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CA2174311A1 - Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring - Google Patents

Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring

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Publication number
CA2174311A1
CA2174311A1 CA002174311A CA2174311A CA2174311A1 CA 2174311 A1 CA2174311 A1 CA 2174311A1 CA 002174311 A CA002174311 A CA 002174311A CA 2174311 A CA2174311 A CA 2174311A CA 2174311 A1 CA2174311 A1 CA 2174311A1
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CA
Canada
Prior art keywords
compound
formula
methyl
cr6r7
cr8r9
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002174311A
Other languages
French (fr)
Inventor
Gregory James Pacofsky
James Russell Pruitt
Patricia Carol Weber
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Bristol Myers Squibb Pharma Co
Original Assignee
Individual
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Publication date
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Publication of CA2174311A1 publication Critical patent/CA2174311A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to the discovery of novel and useful .alpha.-amino acid analogs, and the pharmaceutically acceptable salts and prodrugs thereof, containing a disubstituted pyrrolidine ring conjugated to an .alpha.-amino acid, useful as inhibitors of thrombin.

Description

WO 95109859 ~ l 7 i 31 i PCT/US94111~)49 ~L~
Boropeptide Inhibitors of Thrombin which Contain a Substituted Pyrrolidine Ring Field of the Invention This invention relates to the discovery of novel and useful a-amino acid analogs, and the lO pharmaceutically acceFtable salts or prodrugs thereof, as inhibitors of thrombin. These compounds contain a disubstituted- pyrrolidine ring con~ugated to an a-amino acid functionalized with an electrophilic group such as boronic acids and their esters, a-perhaloketones and l j aldehydes .
Back~ro1~nd of the Invention Thrombin plays several criticaI roles in 20 hemostasis, the normal physiological process by which bleeding from an injured blood vesse' is arrested.
Thrombin cleaves soluble fibrinogen to form insoluble fibrin in the last proteolytic step of botk the e~:trinsic and intrinsic pathways of the coagulation
2~ cascade. Fibrin may be further insolubilized through crosslinking by the thrombin-activated enzyme, factor XIIIa. In addition, thrombin-induced activation of platelets leads to their aggregation and the secretion of additional factors that further accelerate creation 30 of a hemostatic plug. Thrombin also potentiates its own production by the activation of factors V and VIII.
Recent reviews of the roles of thrombin in coagulation have been reported by E enton in Ann. N. Y. Acad. Sci .
485, 5-15 (1986), and ~?enton et al. in E3lood Coagulation 3S and ~iorinolysis 2, 69--75 (l99l) .

WO 95l098S9 217 ~ 3 ~ 1 PCTNS94/1 1049 :, Owing to its mult~ip~e r~o~es in clot ~ormation, inhibition of thrombin offers a therapeutic opportunity for development of anticoagulants useful in the treatment of thrombosis. Specific thrombin inhibitors 5 are anticipated to exhibit few of the adverse side effects, such zs bleeding and interpatient variability, caused by anticoagulants currently in clinical use (B.
Furie and B. C. Furie, The New England Journal of Medicine 326, 800-806 ~1992~ ) .
A number of naturally occurring thrombin inhibitors have been isolated. These include the marine sponge natural products Theonella sp. nazumamide A, a linear tetrapeptide reported by Fusetani et al., Tetrahedron Lett. 32, 7073-q (1991); Theonella sp. cyclotheonamides A and B reported by Fusenati et al., J. Am. Chem. Soc.
112, 7053-4 (1990); and Toxadocia cylindrica toxad~ocial A, a sulfated C47 aldehyde reported by Nakao et al., Tetrahedron Lett. 34, 1511. 4 (1993) . Hirudin, a 65 amino acid polypeptide, is responsible for the antico~gulant activity of the medicinal leech, ~irudo medicinalis. Recombinant versions of hirudin disclosed by Brauer et al. in AU-A-45977/85 and compounds incorporating hirudin fragme~nts that have been disclosed by Maraganore et al. in PCT application WO91/02750;
DiMaio et al . , J. Med. Chem. 35, 3331-3341 (1992);
DiMaio and Konishi, PCT application WO91/19734; Witting et al., Biochem. J. 283, 737-7q3 (1992); Krstenansky in European Patent Application EP 372 503 A2; may be clinically useful anticoagulants as suggested by Fareed et al., Blood Coagulation and Fibrinolysis 2, 135-L47 (1991).
Peptide analogs of thrombin substrates and reaction intermediates also inhibit thrombin. Examples of these include the tripeptide aldehyde (D)-Phe-Pro-Arg-H, disclosed by Ba jusz et al., Int. J. Peptide E'rotein Res.
12, 217-221 (1978); a chloromethyl ketone analog (Ac-wo 95f098S9 ~ 1 7 4 3 i ~ PcrluS94/11û49 he-pro-ArgcH2cl~ disclosed by Kettner and Shaw, ~h~orrb. Res. 14, 969-73 ~1979); polyfluorinated an210gs such as (D)-phe-pro-Arg-cF2-cF3 disclosed by Kolb et al., Al~-B-52881/86; Neises and Ganzhorn, European Patent Application EP 503 203 Al;
Neises et al., European Patent Application EP 504 064 Al); and boronlc acid analogs (Ac- (D)-Phe-Pro-boroArg, Kettner and Shenvi, European Patent Application EP 0 293 881 A2; Kettner et al., J. Biol. Chem. 265, 18289-97 (1990). Borolysine, boroornithine and boroarginine inhibitors that contai]l various amino acid replacements have also been synthesized and shown to inhibit thrombin. Representative examples of these compounds include t-butyloxycarbonyl- (D) -trimethylsilylalanine-Pro-1~ boroArg-pinanediol, disclosed in Metternich, European Patent Application EP 971 651 A2; Ac- ~D~
napthylalanine-Pro-boroArg pinanediol ester, disclosed in Kakkar et al., PCT Application WO 92/07869; N- (t-butyloxycarbonyl) - ~D)-phenylglycyl- ~L)-prolyl- ~L)-arginine aldehyde, disclosed in Gesellchen and Shuman, European Patent Application EP 0 479 489 A2 and J. Med.
Chem. 36, 314-319 (1993); and (HOOC-CH2)2-(L)-,B-cyclohexylalanine-Pro-Arg-CH2-O-CH2-CF3, disclosed by Atrash et al., European Patent Application EP 530 16 2~ Al.
Numerous synthetic thrombln inhibitors, many of which incorporate an arginine or arginine mimic, have also been disclosed. These include arylsulfonylarginine amides such as (2~, 4~) -1- [N2- (3-ethyl-1, 2, 3, q-3G tetrahydro-8-quinolinesulfonyl ) - (L) -arginyl ] -4-methyl-2-piperidinecarboxylate, disclosed by Okamoto et al., ~.S.
Patent No. 4,258,1g2; Okamoto et al., ~liochem. Piophys.
~es. Commun. 101, 440--446 (1981); Kikumoto et al., ~iochemistry 23, 85-90 (1984); amidinophenylalanine derivatives such as (2-naphthylsulfonylglycyl)-4-amidino-phenylalanyl piperidine disclosed in Stuber and wo 95,0g859 2 1 7 4 3 1 i - PCr/US94/11049 Dlckneite, European Patent Application EP 508 22a; amino phenylalanine derivatives, disclosed in Okamolo et 21., U.S. Patent No. 4,895,892; 1_[2-[5_ (dimethylamino) naphth-l-ylsulfonamido] -3- (2-5 imin ohexahydropy r imi di n - 5 -y 1 ) propanoy 1 ] - 4 -methylpiperidine dihydrochloride, disclosed in Ishikawa et al., JP 88/227572 and JP 88/227573); and (R) -N- [ (RS) -1-amidino-3-piperidinylmethyl ] -n- (o-nitro-benzenesulfonamido) indole-3-propionamide, disclosed in 10 Ackermann et al ., European Patent Application EP 4 68 231) . Isoquinolinyl guanidino benzoate derivatives, disclosed by Takeshita et al., European Patent Application EP 435 235 A1; and 2- [3- (4-amidinophenyl) ]propionic acid derivatives, disclosed by Mack et al., PCT Application WO 93/01208 also act as thrombin inhibitors.
Many natural and synthetic thrombin inhibitors contain a 5-membered pyrrolidine rins. In most cases, the pyrrolidine rlng is incorporated into the inhibito~
2C as an integral c~mponent of the amino acid proline, a 2-substituted pyrrolidine, which in turn is bonded to the remaining atoms of the lnhibitor via amide linkages None of the clted references describe or suggest the new thrombin-inhibiting compounds of the presen_ inventio~..
2~ The novel compounds described in the present invention are substituted at the 4-position of the pyrrolidine ring. Although Winter et al., in European Patent Application WO 91/04247, have disclosed that 4-substituted- lL) -proline can mimic a dipeptide within a 30 larger peptide or protein, and variably substituted prolines have been incorporated into compounds includinq bradykinin antagonists disclosed by ~yle et al., J.
Med. '`hem. 34, 2649-2653 (1991); as well as vasopressin analogs Buku et al., J. Med. Chem. 30, 1509-1512 (1987),
3~ no thrombin inhibitors containing a 5-membered 2~L7~311j~
pyrrolidine ring substi tuted in tbe manner described here: have been disclosed.
Despite considerable research in the area, more efficacious and specifi,c thrombin inhibitors are needed 5 as potentially valuable therapeutic agents for the treatment of thrombosis.
Summary of the Invention [ l ] The present inven~:ion provides novel compounds of f ormu la ( I ):
R3--V F~11 N~ r~ CH--A
R10_z H R

