen. A pyridine ring is preferred.
Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butylradical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzylw~y~;a.bonyl radical, BrZ refers to the o-bromobenzylo~yc~bollyl radical, ClZ
refers to the o-chlorobenzyloxycall ollyl 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 10 acetyl, Alk refers to C1 4alkyl, Nph refers to 1- or 2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetr~olyl.
Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodiimide,DMAP refers to dimethylamilloo/-idine, DIEA refers to diisopropylethyl amine, EDC
refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride. HOBt refers to 15 1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DIEA refers to diisopropylethylamine, DML refers to dimethoxyethane, DMF refers to dimethylro~ ..icle, NBS refers to N-bromosuccinimide, Pd/C refers to a p~ m on carbon catalyst, PPA refers to 1-propanephosphonic acid cyclic anhydride, DPPA refers to diphenylphosphoryl azide, BOP refers to benzotriazol-1-yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate, HF refers to hydrofluoric acid, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, PCC refers to pyri~lininm chlorochromate .
Compounds of the formula (I) are generally prepared by reacting a compound of formula (XVI) with a compound of formula (XVII), wherein Ll and L2 are groups which may react to form a covalent bond in the moiety W, by methods generally known in the art.

R'~ (I)u R~ (~I) (XVI) (XVII) (I) Typical methods include coupling to form amide bonds, nucleophilic displacement reactions and p~ m catalyzed couplings.
For in~t~n-~e, when W contains an ether or amine linkage, the bond may be formedby a displacement reaction, and one of Ll and L2 will contain an amino or lly~-~y group W O 97/24122 PCTrUS96/20744 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 L1 and L2 will contain an amino group, and the other will contain a carboxylic acid group. In another approach, Ll may be an aryl or hetelo~yl bromide, iodide or trifluoromethylsulfonyloxy derivative and L2 may contain an amino group and the amide linkage may be formed by p~ m-catalyzed a~ninocarbonylation with carbon monoxide in a suitable solvent such as dimethylformz-mi~le or toluene.
It will be apl,a~ l that the precise identity of Ll and L2 will be dependent upon the site of the linkage being formed. General methods for pl~a~ g the linkage -(CHR")r-U-(CHI~")S-V- are described, for example, in EP-A 0 372 486 and EP-A 0 381 033 and EP-A 0 478 363, which are incorporated herein by reference.
For instance, if V is CONH, L~ may be -NH2, L2 may be OH (as in an acid) or Cl ~as in an acid chloride). For in~t~nt~.e, (2-amino-pyrid-6-yl)(CH2)a-COCl may be reacted with a suitable amine. When L2 is OH, a coupling agent is used.
Similarly, if V is NHCO, Ll may be -CO2H or CO-Cl, L2 may be -NH2. For in.ct~nc~.e, (2-amino-pyrid-6-yl)(CH2)a-NHR' may be reacted with a suitable carboxyolic acid.
Where V is NHSO2, L1 may be SO2Cl, L2 may be -NH2 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 CE~=CH, L1 may be -CHO, L2 may be CH=P-Ph3 Alterrlately, Ll may be CH=P-Ph3 and L2 may be CHO. For instance, (2-amino-pyrid-6-yl)(CH2)a-CHO may be reacted with a suitable phosphorane.
Where V is CH2CH2 may be obtained by reduction of a suitably protected compound wherein V is CH=CH.
Where V is CH20, CH2N or C~ C, Ll may be -OH, -NH or -C= C H,respectively;
L2 may be -Br or -I. Similarly where U or V is OCH2, NR'CH2 or C~ C, Ll may be -CH2Br and L2 may be -OH, -NH or -C= C H, respeclively. For example, (2-amino-pyrid-6-yl)(CH2)a-Br may be reacted with an ~ pliate amine, alkoxide or acetylene.

CA 0224l724 l998-06-26 ~ltPrn~tely, when U or V is C~ C, ~1 may be Br, I or CF3S03, L2 may be C~ C H and the coupling may be catalyzed by p~ m and a base.
Compounds wh~ 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 5 ~1989).
Co~ )oullds wherein V is CH2CHOH may be obtained from a suitably protected compound where V is CH=CH by hydroboration and basic oxidation as disclosed in Tet.
Lett., 31, 231 (1990).
The core 6-7 fused ring fibrinogen template of formula (II) is prepared by methods well known in the art, e.g., Hynes, et al., J. Het. Chem., 1988, 25, 1173; Muller, et al., Helv. Chim. Acta., 1982, 65, 21 18; Mori, et al., Heterocycles, 1981,16,1491. ~Simil~rly, methods for prepalillg benzazepines, 1,4-benzothiazepines, 1,4-benzoxazepines and 1,4-benzodiazepines are known and are disclosed, for in~t~nce, in Bondinell, et al.,Tnt~rn~tional Patent Application WO 93/00095.
Repres~nt~tive fibrinogen antagonist templates may be prepared according to Schemes A - AA, which follow:

W O 97/24122 PCTrUS96/20744 Scheme A describes a method of exemplary fibrinogen receptor templates described in Blackburn, et. al., WO 93/08174.
S~h~ eA

~CO2H ~NH'-bO

NH/~/ 2 ~;NH d,e CH3 ~ O CH3 ~
~i 6 ~ ~CO2H
,~ ~C~H~H~

a) COC12, Na2C03, toluene; b) ,B-alanine benzyl ester tosylate, DMAP, pyridine; c) CH3I, 2,6~ lint~., DMF; d) ot-bromoacetyl bromide, Et3N, CH2C12; e) NaH, DMF, f) Pd(OAc)2, dppf, CO, DMSO, 65~C, 18 h; g) 6-(methylamino)methyl-2-pyri~lin~min~, EDC, HOBT-H20, DIEA, CH3CN; h) H2, 10% Pd/C, EtOH.

W O 97/24122 PCT~US96~0744 Scheme B describes a method of plGpalillg exemplaIy fibrinogen receptor templates described in Blackburn, et. al., WO 95/04057.

Scl.e.~le B

~CO~H ~ b ,~NH~ d ,~ ~ e ~CO2Et ~ ~CO2Et ~NH~ I~N--~?

~N CO2Et h H3C~?

H2N ~ ~ 02H

a) COC12, NaHCO3, toluene; b) ~-alanine ethyl ester hydrochloride, DMAP, pyridine; c) a-bromoacetyl bromide, Et3N, CH2C12; d) NaH, DMF; e) Lawesson's reagent, THF, 50~C, 2 h; f~ CH3I, NaOH, (n-Bu)4N-HSO4, CH2C12, H20, RT, 2 h; g) plupal~yl amine, toluene, pyridine hydrochloride, reflux, 6 h; h) Pd(OAc)2, dppf, CO, DMSO, 65~C, 18 h;
i) 6-(methylamino)methyl-2-pyriflin~Tnine, EDC, HOBT-H20, DIEA, CH3CN; j) LiOH, H20, THF, 18 h.

W O 97124122 PCTrUS96/20744 Scheme C describes a method of ple~ g exemplary fibrinogen l~,C/;~)LOl temrl~tes ~escribed in Porter, et al., EP 0542363.

Scheme C

0~ Boc ~ N ~
N~CO2Et 1~, 'H ~N~
N ~ CO2Et c,d,e ~

~/ 1 f,d,e H NJ~ H2N~N~N

~N ~ C02H ~N ~ CO2H

a) NaBH3CN, HCI, CH30H; b) HCl, r~ioy~n~7 CH2cl2; c) 6-methyl-2-~ph~h~limi~o)pyridine, H2CO~ EtOH; d) NaOH, H20, CH30H; d) hydrazine hydrate, EtOH, reflux; f) 6-l;,--,lllo-lwl}-yl-2-(phth~limil1Q)pyridine~ NaHC03, CH3CN.

W O 97/24122 PCT~US96/20744 Scheme D describes a method of ~lepa~ g exempl~ry fibrinogen receptor t~mpl~t~s described in Porter, et al., EP 0537980.

S~h~ e D

H~
N ~

CO2tBu OH
a,b,c~ ~d,b,c ~, H2N N ~--N~l H2N ~ N
~, N ~ 1~, N ~

OH OH

a) 6-methyl-2-(phth~limido)pyridine, H2CO, EtOH; b~ NaOH, H2O, CH3OH; c~
hydrazine hydrate, EtOH, reflux; d) 6-bromomethyl-2-(ph~h~limi(lo)pyridine, NaHCO3, CH3CN.

_ Scheme E describes a method of preparing exemplary fibrinogen receptor templates described in Beavers, et al., WO 95/25091.

Scheme E

N~ OCH3 H2N~N~ ~", ~OCH3 b,c ~ ~
H2N N ~ N ", ~ NH ~O-Bn O O O

H2NJ~N~ ""~NH ~OH
O O O

a) (6-arnino-2-pyridinyl)propionic acid, BOP-Cl, NMM, CH2C12; b) LiOH, H20, THF;c) ,B-alanine benzyl ester, EDC, HOBT, NMM, CH2cl2; d) H2, 10% Pd/C, AcOH, THF, H20.

Following the procedures of Beavers, et al., WO 95/25091, Example 1, except ~ ~ub~LiLuLiug 3-(6-arnino-2-pyridinyl)propionic acid, Bondinell, et al., WO 95/25091, for N~-Boc-D-lys(Cbz)-OH, gives E-4.

W O 97/24122 PCTrUS96/20744 Scheme F describes a method of ~lGpa~ g exemplaly fibrinogen receptor t~mpl~t~s described in Hartmant et al., EP 0540334.

S.-- ~F

9 O~ ~O b,c >

H2N ~ ~~ N ~~ o, CH3 d H

H2N~ ~~N ~OH

a) 6-aminomethyl-2-pyri(1in~min~, Et3N, benzene; b) 1.0 N LiOH, H20, CH30H; c) ,B-alanine ethyl ester, BOP, Et3N, CH3CN; d3 LiOH, H20, THF, CH30H.

Dimethyl 4-(bromomethyl)benzene-1,3-dicarboxylate, F-l, is treated with a suitably function~li7~1 amine, such 6-aminomethyl-2-pyri-lin~mine, under the general ~ conditions described for 2,3-dihydro-N-(2-carboxy-ethyl)-2-~2-(piperidinyl)ethyl]-3-oxo-lH-isoindole-5-carboxarnide in Hartman, et al., EP 0540334, to give F-4.

PCT~US96/20744 Scheme G describes a method of p~ g exemplary fibrinogen receptor templates described in Egbertson, et al., EP 0478363.

Scheme G

~OCH3 a HO SOzBu ll ~OCH3 b H2N ~,N ~o ~J S02BU

~OH
H2N~NHSO2Bu a) 3-(6-amino-2-pyridinyl)propanol, Ph3P, DEAD, CH2C12, ben7en~; b) 1.0 N LiOH, THF, H20.

N-(n-Butylsulfonyl)-L-tyrosine methyl ester, G-1, is treated with a suitably function~li7.~--d alcohol, such as 3-(6-amino-2-pyridinyl)propanol, prepared foIlowing the procedures of Warter, et al., Or~. Synth. 1943, 23, 83, and Bruekelm~n, et al., J. Chem.
Soc. Perkin Trans. I, 1984, 2801-2807, to give G-3.

CA 0224l724 l998-06-26 W O 97/24122 PCT~US96J20744 Scheme H describes a method of ~l~paling exemplary fibrinogen receptor temrl~t~-s described in Duggan, et al., J. Med. Chem. 1995, 38, 3332.

Scheme H

H2N~ co2H abcd H2N~NH

e,f H2N ~N~CO2H g,h o --~ O CHS
H2N~N~JI~NH CO2H

a) pivaloyl chloride, Et3N, THF, (S)-4-benzyl-2-oxazolidinone; b) Ti(O-i-Pr)C12,acrylonitrile, DlEA, CH2C12; c) H2, PtO2, CH30H, CHCl3; d) NaHC03, CH3CN; e) ~aHMDS, ethyl bromoacetate; f) 1 N NaOH, CH30H; g) 3(R)-methyl-,13-alanine ethyllQ ester HCl, EDC, HOBT, Et3N, DMF; h~ 1 N NaOH, CH30H.

A suitably functionalized carboxylic acid, such as 4-(6-arnino-2-pyridinyl)butanoic acid, H-l, is activated and reacted with a chiral auxiliary such as lithium (S)- 4-benzyl-2-oxazolidinone to form a chiral Evans reagent. ALkylation of the 15 fit~niom enolate with acrylonitrile, followed by nitrile reduction and lactam forrnation affords lactam H-2. ALkylation of the lactam with agents such as ethyl brom(-~ et~te followed by ester saponific~tif n yields the carboxylic acid H-3. The resulting carboxylic acid derivative H-3 is converted to an activated form of the carboxylic acid using, for example, EDC and HOBt, or SOCl2, and the activated form is subsequently reacted with W O 97/24122 PCTrUS96/20744 an a~r~pliate amine, for inct~n.-e the 3(R)-methyl-13-alanine ethyl ester, in a suitable solvent such as DMF, CH2C12, or CH3CN. Depending on whether acid neutralization is required, an added base, such as DIEA or pyridine, may be used. Many additional methods for converting a carboxylic acid to an arnide are known, and ean be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I -VI (pll~licht~-l by Wiley-Tnt~rsçiçnce), or Bodansky, "The Practice of Peptide Synthesis"
(published by Springer-Verlag). Hydrolysis of the ethyl ester is accomplished according to the general con-litic-nc described for the conv~-~ion of H-2 to lEI-3, to provide the carboxylic acid H-4. ~ltçrn:~tively, the intçrm~ t~ carboxylate salt of can be isolated, if 10 desired, or a carboxylate salt of the free carboxylic acid can be prepared by methods well-known to those of skill in the art.

WO 97/24122 PCT~US96/20744 .~ch~ I describes a method of preparing exemplary fibrinogen l~ce~)Lo templates described in WO 93/0786',7.

eI

~CH3 ~ b.c N~ d TS,N~o e Cl Ts--N ~ NOH f Ts ' ~3--~NOH

N--O N--O
Ts--N ~ CO2tBU h Ts--N ~ ~ , CO2H

N--O O CH
Ts ' ~~~ ~CO2Et H2N ~ N~CO2H

W O 97/24122 PCT~US96/20744 a) LDA, THF, allyl bromide; b) NH20H-HCl, EtOH, H20; c) TsCl, NaH, THF; d) 03, CH2C12, CH30EI, DMS; e) NH20H-HCl, NaOAc, CH30H; f) NCS, DMF; g) tert-butyl 3-butenoate, Et3N; h) 4M HCl, dioxane, CH2Cl2; i) ethyl 3-aminobutyrate, EDC, HOBt-H20, DIEA, CH3CN; j) 1.0 N LiOH, THF, H20.
S
The readily available aminopyridine deliv~live I-1, J. Chem. Soc. Perkin Trans. I
1984, 2801, is converted to the alkylated derivative I-2 by the general protocol described by Meakins, J. Chem. Soc. Perkin Trans. I 1984, 2801. Thus, I-1 is deprotonated with an amide base, such as lithium diisopropylarnide or lit_ium bis(trimethylsilyl)amide, and the 10 reslllting m~t~ t~rl species is aLkylated with an a~lupliate alkylating agent, for inct~nce allyl brornide, to afford the butenyl derivative I-2. Generally, THF or ethylene glycol dimethyl ether are the solvents of choice for an alkylation reaction, although THF in the presence of various additives, for in~t~nf~e HMPA or TMEDA, can be used. The 2,5-dimeLhyl~yirole protecting group is conveniently removed at this stage using the general 1~ protocol described by Meakins (see reference above). Thus, I-2 is reacted with hydroxylamine hydrochloride in an a~r~riate solvent, e.g., aqueous EtOH, to afford the corresponding deprotected aminopyridine. Protection of the amino group of this aminopyridine can be accompli~h~d by reaction with a sulfonyl chloride, for instance p-t~ nes~llfonyl chloride, in the presence of a suitable base, generally NaH or an aqueous 20 alkali metal hydroxide, in an inert solvent, preferably THF, to afford I-3. Alternative protecting groups known to those of skill in the art may be used, as long as they are compatible with t_e subsequent chemi~try and can be removed when desired. Such protecting groups are described in Greene, "Protective Groups in Organic Synthesis"
(published by Wiley-Interscience). Oxidative cleavage of the olefin of I-3 to afford the 2~ aldehyde I-4 can be conveniently accomplished by ozonolysis in an inert solvent, usually CH2C12 or a ~ lul~; of CH2C12 and CH30H, followed by in-situ reduction of the ozonide with a suitable reducing agent, generally dimethylsulfide (DMS) or triphenylphosphine. Alternative methods for oxidative cleavage, such as the Lemieux-Johnson reaction, J. Org. Chem. 1956, 21, 478, can also be used. The aldehyde is30 converted to the aldoxime I-5 by standard procedures known to those of skill in the art, and this aldoxime is oxidized to the oxiîminOyl chloride derivative I-6 by the methods described in WO 95/14682 and WO 95/14683. Reaction of I-6 with an ole~m, such as WO 97/24122 PCT/US96/:Z0744 tert-butyl 3-bllt~no~t~, Tet. Lett. 1985, 26, 381-384, in the presence of a suitable base, for instance Et3N or DIEA, in an inert solvent such as benzene or toluene, according to the protocol described in WO 95/14682 and WO 95/14683, gives the cycloadduct I-7. The ~ tert-butyl ester of I-7 is removed under standard acidic conditions, generally TFA in 5 CH2Cl2 or EICl in dioxane, to give the carboxylic acid I-8. The carboxylic acid is activated using, for example, EDC and HOBt, or SOCl2, and the activated form is subsequently reacted with an a~ iate armne, for in~tz~nçe a suitable derivative of ~-~l~nin~, in a neutral solvent, such as DMF, CH2C12, or CH3CN, to afford I-9. Depending on whether acid neutralization is required, an added base, such as DIEA or pyridine, may 10 be used. 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), or Bodansky, "The Practice of Peptide Synthesis" (published by Springer-Verlag). Delivali~/es of ,13--alanine are readily available in either racemic or optically pure form by a variety of methods known to those of skill in the art. A representative method is described in WO 93/07867.
The ethyl ester and sulfonyl protecting groups of I-9 are removed using aqueous base, for example, LiOH in aqueous THF or NaOH in a~ueous CH30H or EtOH. The int~rme~ t~- carboxylate salt is acidified with a suitable acid, for in~t~nf e TFA or HCl, to afford the carboxylic acid I-10. ~lte~ ;;ly, the intl-rm~-Ai~t.o carboxylate salt can be 20 isolated, if desired, or a carboxylate salt of the free carboxylic acid can be prepared by methods well-known to those of skill in the art.

W O 97/24122 PCT~US96120744 Scheme J describes a method of plt;pa~ g exemplary fibrinogen receptor templates described in Alig, et al., EP 0372486.

Sch~"e J

H2N J~NH ~O ~[3 O- ~
al H2N~NH~NH ~o~l3 H2N ~ NH~ NH ~OH
O O

a) (6-arnino-2-pyridinyl)acetic acid, EDC, DIEA, DMF; b) NaQH, H20, CH30H.