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
~l is 2' a) - (C1-Cl2 alkyl) -X, or b) - (C2-Cl2 a1 ken~ X, or c) (C H2)m I! , (CH2)n- X
25 X is -W095/09859 ~ t y ~ `, . ' PCT/17S9~/110~9 ~7~3i1 a) halogen, b) -CN, c ) -N0 d) -CF3~
5 e) -S(O)pR2, f ) -NHR2, g) -NHS (O) pR2, h) -NHC (=NH) H, i ) -NHC (=NH) NHOH, j) -NHC (=NH) NHCN, k ) - NHC ( =NH ) NHR2, 1) -NHC (=NH) NHC (=O) R2, m) -C (=NH) H, n) -C (=NH) NHR2, o) -C (=NH) NHC (=O) R2, p~ -C (=O) NHR2, q) -C (=O) NHC (=O) R2, r) -C (=O) oR2, S) -oR2, 2G t) -OC (=O) R2, U) -OC ~=O) oR2, v) -OC (=O) NHR2, ) -OC (=O) NHC (=O) R~, ~.) -SC (=NH) NHR
2~
R2 is a) hydrogen, b) -CF3 c) C1-C4 alkyl, d) - (CH2)q-ary1;
R3 and R10 are independently~selected at each occurrence from the group consisting of:
a) hydrogen, b) halogen,-c) - (CR6R7) tW (CR8R9) u--R9~

WO 95/09859 ~i 1 7 9 3 1 1 PCT/US94/11049 d) - ~CR6R7 ) tW ( CR8R9) u-aryl, e) - ~CR6R7) tW(CR8F~9) u-heteroaryl, f ) - (CR6R7) tW (CRBR9) u-heterocycle, g) -(CR6R7)tW(CR8R9)u-adamantyl, h) - (CR6R7)tW(CR8R9)U(Cs-c7) cycloalkyl, 5SsS\~
~--W--aryl i) ~1 ll -J w--heteroaryl \~
k) N W
1) ~ 1 N W
~CI~)v m) t ~
WO 95/09859 ~ PCT/11594/11049 2~31~
\~W
~d, rl ~3 W

~ O
lC W
q) W
r) W0951098~9 2 1 7~4 3 1 1 PcrluS94/11049 ~ ~W
s) ~ ~,N
R3 and R10 when taken together form a ring such as:
a) - (CR6R7) t ~CR8R9) u~W- (CR8R9) U (CR6R7) t;
b) -(CR6R7)tW(CR8R9)u-aryl-(CR8R9)uW(CR6R7)t-;
c) - ~CR6R7) tW(CR8R9) u-heteroaryl- (CR8R9) uW (CR6R7) ~,-;
d) -~CR6R7)tW(CR8~.9)u-heterocycle-(CR8R9)uw~CR6R7)t-;
e ) --~CR6R7 ) tW ~CR8R9) u--W- ~CR8R9 ) u~tq- ~ CR6R7 ) t--;
R~ and R5 are independently selected at each occurrence from the group consisting of:
a) hydrogen, b) Cl-C4 alkyl, c) Cl-C4 alkoxy, d) Cs-C7 cycloalkyl, e) pheny1, f ) benzyl;
R6, R7, R8 and R9 are independently selected at each occurrence from the group consisting of:
a) hydrogen, b) C1-C6 alkyl, c) Cl-C6 alkoxy, d) C3-Cg cycloalkyl, e) aryl, f ) heterocycle, g ) heteroaryl, h) -W-aryl, i) - ~CH2) wC (=O) oR4, wo 9~109859 2 1 ~ ~ 3 ~ PcTlUS94/lln49 j ) R6 or R7 can alternatively be taken together with R6 or R7 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons, or k) RB or R9 can alternatively be taken together with RB or R9 on an ad~acent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons;
R11 is a) hydrogen, b) C1-C4 alkyl, c) Cl-C4 thioalkyl, d) - (CR6R7) tW (CR8R9) u-aryl, e) -(CR6R7)tW(CRaR9)u-heteroaryi, f ) - (CR6R7) tW (CR8R9) u-heterocycle;
g) - (CR6R7) tW (CR8R9) u-R9;
0 Rll ~nd V, when taken together, can also be:
a) keto, b) =NR10, c) =C [ (CR6R7) tW (CR8R2) uR9] 2;
d) -(CR6R7)tW(CRBR9)UW-(CR6R7)tW(CRBR9)U-5 A is a) -gyly2 b) -C (=O) CF3, c) -C (=O) CF2CF3, d) -PO3H2 d) -C (=O) H, e) -C (=O) -1-piperdinyl, f ) -C (=O) CH2OCH2CF3, g) CH2Cl h) SO2F;5 yl and y2 are wo 951~9859 2 1 7 ~ 3 i 1 ` Pcr~ss4/1l049 a) -OH, b) -F, c ) -NR4R5 -, d) -C1-Cg alkoxy, or;
S when taken together yl and y2 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, F ~
f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which c2n be ~, S, or O, g) a cyclic boron amide-ester where said chain or i- ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, ~, or o;
~ can be independently selected at each occurence f~o.
2C the group consisting of:
a) - ~CH2)~
b) -C (=O) -, c ) --C ~=O) O-, Q) -C ~=O) NR4-, 2~ e) -O-, f ) --OC ~=O) -, g ) -OC (=o~ o-, h) -OC (=O) NR4-, i ) -NR4-, j) -NR4C (=O) -, k) -NR4C (=O) O-, 1 ) -NR4C ~=O) NR5-, m) -NR4S (O) p-n ) -S ~O) p-, 3~ o) -S(O)pO-, p) _c ~o) pNR~-, 1:

217~311 `
WO 95/09859 ~ '. PC r/US94/1 1049 q) -S (O) pNR4C (=O)--, r) -S (O) pNR4C (=O) NR5-;
V is selected from the group consisting of:
a) - (CH2)x~~
b) - (CH2) xC (=O) -, c) - ~CH2) xC (=O) O-, d) -C (=O) (CH2) x~~
e) -O- (CH2) x~~
f) -O (CH2) xC (=O) -, g) --O(CH2)XC(=O)o-, h) -O (CH2) xC (=O) NR4-, i) -O(CH2)XS~O)p-, j) - (CH2)XS ~O)p-, 1~ k) - ~CH2) xS ~O) pG-, 1) - (CH2) xS ~O) pNR4-, m) - (CH2) xS (O) pNR4C (=O) -, n) --(CH2)Xs(o)pNR4C(=o)NR
o) - (CH2) XNR4-, 2v p) - (CH2) XNR4C (=o) -, q) - ~CEl.2)XNR4C ~=O) O-, r ) - ~ CH2 ) XNR4C ~=O) NR5-, s) - ~CH2) XNR4S (O) p-;
2- z is selected froir. the group consisiting of:
a) - (CH2) x~~
b) --(CH2) yC ~=O) -, c) --C (=O) ~CH2) X-~
d) - ~CH2) xC ~=O) O-, e ) - ~CH2 ) xC (=O) NR4-, f ) - (CH2 ) XNR4-, g ) - ~ CH2 ) XNR4C ~=O) -, h ) - ( CH2 ) XNR4C ~ =O) O-, i) - (CH2) xNR4C (=0) NR5--, =
__ j ) - (CH2) XNR4S (O~ p-, wo 95109859 2 1 7 ~ 3~ 1 . Pcl~nrS94~11049 k) --(CH2) xS (O)p-, l ~ - (CH2 ) xS (O) pNR4--, m can be 0 to 4;
n can be 0 to 4 p can be 0 to 2 1 G q can be 0 to 4;
r, s, t, u, and v are independently selected at each occurrence from 0 to 6, h and x are independently selected at each occurence from 0 to 4;
wlth the follohlng provisos:
2~ (a~ when V is (CH2~ x, x cannot be 0 when R3 is h~ drogen;
(b) when Z is -(cH2~xc(=o~- and -C(=0~ (CH2)X and x is 0, R C canno~ be halogen.
[2; Preferred compounds of formula lI) are those compounds wherein:
30 R1 is (C3-C4 alkyl);
X is selected from the group consisting of:
-NHC (=NH) H, -NHC (=NH) NHR2, -NH2 or -SC (=NH) NHR2;
35 R2 is hydrogen or Cl-C4 alkyl.

WO 95/09859 21~ L ~ PCr/U594/11049 ,~
[3] More preferred compounds of formula (I) are compounds of formula (Ia):

~NS fi CH--B
Rl_Z ¦ ¦ `y2 H
(Ia) or a pharmaceu7 ically acceptable salts or prodrugs 1" 7hereof, wherein:
Rl is (C3-C4 alk~l);
X is selected from the group consisting of:
15 -NP.C (=NH) H, -NHC (=NH) NHR2, -NH2 or -SC (=NH) N~.R-;
R2 is hydrogen or Cl-C4 alkyl; ~
R3 and R10 are independently selected at each oc^~_-rence 2C from the group consisting of:
a ) hydrogen, b) halogen, c) - (CR6R7) tW (CR8R9) U-Rg d) - (CR6R7) tW ~CRaR9) u-~ryl 25 e) -(CR6R7) tW (CR8R9)u-heteroaryl;
R4 and R5 are independently selected at each occurrence from the group consisting of:
a) hydrogen, b) C1-C4 alkyl, WO 95/09859 21~ pcr/L7ss4nlo4s c) C1-C4 alkoxy, d) phenyl, e ) benzyl;
R6, R7, RB, R9 are inde~endently selected at each occurrence from t~le group consisting of:
a) hydrogen b~ C1-C6 alkyl, c) aryl, d) - (CH2) wC (=O) oR4, or;
yl and y2 are a ) -OH, b~ -F, c) -NR4RS-, d) -C1-Cg alkoxy, or;
when taken together yl and y2 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, ~-3 heteroatoms which can be N, S, or O, f ) a cyclic boron amide where said chain or ring contains fro~n 2 to 20 carbon atoms and, optionally, :1-3 heteroatoms which can be N, S, 2~ or O, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
~' can be independently selected at each occurrence from the group consisting of: -~
a) - (cH2) b) -O-, ~5 c) --S (O) p-, d) --NR4-, e) -NR4C ~=O) -, wo gs/og859 ~ ~ 7 4 3~ ~ PCT/US94/11049 f ) -NF~4C (=O) o-V is selected from the group conslsting of:
a) - (cH2) x~, b) -O ~cH2) x~, c) -O~CH2)X~C=O)-, d) - ~cH2) xS (O) p-, e) --(CH2) xN~4-f ) - (CH2) XNR4C (=O) -, g) - (CH2) XNF~4C ~=O) O-;
Z is selected from the group consisiting of:
a) - ~CH2) xC ~=O) -, b) -C ~=O) ~CH2) x~~
c) - ~CH2) xC ~=0)0-, p car, be 0 or 2;
r can be independent ' ~ selected at each occurrence ~rom 0 to 3i s can be independently selected at each occurrence ~rom 0 to li .
~_ t car. be independent ~ y selected at each occurrence from 0 to 2i u can be independently selected at each occurrence fro~.
0 to 2;
3(~
w can be independently selected at each occurrence from 0 to 2;
Y. can be independently selected at each occurrence from 0 to 3; with th~ following provisos:
1~

~j WO 95/09859 2 1 7 4 3~ PCI/US94~11049 ~a) when V is (CH2) x, x cannot be 0 when R3 is hydrogen i ~b) when Z is -(cH2)xc~=o)- and -C(=0) (CH2)X and x is 0, R10 cannot be halogen.
[4] Most preferred compounds of formula (I) are those compounds of formula (Ia) lC
R3--V~H
<~ I r~ CH B~y2 R~--Z
(Ia) or a :pharmaceutically acceptable salt or prodrug thereof, wherein:
;S
R1 is (C3--C4 alkyl);
X is from the group conslsting o~ :
-NHC (=NH) H, -NHC (=NH)NHR2, -NH2 or -SC (=NH) NHR