J-1, prepan d as described in Alig et al., EP 0372486, is con~en~eA with a suitable 10 ~ubsliluled carboxylic acid, such as (6-amino-2-pyridinyl)acetic acid, prepared by ~ saponification of ethyl (6-amino-2-pyridinyl)acetate, Awaya, et al., Chem. Pharm. Bull.
1974, 22, 1414, in the presence of EDC and DIEA, and in a suitable solvent, e.g., DMF or CH3CN, to give J-2. Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such a "Compendium of 1~ Organic Synthesis", Vol. I-VI (published by Springer-Verlag). Hydrolysis of the ester in J-2 is accomplished by saponi~lcation with a suitable reagent, e.g., NaOH, in a suitable solvent, e.g., aqueous methanol. Alt~rn~tively, the benzyl ester in J-2 may be converted to the acid by tre~tm~nt with hydrogen and a suitable catalyst, e.g., Pd/C, in a suitable solvent, e.g., CH30H, EtOH, or AcOH.
Scheme K describes a method of prt;~ g ex~q.mpl~ry fibrinogen receptor templates described in Alig, et al., EP 0505868.

S~ r.t K
~OH

o 3 ~
O-tBu al OH

H2N ~ J3' 2 O-tBu b l ~q~OH

- H2NJ~ 3 a) (6-amino-2-pyridinyl)acetic acid, EDC, DIEA, DMF; b) CF3C02H, CH2C12.

W O 97/24122 PCTrUS96/20744 K-1, prepared as described in Alig et al., EP 0505868, is condensed with a suitable 2,~lb7~ lPA carboxylic acid, such (6-amino-2-pyridinyl)acetic acid, prepared by saponification of ethyl (6-amino-2-pyridinyl)acetate, Awaya, et al., Chem. Pharm. Bull.
1974, 22, 1414, in the presence of EDC and DIEA, in a suitable solvent, e.g., DMF or S CH3CN, to give K-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 Synthesis", Vol. I-VI (published by Springer-Verlag). Hydrolysis of the ester in J-2 is accomplished with trifluoroacetic acid or hydrogen chloride to give K-3.
Alternatively, the ester in K-2 may be saponified with a suitable reagent, e.g., lN NaOH, 10 in a suitable solvent, e.g., CH3OH.

WO 97/24122 PCTnUS96/20744 Scheme L describes a method of ~le~arillg exemplary fibrinogen receptor templates described in WO 93/07867.

S~ ...e L
H2N~NH3 H3N~f--~C03CH3 ~,~ H2N~ N CO2H c 3 o H2Nl ï N~ CO2Et d H2N ~ N '~--J'' ~ CO2H

S O
a) 3-(carbomethoxy)propionyl chloride, DIEA, CH2C12; b) 1.0 N NaOH, CH30H; c) ethyl 3-arnino-4-pentynoate, EDC, HOBt-H20, DIEA, CH3CN; d) 1.0 N LiOH, THF, H20.

A suitably functionalized arnine, such as 2-amino-6-(2-arninoethyl)pyridine, ~Gp~,d following the procedures of Preparation 13 in Bondinell, et al., WO 93/00095, for the plG~dLion of 2-arninopyridine-4-eth~n~.l.i..e dihydrochloride, except sub~ uLillg - 2-amino-6-picoline for the 2-amino-4-picoline is reacted with 3-(carbomethoxy)propionyl W O 97/24122 PCTrUS96120744 chloride in the presence of an a~ u~liate acid scavenger, such as Et3N, DIEA, orpyridine, in a neutral sûlvent, generally CH2C12, to afford L-2. The methyl ester of L-2 is hydrolyzed using aqueous base, fûr example, LiOH in aqueous THF or NaOH in aqueous CH30H or EtOH, and the intermediate carboxylate salt is ~clrlifiçcl with a S suitable acid, for in~t~nçe TFA or HCl, to afford the carboxylic acid L-3. Altern~tively, L-l can be reacted with succinic anhydride in the presence of an appr~,pliate base, such as Et3N, DIEA, or pyridine, in a neutral solvent, gen~-r~lly CH2C12, to afford L-3 directly.
The r~sulting carboxylic acid de,ivative L-3 is converted to an activated form of the carboxylic acid using, for example, EDC and HOBt, or SOC12~ and the activated form is 10 subsequently reacted with an a~ ,pliate amine, for in~tzlnce the known ethyl 3-amino-4-pentynoate (WO 93/07867), in a suitable solvent such as DMF, CH2C12, or CH3CN, to L-4. Depending on whether acid neutralization is required, an added base, such as DIEA
or pyridine, may be used. 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 15 Organic Synthetic Methods", ~ol. I - VI (published by Wiley-Interscience), or Bodansky, "The Practice of Peptide Synthesis" (published by Springer-Verlag). Hydrolysis of the ethyl ester of L-4 is accomplished according to the general contliti-)n~ described for the conversion of L-2 to I,-3, to provide the carboxylic acid L-5. Alternatively, the int~-.rm~ te. carboxylate salt of can be isolated, if desired, or a carboxylate salt of the free 20 carboxylic acid can be prepared by methods well-known to those of skill in the art.

PCT~US96~Z0744 WO 97J24~2.2 Scheme M describes a method of preparing exemplary fibrinogen receptor templates described in Sugihara, et al., EP 0529858.

S.' ~n~~M
O
N N~O-tBu H2N o~o al H2N ~ ~o z b l H2N J~ C02H

a) (6-amino-2-pyridinyl)acetic acid, EDC, DIEA, DMP; b) CF3CO2H, CH2C12.

M-1, prepared as described in Sugihara, et al., EP C~529858, is c(-n-len~ed with a 10 suitable ~lb~LiLuLed carboxylic acid, such as (6-amino-2-pyridinyl)acetic acid, prepared by saponific~ti~ n of ethyl (6-amino-2-pyridinyl)~- et~t~7 Awaya, et al., Chem. Plzarm. Bull.
1974, 22, 1414, to give M-2, and the tert-butyl ester is cleaved with TFA, following the general procedure of Sugihara, et al., Example 59, to give M-3. Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard 15 reference books, such as "Comp~n~ m of Organic Synthesis", Vol. I-VI (pubIished by Springer-Verlag) .

W O 97/24122 PCTrUS96/20744 Scheme N des~rihe~ a method of ple~a,il~g exemrl~ry fibrinogen receptor ~emrlAt~s liescrihe~l in HimmP.l~b~qch, el. al., AIJ-A-86926/91.

SLI~ _~ N

~0 a H2NJ~ 23 ~ O
O-tBu ',~
O-tBu 1~

H2N ~0 ~0 3 ~,~4~
OH
a) 4-[(6-amino-2-pyridinyl)methyl]phenol, Cs2C03, DMF; b) lN NaOH, CH30H.

Compound N-1, prepared as described by Himmelsbach, et al., AU-A-86926/91, Example VI(28), is treated with a suitable substituted phenol, such as 4-C(6-amino-2-pyridinyl)methyl~phenol, prepared from the corresponding anisole, If e, et al., WO
9426715, with hydrobromic acid, following the general method of Himmelsbach et al., Example 3(51), to give N-2. The tert-butyl ester in N-2 is hydrolyzed with lN NaOH in CH30H to give N-3. ~It~.rnsltively, the tert-butyl ester may be cleaved with TPA or HCl 15 in a suitable solvent such as CH2Cl2.

, ~ ~ nus96~0744 Scheme O describes a method of ~ uhlg çxemrl~ry fibrinogen receptor templates described in Linz, et al., EP 0567968.

Scheme O

HZN~J~ NHz HzN~ NH~ ~COZcH3 J,~ b H2N ~ ~ CO2CH3 ~¦, c,d CO2CH3 H2N J~ N~

'~¦, e ~CO2H

H2N ~ N~

a) 6-aminomethyl-2-pyriclin~minç, Ph2POCl, Et3N, DMAP, THF; b) NaH, BrCH2C02CH3, DMF; c) KOtBu, CH3I, DMF; e) LiOH, H20, THF.

Following the procedures of Linz, et al., EP 0567968, except substitl-ting (6-amino-2-pyridinyl)methylamine for 4-cyano~nilint~, gives O-5.

W O 97/24122 PCTrUS96/20744 Scheme P describes a method of preparing exemplary fibrinogen receptor templates described in Wayne, et al., WO 94/22834.

Scl~ e P

Br~J~ 3~ 2 H21~1~ ~0 C~2CHs b l C02CH3 H2N ~ ICH~

~; CO2H

a) 6-(methylamino3methyl-2-pyriflin~nlinp7 CH3CN; b) lN NaOH, CH30H

Following the procedures of Wayne, et al., WO 94/22834, Example 1-2, except substituting 6-(methylamino)methyl-2-pyri ~ i r le for 1 -(4-pyridyl)pi~el dzine gives P-3.

W O 97124122 PCT~US96120744 Scheme Q describes a method of ~repa~ g e~cemI l~ry fibrinogen receptor templates described in Wayne, et al., WO 94122834.

Scheme Q
o ~Co2cH3 ~ H3 0 ~C02CH3 Br~;J~O a H2N N~N~ ~O

COzCH3 b l CO2CH3 H2N ~ ICH~ ~ COzH

a) 6-(methylamino)methyl-2-pyritlin~min~, CH3CN; b) lN NaOH, CH30H

Following the procedures of Wayne, et al., WO 94/22834, Example 3-4, except substituting 6-~methylamino)methyl-2-pyri~1in:~mine for 1-(4-pyridyl)pipt;~ e gives Q-3.

Scheme R describes a method of pl~a~ g exemplary ~Ibrinogen recept~r templates described in Alig, et al., EP 0381033.

Sch: n~ R

1~ ~ so~ ~ b CH~ CHJ~3~

3 O~CO2Bn 4 O CO2Bn d H2N~ I H~3~ e CO2Bn CH O

H2N ~ N

a} ~Boc~20, NaOH, dioxane, H20; b) BrCE~2C02Bn, K2C03, acetone; c) 4M HCl, dioxane; d~ (6-amino-2-pyridinyl~acetic acid, EDC, DI~A, DM~; e) lN NaOH, CH30H.
R-1 is treated with di-tert-butyl dicarbonate and sodium hydroxide in aqueous dioxane to af~ord R-2, which is alkylated on the phenolic oxygen with benzyl bromoacetate and pot~sillm carbonate in acetone to give R-3. The Boc group in R-3 is _ W O 97/24122 ~CT~US96~0744 removed with hydrogen chloride in dioxane, and the resulting R-4 is acylated on nitrogen with (6-amino-2-pyridinyl)acetic acid, prepared by saponification of ethyl (6-amino-2-pyridinyl)~ce.t~te, Awaya, et al., Chem. Pharm. Bull. 1974, 22, 1414, EDC and DIEA in DMF to give R-5. The benzyl ester in R-5 is saponified to give R-6. ~l~ern~tively~ the 5 benzyl ester may be cleaved by tre~tm~nt with H2 and a suitable catalyst, such as Pd/C, in a suitable solvent, such as CH30H, EtOH, or AcOH.
~ Scheme S describes a method of ~,epa~ g exemplary fibrinogen IGceplo templates described in Alig, et al., EP 0381033.
Scheme S
CH~ OH a CH~OI I b H~ CO2CH3 NH~ ~ C02CH3 d H2N ~, ICH~ ~COzCH3 C028n H2N~N~ ,CO2H

a) (Boc)20, NaOH, dioxane, H20; b) BrCH2C02CH3, K2C03, acetone; c) 4M HCI, dioxane; d) (6-amino-2-pyridinyl)acetic acid, EDC, DIEA, DMF; e) lN NaOH, CH30H.
1~
S-l is treated with di-tert-butyl dicarbonate and sodium hydroxide in aqueous dioxane to afford S-2, which is alkylated on the phenolic oxygens with methyl W O 97/24122 PCTrUS96/20744 bromoacetate and potassium carbonate in acetone to give S-3. The Boc group in S-3 is removed with hydrogen chloride in dioxane, and the resulting S-4 is acylated on nitrogen with (6-amino-2-pyridinyl)acetic acid, prepared by saponification of ethyl (6-amino-2-pyridinyl)~cet~t~, ~waya, et al., Chem. Pharm. Bull. 1974, 22, 1414, EDC and DIEA in 5 DMF to give S-5. The methyl esters in R-5 are cleaved by LlG~ t with lM NaOH in CH30H to give S-6.

W O 97/24122 PCTAUS96~0~44 Scheme T describes a method of preparing exemplary fibrinogen receptor templates described in ~im mP.l~hach, etal., EP 0587134.

Scl~e,--e T

H~N~ _ NH~
CO2Et HO CO2Et ~/ b ~N ~ CO2Et HO

c,d --N--4 ~3~CO2Et 1 ~,f 4 H2N ~ S C02H

a) glycolaldehyde dimer, NaBH3CN, H20, CH3CN, pH 6-7; b) (6-phth~limi~lo-2-pyridinyl)m~P.th~n~mint~, COC}2; c) CH3SO2Cl, Et3N, CH2C12; d) NaI, KN(TMS)2 THF, acetone, reflux; e) NH2NH2 H20; f~ 1 N NaOH, E~tOH.

PCTrUS96/20744 Scheme T provides a method for the preparation of 2-oxo-imidazolidine compounds, e.g., T-5, wherein reductive arnination of an amine, for example T-1, with glycolaldehyde dimer and sodium cyanoborohydride, gives a secondary amine, such as T-2. A primary amine, as exemplifled by (6-phth~limido-2-pyridinyl)m~th~n~n ine, is 5 treated with phosgene to give an isocyanate, which is allowed to react, without isolation, with the secondary hydroxyethylamine to give a hydoxyethylurea, as exemplified by compound T-3. The hydroxyl group is converted into a leaving group, such as a methanesulfonate or iodide, and is allowed to cyclize to a 2-oxo-imidazolidine, T-4, employing methods known in the art, ~immPl.~bach, et al., EP 0587134, such as treating 10 the hydroxyethylurea 4 with trifluorosulfonyl chloride and Et3N, followed by NaI and then potassium bis(trimethylsilyl)azide, as described in Himmelsbach, et al., EP 0587134, ~xample III. Treatrnent of T-4 with hydrazine and saponification of the ester give T-5.

W O 97~24122 PCTrUS96/20744 Scheme U provides a method for the ~ a~alion of 1,2,3,4-tet~ahydroisoquinoline compounds as exemplary fibrinogen receptor antagonists, as described in M. J. Fisher et aL, EP 0635492.
~ S.'--neU
MeO~C~Nr MeO~[~N~CO2Et HO~ CF3SO3 ~C~
N ~ CO2Et N ~ CO2Et H2N~NH~ e HO2C~
N~CO2Et N~CO2Et H2N~NH~ ~N~CO2H

a~ ClCH2C02Et, Et3N, DMF; b) BBr3, CH2C12; c) (CF3S02)20, pyridine; d) CO, Pd(OAc~2, PPh3, DIEA, NMP, NH4HCO3, H20; e) (6-amino-2-pyridinyl)meth~n~minP, - EDC, HOBt, DIEA, DMF; i~ (6-amino-2-pyridinyl)m~.th~n~mine, CO, Pd(OAc)2, PPh3, 10 DIEA, NMP, NH4HCO3, H2O; g) lN NaOH, EtOH.

~ Accordingly, a 6-methoxy-3,4-dihydroisoquinoline, such as compound U-1 is prepared by the method described by D. J. Sall and G. L. Grunewald, J. Med. Chem.
1987, 30, 2208-2216. The isoquinoline is treated with a h~lo~cetic acid ester in the presence of a tertiary amine to afford the 2-acetic acid ester, as exemplified by compound U-2. The 6-methoxy compound is converted into the corresponding 6-hydroxy compound by methods known in the art, for example with BBr3, which is converted into the triflate with trifluorosulfonic acid anhydride. Palladium-catalyzed carbonylation affords the 6-5 carboxy compound, such as compound U-5, which is then condensed with an amine, as exemplified by (6-atnino-2-pyridinyl)meth~n~mine, employing a standard amide bond forming reagent to give the desired arnide, such as compound U-6. Saponification affords the title compound of Example W, U-7. Alternatively, the palladium-catalyzed carbonylation reaction with the triflate, exemplified by compound U-4, may be trapped 10 with (6-amino-2-pyridinyl)m~-fh~n~mine to provide, after saponification, the compound of Example W, U-7.

W O 97/24122 PCT~US96~0744 Scheme V provides a method for the preparation of 3,4-dihydroisoquinolin- l-one compounds as exemplary fibrinogen receptor antagonists, as described M. J. Fisher et al., EP 0635492.
.

Scheme V
MeO~ MeO~ b NH ~N~CO2Et ~ 2 ~

HO~ ~ ~N~co2Et 3 O ~ 4 ~

o H2N~f NHJ~ e HO2C~
N~CO2Et ~f N ~,CO2Et 6 ~ 5 ~
'O lg H2N ~ NH~N ~ CO2H

a) 1. LiN(TMS)2, 2. ClCH2C02Et, DMF; b) BBr3, CH2C12; c) (CF3S02)20, pyridine;
d) CO, Pd(OAc)2, PPh3, DIEA, NMP, NH4HCO3, H2O; e) N-(2-10 pyridinyl)ethylene~ min~, EDC, HOBt, DIEA, DMF; f) (6-amino-2-pyridinyl)meth~n~minl~7 CO, Pd(OAc)2, PPh3, DIEA, NMP, NH4HCO3, H20; g) lN
NaOH, EtOH.

W O 97/24122 PCT~US96/20744 Accordingly, the 1-oxo compound V-l, prepared by the method described by D. J.
Sall and G. L. Grunewald, J. Med. Chem. 1987, 30, 2208-2216, is treated with a base, such as LiN(TMS)2, and a haloacetic acid ester to give a 2-acetic acid ester, asexemplified by compound V-2. The 1-oxo compound is then employed in the analogous S series of reactions deployed in Scheme U, sub~LiLuLi~lg the cu,l~s~ollding l-oxo analog, as shown in Scheme U, to provide the title compound of Example X, V-7. As in Scheme IJ, alternatively, the p~ 1ium-catalyzed carbonylation reaction with the triflate, exemplified by compound V-4, may be trapped with an amine, such as (6-amino-2-pyridinyl)meth~n~mine, provides, after saponification, the amide exemplified by the title 10 compound of Example X, V-7.
Scheme W provides a method for the preparation of 6-acylaminotetralin compounds as exemplary fibrinogen receptor antagonists, as described M. J. Fisher et al., EP 0635492.

Scheme W
H2N~ a b N~CO2tBu o N~CO2H

a) (6-amino-2-pyridinyl)acetic acid, EDC, HOBt, DIEA, DMF; b) TFA, CH2C12.
2(}
Accordingly, a 6-arnino-2-tert-butyloxycarbonyl-tetral-1-one, exemplified by compound W-1, which is prepared according to the methods described in M. J. Fisher et al., EP 0635492, is condensed with an activated derivative of a carboxylic acid obtained ~6-arnino-2-pyridinyl)acetic acid to provide, after deesterification, the amide exemplified 2~ by the title compound of Example Y, W-2.