R2 is h~d-oge~ o~ C1-C4 alkyl;
R3 is independently selected froml the group consisting of:
2~ :benzyl, phenyl, phenethyl, (3-phenyl)prcp-1-yl, (2-methyl-l-phenyl) prop-2-yl, (2-methyl-2-phenyl) prop-1-yl, 1, l-diphenylmethyl, phenoxymethyl, phenylsulfonylmethyl, 2- (m-fluorophenyl) ethyl, 2-(3-pyridyl)ethyl, (m-aminophenyl)methyl, (m-, -.
~, WO 95/09859 ~ PCrNS94/1~049 methylphenyl ) methyl, (p-methylphenyl ) methyl, 1-naphthylmethyl;
R10 is independently selected from the group consisting
5 of:
methyl, t-butoxy, benzyloxy, phenethyl, benzyl, phenoxymethyl, isopropyl, isoamyl, N-methyl-N-t-butoxycarbony~Am;n~ -thyl, N-methylaminomethyl, (m-methyl) phenethyl, (m-fluoro) phenoxymethyl, (m-lG methyl) phenoxymethyl, (3-pyridyl) ethyl R11 is hydrogen;
yl and y2 are -a) -OH, b) -F, c) -NR4R5 -, d) -C1-Cg alkoxy, or;
wher. taken together yl and y2 form:
2~ e) a cycl~ c boron ester where said chain or ring contains from 2 to 20 carbcn atoms and, optionally, 1-3 ~ieteroatoms which can be N, S, or o, f ) a cyclic boron amide where said chain or ring 2~ contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or C, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, 3G optionally, 1-3 heteroatoms which c2n be 11, S, or O;
V is independently selected from the group consisting of:
'~ O, -OC(=O)-,, S, --NH-;
~i is -C (=O) - . :

~174311 ~j WO 95/09859 = = ~ = = ' ` PCII/US9.l/11049 [5] Specifically preferred compounds of formula (I) are those compounds of formula (Ib):

~--~1 H 2N .~B~o,~
0~ N Ho C H3 /~NJ~ Rl (Ib) selected from the list consisting of:
lC
the compound of formula (Ib) wherein R3 is phenyl and Rl is methyl;
rhe compound of formula (Ib) wherei.. R3 is _~- phenylmethyl and R]-0 is methyl;
tne compound of formula (Ib) wherein R3 is phenethyl and B10 is methyl;
the compound of formula (Ib) wherein R3 is 3-phenylprop-1-yl and R10 is methyl;
the compound of formula (Ib) wherein R3 is 1,1-dimethyl-2-phenylethyl and R10 is methyl;
the compound of formula (Ib) wherein R3 is 2, 2-dimethyl-2-phenylethyl and Rl is methyl;

W095/09859 217431i ~ ~ ` PCTNS94/11049 ,~
the compound of formula (Ib) wherein R3 is diphenylmethyl and R10 is methyl;
the compound of formula (Ib) wherein R3 is phenoxymethyl and R10 is methyl;
the compound of formula (Ib) wherein R3 is phenylsulfonylmethyl and R10 is methyl;
the compound of formula (Ib) wherein R3 is (m-fluorophenyl)ethyl and R10 is methyl;
the com~pound of formula (Ib) wherein R3 is (3-p~idylel:h~l ) and R10 is methyl;
the compound o~ formula (Ib) wherein R3 is phenylethyl and R10 is phenethyl.
20 [6~ l~lso specifically preferred compounds of formula (IJ are those compounds of formula (Ic):
H 2N ~B~
0~,,NH CH3 ~N Rl R3 ~`
~Ic) selected from the list consisting of:
the compoun~d of formula (Ic) wherein V is sulfur, R3 is phen~l and R10 is phenmethyl;

~ WO95109859 217~311 PCT/US94/11049 the compound of formula ~Ic) wherein V is oxygen, R3 is phenylmethyl and RlO is phenethyl;
the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and RlO is 3-phenylpropyl;
the compound of formula tIc) whereln V is oxygen, (m-methyl)phenoxymethyl and R10 is 3-phenylpropyl;
the compound of formula (Ic) wherein V is oxygen, (m-fluoro)phenoxyl~ethyl and RlO is 3-phenylpropyl the compound of formula (Ic) whereir. V is oxygen, R3 is phenylmethyl and RlO is (m-methylphenyl ) ethyl;
the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and RlO is (m-fluoro)phenethyl;
the compound of formula (Ic) wherein v is oxygen, R3 is phenylmethyl and RlO is phenoxymethyl;
the compound of formula (Ic) wherein V is oxygen, R3 is (m-fluorophenyl)methyl and RlO is phenethyl;
the compound of formula (Ic) wherein V is amino, R3 is phenylmethyl and RlO is phenethyl;
the compound of formula ~Ic) wherein V is oxygen, R3 is phenylmethyl and RlO is methyl;
- the compound of formula (Ic~ wherein V is oxygen, R3 is phenylmethyl and RlO is 2-propyl;

WO 95/09859 ~17 4`3 t 1 ` PCTIUS94/11049 ~
the compound of formula (Ic) wherein v is oxygen, R3 is phenylmethyl and R10 is isoamyl;
the compound of formula (Ic) wherein V is oxygen, R3 is (m-methylphenyl)methyl and R10 is methyl;
the compound of formula (Ic) wherein V is oxygen, R3 is (p-methylphenyl)methyl and R10 is methyl;
the compound of formula (Ic) wherein V is oxygen, R3 is (l-naphthyl)methyl and R10 is methyl;
the compound of formula (Ic) wherein V is oxygen, R3 is phenylmeth~ l and R10 is N-methyl-N-t-butoxycarbonylaminomethyl;
the compound of formula (Ic) wherein V is o~:ygen, R3 is phenylmethyl and R10 is N-methylaminomethyl.

[, ] P.lso specific~lly preferred compounds cf formula ( ~ ) are those com~ounds of formula ¢Id):
OH
H 2N ~ O H
O~, N H
~NJ~ R1 o (Ic) selected from the list consisting of: -the compound of formula (Id) wherein V is oxygen, 3C R' is phenylmethyl and R10 is phenethyl;

17~311 WO 95/09859 1 Pcr/Uss4/1104s the compound of formula (Id~ wherein V is oxygen, R3 is (m-fluorophenyl)methyl and R10 is phenethyl.
the compound of formula (Id) wherein V is oxygen, R3 is phenylmethyl and R10 (m-methyl) phenethyl;
Detailed DescriDtion of the Invention The " (D) " prefix for the foregoing abbreviations lndicates the amino acid is in the (D)-configuration.
"D, L" indicates the ami]lo acid is pre'sent as a mixture ;~ of the (D)- and the (L)-configuration. The prefii: "boro"
indlcates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic acid ester. For example, if Rl is isopropyl and yl and y2 are OH, the C-terminal residue is abbreviated "boroVal-OH" or 20 "~oroValine" where "-OH" indicates the boronic acid is in the form of the free acid. The pinanediol boronic acid ester and the pina-ol boronic acid ester are abbre-~iated "-CloHl6" and "-C6H12", respectively.
E~.amples of other useful diols for esterification hith ~_ the boroni-c acids are 1,2-ethanediol, 1,3-propanediol, 1, 2-propanediol, 2, 3-butanediol, 1, 2-d isopropylethanediol, ~, 6-decanediol, and 1, 2-dicyclohexylethanediol. Some common abbreviations used herein are: CBZ or Z, ]~enzyloxycarbonyl; BSA, 3C benzenesulfonic acid; T~IF, tetrahydrofuran; Boc-, t-butoxycarbonyl-; Ac-, acetyl; pNA, p-nitroaniline; DMAP, 4-dimethylaminopyridine; HOBT, l-hydroxybenzotriazole and hydrate thereof; DCC, 1,3-dicyclohexylcarbodimide;
Tris, Tris ~hydroxymethy:L)aminomethane; MS, mass __ spectrometry; FAB/MS, fast atom bombardment mass spectrometr~. LRMS and HRMS are low and high resolution 2~