W O97124122 PCT~US96~0744 Scheme X provides a method for the preparation of 6-~mino~cyltetralin compounds as exemplary fibrinogen receptor antagonists, as described M. J. Fisher et a., EP 0635492.

S Scheme X
HO~ ~ o~CO7E2 H2N ~f NH~ c HO2C~CO2Et O le H~N~NH~co2H

a) (CF3SO2)O, pyridine; b) CO, Pd(OAc)2, PPh3, DIEA, NMP, NH4HCO3, H2O; c(6-amino-2-pyridinyl)mtoth~n~mine, E~C, HOBt, DIEA, DMF; d) (6-amino-2-pyridinyl)m~thslnzlmin~ CO, Pd(OAc)2, PPh3, DIEA, NMP, NH4HCO3, H20; e) lN
NaOH, EtOH.

Accordingly, an ethoxycarbonylmethyl-6-hydroxy-tetral-1-one, exemplified by compound X-1, which is prepared according to the methods described in M. J. Fisher et 15 al., EP 0635492, is treated with triflic anhydride to provide the triflate, as exemplified by compound X-2, which is employed in a p~ m-catalyzed call,onylation reaction to afford a carboxylic acid, such as compound X-3, which is then condensed with an amine such as (6-amino-2-pyridinyl)...~t~ min~ to provide, after ~leest.orification, the 6-W O ~7/24122 PCT~US96/20744 aminoacyl compound e~cernrlified by Example Z, X-5. ~Itt~.rn~tively, the p~ m-catalyzed carbonylation reaction with the triflate exemplified by compound X-2, may be trapped with (6-amino-2-pyridinyl)m~.th~n~mine to provide, after saponification, tne corTesponding 6-aminoacyl compound X-5.
S Scheme Y provides a method for the p~ dlion of 5-acylarninobenzofuran and 5-acylaminodihydrobenzofuran compounds as exemplary fibrinogen receptor antagonists, as described in M. L. Denney, et al., EP 0655439.

Scheme Y
02N~[~CHO a 02N~CHO

02N~ EtO2P~OEt ~CO2Et H2N~ + ~0~CO2Et lf'9 lf'~
H2N~NH~ , ~NH~co2H
a) BrCH2C02Et, K2co37 NaI, THF; b) 1. DB [J, EtOH, 2. HCI, EtOH; c) DiBAL, -78~C, THF; d) NaH, THF; e) H2, 10% Pd/C, EtOH; f) (6-amino-2-pyridinyl~acetic acid, EDC, HOBT, Et3N, DMF; g) lN NaOH, CH30H.

PCT/USg6~20744 Accordingly, a S-nitrosalicylaldehyde, exemplified by co~ uulld Y-l, is treated with a haloacetic acid ester to give the phenoxyacetic acid ester, exemplified by compound Y-2. A 2-alkoxycarbonylfuran, exemplified by co~ oulld Y-3, is obtained by treating the aldehyde with base, for example with DBU. The 2-alkoxycarbonyl group is S reduced to the aldehyde, for example with DiBAL. Wittig reaction affords the 2-acrylate ~ ester, exemplified by compound Y-5, which is reduced to the benzofuran-2-propionic acid ester, exemplified by compound Y-6 and the dihydrobenzofuran-2-propionic acid ester, exemplified by compound Y-7. The amine Y-6 is then condensed with an activated derivative of a carboxylic acid, such as (6-amino-2-pyridinyl)acetic acid, to provide, after 10 ~l~csle. ;r~ tion, the amide exemplified by the title co~ ound of Example AA, Y-8.
~ltern~tively, the amine Y-7 is condensed with an activated derivative of a carboxylic acid, such as (6-amino-2-pyridinyl)acetic acid, to provide, after dççsterifi~tion, the amide y g.

W O 97/24122 PCTrUS96/20744 Schemes Z-l, Z-2 and Z-3 provide a method for the p.tl~al~lion of 5-aminoacylbenzofuran and 5-~mino~yldihydrobenzofuran compounds as exemplary fibrinogen receptor antagonists, as described in M. L. Denney, et al., EP 0655439.

S ScL~ e Z-l HO~CO2Et -- ~CO2Et TBDMSO ~ EtO2P ~ TBDMSO ~ CO2Et ~/d,e HO~CO2Et HO~CO2Et a) TBDMS-CI, imidazole, THF; b)DiBAL, -78~C, THF; c) NaH, THF; d) H2, 5% Pd/C, EtOH; e) Et4NF, THF.

PCT~US96~0744 Scheme Z-2 HO~OO Et CF3503~oo2Et 6 d O
H2N~ NHJ~ HO2C~

O CO2Et ~ CO2Et l e O

H2N~\NHJ~ CO2H

a) (CF3SO2)20, pyridine; b) CO, Pd(OAc)2, PPh3, DIEA, NMP, NH4HCO3, H20; c) (6-amino-2-pyridinyl)m~oth~n~mine, EDC, HOBt, DIEA, DMF; d) (6-amino-2-pyridinyl)m~th~n~mine, CO, Pd(OAc)2, PPh3, DIEA, NMP, NH4HCO3, H20 e) lN
NaOH, EtOH.

W O 97~24122 PC~rUS96~0744 S~ Z-3 HO~,~ ~ CF3SO3~ , W - o>~co2Et ~--o>~~~2H

H2N~NHJ~ ~ HO2C~
~ C02Et ~ CO2Et O 1 e H2N~NH~ ~ ~CO2H

a) (CF3S02~20, pyridine; b) CO, Pd(OAc)2, PPh3, D~A, NMP, NH4HCO3, H20; c) (6-amino-2-pyridinyl)meth~nz-mine, EDC, HOBt, DIEA, DMF; d) (6-amino-2-pyridinyl)m~thSlnzlmine, CO, Pd(OAc)2, PPh3, DIEA, NMP, NH4HCO3, H20; e) lN
NaOH, EtOH.

Accordingly, a 5-hydroxybenzofuran-2-carboxylic acid ester, such as compound Z-l-l, prepared in the manner of M. L. Denney, et al., EP 0655439, is treated with TBDMS-~l to provide the TBDMS deliv~tiv~ of the ester, Z-1-2. The ester is reduced to an aldehyde, such as compound Z-1-3. Wittig reaction affords an acrylic acid ester, as çxemplified by compound Z-1-5. Catalytic reduction affords a benzofuran-2-acetic acid ester and a dihydrobenzofuran-2-acetic acid ester. Cleavage of the silyl ether group of each ester, by methods known to the art, affords a benzofuran-2-acetic acid ester, as exemplified by compound Z-1-6 and a dihydrobenzofuran-2-acetic acid ester as exempli~led by compound Z-1-7.

W O 97/24122 PCT~US96~0744 As shown in Schemes Z-2 and Z-3, each phenol may be converted to a carboxylic acid via p~lk~ m-catalyzed carbonylation, such as compound Z-2-9 or Z-3-13, which are then con(l~n.~e(l with an amine, such as (6-amino-~-pyridinyl)meth~nz~mint-, to provide, after deesterification, the amide of the title c~ ou--d of Example CC (Z-2-11) 5 or DD ~Z-3-15). ~ltPrn~tively, the p~ m-catalyzed carbonylation reaction with the - triflates exemplified by compounds Z-2-8, or Z-3-12, may be trapped with (6-amino-2-pyridinyl~m~th~n~min~ to provide, after deestP.rific~tion, the c~--es~onding 6-~n~in~ryl compounds, Example CC (Z-2-11) or DD (Z-3-15).
Scheme AA describes a method of ~lGpa~ g a fu~her exemplary fibrinogen 10 receptor template.

Scheme AA

l l a,b O l l c H2N CO2Et H2N ~ NH ~ C02Et H2N ~ NH ~ N ~ CO2Et d o 11 H2N ~ ~ NHJ~ N ~ CO2H

o a) Boc-Gly, EDC, HOBT, DIEA, CH3CN; b) TFA, CH2C12; c) 4-(6-amino-2-pyridinyl~butanoic acid, EDC, HOBT, DIEA, DMF; d) lN LiOH, THF, CH3CN.

The preparation of the interm~rlizltl~. AA-2 begins with the coupling of the known ethyl 3-amino~-pentynoate (WO 93/07867) with commercially available tert-W O 97124122 PCTrUS96/20744 butoxycarbonylglycine ~Boc-Gly) under standard peptide bond forming conditions. The product of this reaction is deprotected to AA-2 under acidic conditions which are known to effect removal of a Boc protecting group. The two interm~ t~,c AA-2 and 4-(6-arnino-2-pyridinyl)butanoic acid are coupled under standard peptide coupling conditions S to give AA-3, which is hydrolyzed to AA-4 with lithium hydroxide in aqueous THF and CH3CN.
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, tlydrofluoric, 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 ~lk~lin~ reagent, such as a hydroxide, carbonate or ~lkoxic~e, cont~ining the a~l~liate cation; or with an ~plvpliate organic amine.Cations such as Li+, Na+, K+, Ca++, Mg~ and NH4+ are specific examples of cations present in pharm~eutically acceptable salts.
This invention also provides a ph~rm~cellti~l composition which comprises a compound according to formula (I) and a pharm~eutir~lly acceptable carrier.
Accordingly, the compounds of formula (I) may be used in the manufacture of a medicament. Ph~rm~-elltical compositions of the compounds of formula (I~ prepared as hereinbefore described may be form~ as solutions or lyophilized powders for parenteral ~-iminictration. Powders may be reconctitllted by addition of a suitable diluent or other ph~rm~reutically acceptable carrier prior to use. The liquid fi~rm~ tion may be a buffered, isotonic, aqueous solution. Examples of suitable ~lilllentc are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formlll~tion is especially suitable for parenteral ~tlminictration, but may also be used for oral ~(1minictration or contained in a metered dose inhaler or nebulizer for incll~flAtion. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, m~nnitol, sodium chloride or sodium citrate.
~ltern~t~ly, these compounds may be encapsulated, tableted or ~l~al~,d in a emulsion or syrup for oral a lminictration. Ph~ reutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, m~ne~illm stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid 3~ carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sllct~inçcl release m~t~ri~l such as glycclyl mono~le~al~ or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between W O 97124122 PC~US96nO74~

about 20 mg to about 1 g per dosage unit. The ph~rm~eutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, gr~n~ tin~, and compressing, when necessary, for tablet forms; or milling, mixing and fil}ing for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
Such a li~uid formulation may be ~(lmini~tcred directly p.o. or filled into a soft gelatin C~I)S~
For rectal ~lminictration, 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 inct~nçe" these compounds are useful for the tre~tm~nt of diseases wherein loss of the bone matrix creates pathology.
Thus, the instant compounds are useful for the treatment of ostoeporosis, hyperparathyroidism, Paget's flice~ce, lly~ ;alcemia of m~ n~ncy, osteolytic lesions produced by bone mPt~ctAci~, bone loss due to imrnobilization or sex hormone deficiency.
The compounds of this invention are also believed to have utility as antitllmnr,~ntiinllAmm~tory, anti-angiogenic and anti-metastatic agents, and be useful in the treatment of cancer, atherosclerosis and restenosis.
The peptide is A-lminictered either orally or parenterally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption, or other such indication. The ph~rrn~reutic~l composition cont~ining tne peptide is ~ mini~tered at an oral dose of between about 0.1 to about 50 mg/kg in a manner conci.ctent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/l~g.
For acute therapy, parenteral ~lmini~tration is preferred. An hlll~v~llous infusion of the peptide in 5% dextrose in water or normal saline, or a sirnilar formulation with suitable excipients, is most effective, although an intr~mllscul~r bolus injection is also useful.
Typically, the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg. The compounds are zl~imini~t~.red 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 tne compounds are ~rlmini~tered is readily determined by one routinely skilled in the art by comp~ring 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 theconcentration of compound which is required to have a given pharmacological effect.

W O97/24122 PCTrUS96/20744 INHIBITION OF VITRONECTIN BINDING
Solid-Phase [3H]-SK&F-107260 Binding to av~3: Human placenta or human platelet ocv,~3 (0.1-0.3 mg/rnL) in buffer T ~cnnt~ining 2 mM CaC12 and 1% octylglucoside) was diluted with buffer T cont~ining 1 mM CaC12, 1 mM MnCI2, 1 mM MgCl2 (buffer A) S and 0.05% NaN3, and then immP(1i~tely added to 96-well ELISA plates (Corning, New York, NY) at 0.1 mL per well. 0.1 - 0.2 llg of av~l33 was added per well. The plates were incubated overnight at 4~C. At the time of the e~e. i ., .f .nt, the wells were washed once with buffer A and were incubated with 0.1 mL of 3.5% bovine serum albumin in the sarne buffer for 1 hr at room temperature. Following in- llb~tion 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 MnC12, 1 mM Mgcl2) to a final compound concentration of 100,uM. This solution is then diluted to the required final compound concentration. Various 1~ concentrations of unlabeled antagonists (0.001 - 100 IlM) 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 te~ eldture. Following incubation thewells 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 ~letermin~(l by liquid scintillation counting with the addition of 3 mL Ready Safe in a Beckm~n LS L}quid Scintillation Counter, with 40%
efficiency. Nonspecific binding of r3H]-SK&P-107260 was ~letermin~cl in the presence of 2 ~M SK&F-107260 an-d was consistently less than 1% of total radioligand input. The ICso ~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 K; (dissociation constant of the antagonist) was calculated according to the equation: Kj = ICso/(1 + L/Kd), where L and Kd were the concentration and the dissociation constant of [3H~-SK&F-107260, respectively.
Compounds of the present invention inhibit vitronectin binding to SK&F 107260 in the concentration range of 0.01 to 25 micromolar. Preferred compounds inhibitvitronectin binding at a concentration of less than 1 micromolar.
Compounds of this invention are also tested for in vifro and in vivo bone resorption in assays standard in the art for evaluating inhibition of bone formation, such as the pit formation assay disclosed in EP 528 587, which may also be ~-e.r~ ed using 35 human osteoclasts in place of rat osteoclasts, and the ova~ oi,~l rat model, described by Wronski et al., Cells and Materials 1991, Sup. 1, 69-74.

_ W O 97/24122 PCTrUS96/20744 PAl~ATIIYROIDECTOMIZED RAT MODEL
Each ~ l group consists of 5-6 male Sprague-Dawley rats. The rats are parathyroide-;lull~i;~d (by the vendor, Taconic Farms) 7 days prior to use. Twenty four hours prior to use, circ~ tin~ ionized c~lrillm levels are measured in whole blood imm~Ai~tely after S it has been withdrawn by tail vGnil,u.lcture into h~ tubes. Rats are included if ionized Ca level (lllca~ul~d with a Ciba-Corning model 634 c~lcillm pH analyzer) is 21.2 mM/L. The rats are then put on a diet of calcium-free chow and deionized water. At the start of the e~ lellL the rats weigh a~pro~ llately 100g. Baseline Ca levels are measured and the rats are ~rlmini~tered control vehicle (saline) or compound (dissolved in saline) as a single 10 intravenous (tail vein) bolus injection followed imm~ tely by a single sllbcllt~n~ous injection of either human parathyroid hormone 1-34 peptide ~hPTHI-34, dose 0.2mglkg in saline/0.1~o 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 ~Amini~tration.

Each ~ group consists of 8-10 male Sprague-Dawley or Wistar rats of approximately 3040g body weight at the start of the experim~nt The agent being tested is ~Aminict~red by an a~ plo~liate route as single or multiple daily doses for a period of seven days. Prior to ~flminictr~fion of the first dose, the rats are given a single dose of a fluorescent 20 marker (tetracycline 25mg/kg, or calcein 10mg/kg) that labels the position of bone forming sllrfaeç~ 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 mi~lch~ft region of the ulna are cut in the cryostat. The rate of bone resorption is 25 measured molphometrically in the medial-dorsal portion of the cortical bone. The mea~u~ ent is done as follows: the amount of bone resorbed at the periosteal surface is equal to the Ai~t~nre by which the periosteal surface has advanced towards the fluorescent label which had been incol~ul~ted at the ~nAost~l bone formation surface on day zero; this ~ t~nre is c~k ~ tP-d by subtracting the width of bone between the label and the periosteal surface on 30 day 7 fro~n the width on day zero; the resorption rate in microns per day is calculated by dividing the result by 7.

HUMAN OSTEOCLAST RESORPTION ASSAY ("PIT ASSAY") ~ Aliquots of osteoclastoma-derived cell ~u~pensions are removed from liquid nitrogen 35 strorage, warmed rapidly at 37~C and washed xl in RPMI-1640 m.-A~Ilm by cc~l.iru~ion (1000rpm, 5 mins at 4~C).

CA 0224l724 l998-06-26 W O97/24122 PCT~US96/20744 ~ Aspirate the medium and replace it with murine anti-HLA-DR antibody, diluted 1:3 in RPMI-1640 medium. Incub~te for 30 mins on ice and mix the cell sllspension frequently.
~ The cells are washed x2 with cold RPMI-1640 by centrifugation (lOOOrpm, 5 mins at 4~C~ and the cells are Lldll~.re~lcd to a sterile 15 ml centrifuge tube. The number of S mononuclear cells are enumerated in an improved Neubauer counting chamber.
~ Sufficient magnetic beads (5 / mononuclear cell), coated witn goat anti-mouse IgG, are removed from their stock bottle and placed into 5 mI of fresh m~-1ium (this washes away the toxic azide preservative). The m~ m 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 incllbz-ft~d for 30 mins on ice.
The suspension is mixed frequently.
~ The bead-coated cells are immobilized on a magnet and the rem~ining cells (osteoclast-rich fraction) are decanted into a sterile 50 ml centrifuge tube.
~ Fresh m-o-lium 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.5xlO4/rnl in EMEM mP~ m, supplçm~nted with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate.
~ 3ml aliquots of the cell suspension ( per treatment) are decanted into 15ml centrifuge tubes. The cells are pelleted by centrifugation.
~ To each tube 3ml of the appropliate treatment are added (diluted to 50 uM in the EMEM medium). Also included are ~?pl~l;ate vehicle controls, a positive control (87MEMl diluted to 100 ug/ml) and an isotype control (IgG2a diluted to 100 ug/ml).
Incubate at 37~C for 30 mins.
O.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 3(~ then placed into fresh treatment or control. Incubate at 37~C for 48 hours.tartrate r. :~qnt acid P~ qtq~e ~trap) ~ ~)ce-lul ~ (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.
~ T~ey 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 rnins at 4~C.

W O 971Z4122 PCT~US96~0744 ~ 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.
s ~ ~NHIBITION OF RGD-MEDIATED GPIIB-IIIA BINDING
pnri~ tion of GPIIb-ma Ten units of olltfl~t~ , 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 10 mM CaCl2 at 4~C for 2 h. The lysate was centrifuged at 100,000g for 1 h. The sur~rn~t~nt 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%
octylglllcosi(1~ (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 cont~tining lO~o 15 dextrose. All procedures were performed at 4~C. The GPIIb-IIIa obtained was >95%
pure as shown by SDS polyacrylamide gel electrophoresis.

Incorporation of GPIIb-IIIa in Liposomes.
A rnixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti 20 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 protein:phospholipid ratio of 1:3 (w:w). The mixture was resuspended and sonicated in a bath sonicator for 5 min. The mixture was then dialyzed overnight using 12,000-14,000 molecular weight cutoff dialysis tubing against a 1000-fold excess 25 of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes). The GPIIb-ma-cont~ining 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 nçecle-l 30 Competitive Binding to GPIIb-IIIa The binding to the fibrinogen receptor (GPIIb-ma) was assayed by an indirect competitive binding method using [3H]-SK&F-107260 as an RGD-type ligand. The b~ding assay was ~ roll,.ed in a 96-well filtration plate assembly (Millipore Corporation, Bedford, MA) using 0.22 um hydrophilic durapore membranes. The wells 35 were precoated with 0.2 mL of 10 ,ug/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at room te~ ?el~t~ for 1 h to block non~pecific binding. Various concentrations of unlabeled ben7~ 7~pines were added to the wells in quadruplicate. [3H]-SK&F-W O 97/24122 PC~AUS96/2074~

107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 ,ug of the purified platelet GPIIb-IIIa-cont~inin~ liposomes. The mixtures were incubated for 1 h at room te~ e.dlule. The GPIIb-ma-bound [3H]-SK&F-107260 was seperated f~om the unbound by filtration using a Millipore filtration manifold, 5 followed by washing with ice-cold buffer (2 times, each 0.2 rnL~. Bound radioactivity rem~ining on the filters was counted in 1.5 mL Ready Solve (Beckman In~ e~
Fullerton, CA) in a P~eckm~n Liquid Sçintill~tion Counter (Model LS6800), with 40~0 ef~lciency. Nonspecific binding was~~etermin~-l in the presence of 2 ~M unlabeled SK&F-107260 and was con~i~t.olltly less than 0.14% of the total radioactivity added to 10 the sarnples. All data points are the mean of quadruplir ~tt~ 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 eql ilihrillm dissociation constant (Ki) of the antagonist based 15 on the Cheng and Prusoff equation: Ki - IC501(1+L/Kd), where L is the concentration of ~3H]-SK&F-107260 used in the colllpeliliv~ binding assay (4.5 nM), and Kd is thedissociation constant of [3H~-SK&F-107260 which is 4.5 nM as cll termined by Scatchard analysis.
Preferred compounds of this invention have an affinity for the vitronectin receptor 20 relative to the fibrinogen receptor of greater than 4: 1. More preferred compounds have a ratio of activity of greater than 10: 1.

Vascular smooth muscle cell ~ lion assay The compounds of the instant invention were tested for their ability to inhibit the 25 migration and proliferation of smooth muscle tissue in an artery or vein in order to assess their ability to prevent restenosis of an artery, such as that which typically occurs following angioplasty.
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 30 p~res of 8 um (Costar). The lower surface of the filter was coated with vitronectin. Cells were suspended in DMEM supplem~.nt~d with 0.2% bovine serum albumin at a concentration of 2.5 - 5.0 x 106 cells/rnL, 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 c~ al ~ ellt of the chamber. The 35 lower compartment contained 0.6 mL of DMEM supplemented with 0.2% bovine serum albumin. Incubation was carried 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.

t F
Nuclear m~nPtic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDC13 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD30D is tetradelltP.ric mPthanol. ~hPmie~l shifts are reported in parts per million (o) 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, a~p-~palelll, br=broad. J in(lie~tes the NMR coupling constant measured in Hertz. Infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared s~e~ olllGtel in tr,-n~mi~ion mode. IR band positions are reported in inverse wav~llullll~e.~ (cm-l). Mass spectra were taken on either VG 70 FE, PE Syx API m, or VG ZAB HF instrum~nt~, using fast atom bombal.illlent (FAB) or electrospray (ES)ionization techniques. FlemPnt~7l analyses were obtained using a Perkin-Elmer 240C
elemental analyzer. Melting points were taken on a Thomas-Hoover melting point aL)~aldLLls 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 chl~ulliat~graphy. 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 Be(~'~mzln chromatographs. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5 ~1 Apex-ODS in~lic~t~s an octadecylsilyl derivatized silica gel chromatographic support having a nl~min~l particle size of 5 ~, made by Jones Chromatography, Littleton, Colorado. YMC ODS-AQ~) is an ODS chromatographic support and is a registered tr~ Pm~rk of YMC Co. Ltd., Kyoto, Japan. PRP-1~) is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered tr~lPm~rlc of ~milton Co., Reno, Nevada. Celite(~ is a filter aid composed of acid-washed ~ t~mzlreous silica, and is a registered tr~-lPm~rk of Manville COIP., Denver, Colorado.
Methyl (+)-7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-lH-1,4-ben7o~ 7~pine-2-acetate and methyl (+)-7-carboxy-2,3,4,5-tetrahydro-3-oxo~-phenylethyl-lH-1,4-benzodiazepine-2-acetate was prepared by the method of Bn~-lin~ll et al. WO 93/00095.
Tert-butyl 3-(l),ulllolllethyl)-4-fluorobel zoate and methyl ~S)-7-carboxy-2,3,4,5-W O 97124122 PCTrUS96/20744 tetrahydro-4-methyl-3-oxo-lH-1,4-benzodiazepine-2-acetate was prepared by the method of Bondinell et al. WO 95/18619.

PREPARATION OF INTERMEDIATE COMPOUNDS
s Prepar~tion A

Pl~dtion of Ben7,yl 3-r3~4-dihyro-8-carboxy-1-methyl-2.5-dioxo-lH-1.4-benzodiazepinel-4-propanoate a) 4-Iodo-2-amino benzoic acid Oxidation of 4-iodo-2-nitrotoluene according to Sasson, et. al., J. Org. Chem.
1986, ~1, 2880-83, to give 4-iodo-2-nitro benzoic acid followed by reduction of the nitro group using iron and acetic acid gives the title compound.
b) 7-Iodoisatoic anhydride To a mechanically stirred ice cold solution of the compound of Plc~udlion A(a) (2Ç.3 g, 0.1 mol), Na2CO3 (10.6 g, 0.1 mol) and H2O (250 mL), is slowly added, via an addition funnel, a solution of 1.93M COC12 in toluene (80 mL). After 2 h, the ~lG.ii~iLat~d product is isolated by filtration, and the solid is washed ~uccç~sively with H2O (200 mL), a 1: l mixture of EtOH:Et2O (300 rnL), and Et2O (200 mL), and dried under vacuum to yield the title compound.

c) Benzyl N-(2-amino4-iodobenzoyl)-,13-alanine A n~gneti~ ~lly stirred solution of the compound of Preparation A(b) (5.0 g, 0.0173 mol)"B-alanine benzyl ester tosylate (5.85 g, 0.0173 mol), and DMAP (0.5 g, 0.0041 mol) in pyridine (35 mL) is heated for 2 h at 80~ C. The reaction mixture is allowedl to cool to RT and concentrated. The rçsl-lting residue is dissolved in EtOAc (100 mL), and washed successively with 10% cupric sulfate (2 x 50 mL), saturatedNa~ICO3 ~1 x 50 mL) and brine (1 x 50 mL), dried (Na2S04), filtered, and concentrated to afford the title compound after chromatography (silica gel, 1: 1 EtOAc/hexanes).

W O 97124122 PCT~US96~0744 d) BenzylN-(2-methylamino-4-iodobenzoyl)-,~-alanine A magnetically stirred solution of the compound of Plc~dtion A(c) (2.0 mmol), 2,6-lutidine (0.35 mL, 3.0 mmol) and CH3I (0.19 mL, 3.0 mmol) in DMF (15 rnL) isheated at 50~C for 15 h. The reaction mixture is allowed to cool to RT and concentrated.
S The re.sl-lting residue is dissolved in EtOAc (75 mL), and washed successively with 10 Yo citric acid (1 x 50 rnL), saturated NaHCO3 (1 x 50 mL) and brine (1 x 50 mL), dried (Na2SO4), filtered, and concentrated to afford the title compound after chromatography (silica gel, gradient, 35-65% EtOAc/hexanes).

e) Benzyl3-[3,4-dihyro-8-iodo-1-methyl-2,5-dioxo-lH-1,4-benzodiazepine}-~
propanoate To a cold (-30~C) magnetically stirred solution of the compound of Pr~aldtion A(d) ~0.305 g, 0.69 mmol), Et3N (0.144 g, 1.04 mmol) in CH2C12 (3 mL) is added slowly a solution of a-bromoacetyl brornide (0.09 rnL, 1.04 mmol) in CH2C12 (2 rnL) 15 under argon atmosphere. The reaction rnixture is allowed to warm to RT and stir for 2 h.
The mixture is diluted with CH2C12 (40 rnL) and washed succes~ively with 10% citric acid (1 x 50 mL), saturated NaHCO3 (1 x 50 mL), dried (Na2S04), filtered, and concentrated. The res-~lting residue is dissolved in DMF (3 rnL) and added via an addition funnel to a slurry of NaH (25 mg, 1.04 mmol) in DMF (2 mL) which is cooled to 20 0~C. After 2 h of stirring, the ll~ Ule iS poured into an ice cold solution of 10% citric acid (50 r~L) and extracted with EtOAc (3 x 40 mL). The combined extracts are washed with saturated NaHCO3 ~ 1 x 50 mL), dried (Na2SO4), filtered, and concentrated to afford the title compound after chromatography (silica gel, gradient, 40-70% EtOAc/hexanes).

f) Benzyl 3-[3,4-dihyro-8-carboxy-1-methyl-2,5-dioxo-lH-1,4-benzodiazepinel-4-propanoate A solution of the compound of PlGpa,~lion A(e) (3.2 mmol), Pd(OAc)2 (0.16 rnmol), and 1,1'-bis(diphenylphosphine)ferrocene (0.64 mmol, ) in DMSO (20 mL) is heated to 65~C under a carbon monoxide balloon for 18 h. The reaction rnixture is diluted with water, acidified with 1 N HCl and extracted with CH2C12~ The combined W O 97/24122 PCTrUS96/20744 organic extracts are washed with water, dried (Na2SO4), filtered, and concentrated to afford the title co.l.~oulld after chromatography (silica gel).

Preparation B
Ethyl 3-r4H-;midazor 1 '~-a~ r 1 .41benzodiazepine-5(6H)- 1 -mPthyl-6-oxo-9-carboxyl-5-proparloic acid a) Ethyl N-(2-amino-4-iodobenzoyl)-,B-alanine A magnetically stirred solution of the compound of Plep~d~ion A(b) (0~0173 mol), ~13-alanine ethyl ester hydrochloride (0.0173 mol), and DMAP (0.5 g, 0.0041 mol) in pyridine (35 mL) is heated for 2 h at 80~C. The reaction ll~i~lulc is allowed to cool to RT
and concentrated. The resulting residue is dissolved in EtOAc (100 mL), and washed successively with 10% cupric sulfate (2 x 50 rnL), saturated NaHCO3 ( 1 x 50 mL) and brine (1 x 50 rnL), dried (Na2SO4), filtered, and concentrated to afford the title compound after chromatography (silica gel, 1:1 EtOAc/hexanes).

b) Ethyl 3-[3 ,4-dihyro-8-iodo-2,5-dioxo- 1 H- 1 ,4-benzodiazepine]-4-propanoateTo a cold (-30~C) magnetically stirred solution of the compound of Preparation B(a) (0.69 mmol), and Et3N (0.144 g, 1.04 mmol) in CH2C12 (3 mL) is added slowly a solution of a-bromoacetyl bromide (0.09 mL, 1.04 rnmol) in CH2C12 (2 rnL) under argon atmosphere. The reaction rnixture is allowed to warm to RT and stir for 2 h. The mixture is diluted with CH2C12 (40 mL) and wash succes~ively with 10% citric acid (1 x 50 rnL), saturated NaHCO3 ( 1 x 50 rnL), dried (Na2so4)~ filtered, and conce~ dled. The resl-lting residue is dissolved in DMF (3 mL) and added via an addition funnel to a slu~y of NaH (25 mg, 1.04 mmol) in DMF (2 rnL) which is cooled to 0"C. After 2 h of stirring, the mixture is poured into an ice cold solution of 10% citric acid (50 mL) and extracted with EtOAc (3 x 40 mL). The combined extracts are washed with saturated NaHCO3 (1 x 50 rnL), dried (Na2S04), filtered, and concentrated to afford the title compound after chromatography (silica gel).

W O 97/241~2 PCT~U696~0744 c) Ethyl-3-[3 ,4-dihyro-8-iodo-2-thioxo-5-oxo- 1 H- 1 ,4-benzodia_epine]-4-propanoate To a solution of the compound of P~cpa~dlion B(b) (1.0 g, 2.49 mmol) in THF (10 mL) at RT and under an atmosphere of nitrogen is added ~awesson's reagent ( 1.0 g) and 5 the reaction is heated at 50~C for 2 h. The reaction mixture is allowed to cool to RT and is concentrated. Purifying the resulting residue by chromatography (silica gel, gradient, 4Q-60% EtOActhexane) gives the title coml,oulld.

d) Ethyl 3-[4H-imidazo[ 1 ,2-a][ 1 ,4]benzodiazepine-5(6H)- 1 -methyl-6-oxo-9-iodo]-5-10 propanoate To a vigorous}y stirred biphasic solution of the compound of Preparation B(c) (0.95 g, 2.27 mmol), CH3I (0.2 g) and a catalytic amount of tetrabutylammonium hydrogen sulfate in CH2C12 (10 mL) and H20 (10 mL), is added 2 N NaOH (1.2 mL) at RT. After 2 h, the layers are separated and the aqueous layer is washed with CH2C12 (2 x 25 mL). The combined organic extracts are dried (Na2S04), filtered, and concentrated.
The resulting residue is dissolved in toluene (10 mT ) and allowed to react with ~lu~al~yl amine (0.64 mL) and pyridine hydrochloride (0.23 g). The reaction is heated to reflux for 6 h, allowed to cool to RT, and concentrated to give the title compound after chromatography (silica gel, EtOAc).
e) Ethyl 3-[4H-imidazo[1,2-a~[1,4]ben7Orli~7epine-5~6H)-1-methyl-6-oxo-9-carboxy]-5-propanoic acid A solution of the compound of Plcpa,dlion B(d) (3.2 mmol), Pd(OAc)2 (0.16 mmol), and 1,1'-bis(di~llel,yl~hosphine)ferrocene (0.64 mmol) in DMSO (20 mL) is25 heated at 65~C under a carbûn monoxide balloon for 18 h. The reaction ~ Llulc is diluted with H2O, acidified with 1 N HCl and extracted with CH2Cl2 (3 x). The combined organic extracts are washed with H2O, dried (Na2SO4), filtered, and concentrated to afford the title co"lpoulld after chromatography (silica gel).

W O 97124122 PCTrUS96/20744 Pl~al~tion C

p~eparation of Ethyl 4~ d~ yl)- 1 -piperidineacetate 5 a) Ethyl 4-~4-(tert-butoxycarbonyl)-1-~ipe~ yl]-l-piperi~lin~a-~etate The titled compound is prepared from tert-butyl 1-pi~ in~c~rboxylate (Aldrich) and ethyl 4-oxo-1-piperidineacetate (Porter, et. al., EP 0 542 363 A2) by reductive amination with NaBH3CN according to the method of Porter, et. al., EP 0 542 363 A2.

10 b) Fthyl 4-(1-pipcLa~ yl)-1-pip~ri~line~ce.tate A solution of Pr~aldlion C(a) and 4M HCl in dioxane/CH2C12 is stirred at RT
for 18 h. The reaction mixture is concentrated to give the title compound as thehydrochloride salt.

~lc;~al~lion D

Preparation of 6-Methyl-2-(phth~limido)pyrillinP.
A mixture of 6-methyl-2-arninopyridine and neat phthalic anhydride is heated for5 h, diluted with aqueous NaHCO3, and extracted with EtOAc. The combined extracts are dried and evaporated to give the title compound.

Plt;paialion E

Preparation of 3-(6-Amino-2-pyridinyl)propanol a) l-L6-(3-Hydroxypropyl)-2-pyridinyl]-2,5-dimelhyl~yllvle Following the procedure of Warter, et. al., Org. Synth. 1943, 23, 83, for the p~ aldLion of 2-(3-hydro~y~lopyl)pyridine, except substituting 1-(6-methylpyridin-2-yl~-2,5-dimethylpyrrole for the 2-meLhylL,y-idine, J. Chem. Soc., Perkin Trans. 1, 1984, 2801-2807, gives the title compound.

W O 97124122 PCTAUS96~0744 b) 3-(6-Amino-2-pyridinyl)propanol Following the procedure of Bruekelman, et. al., J. Chem. Soc. Perkin Trans. 1, 1984, 2801-2807, for the pl~alaLion of 2-amino-6-ethyl~ylidine, except sub~ g the compound of Plep~Lion E(a) for 1-(6-el~lyl~yl;din-2-yl)-2,5-dim~Lhyl~y,lole, gives the S title co--,poul,d.

Preparation F

Preparation of 4-r6-(Toluenesulfonylamino)-2-pyridinyll-1-propanol oxime a) 4-[6-(2,s-Dilllc;lhyll~yl~ - 1 -yl)-2-pyridinyl]- 1 -butene Following t'ne procedure of Me~kin~, J. Chem. Soc. Perkin Trans. I, 1984, 2801, for the alkylation of 6-(2,5-dimethylpyrrol- 1-yl)-2-picoline, except using allyl brornide as the alkylating agent, the title compound is prepared.
b) 4-(6-Amino-2-pyridinyl)-1-butene Following Procedure B, described Me~kin~, J. Chem. Soc. Perkin Trans. I, 1984, 2801, the compound of Plt~dtion F(a) is deprotected to give the title col,l~oulld.

c) 4-[6-(Toluenesulfonylarnino)-2-pyridinyl]-1-hutene Sodium hydride (55 mmol) is added carefully to a solution of the compound of Pl~alaLion F(b) (50 mmol) and 4-toluenesulfonyl chloride (55 mmol) in dry THF (200 mL). The reaction is stirred at RT until complete, then is quenched with saturated NH4Cl (200 rnL), and the mixture is extracted with EtOAc. The combined organic extracts are dried ~MgSO4) and concentrated, and the residue is purified by chromatography (silica gel) to give the title compound.

d) 4-[~-(Toluenesulfonylamino)-2-pyridinyl l- 1 -propanal Ozone is bubbled into a solution the compound of Pi~;palaLion F(c) (40 mmol) in CH2C12 (160 mL) and CH30H (40 mL) at -78~C until the blue color persists, then the excess ozone is removed by bubbling argon through the solution. Ory dimethylsulfide W O 97124122 PCTrUS96/20744 (excess) is added, and the reaction is warmed to RT. The reaction is stirred at RT until complete, then is concentrated, and the residue is chromatographed (silica gel) to afford the title compound.