WO 95109859 2 ~ 7 4 31 I PCTIUS94/11049 ~
mass spectrometry, respectively, using ammonla (NH3-CI) or methane ~CHq-CI) as an ion source.
It is understood that many of the compounds of :the present invention contain one or more chiral centers and 5 that these stereoisomers may possess distinct physical and biological properties. ~he present invention comprises all of the stereoisomers or mixtures thereof.
If the pure enantiomers or diasteromers are desired, they may be prepared using starting materials with the lO appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard techniques, including chiral chromatogrsphy and recrystalli:~ation of diastereomeric salts.
When an~ variable (for example, Rl through RlO, m, l- n, W, Z, etc. ~ occurs more than one time in any constituene or ir. formula (I), Dr any other formula herein, its definition on each occurrence is independen.
of ts definition at every other occurrence.
In the instance that a subscript of a group is 0, 2C it is intended to mean that= the previous group is bonded directly with the next group in the sequence. For example, when:
R3 is - (CR6R7) t-w- (CR8R9) u-aryl, snd u is 0 -. is the ssme as:
~_ - (CR6R7 ) t-W-aryl .
As described broadly above for R6 and R7, in the case "where R6 (R8) or R7 (R9) can alternatively be taken together with R6 (R8) or R7 (R9) on an ad~acent carbon atom to form a direct bond", this can only occur when t 3G (u) is greater than l. ~he structure that would result f rom:
R3 is -(CR6R7)t-W-(CR8R9)u-aryl~ t = 2, u=2,6 and R7 are taken to for a double bond, and R8 and R9 taken to be a triple bond 3_ would be:
-CP6=CR7-W-C_C-aryl .
2~

~ WO 95/09859 2~ ~ 7 4 311 Pcr/uss4nlo4s The term "amine-blocking group" or "amine-protecting group" as used herein, refers to va ious acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms.
5 Substituents on these groups may incIude either alkyl, aryl and alkaryl which l~ay contain the heteroatoms, O, S, and N as a substituent OI as an inchain component. A
number of amine-blocking groups are recognized by those skilled in the art of organic synthesis. Examples of lO suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl (also referred to as t-butyloxycarbonyl) 1~ or adamantyloxycarbony'. Gross and Meienhofer, eds., ~rne Peptides, Vol 3; 3-88 (1981), Academ.ic Press, New York, and Greene and Wuts Protective Groups in Orga~ic Synthesis, 315-405 (l991), ~. Wiley and Sons, Inc., Ne York describe numerous suitable amine protecting groups 2'` and they are incorporated herein by reference for that purpose .
"Amino acid residues" as used herein, refers to na.ural or unnatural amino acid of either (D)- or (L)-configuration. I~atural amino acids residues are Ala, 2_ Arg, Asn, Asp, Cys, Gln, Giu, Gly, ~.is, Ile, Leu, Lys, Me., Phe, Pro, Ser, Thr, Trp, Tyr, and Val. Roberts anQ
Vellaccio, The Peptides, Vol 5; 341-449 ~1983), Academic Press, New York, describe numerous suitable unnatural amino acids for use in this application and is 30 incorporated herein by reference for that purpose.
"Amino acid residue" also refers to various amino acids where sidechain ful~ctional groups are coupled with - appropriate protecting groups known to those skilled in the art. "The Peptides", Vol 3, 3-88 (1981) describes 35 numerous suitable protecting groups and is incorporated here -. by reference for that purpose.

~7,~31~ ~
Wo 95/098S9 PCr/US94111049 As used herein, "alkyl " is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specif ied number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen ~
bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- and polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which ma~ occur in any stable point along the chain, such as ethenyl, propenyl, and the like. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo.
The term "aryl" is defined as phenyl, fluorenyl, bipheny1 and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents .
2C The term "heteroaryl" is meant to include 5-, 6- or lO-membered mono- or bicyclic aromatic rings which can optionall~ contain from 1 t4 3 heteroatoms selected from the group consisting of O, N, and Si said ring ~s) may be u-.substituted or include optional substitution with one to three substituents. Included in the definition of the group heteroaril, but not limited to, are the following: 2-, or ~-, or 4-pyrid~-l; 2-or 3-furyl; 2- or 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; l-,~ or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; l- or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl; 2-o 4- or 5-imidazolyl; l- or 2- benzimidazolyl; 2- or 4-or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isQxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-p~rimidinyl; 2-pyra~in~l; 2-triazinyl; 3- or 4-Wo 951098s9 2 1 7 ~ 3 1 1 PCr/USs4/11049 cinnolinyl; l-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl ring. Pdrticularly preterred are 2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or q-quinolinyl; or l-, 3-, or 4-isoquinolinyl.
The term "heterocycle" is meant to include 5-, 6-or lO-membered mono- or bicyclic rings which can optionally contain from l to 3 heteroatoms selected from the group consisting cf 0, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents. Included in the definition of the group heterocycle, but not limited to, 2- or 3-pyrrolidinyl, a 2-, 3-, or 4-piperidin~l, or a l-, 3-, or 4-tetrahdroisoquinolinyl, l-, 2-, or 9-lS tetrahydroquinolinyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothiophene, l-, 2-, 3-, or 4-piperazinyl, and l-, 2-, 3-, or 4-morpholino. Particularly preferred are l-, 3-, or 4-tetrahdroisoquinolinyl, 2- or 3-p~rrolidinyl, and 2-, 3- or 4-piperidinyl.
2~ The substituen,s that may be attached to the aryl, heteroaryl or heterocycle ring (s) m~ be independently selected at each occurrence from the group consist ing of:
halogen, -CF3, Cl-C4 alkyl, nitro, phen~ ', cya~o, 2_ - (CH2) rR~ - (CH2) rC (=0) (CH2) sR, - (CH2) rC (=0) 0 (CH2) sR, - (CH2~ rC (=0) N [ (CH2,~ sR~] [ (CH2) sR5], met~.~ ienedioxy, Cl-C4 alkoxy, -CH2) r (CH2) sR4~ - (CH2) rOC (=O) (CH2) sR4 - (CH2) rOC (=0) O(CH2) 3R4, 3C - (CH2) rOC (=0) N [ (CH2) sR4] [ (CH2) sRS] ~
-(CH2)roC(=o)N[(CH2)sR4] [C(=O) (CH2)sRS], -(CH2)rs(o~p(CH2)sR4, --(CH2)rS(o)p(CH2)sC(=o)R4, - - (CH2) rS (O) p (CH2) 5C (=O) oR4, - (CH2) rS (O) pN [ (CH2) sR4] [ (CH2) 5R5], ~_ -(CH2)rS(O)pN[ (CH2)sR4] [C(=0) (CH2)~R5], ~ (C~2) rN [ (CH2) sR4] [ (C}i2) sRS] ~
~, .