S e~ 4-[6-(Toluenesulfonylamino~-2-pyridinyl]-1- propanal oxime Hydroxylarnine hydrochloride (33 mmol) is added to a solution of the compound of Preparation F(d) (30 mrnol) and anhydrous NaOAc (66 mrnol) in CH30H (150 mL) at 0~C. The reaction is stirred at 0~C until complete, then is concentrated, and the residue is partitioned between H20 and EtOAc. The layers are separated, and the aqueous layer is extracted with EtOAc. The combined organic layers are washed sequentially with 5%
NaHC03 and saturated brine, dried (MgS04), and concentrated to afford the title compound.

Prt;l>ala~ion G
p~dtion of (6-Amino-2-pyridinyl)acetiç acid Ethyl (6-amino-2-pyridinyl)~cetStte, Awaya, et. al., Chem. Pharm. Bull., 1974, 22, 1414, (1 rnrnol) is treated with lN NaOH (1.5 mmol) in CH30H (20 mL). The rnixture is concentrated, extracted with CH2C12, and the aqueous phase is adjusted to pH 5 to give the title compound.

Preparation H

Ple~ation of 6-(2-Arninoethyl)-2-pyri-lin~rnine dihydrochloride ~ollowing the procedures of P'~ lion 13 in Bondinell, et al., WO 94/14476, for the preparation of 2-aminopyridine-4-eth~n~min~ dihydrochloride, except sub~ uLil,g 2-(acetylarnino)pyridine-6-carboxylic acid for the 2-(acetylarnino)pyridine-4-carboxylic acid, the title compound is prepared.

WO 9712.4122 PCT/US96~20744 P~ )aLation I

P}~ lion of 4-r(6-Amino-2-pyridinyl)methyllphenol 4-[(6-Amino-2-pyridinyl)methyl]anisole, Ife et. al., WO 9426715, is heated with concentrated hydrobrornic acid to afford the title compound.

Preparation J

Ple~aLion of Benzyl 4-r2-(methyl~mino)acetyllphenoxyacetate hydrochloride a) 4-[N-Boc-2-(methylarnino)acetyl]phenol A solution of di-tert-butyl dicarbonate (5.96 g, 27.3 mrnol) in 1,4-dioxane (25 mL) was added dropwise at 0~C to a rnixture of 4-~2-(methylarnino~acetyl]phenol hydrochloride (5.0 g, 24.8 mrnol), 1,4-dioxane (30 mL), H20 (25 mL), and 1.0 N NaOH
(25 mL? 25 rnrnol). After 24 h, the reaction was warmed to RT and stirred for 1.5 h.
More 1.0 N NaOH (25 mL, 25 rnrnol) was added, and the reaction was stirred for an additional 0.5 h at RT, and concentrated. The residue was diluted with EtOAc (80 mL), and the rnixture was acidified to pH 2 using 1.0 M NaHSO4. The resulting rnixture 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%): 1HNMR (250 MHz, CDC13) o 6.70-8.05 (m, 4 H), 4.53 (s, 2H), 2.98 (s, 3H), 1.50 (s, 9H).

b) Benzyl 4-[N-Boc-2-(methylarnino)acetyl]phenoxyacetate A rnixture of the compound of Preparation J(a) (5.04 g, 19.0 mmol) and K2C03 (2.63 g, lg.O rnrnol) in acetone (100 mL) was stirred at reflux under argon for lh. The mixture was cooled to ~T and benzyl bromoacet~t~ (5.23 g, 22.8 rnrnol) 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. The residue was dissolved in CH2C12 (300 mL) and washed sequentially with H20 (50 mL) and brine (50 mL).
~rying (Na2S04), concentration, and flash c~ulllalography ( silica gel, 1:3 W O 97/24122 PCTrUS96/20744 EtOActhexanes) yielded the title compound (7.28 g, 93%): lH NMR (250 MHz, CDCl3) o 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 rnixture of the compound of Preparation J(b) (7.26 g, 17.57 mmol) and 4 M
HCl in 1,4-dioxane (150 mL) was stirred for 1 h at RT. Concelltldtion and trituration with Et2O afforded the title compound as a white powder (5.93 g, 97%): lH NMR (250 MHz, CD30D) ~ 7.05-8.00 (m, 9 H), 5.23 (s, 2H), 4.88 (s, 2H), 4.65 (s, 2H), 2.80 (s, 3H).
Preparation K

Preparation of Dimethyl 4-r2-(methylamino)acetyll-1.2-phenylenedioxydiacetate llydrochloride a) 4-[N-Boc-2-(methylamino)acetyl]-1,2-dihydroxybenzene Following the procedure of PlGpaldLion J(a), except s~lb~iL~ adrenalone hydrochloride (5.0 g, 23.0 mrnol) 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]+.

b) Dimethyl 4-[N-~oc-2-(-methylamino)acetyl]- 1,2-phenylenedioxydiacetate Pollowing the procedure of Pr~al~tion J(b), except substituting the compound of Preparation K(a) (0.9 g, 3.2 mmol) for the compound of P~ alion J(a) and methyl bromc-~ef~te (1.23 g, 8.0 mmol) for benzyl bromoacet~te, the title compound (1.11 g, 81%) was prepared: MS (ES) m/e 426.2 [M+H]+.

CA 0224l724 l998-06-26 W O~7~4122 PCT~US96~0744 c) Dimethyl 4-~N-Boc-2-(methylamino)acetyl]-l~2-phenylenedioxy~ cet~
hydrochloride Following the procedure of Preparation J(c), except subs~ ; the co~ ound of Pl~paldlion K(b) (1.11 g, 2.6 mmol) for the compound of F~epald~ion J(b), the title S compound was prepared (1.1 g, q~ nti~?,tive): MS (ES) m/e 326.0 [M+H]+.

Preparation L

Preparation of (6-Phthaloyl-2-pyridi~yl)meth~n~,nine Following the procedure of Preparation T, except ~,nl~slil.. l;.~ ammonia for methylamine, gives the title compound.

Preparation M

Preparation of Ethyl (6-carboxy-1.23.4-tetrahydroisoquinolin-2-yl~acetate a~ Ethyl (6-Metnoxy- 1 ,2,3,4-tetrahydroisoquinolin-2-yl)acetate A solution of 6-metnoxy- 1 ,2,3,4-tetrahydroisoquinoline, Sall and Grunewald, J.Med. Chem. 1987, 30, 2208-2216, (1.1 rnmol), ethyl chloroacetate (1.17 mmol), and K2CO3 (1.17 mmol) in CH3CN (10 mL) is stirred for 18 h. The mixture is partitioned ~etween EtOAc and H20. The organic phase is concentrated to an oil, which is purified ~y chromatography (silica gel, gradient, 20-80% EtOAc/hexane) to afford tne title compound.

'~ Bthyl (6-Hydroxy- 1,2 ,3 ,4-tetrahydroisoquinolin-2-yl)acetate A solution of the compound of Preparation M(a)(0.249 g, 1.0 mmol), lM BBr3 in CH~C12 (1.0 mL, 1.0 mmol) is stirred at -70~C for 2 h and then stirred at RT for 12 hr.
The solution is concentrated, and the solution of the rç~-lltin~ oil in EtOAc is washed with H2O, ~% NaHCO3, and H2O, dried (Mg2SO4), filtered, and concentrated to an oil to afford the title compound (0.223 g, 95%) -CA 02241724 l99X-06-26 W O 97/24122 PCT~US96/20744 c) l~thyl [6-(trifluoromethy}sulfonyloxy)- 1,2,3,4-tetrahydroisoqulnolin-2-yl]acetate A solution of the compound of Preparation M(b)(0.235 g, 1.0 rnmol), trifluorosulfonic acid anhydride (0.23 rnL, 1.1 mmol,) and Et3N (0.32 mL, 1.5 mmol) in C~I2C12 (5 mL) is stirred for 8 h. The solution is concellL,dtcd to an oil which is taken up in EtOAc. The organic phase is washed with 5% NaHCO3 and H2O. The organic phase is dried (Na2SO4), filtered, concentrated to afford the title compound (0.300 g, 82%) d) Ethyl (6-carboxy- 1,2,3,4-tetrahydroisoquinolin-2-yl)acetate A solution of the compound of Preparation M(c)(0.367 g, 1.0 mrnol), Pd(OAc)2 (0.022 g, 0.1 mmol,), Ph3P (0.262 g, 1.0 mmol), diisopropylamine (0.34 mL, 2.5 mmol), and NMP (5 mL) in 10% NH4CO3 is stirred for 8 h under an atmosphere of CO. The solution is concentrated to an oil which is purified by chromatography (silica gel, gradient, 10-33~o CH3OH/CH2C12) to afford the title compound (0.19 g, 72%).

Pl~l)a,dtion N

Preparation of l~thyl f6-carboxy-1.2.3.4-tetrahydro-1-oxo-isoquinolin-2-yl)acetate a) 3~ithyl (6-Methoxy- 1 -oxo- 1,2,3,4-tetrahydroisoquinolin-2-yl)acetate A ~ LLUl~ of 6-methoxy- 1,2,3,4-tetrahydro- 1-oxo-isoquinoline, Sall and Clunew~ld, J. Med. Chem., 1987, 30, 2208-2216, (0.39 mmol) andNaH (0.17 g, 0.43 mmol, Ç0% oil dispersion) in THF (5 rnL) is heated to reflux for 1 h and then allowed to cool to RT. Ethyl chloro~et~t~ (0.43 rnmol) is added and the mixture is allowed to stir for 1 h. The ~ lwt; is quenched with H20 (10 rnL) and washed with EtOAc. The organic layers are combined, washed with H20 (10 rnL) and concentrated to an oil which is purified by (silica gel, gradient, 10-33% CH30H/CH2C12) to afford the title compound.

W ~97l~4122 PCTAUS96~0744 b) Ethyl (6-Hydroxy- 1 -oxo- 1,2,3,4-tetrahydroisoquinolin-2-yl)acetate A solution of the compound of P~ald~ion N(a) (0.263 g, 1.0 mmol) and lM
BBr3 in CH2Cl2 (1.1 mL) is stirred at -70~C for 2 h and then at RT for 4 h. The solution is conce~tr~t~d to an oil which is taken up in EtOAc. The organic phase is washed with 5 H2O, 5% NaHCO3, H2O, dried (MgSO4), filtered, and concentrated to afford the title compound (0.20 g, 80%).

c~ Ethyl [6-(trifluoromethylsulfonyloxy)- 1,2,3,4-tetrahydro- 1 -oxo-isoquinolin-2-yl]acetate A solution of the compound of Preparation N(b) (3.4 mmol) and trifluorosulfonic acid anhydride (3.4 mmol, mL) in pyridine (5 rnL) is chilled at 0~C and allowed to warm RT for 1 h. The mixture is quenched with H2O (5 mE) and washed with EtOAc. The organic layers are combined, washed with H2O (7 mL) and concentrated to an oil. The residue is purified chromatography (by silica gel, gradient, 14-75% EtOAc/hexane) to 1 ~ afford the title compound.

d) Ethyl (6-carboxy-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)acetate A solution of the compound of Preparation N(c) (0.23 g, 1.0 mmol), Pd(OAc)2 ~0.026 g, 0.1 mmol), Ph3P (0.262 g, 1.0 mmol), diisopropylamine (0.23 mL, 2.0 mmol) and NMP (7 mL~ in 10% NH4CO3 is stirred for 8 h under an atmosphere of CO. The solution is concentrated to an oil which is purified by chromatography (silica gel, gradient, 25-75% CH3OH/CH2Cl2) to afford the title compound (0.31 g, 70%).

Preparation O
P1GP~liOn of Ethyl (6-carboxy-tetralin-2-yl)acetate Ethyl ~6-(trifluoromethylsulfonyloxy)-tetralin-2-yl]acetate Following the procedure of PlG~aldlion M(c), except ~.ul~.Lilu~ g ethyl (6-hydroxy-tetralin-2-yl~ret~tf, Fisher, et. al., EP 0635492, Scheme 6 and Example 20, parts A-D for the compound of Preparation M(b), gives the title compound.

b) Ethyl (6-carboxy-tetralin-2-yl)acetate Following the procedure of P~ )a~dlion M(d), except substitl-tin~ the compound of Preparation O(a) for the compound of Preparation M(c), gives the title compound.
Pr~L,~dlion P

P~ al~Lion of Ethyl (5-aminobenzofuran-2-yl)propionate and ~t~yl (5-amino-2.3-tli~ydro-benzofur~n-2-yllpropionate a) 2-(Ethoxycarbonyl)methoxy~5-nitroben7~klehyde A solution of S-nitrosalicylaldehyde (Aldrich) (0.167 g, 1.0 mrnol), ethyl bromoacetate (0.166 g, 1.0 mmol), K2C03 ( 0.276 g, 2.0 mmol) and NaI (0.015 g, 0.1 rnmol~ in THF (10 mL) is heated to 80~C for 24 h. The solution is concentrated and the lS residue is purified by chromatography (silica gel, gradient, 5-20% CH30H in CH2C12) to afford the title compound (0.20 g, 87%) b) Ethyl (5-nitrobenzofuran-2-yl)carboxylate A solution of the compound of Preparation P(a) (0.229 g, 1.0 mmol) and DBU
~0.152 g, 1.0 mrnol) in EtOH (10 mL) is allowed to stir at RT for 18 h. The solution is concentrated and the residue is treated with EtOH (10 mL). The solution is bubbled with HCl gas for 2 min and refluxed for 5 h. The solution is concentrated and the residue is treated with EtOAc. The organic phase is washed with H2O, 5% citric acid, H2O, 5%
NaHCO3, and H20. The organic phase is con~;e~ d to afford the title compound ~0.19 g, 81%).

c} Ethyl (S-nitroben~ofuran-2-yl)carboxaldehyde A cold solution (-78~C) of the compound of Example 20(b) ( 0.235 g, 1.0 mmol) in THF (5 rnL) is treated with lM DiBAL in THF (1.0 mL, 1.0 mmol). The solution is stirred at -78~C for 30 min and at RT for 3 h. The solution is treated with CH3CO2H (3 mL) followed by H20 (2 mE). The solution is concentrated and the residue is treated _ W O 97~24~22 PCT~US96/20744 with toluene to azeotrope off the acetic acid. Drying in vacuo afforded the title compound (0.100 g, 52%) d) Ethyl (S-nitrobenzofuran-2-yl)propenoate A solution of triethyl phosphonoacetate (0.224 g, 1.0 mmol) in THF (5 mL) is treated with NaH (60% suspension in mineral oil, 0.04 g, 1.0 mmol) at 0~ C for 1 h. To the solution is added the compound of Preparation P(c)(0.235 g, 1.0 mmol). The solution is stirred at RT for 18 h, concentrated, and the residue is purified by chromatography (silica gel, gradient, S-20% EtOAc/hexane) (EtOAc/Hexane 0.5:9 to 4: 1) to afford the title compound (0.2g, 77%).

e~ Ethyl (S-aminobenzofuran-2-yl)propionate and Ethyl (5-amino-2,3-dihydrobenzofuran-2-yl]propionate A solution of the compound of P~c;pa.~Lion P(d) (0.261 g, 1.0 mmol) in EtOH (S
mL) cont~ininp; 10% Pd/C (0.026 g) is hydrogenated at 45 psi for 1 h. The solution is filtered through Celite and the filtrate is concentrated and chromatographed (silica gel, ~r;~1ient, 25-75% EtOAc/hexane) affords the title compounds.

P~ al~Lion Q
Preparation of Ethyl (5-carboxy-benzofuran-2-yl)propionate a~ Ethyl [5-(tert-butyklim~othylsilyloxy)benzofuran-2-yl]carboxylate A solution of ethyl [5-(hydroxy)benzofuran-2-yl]carboxylate, Denny, et. al., EP
0655439, (0.206 g, 1.0 mmol), tert-(butyl)dimethylsilyl chloride (0.23 rnL, 1.0 mmol) and imidazole ( 0.34 g, 1.0 mmol) in TEIF is allowed to stir for 4 h. The solution is COIlf e.~ ed and the residue is treated with EtOAc. The organic phase is washed with H2O, dried (Na2SO4), and concentrated to afford the title compound (0.35 g, 90%).

b~ Ethyl [S-[tert-(butyl)dimethylsilyloxy]benzofuran-2-yl]propenoate W O 97/24122 PCTrUS96120744 Following the procedure of Preparation P~c) and (d), except sub~.l il " 1 illg the compound of l"~ aldlion Q(a) for the compound of Preparation P(b), gives the title compound.

c) Ethyl [5-(hydroxy)benzofuran-2-yl]propionate and Ethyl [5-hydroxy-2,3-dihydro-benzofuran-2-yl3propionate A mixture of the compound of Plcpaldlion Q(b) (0.234g, 1.2 mmol) and 10%
PdlC (0.023 g, 10% wt) in EtOH( 5 mL) is hydrogenated at 50 psi for 1 h. The mixture is ~lltered through Celite and concentrated. A solution of the residue (0.34 g, 1.0 mrnol) and Et4NF (0.149 g, 1.0 mmol) in THF (10 mL) is allowed to stir at RT for 18 h. The solution is concentrated and purified by chromatography (silica gel) to give the title co~ ounds (0.25 g, 57%).

d) Ethyl [S-(trifluoromethylsulfonyloxy)benzofuran-2-yl]propionate Following the procedure of Pr~pal~lion M(c), except sub~.l ;l ul i .-~ ethyl [S-(hydroxy)benzofuran-2-yl]propionate of Plt;palalion Q(c) for the compound of P~ ~dlion M(b), gives the title compound.

e) Ethyl (S-carboxy-benzofuran-2-yl)propionate Following the procedure of Pl~aldtion M(d), except subsituting the colllpound ofPreparation Q(d) for the compound of Preparation M(c), gives the title compound.
Preparation R

Preparation of Ethyl (5-carboxy-2.3-dihydro-benzuruldn-2-yl)propionate a) Ethyl [5-(trifluoromethylsulfonyloxy)-2,3-dihydro-benzofuran-2-yl]propionate Following the procedure of Plt;paldlion Q(d), except sub~ ethyl rs-hy~lo~y-2,3-dihydro-benzofurdn-2-yl3propionate from Pl~aldLion Q(c) for etnyl [S-~hydroxy)benzofuran-2-yl]propionate from Preparation Q(c), gives the title colllpoul,d.

W O 97~4122 PCTAUS96~0744 b) Ethyl (5-carboxy-2,3-dihydro-benzofuran-2-yl3propionate Following the procedure of Pl~.aldlion Q(e), except ~,ub~ uLi~lg the compound ofPreparation R(a) for the compound of P,c;paldlion Q(d), gives the title compound.
Preparation S

Pl~aldlion of Ethyl (+)-3-r(~lycyl)aminol-4-pentynoate trifluoroacetate a) Ethyl (+)-3-[[(N-tert-butoxycarbonyl)glycyl]amino]-4-pentanoate DIEA (0.92 mL, 5.32 mmol) was added to a stirred solution of ethyl (+)-3-amino-4-pentynoate (0.3 g, 2.13 mmol), Boc-Gly (0.56 g, 3.19 mmol), HOBt ~ H2O (0.43 g, 3.19 mmol), and EDC (0.61 g, 3.19 mmol) in anhydrous CH3CN (15 mT.) at RT. After 34 h, the reaction mixture was concentrated, diluted with CH2Cl2 (70 mT ), and washed sequentially with 5% NaHCO3 (2x15 mL) and brine (15 mT.). Drying (MgSO4), concentration, and chromatography (silica gel, 1:1 EtOAc/hexane) gave the title compound (0.5 g, 79%) as a colorless oil: MS (ES) m/e 299.2 (M+H)+.

b~ Ethyl (+)-3-[(glycyl)amino~-4-pentynoate trifluoroacetate A solution of TFA (5 mL) and CH2C12 ( 15 mL) at RT was added all at once to the compound of Plepa dtion S(a) (0.5 g, 1.68 rnmol). After 30 min, the solution wasconcentrated, and the residue was reconcentrated from toluene (to remove residual TFA) to afford the title compound (0.55g, 106%) as a light yellow syrup: MS (ES) m/e 199.2 ~M+H)+.
Ple~aldlion T

Preparation of 6-(Methylamino)methyl-2-pyridin~mi~lle ? 6-Bromomethyl-2-(phth~limi~lo)pyridine (prepared according to the method of US
4,490,533)(1.1 g, 3 mmol) was added to a solution of ethanol (100 mL) saturated with methylamine at 0~C. The resulting solution was stirred at 0~C for 2 h, concentrated to a volume of 20 mL, and treated with hydrazine hydrate ( 1 mT., 20 mmol). The res-lltin~
solution was heated to reflux for 2 h, conce~ dl~d7 and the residue was chromatographed CA 0224l724 1998-06-26 W O 97/24122 PCTrUS96/20744 (silica gel; step gradient, 5%-15% CH3oH/cH2cl2) to give the title compound as ayellow oil (0.15 g, 32%): lH NMR (400 MHz, DMSO-d6) o 7.34 (t, J=7.8 Hz, lH), 6.55 (d, J=7.1 Hz, lH), 6.47 (d, J=8.3 Hz, lH), 3.93 (s, 3H), 2.61 (s, 3H).
Preparation U
Preparationof 6-~minomethyl-2-pyri-1in~min~

a) 2-(phth~limido)methyl-6-(phthzllimido)pyridine A mixture of 6-bromomethyl-2-(phths~limi~c))pyridine (US 4,490,533)(0.4 g, 1.2 mmol), potassium phthzllimide (0.30 g, 1.6 mmol), and DMF (4 mL) was stirred at RT for 18 h, concentrated, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried (MgSO4), and concentrated. The residue was recryst~lli7-~cl (CHC13) to give the title compound as a white solid (0.4 g, 83%): MS (ES) m/e 383.9 [M+H]+.

b) 6-Aminomethyl-2-pyri-lin~mine A solution of the compound of Plcpa dLion U(a)(0.4 g) and hydrazine hydrate (2 mL) in ethanol (10 mL) was heated to reflux for 2 h, filtered, and the filtrate was 20 concentrated. The residue was triturated with CHC13, and the organic extracts were combined and concentrated to give the title compound as an amber oil (0.09 g, 70%): MS
~ES) rnJe 123.7 [M+H]~.

Preparation V
P-~alAlion of N-Ethyl-6-(aminomethyl)-2-pyr;~lin:~mine 6-(Acetylamino~picolin~mi(le (Farmaco Ed. Sci., 1959, 14, 594) (0.3 g, 1.67 rnmol) suspended in dry THF (5 mL) was added dropwise to a solution of lM LAH inTHF (16.7 mL) cooled to 0~C. The suspension was allowed to warm to RT and was 30 heated to reflux for 4 h. The mixture was cooled, carefully treated with H2O and 10%
NaOH, and filtered. The filtrate was dried (MgS04), concentrated, and the residue was azeotroped several times with toluene. The reslllting llU~Lul~ was conceîntr~tecl to give the title compound (0.25 g, 99%): MS (ES) m/e 152 [M+H]+.

CA 0224l724 l998-06-26 W O97/24122 PCT~US96/20744 P~eparation W

Preparation of 4-(Methylaminomethyl)-2-pyrimi~lin~min~
~ A suspension of NaOAc (0.39 g, 4.8 mmol) in a solution of methylamine hydrochloride ( 0.39 g, 5.8 mmol) in EtOH (30 mL) was stirred 10 min at RT and 4-- formyl-2-pyrimi-lin~min~ (obtained by the method of WO 9502591) (0.30 g, 2.4 mmol) was added in one portion. The mixture was stirred 30 min and NaBH3CN (0.09 g, 1.44 mmol) was added. The resulting suspension was stirred 16 h, filtered, and concentrated.
The residue was partitioned between CH2C12 (150 mL) and 5% Na2C03 (20 rnL). The aqueous layer was extracted with CH2Cl2 (4 x 25 mL), and the combined organic layers were dried (K2CO3) and concentrated to give the crude title com~oulld (0.40 g): MS (ES) m/e 139 [M+H]+.

EXAMPLES
lS
Fx~rnple 1 Plc;~dtion of ($)-7-rrr(6-Amino-2-pyridinyl)methyllmethylaminolcarbonyll- 2.3~4~5-tetrahydro-4-methyl-3-oxo- I H- 1 ~4-benzodiazepine-2-acetic acid a) Methyl (S)-7-[[[(6-amino-2-pyridinyl)methyl]methylamino]carbonyl]- 2,3,4,5-tetrahydro-4-methyl-3-oxo- lH- 1,4-benzodiazepine-2-acetate EDC (0.25 g, 1.3 rnmol) was added to a solution of methyl (S)-7-carboxy-2,3,4,5-tetrahydro4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (0.32 g, 1.1 mmol), thecompound of Plepalalion T (0.15 g, 6.02 mmol), HOBT-H2O (170 mg, 1.3 mmol), and DIEA (0.9 mL, 4.4 rnmol) in anhydrous CH3CN (5 rnL) at RT. After 21 h, the reaction was concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography (silica gel, step gradient, 2%-7% CH3OH/CH2C12) to give the title compound (0.22 g, 48%): MS (ES) m/e 412.4 [M+HJ+.

b) (S)-7-[[[(6-Amino-2-pyridinyl)methyl~methylamino~call,ullyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-lH- 1,4-benzodiazepine-2-acetic acid A solution of the compound of Example 1 (a) (0.22 g, 54 mmol), LiOH-H2O
(0.033 g, 0.79 mmol), THF (5 mL), and water (2 mL) was stirred at RT ovçrnight The mixture was concentrated and the residue was dissolved in water. The resulting solution was brought to pH 5 with 3N HCl and allowed to stand. The crystals that formed were W O 97/24122 PCTrUS96/20744 collected by filtration and dried to give the title compound as a pale yellow solid (0.125 g, 59%): MS (ES) m/e 398.4 [M+H~+. Anal. Calcd for C2oH23Nso4 3/8 H2O: C, 59.43;
H, 5.92; N, 17.33. Found: C, 59.42; H, 5.73; N, 17.18.
Fxample 2 Preparation of (S~-7-rrr(6-Amino-2-pyridinyl)methyll~minolcarbonyll-2~3.4.5-tetrahydro-4 m~thyl-3 -oxo- 1 H- 1.4-benzodiazel?i n ~-2-acetic acid a) Methyl(S)-7-[[[(6-amino-2-pyridinyl)methyl]amino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo- 1 H- 1,4-benzodiazepine-2-acetate Following the procedure of Example l(a), except sub~ u~ the compound of Preparation U(b) for the compound of l''lepalation T, gave the title compound as a white foam: MS (ES) m/e 398.0 [M+H]+.
b) (S)-7-~[[(6-Arnino-2-pyridyl)methyl]amino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo- lH- l ,4-bçn7o~ 7~pine-2-acetic acid Following the procedure of Example l(b), except sul)~LilL~ g the compound of Example 2(a) for the compound of Example 1 (a), gave the title compound as a white solid: MS (ES) m/e 384.2 [M+H]+. Anal. Calcd. for C1gH2lNsO4 - 1.25 H2O: C, 56.22;
H, 5.83; N, 17.25. Found: C, 56.01; H, 5.99; N, 16.92.
Example 3 Prep~ration of (S)-7-rrr(6-Ethylamino-2-pyridinyl)methyll~minolcslrbonyl~-23.4.5-tetrahydro-4-metl~y1-3-oxo- 1 H- 1 ~4-~oenzodi~epine-2-acetic acid a) Methyl (S)-7-[[[(6-ethylamino-2-pyridinyl)methyl~amino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo- l H- 1 ,4-ben~o~ 7P,pine-2-acetate A mixture of the compound of Preparation V (0.25 g, 1.65 mrnol), methyl (S)-7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-oxo-lH-1,4-benzodiazepine-2-acetate (0.58 g, 2 mmol), EDC (0.38 g, 2 mmol), and HOBT-H20 (0.26 g, 2 mmol) in DMF (20 mL) was stirred at RT overnight. The mixture was concenll~t~d~ and the residue was treated with 5% Na2CO3 and extracted with CH2C12 (3 x 30 mL). The combined organic extracts were washed with H2O, dried (MgSO4), concentialed. The residue was chromatographed ~silica gel, 5% CH30H/CH2C12) to give the title compound (0.16 g, 23%): MS (E~S) m/e 426 [M+H]+.

-W O97/2412Z PCT~US96~0744 b) (S)-7-[[[(6-Ethylamino-2-pyriinyl)methyl]amino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3 -oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acid t The compound of Example 3(a) (0.16 g, 0.4 mmol) was dissolved in CH30H (10 mL) and THF (1 mL), and treated with lN NaOH (0.5 mL). The mixture was stirred overnight, concentrated, and the residue was dissolved in H2O and extracted withCH2Cl2. The pH of the aqueous phase was adjusted to 5.5-6 with dilute HCl, and the solid which formed was filtered, washed with H2O and Et2O, and dried to give the title compound (0.11 g, 73%): MS (ES) m/e 412 [M+H]+. Anal. Calcd for C21H2sNsO4 0.625 H2O: C, 59.91; H, 6.08; N, 16.21. Found: C, 59.67; H, 6.26; N, 16.51.

Ex~-nple 4 Preparation of (+~-7-rrr(2-Amino-4-pyrimidinyl)methyllmethylaminolcarbonyl~-2~3~4~5-tetrahydro-4-methyl-3-oxo- 1 H- 1 ~4-benzodiazepine-2-acetic acid a) Methyl (+)-7-[[[(2-arnino-4-pyrimidinyl)methyl]methylarnino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo- 1 ,4-benzodiazepine-2-acetate A solution methyl (+~-7-(chlorocarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-lH-1,4-benzodiazepine-2-acetate hydrochloride (0.43 g, 1.2~ mmol) in CH2Cl2 (45 rnL) was added dropwise to a solution of the compound of Preparation W (0.34 g, 2.5 mmol) and pyridine (0.60 g, 7.6 mmol) in CH2Cl2 (50 mL). The resulting suspension was stirred 20 h, filtered, and extracted with 5% Na2CO3 (30 rnL). The organic layer was dried (Na2SO4) and concentrated to dryness to give a brown solid which was purified by~ aiali~e TLC Rf 0.58 (Whatman PLK5F, 10% CH3OH/CH2Cl2) to give the title compound (0.38 g, 74%): MS (ES) m/e 413 [M+H]+.

b) (~t)-7-[{[(2-Amino~-pyrimidinyl)methyl]methylamino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3 -oxo- 1 H- 1 ,4-benzodiazepine-2-acetic acid A solution of the compound of Example 4(a) in a ll~ Lule of CH30H (30 mL) and 0.5 N NaOH (6.0 mT.) was heated at 50~C for 2 h, cooled to RT, and treated with TFA
(1.0 mL). The solution was evaporated to dryness and the residue was purified by HPLC
tR 21.0 min (ODS-AQ, 50 X 250 mm, 90 mL/min, 86:14 CH3CN:H2O-0. 1% TFA, UV
detection at 220 nm) to give the title compound (0.150 g): MS (ES) m/e 399~M~H]+.
3~

W O 97/24122 PCT~US96/20744 Ex~n~le S

Pl~ala~ion of 3-r3.4-Dihydro-8-rrr(6-~mino-2-pyridinyl)methyllmethyl~minolcarbonyll-1 -methyl-2 .5-dioxo- 1 H- 1 .4-benzodiazepinel-4-pro~ ,noic acid a) 33enzyl3-[3,4-dihydro-8-[C[(6-amino-2-pyridinyl)methyl3methylamino]carbonyl]-1-methyl-2,5-dioxo- 1 H- 1 ,4-benzodiazepine]-4-propanoate EDC (0.25 g, 1.3 mmol) is added to a solution of the compound of Plepal~lion -A(f) (1.1 mmol), the compound of Plel3dlation T (1.1 rnmol), HOBT-H20 (170 mg, 1.3 mmol~, and DIEA (0.9 rnL, 4.4 mmol) in anhydrous CH3CN (5 mL) at RT. After 21 h,the reaction is conce~ d~ed and the residue is purified by chromatography (silica gel) to af~ord the title compound.

b) 3-[3,4-Dihydro-8-[[[(6-amino-2-pyridinyl)methyl]methylamino]carbonyl]-1-methyl-2,5-dioxo- 1 H- 1 ,4-benzodiazepine]4-propanoic acid A mixture of the compound of Example 5(a) (2 mmol) and 10% Pd/C (0.02 g) in EtOH ~100 mL) is hydrogenated in an atmosphere of H2 (50 psi) for 6 h. The catalyst is remov~d by filtration, and the filtrate is concentrated to afford the title compound.

Fx~mple 6 Preparation of 3-r4H-imi~1~7orl.2-alrl.41benzotli:~7~pine-Sf6H)-l-methyl-6-oxo-9-rrr(6-~mino-2-pyridinyl)methyllmethylamino~carbonyll-5-propanoic acid a) Ethyl 3-r4H-imida~o~1,2-a][1,41benzodiazepine-5(6H)-l-methyl-6-oxo-9-[[~(6-amino-25 2-pyndyl)methyl]-N-methylamino]calllol-yl]-S-propanoic acid EDC (0.25 g, 1.3 mmol) is added to a solution of the coml)oulld of Pl~a dtion B(e) ~1.1 mmol), the compound of Preparation T (1.1 rnmol), HOBT-H2O (170 mg, 1.3 mmol), and DIEA (0.9 mL, 4.4 mmol) in anhydrous CH3CN (5 mL) at RT. After 21 h, the reaction is concentrated and the residue is purified by chromatography (silica gel) to 30 afford the title compound.

W O97124122 PCTrUS96120744 b~ 3-[4H-imidazo[ 1 ,2-a] [ 1 ,4]benzodiazepine-5(6H)- 1 -methyl-6-oxo-9-[[[(6-amino-2-pyridyl)methyl]-N-methylamino]carbonyl]-5-propanoic acid lM LiOH (3.8 mL, 3.8 mmol) is added dropwise to a solution of the compound of Fx~mrle 6~a) (2.5 rnmol) in 1:1 CH30H:THF (20 rnL) at RT. The resulting mixture is stirred for 20 h and concentrated. The residue is dissolved in H20 and acidified with TFA
(20%) to afford the title compound after chromatography.

Ex~rnple 7 Prep~ration of 4-r4-r2-f6-Amino-2-pyridinyl)ethyll-1-piperazinyll-1-piperi~in~.a etic acid a~ Ethyl4-[4-~2-t6-(phth~limido)-2-pyridinyl]ethyl]-1-piperazinyl]-1-(piperidinyl)acetate According to the methods of Shoeb, et. al., Ph~ zie, 1978, 33, ~81, and Finkelstein, et. al., J. Amer. Chem. Soc., 1951, 73, 302, a mixture compounds of~pa.~.tion C(b), P~ lion Dt and formaldehyde in EtOH is heated to reflux for 1 h, cooled, diluted with aqueous NaHC03, and extracted with EtOAc. The combined organic extracts are dried, eva~30-~lt;d, and flash chromatographed to give the title compound b) 4-[4-~2-~6-(Ph~h~limido)-2-pyridinyl]ethyl]-l-piperazinyl]-l-pipericlin~ etic acid A solution of Example 7(a) in NaOH /CH30H is stirred at RT for 18 h. The mixture is neutralized with HOAc and fîltered to give the title col,lpoulld.

c) 4-[4-[2-(6-Amino-2-pyridinyl)ethyl]-1-pil)el~zillyl]-1-pipçriflin~(eticacid A solution of Example 7f~b) and hydld~ e hydrate in EtOH is heated to reflux for2 h.. The mixture is neutralised, desalted, and lyophilized to give the title compound.

Ex~r~ple 8 Pl~dlion of l-Hydroxyl-4-r4-rf6-amino-2-pyridinyl)methyll-1-pil~elA~ yl]-cyclohexaneacetic acid W O 97/24122 PCTrUS96/20744 a) 1,1-Dimethylethyl 1-hydroxyl~-[~[(6-phth~limido-2-pyridinyl)methyl]-1-pipt;~ yl]-cyclohex~n~ etate A mixture 1,1-dimethylethyl 1-hydroxyl-4-(1-pi~ yl)-cyclohex~nP~cet~te7 S Porter, et. al., EP 0 537 980 A1, 6-bromomethyl-2-(phth~limi<lQ)pyridine, US 4,490,533, and NaHCO3 in CH3CN is warmed. The mixture is concentrated and the residue is partitioned between H2O and EtOAc. The organic phase is dried ~Na2SO4), concentrated, and the residue is chlolllalographed (silica gel) to give the title compound.

b) l-Hydroxyl-4-[4-[(6-phth~limic1o-2-pyridinyl)methyl]-l-pil)e~dzillyl]
cyclohex~nearetic acid A solution of Example 8~b) in 4M HCI/dioxane/CH2C12 is stirred at RT for 18 h.
The mixture is ~va~o~ated and filtered to give the title compound.

c) 1-Hydroxyl-4-[4-[(6-amino-2-pyridinyl)methyl]-1-~ i"yl]-cycloh~ nea-~etic acid A solution of the co,ll~ound of Example 8(b) in EtOH is treated with hydrazine hydrate and warmed. The ~ lule is concentrated and chromatographed (silica gel) to give the title compound.
F.xample 9 1 ion of 1-Hydroxyl-4-r4-r2-(6-amino-2-pyridinyl)ethyll- 1-piperazinyll-cyclohex~ne~eti~ acid 2~ Following the general procedure of Example 7, except substittlting 1,1-dimethylethyl l-hydroxyl-4-( l-pi~ yl)-cyclohexaneal~et~te for the compound of P~ alion C(b), gives the title compound.