WO 95/09859 2 ~ 7 ~ PCT/US94111049 - ~CH2) rN [ (CH2) sR4~ IC (20) (CH2) 8RS] t --~CH2) rN [ (CH2) sR4] [C (=O) O (CH2) sRS], -(CH2)rN[ (CH2)sR4]CoN[ (CH2)sR4] [ (CH2)sRS], - (CH2) rN [ (CH2) sR4] C (=o) -N [ (CH2) sR4 ] [C (=O) (CH2) sRS], S - (CH2) rN [ (CH2) sR4] [S (O)p(CH2)sRs] .
By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent .
As used herein, "pharmaceutically acceptable salts"
refe- to de~ivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making - ac~d or base salts o~ the compound of formula (I) .
E~:amples of pharmaceutically acceptable salts include, bu~ are no~: limited to, mlneral or organic acid saLts of basic residues such as amines; alkali or organic salts of acldic resldues such as carboxylic aclds and the like .
Pharmaceutically acceptable salts o~ the compounds o~ the invention can be prepared by reacting the free acid or base forms of these compounds with a sloichiometric amount of the appropriate base or acid in 2~ water or in an organic solvent, or in a mixture o~ l:he two; generally, nonaqueous media like ether, ethyl acetate, methanol, ethanol, isopropanol, or acetDnitrile are preferred. Lists of suitable salts are found ln R~rin~ton's ph~rr~ceutlcal Sciences. 17th ed., Mack 3C Publishing Company, Easton, PA, 198S, p. 1418, the disclosure of which is hereby incorporated by reference.
"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is ^~ administered IO a mammalian subjecl. Prodrugs of the 2~

Wo 951098~9 2 1 7 4 3 1 `1 ~ ~ PCT/USg~ o~9 compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modlfications are cleaved, either in routine manipulation or in viv~, to the parent compounds.
5 Prodrugs include compounds of formula (I) wherein hydroxy, amine, or sulfhydr~ l groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but 10 are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups ln the compounds of formula (I) .
S~nthesis ~iscussion 1~ Compounds of formula (I) can be preparec using the synthetic sequences that follow. The solvents employed are compatible with the reagents selected and the transforma~ions being performed. It ~ will be understood by those skilled in the art of organic synthesis that 2C the order of the transformations proposed will be conslstent with functionality present in the molecules a~d ma~ require ~udgements during the selection of a Frocedure for prepara~ ion of a compound of the invent ion .
2~ The general synthesis of N-acyl-~- (acyloxy) proline intermediates can be prepared by sequential acylations of the amine and hydroxyl functionalities and is shown in Scheme 1.
3G Sche~e 1 WO 95/09859 ~ 1,7i4,3~ PCT/US94/11~49 PhCH20 0 PhCH20 0 ~NH HCI ,~ ~N Rto HO HO
(Il) PhCH2O O HO~O
R3J~ O R3J~ O
(111) (IV) Thus, as an example, (1)-4-hydroxyproline benzyl ester hyàrochloride, which is commercially available, or any other suitably protected hydroxyproline, can be treated with a trialkylamine base, typically 9-methylmorpholine, and an acid chloride (RlOCOCl) to afford acyIation product (II) selectively. The hydroxyl group can be converted to a corresponding ester by treatment with a lC second acid chloride (R3COCl) in the presence of a tri~lkylamine or heterocyclic amine base, such as p,~idine, and a suitable catalyst, such as but not limi~ed to DMAP to generate (III) . The carboxylic acid o~ the proline moiety can be liberated by hydrogenation using conditions reported by Hartney and Simonoff, Org.
~eact. VII, 263 (1953) wherein an alcohol solution of the compound (III) may be affected under an atmosphere of hydrogen gas using a suitable catalyst, prefe~rably platinum or palladium on carbon catalyst, to provide 2G (IV) One may vary the transformations indicated above depending upon the nature of the groups to be appended.
One may employ alternative methods such as a mixed anhyd-ide coupling, as reported by Anderson, et al. J.
AJn. Chern. Soc. 89, 5G12 (1967); o~ the DCC/HOB~ protocol ~ wo gsl098s9 2 1 7 ~ 3 1 1 PCr/US94111049 described by Konig, an~ Geiger, Chem. 13er. 103, 788 (1970) to form the requisite amide bond. Also, the DCC/DMAP esterification procedure, reported by Hassner, and Alexanian, ~etrahedron Lett. 19, 4475 ~1978) has proved useful for performing the second acylation reaction. Finally, one may choose an ester other than benzyl which might be removed hydrolytically or photilytically, such as photlytic deprotection. For example, with a methyl ester of (II), treatment of an 10 alcoholic solution of the compound with a solution of sodium hydroxide so as to deliver 1 equivalent amount of NaOH followed by acidification should provide the carboxylic acid.
The N-acyl-4- ~alkoxy) proline intermediates can 15 prepared as shown in Scheme 2.
S cheme 2 HO O HO O
N-P ~ ~N-~
HO R30~
(V) (Vl) P=BOC:CBZ
PhCH20 0 HO O
~NH , ~N Rl R30~ R30~
(Vll) (Vlll) The hydroxyl function of an N-protected 4-hydroxyproline (V) can be alkylated according to the method of Smith et al., J. Med. Cllelr. 31, 875 (1988), by treatment with an alkali metal hydride, such as but not limited to sodium 2c hydride and an alk:' h21ide (R3X) to give (VI) . Removal _l 2~7~311 WO95109859 ~ PCTIIIS94111049 ~
,, ~
of the ~ protecting group by an appropriate method know to one of skill in the art can provlde ~VII): the t-butyl carbamate can be cleaved upon treating with acid under anhydrous conditions; for example, trifluoroacetic 5 acid in dichloromethane solution removes the t-butyl urethane of derivatives of ( LV) at ambient temperature as reported by Bryan et. al., J. Am. Chem. Soc. 99, 2353 ~1977); alternatively anhydrous hydrogen chloride in dioxane may be used to prepare the HCl salt. Other l0 methods for protection of the amine are delineated in Greene and Wuts ~l99l) . The use of benzyl urethane is also viable where hydrogenation over palladium catalyst deliveres the free amine (VII) . Acydlation by one of the methods discussed previously can provide ~VIII) .
The 4-amino and 4-mercaptoproline intermediates useful for the synthesis of compounds of the formul2 (I), wherein V is S, NH or derivatives thereof, can be prepared according to Scheme 3. The hydroxyproline ester (IX), wherein the amine is protected as the BOC or 28 CBZ, can be reacted with carbon tetrachloride/
triphenylphosphine accQrding to the method of ~ebb and Eigenbrot, J. Org. Chem., 56, 3009 (I991), to provide the chloride (X) with inversion of stereochemistry. The chloride can be displaced by a sulfur nucleophile, again ~' witr. inversion o~L sterochemistry in a manner similar to that reported by Smith et al. (1988) to provide the displacement producT (XIIb), sulfur-containing pro:line~.
Sim.ilarly, the chlQride can be displaced by sodium a:zide, ~-hich. is reduced to the primary amine and 3û converted by reductive amination to provide the displacement products (XIIa), nitrogen-containing prolines. The R3 group in (XII) used in the displacement reaction need not be the ultimate R3 of formula (I); methods for their removal are well known to 3' those skille~ in the art of organic synthesis. Methods fo- the a~ ,achmen. c~ preferred R3 are described herein .