, W O 97124122 PCT~US96/20744 Fx~m~ple 10 Preparation of 4-~4-[(6-Amino-2-pyridinyl)methyll-1-pipera~inyl~-1-piperi~1ine~eeti~: acid Following the general procedure of Example 8, except sub~liluLillg the compound S of Preparation C(b) for l,l-dimethylethyl l-hydroxyl-4-(l-~ipt;ld~ yl) cycloh~x~ne~cet~te, gives the title compound.

F~r~n~?le 1 1 10 Preparation of N-rl l-rr2-(6-Amino-2-pyridinyl)ethyllcarbonyll-3-piper~ yllcarbon ,B-alanine Following the procedures of Beavers et. al., WO 95/2~091, Exarnple 1, except sub~ g (6-amino-2-pyridinyl)propionic acid, Bondinell, et. al., WO 94/14775, forN~Boc-D-lys(Cbz)-OH, gives the title compound.

F.x~m~ 1 2 Plc~ dLion of 2-r(6-Amino-2-pyridinyl)methyll-5-r2-(carboxy-ethyl)amino~carbonyll -2.3-dihydro-3-oxo- 1 H-isoindole Following the procedures of Preparation 1-12 in Hartman, et. al., EP 0 540 334 A1, for the plc~aldlion of 2,3-dihydro-N-(2-carboxy-ethyl)-2-[2-(piperidinyl)ethyl}-3-oxo-lH-isoindole-S-carboxamide, except substituting the compound of Preparation U for Boc-4-piperidine-2-ethylamine, gives the title compound.

E~ample 13 Pl~dudlion of (5)-2-~Butylsulfonylamino)-3-r4-rr3-(6-~min- -2-pyridinyl)propylloxylphenyllpropionic acid Following the procedures of Egbertson, et al., EP 0478363 A2, for the plG~dlion of 2-5-(butylsulfonylamino)-3-~4-(N-benzyloxycarbonylpirçri(1in4-yl)-2,2-dimethyl~butyloxyphenylpropionic acid, except substituting the compound of Plc;pa~ion E(b) for 4-[4-(N-benzyloxycalbollyl~ipelidin-4-yl)-2-methyl]pentan-2-ol in, gives the title compound.

W O 97/24122 PCTrUS96/20744 F.x~3mple 14 lion of N-r3(R)-r2-(6-Amino-2-pyridinyl) ethyll-2-oxopiperidinyl~acetyl~-3fR)-methyl-,B-alanine S Following the procedure of Duggan, et. al., J. Med. Chem. 1995, 38, 3332, except ~ub~lituling (6-amino-2-pyridinyl)butanoic acid, Bondinell, et. al., WO 94/14775, for (N-Boc-piperidin-4-yl)butanoic acid, gives the title compound.

F.xzlml?le 15 P~ alion of 3-rrr3-r2-(6-~minopyrid-2-yl)ethyllisoxazolin-5(R.S)-yllacetyllaminol-3(R.S)-methylylopa"oic acid a) 4-[6-(Toluenesulfonylamino)-2-pyridinyl]-1-butanoxirninoyl chloride Following the procedure of F~r~mI)le l(b) in WO 95/14682, except substituting the compound of Pl~dtion F(e) for the 4-cyanobenzoxime, the title compound is prepared.

b) tert-Butyl [3-[2-[(6-toluenesulfonylarnino)-2-pyridinyl~ethyl]isoxazolin-5(R,S)-20 yl]acetate Following the procedure of Example l(d) in WO 95/14682, except substituting the compound of Example 15(a) for 4-cyanobenzoximinoyl chloride, and substituting tert-hutyl 3-butenoate for methyl 3-butenoate, the title compound is prepared.

25 c) r~-[2-[(6-Tolller~s~llfonylamino)-2-pyridinyl]ethyl~isoxazolin-5(R,S)-yl]acetic acid 4 M HCl in dioxane (10 mL) is added to a solution of the compound of Example l~(b) ~5 mmol) in CH2CH2 (40 mL) at 0~C. The reaction is stirred at RT until complete, then is concentrated to afford the title compound.

-W ~97J24122 PCT~US96~744 d) Ethyl 3-[[3-[2-(6-aminopyrid-2-yl)ethyl]isoxazolin-S(R,S)-yl]acetyl]amino-3(R,S)-methylpropanoate EDC (1.2 mmol) is added to a solution of the compound of ~xample 15(c) (1 mmol~, ethyl 3(R,S)-aminobuLyl~te (1.2 mmol), HOBt ~ H20 (1.2 mmol), and DIEA (4- 5 mmol~ in anhydrous CH3CN (5 mL) at RT. The reaction is stirred at RT until complete, then is concentrated, and the residue is purified by ch,~ atography (silica gel) to afford the title compound.

e) 3-[~[3-[2-(6-Aminopyrid-2-yl)ethyl]isoxazolin-5(R,S)-yl]acetyl]amino]-3(R,S)-methylpropanoic acid 1.0 N LiOH (2.5 mmol) is added to a solution of the compound of Example 15(d) (0.5 mmol) in THF (2.5 mL). The reaction is stirred at RT until complete, then is neutralized with 1.0 N HCl. The solution is concentrated and the residue is purified by reverse-phase chromatography to afford the title compound.
Fx~mple 16 Plt;pa ~tion of N-r3-rrr(6-Amino-2-pyridinyl)rn~tllyllcarbonyll~min~ lbenzoyll-~-alaninç

2l) a~ Benzyl N-[3-[[~(6-amino-2-pyridinyl)methyllcarbonyl]amino]benzoyl]-~ nin:-te A mixture of benzyl N-(3-aminobenzoyl)-,B-~l~nin~te, Alig, et. al., l~P 0372486,(1 rnmol}, the compound of Pl~aldtion G (1 mmol), EDC (1.5 mmol), and DIEA (3 mmol~ in DMF (25 rnL) is stirred at RT. The mixture is poured into 5% NaHCO3 andextractedL with EtOAc. The combined organic phase is washed with H20, dried (MgSO4), and c~llce~ ted. The residue is chromatographed (silica gel) to give the title compound.

b) N-[3-[[[(6-Arnino-2-pyridinyl)methyl]carbonyl]arnino]benzoyl]-,13-alanine A mixture of the compound of Exarnple 16(b)(1 mmol) and lN NaOH (1.5 mL) in CH30H ~20 mL~ is stirred and concentrated. The residue is dissolved in H20, extracted with CH2Cl2, and the aqueous phase is adjusted to pH 5 with dilute HCl to give the title cu~ oll~d.

W O 97124122 PCTrUS96/20744 Example 17 E~reparation of rrl-rN-rr(6-Amino-2-pyridinyl)~methyllcarbonylltyrosyll-4-5 pipçridinylloxylacetic acid a) tert-Butyl [[ 1 -[N-~(6-amino-2-pyridinyl)methyl]carbonyl]tyrosyl]-4-piperidinyl]oxy]acetate A ~ ulc; of tert-butyl [(l-tyrosyl~-piperidinyl)oxy]~et~P, Alig, et. al., EP
372486, ~1 mmol), the compound of Preparation G ( 1 mmol), EDC (1.5 mmol), and DIEA (3 mmol) in DMF (25 mL) is stirred at RT. The mixture is poured into 5%
NaHCO3 and extracted with EtOAc. The combined organic phase is washed with H2O, dried (MgSO4), and concentrated. The residue is chromatographed (silica gel) to give the title compound.
b3 [[ 1 -[N-[[(6-Amino-2-pyridinyl))methyl]carbonyl]tyrosyl]-4-piperidinyl]oxy]acetic acid A ~ iLul~ of the compound of Example 17(a)(1 mmol) and CF3C02H in CH2Cl2 is stirred and concentrated to give the title compound.

Ex~mrle 18 plepal~lion of (~ 3-1 rrr2-(6-Aminopyrid-2-yl)ethyll~minolsuçcinoyll~minol-4-~entynoic acid a~ Methyl 4-~[2-(6-aminopyrid-2-yl)ethyl]arnino]-4-oxobutyrate 3-Carbometho~Ly~-~,pionyl chloride (0.74 mL, 6.0 mmol) is added at 0~C to a stirred solution of the compound of Pl~a alion H (5.0 mmol) and DIEA (4.4 ml, 25mmol~l in d~y CH2Cl2 (50 mL). After stirring for 1.5 hr at RT, the reaction mixture is diluted with CH2Cl2 (50 mL) and washed sequentially with H20 (25 ml) and 5%

, CA 0224l724 l998-06-26 W O 97J24122 PCT~US96/20744 NaHCO3 (25 mL). The organic layer is dried (MgSO4), concentrated, and reconcentrated from toluene. Chromatography (silica gel) gives the title compound.

b) 4-[~2-(6-Aminopyrid-2-yl)ethylJamino]-4-oxobutyric acid A ~ Lulc~ of the compound of Example 18(a) (530.6 mg, 2.0 mmol), 1.0 N LiOH
~3.0 rnL, 3.0 mmol), THF (10 rnL), and H20 (7 mL) is stirred at RT overnight, then is concentrated to dryness. The residue is taken up in H20 (5 mL) and neutralized with 1.0 N HCl. 'rhe ~l~cipiL~Le is collected and dried in vacuum to give the title compound.

c) Ethyl (i)-3-[[[[2-(6-aminopyrid-2-yl)ethyl]amino]succinoyl]amino]~-pentynoateEDC (230 mg, 1.2 mmol) is added to a solution of the compound of Example 18(b) (203.3 mg, 1.0 mmol), ethyl (+)-3-amino~-pentynoate, WO 93/07867, (169.4 mg, 1.2 mmol), HOBt ~ H20 (162.2 mg, 1.2 mmol), and DIEA (0.70 mL, 4 mrnol) in anhydrous CH3CN (5 mL) at RT. The reaction is stirred at RT overnight, then is concentrated to dryness. The residue is chromatographed (silica gel) to give the title colnp-3ul.d.

d) (+)-3-[~[[2-(6-Arninopyrid-2-yl)ethyl~amino]succinoyl]amino]-4-pentynoic acidA mixture of the compound of Example 18(c) (187.2 mg, 0.5 mmol), 1.0 N LiOH
(0.75 mL, 0.75 mmol), THF (2.5 mL), and H20 (1.7 mL) is stirred at RT overnight, then is concentrated to dryness. The residue is taken up in H2O (2 mL) and acidified with TFA. ODS chromatography followed by lyophilization of the purified material gives the title colllpou,ld.

Fx~m.~le 19 Prel2~ration of (S)~-rrr(6-Amino-2-pyridinyl)methyllcarbonyllglycyl~-3-m~thnxycall,onylmethyl-2-oxopiperazine-1-acetic acid Following the procedure of Sugihara, et. al., EP 0529858, Example 59, except su~ u~ g the compound of Preparation G for 4-~mirlinobenzoic acid hydrochloride, gives th~ title compound.

CA 0224l724 l998-06-26 W O 97/24122 PCT~US96/2074 Fxample 20 PLepaldtion of (3s~5s)-s-r4-r(6-A~m--inQ-2-pyridinyl)metl~ phenyl~oxy~ yll-3 5 carboxymethyl-2-pyrrolidinone a) (3S,5S)-5-[4-[(6-Amino-2-pyridinyl)methyl~phenyl]oxymethyl~-3-[(tert-butoxycarbonyl)methyl] -2-pyrrolidinone Following the procedure of ~imm~l~bach, et.al., AU-A-86926/91, E~ mple 3(51), except sub~ Ig the compound of Preparation I for 4'-cyano-3'-fluoro-4-(hydroxy~biphenyl, gives the title compound.

b) (3S,5S)-5-[4-[(6-Amino-2-pyridinyl)methyl3phenyl1oxymethyl]-3-carboxymethyl-2-pyrrolidinone Following the procedure of ~imm~lc~ h, et. al., AU-A-86926/91, Example 7(93~, except sub~ the compound of Example 20~a) for (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]-5-[(4'-amidino-3'-fluoro-4-biphenylyl)oxymethyl]-2-pyrrolidinone, gives the title compound.

Fx~ ?le 21 Prepar~tion of l-r(6-~mino-2-pyridinyl)m~thyl~-3-r4-(2-carboxyethyl)phenyll-4-,rn~.thnxy-3-pyrrolin-2-one Following the procedures of Linz, et. al., EP 0567968, except substitlltin~ the 25 compound of Pr~al~lion U for 4-cyanoaniline, gives the title compound.

Fxz~ 22 Preparation of 4-rrr(6-Amino-2-pyridinyl)methyllmçthylamino~acetyllphenoxyacetic acid W O 97~24122 PCTAJS96~0744 a) Methyl4-[[[(6-amino-2-pyridinyl)methyl]methylamino]acetyl]phenoxyacetate Following the procedure of Wayne et. al., WO 94/22834, Example 1, except sul,sl il ~ g the compound of Pl~pa alion T (1 mmol) for 1-(4-pyridyl)pipel~zine, gives the title colllpo~lnd.
b) 4-[[[(6-Amino-2-pyridinyl)methyl]methylamino]acetyl]phenoxyacetic acid Following the procedure of Wayne et. al., WO 94/~834, Fx~mple 2, except substitnting the compound of F~mr)le 22(a) for methyl 4-[2-[4-(4-pyridinyl)~ipeldzi yl]acetyl]phenoxyacetate, gives the title compound.
Fxample 23 Pl~epa dtion of 2.2'-rr4-rrr(6-Amino-2-pyridinyl~lnethyllmethylaminolacetyll-1.2-phenylenelbis(oxy)~bis-acetic acid a) Dimethyl 2,2'-[[4-[[[(6-amino-2-pyridinyl)methylJmethylamino]acetyl]- 1,2-phenylene]bis(oxy)]bis-acetate Following the procedure of Wayne et. al., WO 94/22834, Example 3, except substituting the compound of Plc;p~tion T for 1-(4-pyridyl)pipe~ e, gives the title compound.

b) 2,2'-[[4-[[l(6-Amino-2-pyridinyl)methyl]methylamino]acetyl]-1,2-phenylene]bis(oxy)]bis-acetic acid Following the procedure of Wayne et. al., WO 94/22834, Example 4, except sub~Liluli-lg the compound of Example 23(a) for dimethyl 2,2'-~4-[2-~4-(4-pyridinyl)piperazin-1-yl)acetyl]phenylene-1,2-dioxy]~ et~te, gives the title c~ poulld.

Fxample 24 30 Preparation of 4-rrrr(6-~mino-2-pyridinvl)methyllcarbonyllmethyl:-minol acetyllphenoxyacetate W O 97124122 PCT~US96/20744 a) Benzyl 4-[[[t(6-amino-2-pyridinyl)methyl]cal130nyl] methylamino] acetyl]
phenoxyacetate A mixture of the compound of Plc~aldLion J(c)(1 mmol), F~alalion G (1 mmol), S EDC (1.5 mmol), and DIEA (3 mmol) in DMF (25 mL) is stirred at RT. The mixture is poured in to 5% NaHC03 and extracted with EtOAc. The organic phase is washed with H20, dried (MgS04), and concentrated. The residue is chromatographed (silica gel) to give the title compound.

10 b) 4-[[[[(6-Amino-2-pyridinyl)methyl]carbonyl]methylamino]acetyl]phenoxyacetate The compound of Example 24(a)(1 mmol) and lN NaOH (1.5 mL) in CH30H (20 mL) is stirred and concentrated. The residue is dissolved in H20, extracted withCH2C12, and the aqueous phase is adjusted to pH S with dilute HCl to give the title compound.
Rx~n~ple 25 PlelJa~ on of 4-rrrr(6-Amino-2-pyrir1inyl~methyllcarbonyllmethyl:~minolacetyl~-1,2-ph.~nylenedioxydiacetic acid ~0 a) Dimethyl 4-[~[[(6-amino-2-pyridinyl)methyl]carbonyl]methylamino]acetyl]-1,2-phenylenedioxydiacetate Following the procedure of Example 24(a), except sub~lilu~ g the compound of E~?~dlion K(c) for the compound of ~l~p~dlion J(c), gives the title compound.
~5 b) 4-[[[[(6-Amino-2-pyridinyl)methyl]carbonyl]methylarnino]acetyl]-1,2-phenylenedioxydiacetic acid Following the procedure of procedure of Example 24(b), except substituting the compound of Example 25(a) for the compound of Example 24(a), gives the title 30 compound.

W O 97~24~22 PCT~US96120744 E~x~n~le 26 Prepar~tion of l-rr2-Amino-6-pyridinyl)methyll-3-r4r2-(carboxy)ethyl)lphenyll-3-oxo-imi(1~7- lidine a3 Ethyl 2-[4-(2-}1ydlo~yelllylamino)phenyl]propionate Following the procedure of Himmelsbach, et. al., EP 0587134, Example V, glycolaldehyde dimer (Aldrich) ( 1 mrnol) is added to a solution of methyl 2-(4-aminuplleLIyl)propionate, (1 mmol) in aqueous CH3CN (pH 6-7) (10 mL), followed by NaBH3CN (1.2 mmol), and the ~ lule is allowed to stir for 1 h. The ~ Lule is concentrated to an oil, and the residue is dissolved in a mixture of ice water and EtOAc.
The aqueous layer is neutralized with 4 N NaOH and washed with EtOAc. The organic phase is concentrated and a solution of the resulting oil in EtOAc is chromatographed ~silica gel, gradient, 5-30% CH30H/CH2C12-0.1% HOAc). The fractions cont~ining the product are combined and concentrated to give the title compound.

b~ N-[~2-Phthaloyl-6-pyridinyl)methyl]-N'-hydroxyethyl-N'-L4[(2-ethoxycarbonyl)ethyl)]phenyl] -urea Following the procedures of Himrnelsbach, et. al., EP 0587134 and EP 0612741, a solution of the compound of PlcpaldLion L (1 mmol) and COC12 (1.1 mmol) in THF (20 mL) is allowed to stir at -20~C for 20 min. The compound of Example 26(a) ( 1 mmol) is added to the solution and the reslllting mixture is allowed to stir and warm RT for 18 h.
The resllltin~ solution is concentrated and a solution of the reslllting residue in EtOAc is washed with 5% citric acid followed by H2O. The organic phase is concentrated and a solution of the resulting oil in EtOAc is chromatographed (silica gel, gradient, 5-30%
CH3OHICH2C12-0.1% HOAc). The fractions cont~ining the product are combined and concentrated to give the title co~ und.