WO 9S/09859 I ~~ ~ PCT/US94/11049 S chQme 3 Alkyl-O O Alky~-O O
~N P ~N P 1.) depro~ect HO Cl~~ 2-) R10-Z.CI
(D3 (X) 1.) R3S(-) or Alkyl-O O 1a.) N3(-) 1b.) reduction HO O
p~V` R10 lC ) aCylation or reduCtiVe aminat!n Cl 2.) liberateacid (Xl) (Xlla) V b NHR~
(Xllb) V is SR3 P is a protectin~ group (ie., CBZ, Boc) These disubstituted prolines (XIIa,b) can be used in an analogous manner to that of (IV) or ~VIII) described hereafter The construction of thrombin inhibitors of the lC present invention requires the coupling of either of the aforementioned intermediates, (IV~, (VIII), or (XII) with a boron-containing fragment followed by manipulation of the pendant functionalities, as shown in Scheme q 1~
S cheme 4 _ _ ~17~
W0 95/09859 ~ = PCTNS94/11049 O O H
Br ~BO~ Br ~Bo~i3 HCI H2N Me 0~, NH Me ~N--Z-R10 (Xm~ R3-V
H H
N3 ~B,O~j3 H2N ' o~a 0~, NH Me 0~, NH Me ~N--Z-R10 ~N--Z-R10 R3-V (Xv) R3-V
OH
H2N ,BOH
0~, NH
~N--Z-R10 Tne synlhesis of borolysine-containing throlrbin inhibitors (XVII~ begins with the coupling of am.ine hydrochloride (XIII), disclose~ by Etettner and Shenvi U.S. Patent l~o. 5.187.197, to provide amide (XIV) . I~.
p-actice, one may choose from several well-known methocs o prepare ~XIV) in suitably pure form, as purific2tion o~ this intermediate is oftentimes impractical. One lC me.hod calls for the cor[bination of (XIII) and the acid chloride derived from (IV), (VIII) or (XII) in the presence of an amine base, such as but not limited to pyridine. Alternatively, one may employ either the mixed anhydride method, which involves mixing the acid 15 to be coupled with an alkylchloroformate and an tertiary amine base, such as, but not limited to, ~-butyl chloroformate and 9-methylmorpholine, followed b~
1' _ WO 95/09859 ~ ~ 7 4 3 ~ 1 s PCTIUS94~ 149 addition of the amine discussed previously, to- prepare (XIV) from (IV), (VIII) or (XII); additionally the DCC/HOBT method may be used to access amines XIV and/or XII
Conversion of the bromide to the ~; group in Rl of formula (I) can be accomplished by first reaction of bromide (X) with an in~arganic azide, such as sodium or potassium azide, in an anhydrous poLar aprotic solvent, such as acetone, N,N-dimethylformamide or methyl sulfoxide at temperatures ranging from ambient to 130~C;
typically reaction witl~ sodium azide in N, N-dimethylformamide at 6~-70 C for several hours provides (XV). Subsequent reduction of the azide function to the amin-e (XVI) is effected by catalytic hydrogenation of 1~ the azide in a solvent, such as an alcohol or ethyl acetate using a suitable transition metal catalyst under an atmosphere of hydrogen gas. Reduction of the azide (XX) in the presence of sulfur-c~ntaining prolines (XV, where V is S) can be done according to the method of Knowles et al, ~etrahedron Lett., p. 3663 (1978) to provide the amines (XXI) . A variety of alternative me~hods can be found in the monograph by Hudlicky, Reduct:ions In Or~anic Synthesis, John ~'iley and Sons, pp. 134 (1984) . The amine (XVI) can be isolated as the 2~ free base or a salt, typically, but not exclusively hydrochloride or benzenesulfonate; other salts which impart improved physical properties may be preferred.
The method described by Matteson et al., J. Am.
Chem,. Soc. 102, 7590 (1980) discloses a procedure for 3C removing the pinanediol ester, however, the method employs reagents which may decompose the desired product. ~he preferred method for preparation of the free boronic acid (XVII~ involves transesterification in the presence of excess phenylboric acid.
_, W095/09859 ~3~ PCT/US94/11049 The amidine-type analogs, where the X yroup in Rl of formula (I) is modified, can be prepared as shown in Scheme 5.
Schcme 5 Br ,B ~ _ Br ~B ~3 HCI NH 2 Me ~, NH Me (XVIII) ,~N--Z-R 10 R V (X~
O H 0~3 ,2~N--Z-R 10 . J~N--Z-R 10 (XXI) X - NH 2 (XX111) R - NHC(=NH)NH 2 ,OH
X B~oH
0~, NH
~C~N--Z-R 10 (XXV) R = NHC(=NH)H
(XXVI) R = NHC(=NH)NH 2 (XXVII) R = NHC(=NH)NHCH 3 The guanidinium analogs can be prepared in a similar lC manner starting from amine hydrochloride (XVIII) . Amide bond formation using one of the methods previously described provides (XIX), which can be converted to the azide (XX) by nucleophilic displacement of the bromide.
Reduction of the azide using conditions already ~17~3~
~ro gslos859 PCT/rTss4/ll04s descrlbed can provide the amine (XXI) . Preparation of formamidine (XXII) can be accomplished by reaction of amine (XXI ) with ethyl formimidate hydrochloride in the presence of D~qAP according to the method of Ohme and Schmitz, Angew, Chem mt . Ed 6, 566 (1967) . Elaboration of (XXI) to guanidine (XXIII) can be accomplished by reaction with formamidinesulfonic acid in the presence of DMAP, according to that described in Kim et al., Tetrahedron Lett. 29, 3183 (1988), whereas the analogous N-methylguanidine (XXI~') can be produced when N-methyl-formamidinesulfonic acid is employed according to the method of Walter and Rauden, ~iebig Ann. Chem. 722, 98 (lg69) . As before, transesterification wi~h phenylboric acid yields aclds (XXV) - (XXVIII) .
1~ ~ The compounds of 40rmul2 (I), wherein X is isothiouronium can be Frepared as shown in Scheme 6.
Schezne 6 (xrx) H r~J~s~~B ~K3 O~, NH Me ~[~N--Z-R

(xxvllr) NH OH
N S , B OH
0~, NH
~N--Z-R~

(x~a~

~7 W0 95/09859 ~ PCT/US94/11049 ~ 31'f`
Starting from intermediate bromide (XIX), the ;~ group in formula (I) can be introduced directly by displacement of the halide using thiourea as the nucleophilic ~pecies thereby providing boronic ester (XXVIII) . As described 5 previously, transesterification using phenylboric acld yields ~XXIX) .
Ex~ le~
E~r~le 78 Nl-[ (4R)-N-Acetyl-9-(3-phenylpropionyl)oxy-~L)-prolyl]-R-borolysine, (+)-pinanediol ester Pa-t A: ~o a solution of (4R) -4-hydroxy- (L)-proline benzyl ester hydrochloride (2.67 g, 1.04 mol) in dichloromethane (CH2C12, 50 mL) at 0 C was added 4-metnylmorpholine (2.50 mL, 2.28 mmol) followed by acetyl chloride (0.72 mi" 1.09 mmol) . The reaction mixture was wa~med to roon~ temperature over 12 hours and ethyl 2C acetate (EtOAc, ca. 200 mL) was added. The organic `~ ayer was washed with saturated aqueous sodium Dicarbonate (NaHCO3, 1 x 30 mL), water (H2O, 1 x 30 mL), saturated aqueous sodium chloride (NaCl, 1 x. 30 mL)=, dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure . ~he resulting oil (1. 94 g, 71 yield) solidified on standing at room temperature. A
sample o~ (4R) -N-acetyl-4-hydroxy- (L)-prGline benzyl ester was recrystallized fr.om hexanes:EtOAc to give white plates, mp 99-102 C (orthorhombic, P212121, a =
3C 9.216, b = 9.315, c 15.420 A) . lH NMR (300 MHz, CDC13) 7.35 (comp, 5H), 5.17 (s, 2H), 4.63 (m, lH), 3.79 (dd, J= 10.6,4.6 Hz, lH), 3.50 (d, J= 10.6 Hz, lH), 2.29 (d, J= 4.4 Hz, lH), 2.24 (m, lH), 2.11 (m, lH), 2.09 (s, 3H); LRMS 264 (M+H, base), 281 (M+NH4) i Anal. Calcd for 3c Cl~:il7NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.84i H, 6.~1; N, 5.3~. ~