W O97/24122 PCTrUS96/20744 c) Nl-[(2-Phthaloyl-6-pyridinyl)methyl]-N3-[4[(2-ethoxycarbonyl)ethyl)]phenyl]-2-oxo-imi~l~7Olidine ~ollowing the procedures of Himmelsbach, et. al., EP 0587134, Example m, and 13P 0612;'41, a solution of the compound of Example 26(b) (1 mmol), methanesulfonyl chloride (1.2 mmol) and Et3N (1.2 rnmol) in CH2C12 (5 rnL) is allowed to stir at 0~C for 1 h. The rnixture is partitioned between H2O and CH2C12. The organic phases are combined, dried (Na2so4)~ and concenlldled. A solution of the residue and NaI (1.1 mmol) in acetone (S mL) is heated to reflux for 3 h and then concentrated. Potassium bis(trimethylsilyl)azide (1.2 mmol) is added to a solution of the resl-lsing oil in DMF (S
mL), cooled to 0~C. The solution is allowed to warm to RT over 30 min and concentrated to give an oil. The oil is partitioned between H2O and CH2Cl2. The organic phases are combined, dried (Na2SO4), and concentrated. A solution of thereSlliting oil in EtOAc is chromatographed (silica gel, gradient, 5-30% CH3OH/CH2Cl2-0.1% HOAc). The fractions c-)nt~ining the product are combined and concentrated to give the title compound.

d) Nl-[(Arnino-6-pyridinyl)methyl]-N3-[4[(2-carboxyl)ethyl)}phenyl~-2-oxo-imitl ~7:01idine Following the procedures of E~immel~b~h, et. al, EP 0587134, Example III, and EP 0612741, a solution of the compound of Example 26(c) (1 mmol) and hydrazine hydrate ~1.1 mmol) in EtOH (10 mL) is allowed to stir for 18 h. The solution concentrated and the residue is partitioned between H2O and EtOAc. The organic phases are combined and concentrated. A solution of the resulting oil in THF (S mL) and 1 N
NaOH ~1.2 mL, 1.2 mmol) is allowed to stir for 18 h. The mixture is neutralized with conc HCl and chromatographed (silica gel, gradient, 5-30% CH30H/CH2C12-0.1%
HOAc). The fractions Contz~inin~ the product are combined and concentrated to give the title compound.

W O 97124122 PCTrUS96/20744 Example 27 Plep~alion of r6-rrr(6-Amino-2-pyridinyl)methyllmethylaminolcarbonyl]-1~2.3~4-tetrahy~roisoquinolin-2-yllacetic acid a) Ethyl [6-[[[(6-amino-2-pyridinyl)methyl]methylamino]carbonyl]- 1,2,3,4-tetrahydroisoquinolin-2-ylJacetate A solution of the compound of Plel)aldlion M~d) (0~263 g, 1.0 rnmol), the compound of P,e~al~lion T (0~34 g, 1~0 mmol), EDC (0~191 g, 1~0 mmol), HOBt (0~151 g, 1.0 mmol) and Et3N (0.235 mT, 2~0 mmol) in DMF (7 mL) is stirred for 8 h. Thesolution is concentrated to an oil which is purified by chromatography (silica gel, gradient, 10-33% CH3OH/CH2C12) to afford the title compound (0~32 g, 77%) b) ~6-[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonyl]-1,2,3,4-lS tetrahydroisoquinolin-2-yl]acetic acid A solution of the compound of Example 27(a) (0.42 g, 1.0 mmol) in lN NaO~I
(1.5 rnL, 1.5 mmol) and EtOH (S mL) is stirred for 8 h. The solution is concentrated to an oil which is purified by chromatography (silica gel, gradient, 10-33%
CH30HlCH2C12) to afford the title compound (0.35 g, 76%).
Fx~mrle 28 Plc;palalion of ~6-rrr(6-Amino-2-pyridinyl)methyllmethylaminolcarbonyll-1.2.3.4-tetrahydro-l-oxo-isoquinolin-2-yllacetic acid a) Ethyl [6-[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonyl]-1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl]acetate Following the procedure of Example 27(a), except sub~ ir-g the compound of rlt;;y~uaLion N(d) for the compound of Preparation M(d), gives the title compound.

W O9712412~ PCTrUS96/20744 ~Itern:~tively, a solution of the co~ ound of ~lc~alalion N(c) (0.23 g, 1.0 mmol), Pd(OAc)2 (0.026 g, 0.1 mmol), the compound of PIG~a,alion T (0.31 g, 1.0 mmol), Ph3P
(0.262 g, 1.0 mmol), diisopropylamine (0.25 mL, 2.1 mmol), and NMP (7 mL) in 10%NH4CO3 is stirred for 8 h under an atmosphere of CO. The solution is concentrated to an S oil which is purified by chromatography (silica gel, gradient, 25-75% CH3OH/CH2C12) to afford the title compound(0.26 g, 76%) b) [6-[[[(6-Arnino-2-pyridinyl)methyl]methylamino]carbonyl]-1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl]acetic acid Following the procedure of Example 27(b), except subsLiluli~lg the compound of Example 28(a) for the compound of Example 27(a), gives the title compound.

Ex~ ple 29 Ple~,~dlion of r6-rrrr~6-Amino-2-pyridinyl)methyllcarbonyllaminoltetralin-2-yllacetic acid a) tert-Butyl [6-[~[(6-Amino-2-pyridinyl)methyl]carbonyl]amino]tekalin-2-yl]acetate Following the procedure of Example 27(a), except substituting tert-butyl (6-arnino-tetr~lin-2-yl)acetate [Fisher, et. al., EO 0635492, Scheme 12 and Example 28, parts A-D] ~or the co~ ound of Preparation M~d) and substituting the compound ofP.e~aral ion G for the compound of Preparation T, gives the title compound.

b) [6-[[[~(6-Amino-2-pyridinyl)methyl]carbonyl]amino3tetralin-2-yl]acetic acid A solution of the compound of Example 29(a) (0.32 g, 1.0 mrnol) and TFA ~5 mL~ in CH2C12 (5 mL) is allowed to stir for 1 h. The solution is concentrated to an oil which is treated with E~t20. Filtration and drying in vacuo afforded the title compound (0.15g, 50~O) CA 0224l724 l998-06-26 W O 97~24122 PCTfiU~96~07~4 E3~camE~le 30 Preparation of r6-rrrr(6-Amino-2-pyridinyl)methyllmethylam~ inolearbonylltetralin-2-yl~acetic acid Following the proeedure of Example 27, exeept sub~iLulillg the eompounds of ;pa~lion O(b) for the compound of Preparation M(d), gives the title eompound.

F.x~ ?le 31 Plc;p~dlion of ~5-rrrr(6-Amino-2-pyridinyl)methyllearbonyllaminolbenzofuran-2-yllpropionic aeid Following the procedure of Example 27, except sub~liluLillg ethyl (5-aminobenzofuran-2-yl)propionate from Preparation P(e) for the eompound of Ple~aldtion M(d), gives the title e~lllpoulld.
Ex~nlple 32 Pl~p~d~ion of rS-rrrr(6-Arnino-2-pyridinyl)methyllearbonyllamino~-2.3-dihydro-benzofuran-2-yllpropionic acid Following the procedure of Example 27, except sub~ uling ethyl (5-amino-2,3-dihydro-benzofuran-2-yl)propionate from Preparation P(e) for the eompound of lion M(d), gives the title eompound.

Examl;?le 33 E~ydldlion of rS-rrrr(6-Amino-2-pyridinyl)methyllmethylaminolearbonyllbenzofuran-2-yll~,lu~ionic aeid Following the procedure of Example 28, exeept substitllting the eompounds of Pl~alion Q(d) or (e) for the compounds of P,epaldlion N(e) or (d), gives the title eompound.

WO 97124122 PCT~US96/20744 E7cample 34 Ple~ lion of rS-rrrr(6-Amino-2-pyridinyl)methyllmethylamino~carbonyl~-2.3-dihydro-be, l7.~ful all-2-yll-propion ic acid Following the procedure of Example 28, except substitllting the compounds of Plep~dlion R(a) or (b) for the compounds of P~ tion N(c) or (d), gives the titlecompound.
E~n~le 35 Preparation of (+)-3-rrr4-(6-~mino-2-pyridinyl)butanoyll~lycyllaminol-4-pentynoiç acid a) Ethyl (+~-3-[[[4-(6-Amino-2-pyridinyl)butanoyl]glycyl]arnino~-4-pentynoate DIEA (5.43 rnmol) is added to a stirred solution of the compound of Plc;~aldlionS(b) ~1.76 rnmol), 4-(6-amino-2-pyridinyl)butyric acid, Bondinell, et. al., WO 94/14775, (1.55 mmol), HOBt H20 (2.33 rnmol), and EDC (2.33 mmol) in anhydrous CH3CN (15 mL) at RT. The reaction llli~lUIC; iS stirred, concentrated, diluted with CH2C12 (100 mT )~
and washed sequentially with 5% NaHC03 and brine. Drying (MgSO4), concentration,and ~hromatography (silica gel, CH30H/ CH2C12) gives the title compound.

b) (+)-3-[[[4-(6-Arnino-2-pyridinyl)butanoyl]glycyl]amino]-4-pentynoic acid 1.0 N LiOH (0.71 mmol) is added dropwise at RT to a mixture of the compound of Exarnple 35(a) (0.285 mmol) in THF (5 rnL), H20 (5 rnL) and CH3CN (1 mL). Thernixture is stirred, concentrated to a small volume, and cooled in an ice bath before neutralizing with 1.0 N AcOH (0.70 mL). The solution is lyophilized and the residue is purified by chromatography (ODS, CH~CNtH20-O. 1% TFA) to give the title compound.

The above description fully discloses how to make and use the present invention.However, the present invention is not limited to the particular embo-limPnt~ described hereinabove, but in~ s 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 incorporated herein by reference as though fully set forth.

Claims (17)

What is claimed is:
1. A compound according to formula (I):

wherein A is a fibrinogen antagonist template;
W is a linking moiety of the form -(CHRg)a-U-(CHRg)b-V-;
Q1, Q2 and Q3 are independently N or C-Ry, provided that no more than one of Q1, Q2 and Q3 is N;
R' is is H or C1-6alkyl, C3-7cycloalkyl-C0-6alkyl or Ar-C0-6alkyl R" is R', -C(O)R' or-C(O)OR';
Rg is H or C1-6alkyl, Het-C0-6alkyl, C3-7cycloalkyl-C0-6alkyl or Ar-C0-6alkyl;
Rk is Rg, -C(O)Rg or -C(O)ORg Ri is H, C1-6alkyl, Het-C0-6alkyl, C3-7cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl-U'-C1-6alkyl, C3-7cycloalkyl-C0-6alkyl-U'-C1-6alkyl or Ar-C0-6alkyl-U'-C1-6alkyl;
RY is H, halo, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S(O)r-, -CO2Rg, -CORg or -CONRg2;
U and V are absent or CO, CRg2, C(=CRg2), S(O)c, O, NRg, CRgORg, CRg(ORk)CRg2, CRg2CRg(ORk),C(O)CRg2,CRg2C(O),CONRi,NRiCO,OC(O),C(O)O, C(S)O, OC(S), C(S)NRg, NRgC(S), S(O)2NRg, NRgS(O)2 N=N, NRgNRg, NRgCRg2, NRgCRg2, CRg2O, OCRg2, CRg=CRg, C~C, Ar or Het;
a is 0, 1 or 2;
b is 0, 1 or 2;
c is 0, 1 or 2;
r is 0, 1 or 2;
u is 0 or 1; and v is 0 or 1;
or pharmaceutically acceptable salts thereof;
provided that:

(i) when v is 0, and R', R" and Ry are H, and Q1-Q3 are CH, W-A is not 7-aminocarbonyl-2,3,4,5-tetrahydro-3-oxo-4-methyl-1H-1,4-benzodiazepine-2-acetic acid, 7-aminocarbonyl-1-acetyl-2,3,4,5-tetrahydro-3-oxo-4-methyl-1H-1,4-benzodiazepine-2-acetic acid, or 7-aminocarbonyl-2,3,4,5-tetrahydro-3-oxo-methyl-1H-1-benzazepine-2-acetic acid, or the methyl esters thereof;
(ii) when v is 0 or 1 and R', R" and Ry are H, and Q1-Q3 are CH, W-A is not 3-propanoyl-glycyl-aspartyl-phenylalanine, or , and the benzyl esters thereof.
2. A compound according to claim 1 in which Q1, Q2 and Q3 are each CH, and u is 0.
3. A compound according to claim 1 in which R' is H and R" is H or C1-4alkyl.
4. A compound according to claim 1 in which W is -(CHRg)a-CONRi- or -(CHRg)a-NRiCO-.
5. A compound according to formula (I) in which A is chosen from the group of , , , A is ;

and and which has 13-14 covalent bonds between the acidic moiety and the first nitrogen in the pyridine ring.
6. A compound according to claim 1 in which is:

wherein A1-A2 is NR1-CH, NC(O)R3-CH, N=C, CR1=C, CHR1-CH, O-CH or S-CH;
R1 is H, C1-6 alkyl or benzyl;
R2 is (CH2)qCO2H;
R4 is H, C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, or C3-6cycloalkyl-C0-6alkyl; and q is 1,2 or 3.
7. A compound according to claim 6 wherein A1-A2 is NH-CH and R2 is CH2CO2H.
8. A compound according to claim 7 wherein W is -(CHRg)a-CONRi- or -(CHRg)a-NRiCO-.
9. A compound according to claim 1 which is:
3-[3,4-Dihydro-8-[[[(6-amino-2-pyridinyl)methyl]methylamino]carbonyl]-1-methyl-2,5-dioxo-1H-1,4-benzodiazepine]-4-propanoic acid;
3-[4H-imidazo[1,2-a][1,4]benzodiazepine-5(6H)-1-methyl-6-oxo-9-[[[(6-amino-2-pyridinyl)methyl]methylamino]carbonyl]-5-propanoic acid;
4-[2-(6-Amino-2-pyridinyl)ethyl]-1-piperazinyl]-1-piperidineacetic acid;

1-Hydroxyl-4-[4-[(6-amino-2-pyridinyl)methyl]-1-piperazinyl]-cyclohexaneacetic acid;
1-Hydroxyl-4-[4-[2-(6-amino-2-pyridinyl)ethyl]-1-piperazinyl]-cyclohexaneacetic acid;
4-[4-[(6-Amino-2-pyridinyl)methyl]-1-piperazinyl]-1-piperidineacetic acid;
N-[[1-[[2-(6-Amino-2-pyridinyl)ethyl]carbonyl]-3-piperidinyl]carbonyl]-b-alanine;
2-[(6-Amino-2-pyridinyl)methyl]-5-[2-(carboxy-ethyl)amino]carbonyl];
-2,3-dihydro-3-oxo-1H-isoindole;
(S)-2-(Butylsulfonylamino)-3-[4-[[3-(6-amino-2-pyridinyl)propyl]oxy]phenyl]propionic acid;
N-[3(R)-[2-(6-Amino-2-pyridinyl)ethyl]-2-oxopiperidinyl]acetyl]-3(R)-methyl-b-alanine;
3-[[[3-[2-(6-Aminopyrid-2-yl)ethyl]isoxazolin-5(R,S)-yl]acetyl]amino]-3(R,S)-methylpropanoic acid;
N-[3-[[[(6-Amino-2-pyridinyl)methyl]carbonyl]amino]benzoyl]-b-alanine;
[[1-[N-[[(6-Amino-2-pyridinyl))methyl]carbonyl]tyrosyl]4-piperidinyl]oxy]acetic acid;
(~)-3-[[[[2-(6-Aminopyrid-2-yl)ethyl]amino]succinoyl]amino]-4-pentynoic acid;
(S)-4-[[[(6-Amino-2-pyridinyl)methyl]cabonyl]glycyl]-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid;
(3S,5S)-5-[4-[(6-Amino-2-pyridinyl)methyl]phenyl]oxymethyl]-3-carboxymethyl-2-pyrrolidinone;
1-[(6-Amino-2-pyridinyl)methyl]-3-[4-(2-carboxyethyl)phenyl]-4-methoxy-3-pyrrolin-2-one;
4-[[[(6-Amino-2-pyridinyl)methyl]methylamino]acetyl]phenoxyacetic acid;
2,2'-[[4-[[[(6-Amino-2-pyridinyl)methyl]methylamino]acetyl]-1,2-phenylene]bis(oxy)]bis-acetic acid;
4-[[[[(6-Amino-2-pyridinyl)methyl]carbonyl]methylamino]acetyl]phenoxyacetate;
4-[[[[(6-Amino-2-pyridinyl)methyl]carbonyl]methylamino]acetyl]-1,2-phenylenedioxydiacetic acid;
1-[(2-Amino-6-pyridinyl)methyl]-3-[4[2-(carboxy)ethyl)]phenyl]-3-oxo-imidazolidine;
[6-[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonyl]-1,2,3,4-tetrahydroisoquinolin-2-yl]acetic acid;
[6-[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonyl]-1,2,3,4-tetrahydro-1-oxo-isoquinolin-2-yl]acetic acid;
[6-[[[[(6-Amino-2-pyridinyl)methyl]carbonyl]amino]tetralin-2-yl]acetic acid;
[6-[[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonyl]tetralin-2-yl]acetic acid;
[5-[[[[(6-Amino-2-pyridinyl)methyl]carbonyl]amino]benzofuran-2-yl]propionic acid;
[5-[[[[(6-Amino-2-pyridinyl)methyl]carbonyl]amino]-2,3-dihydro-benzofuran-2-yl]propionic acid;

[5-[[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonyl]benzofuran-2-yl]propionic acid;
[5-[[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonyl]-2,3-dihydro-benzofuran-2-yl]-propionic acid; or (~)-3-[[[4-(6-Amino-2-pyridinyl)butanoyl]glycyl]amino]-4-pentynoic acid.
10. A compound according to claim 1 which is:
(S)-7-[[[(6-Amino-2-pyridinyl)methyl]methylamino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic;
(S)-7-[[[(6-Amino-2-pyridinyl)methyl]amino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid;
(S)-7-[[[(6-Ethylamino-2-pyridinyl)methyl]amino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid; or (~)-7-[[[(2-Amino-4-pyrimidinyl)methyl]methylamino]carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid.
11. A pharmaceutical composition which comprises a compound according to any one of claims 1-10 and a pharmaceutically acceptable carrier.
12. A method of treating a disease state in which antagonism of the vitronectin receptor is indicated which comprises administering a compound according to claim 1.
13. A method according to claim 12 for inhibiting angiogenesis or treating atherosclerosis, restenosis, inflammation, cancer or osteoporosis.
14. The use of a compound according to any one of claims 1-10 in the manufacture of a medicament.
15. The use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the inhibition of the vitronectin receptor in a mammal in need thereof.
16. The use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the treatment of atherosclerosis, restenosis, inflammafion, cancer or osteoporosis.
17. A process for preparing a compound of formula (I) as defined in claim 1, which process comprises reacting a compound of formula (XVI) with a compound of formula (XVII):

L1-A
(XVII) wherein:
Q1, Q2, Q3, RY, R', R", u, v and A are as defined in formula (I), with any reactive functional groups protected; and L1 and L2 are groups which react to form a covalent bond in the moiety W as defined in formula (I);
and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
CA002241724A 1995-12-29 1996-12-20 Vitronectin receptor antagonists Abandoned CA2241724A1 (en)

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