WO 95/09859 2 1 7 ~ 3 1~1 . PCT/US94/11049 , , ,. " , .
Part B: ~o a solution of the product from Part A (370 mg, 1.41 mmol) and pyridine (0.I7 mL, 2.10 mmol~ in CH2C12 (14 mL) at 0 C was added 3-phenylpropionyl chloride (0.23 mL, 1.55 mmol~ . The reaction mixture was warmed to room temperature over 3 hours and added to EtOAc (ca. 75 mL~. The organic layer was washed with sat. aq. NaHCO3 (1 x 25 mL), half-saturated aqueous copper (II) sulfate (1 x 25 mL), sat. aq. NaCl (1 x 25 mL), dried (Na2SO4) and was concentrated under reduced pressure. The residue was purified by flash chromatography, elution with 2 :1 EtOAc-hexanes to give (4R) -N-acetyl-4- (3-phenylpropionyl) oxy- (L) -proline benzyl ester (340 mg) as an oil in 61~ yield. lH NMR ~300 MHz, ~_ CDC13) ~ 7.37 (comp, 5~.), 7.28 (m, 2H), 7.19 (m., 3H), 5.30 (m, lH), 5.18 (m., 2H), 4.51 (dd, ~= 8.4, 8 0 Hz, lH), 3.84 (dd, J= 11.7, 4.7 Hz, lH), 3.46 (d, J= 11.7 H~, lH), 2.93 (t, J= 7.5 Hz, 2H), 2.64 (t, J= 7.5 Hz, 2H) 2.28 ~m, lH), 2.13 (m, lH), 2.03 (s, 3H); LRMS 396 (M+H, base) .
~art C: A so}ution of the product from, Part R (340 mg, G.~6 mmol) ~ogether with palladium on charcoal (55 mg) ln me.hanoi (MeO~., 9 mL) was stirred under hydroger. (1 ~_ a-rr.) for 2 hours. The reaction mixture was filtered -,hroug~. a pad Or -Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give (4R)-N-acetyl-4-(3-phenylpropionyl)oxy-~L)-proline (245 mg) as a foam in 93~ yield. lH NMR (300 3C MHz, CDC13) ~ 7.27 (comp, 5H), 5.28 (m, lH), 4 57 (t, J=
7 7 Hz, lH), 4 38 (br s, lH), 3~76 (dd, J= 11~ 9, 4 5 Hz, lH), 3~49 (s, lH), 2~95 (., J= 7~3 Hz, 2H), 2 66 (t, J=
7 3 Hz, 2H), 2.56 (m, lH), 2.26 ~m, lH), 2 07 (s, 3H);
LRMS 306 (M+H), 173 (base) _ _ :

WO 95/09859 ~ PCT/US94111049 ~17~311 Part D: To a solution of the product from Part C~ (240 mg, 0.79 mmol) and 9-methylmorpholine (0.26 mL, 2.36 mmol) in tetrahydrofuran (THF, 6 mL) at -20 C was added i-butyl chloroformate ~0.11 mL, 0.87 mmol) after which 5 the reaction mixture was stirred for 2 minutes. A
solution of ~lR)-5-bromoaminopentane-1-boronic acid ~+)-pinanediol ester ~299 mg, 0.79 mmol) in l\~,N-dimethylformamide ~DMF, 2 mL) was added, the reaction was stirred at -20 C for :15 minutes and warmed to room 10 temperature over 18 hours. The reaction mixture was poured into EtOAc ~ca. 50 mL) and washed with E2O (3 x 15 mL), and sat. aq. NaCl ~1 x 15 mL) dried ~Na2SO4) and concentrated under reduced pressure to give ( lR) -5-bromo- [ (4R) -I~-acetyl-4- ~3-phenylpropionyl) oxy- (L) -15 Drol~' ]aminopentane-1-boronic acid, (i) -pinanedicl ester (~75 mg) as an oil in 96~ yield. LRMS 631, 633 ~M+H), 55_ (base) .
.

Part E: A mixture of the product from Part D (470 mg, 0.75 mmol) and sodium azide ~NaN3, 97 mg, 1.50 mmol) in DM- (8 mL) was heated at 65-70 C for 9 hours. The mix.ure was poured into EtOAc ~ca. 75 mL) . and washed w ~h H2O (3 x 20 m~), sat. aq. NaCl ~1 x 20 mL), dried (Na2SO4), and concentration~under reduced pressure .o 2-- give (lR) -5-azido- [ (4R) -11-acetyl-q- (3-phe-.ylpropionyl) oxy- (L)-prolyl~ aminopentane-l-boronic acid, (+)-pinanediol ester. (403 mg) as an oil in 91 yield. LRMS 594 (M+H, base) .
3C Part F: A solution of the product from Part E (388 ms, 0 . 65 mmol) in MeOH (7 mL) together with palladium hydroxide on charcoal 135 mg) was stirred under hydrogen (1 atm) for 3 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give 320 mg of the title compound as a foam in 86r WO 95/lJ9859 2 ~ 7 4 311 PCr/17S9~1nlO49 !
yield. LRMS 568 (M + 1, base); HRMS Cacld for C31H47BN306: 56~3.3558. Found: 5613.3553.
1:: ~ A 1~,7 1 e 1 5 q Nl- [ ( qR) -N- ( 3-Phenylproplonyl ) -4- (benzyl ~ oxy- ~L) -prolyl ~ -R-borolys ine, benzenesulfonate lo a mlxture of E.~ample 303 (1.95 g, 2.52 mmol~ in H2O (10 mL~, Et2O (15 mL~, and sufficient MeOH (ca. 1.5 mL) to maintain a clear, biphasic system was added phenylboric acid (1.54 g, 12.6 mmol). The mixture was stirred for 14 hours, the layers were separated and the aqueous phase was eYtracted with Et2O ~5 x 20 mL). The 15 aqueous layer was concentrated under reduced pressure to give the title compound (1.20 g) as an amorphous powder in 75t yield. LRMS 482 (Mt~), 464 (base); HRMS Calcd for C28H39BN3O5 (ethylene gycol ester): 50~3.2983. Found:
503 . 2999 .

~ATn?le 302 Nl - [ ~ 4R) -N- ~ 3-Pheny].propionyl ) -4- ~phenyl ) thio- (L) -prolyl]-R-borolysine (t-)-pinanediol ester, hydrochloride Part A: The commercially available starting material, (4R) -N-BOC-9-hydroxy- (L)-proline methyl ester was dissolved in CH2C12 ~140 mL) and carbon tetrachloride ~140 mL) and triphenylphosphine (42.56 g, 162.2 mmol) was added. The mixture was allowed to stir for 2 hours, 30 ethanol (15 mL) was added and stirring was continued for an additional 16 hours. The mixture was concentrated - under reduced pressure to 100 mL, cooled to -20 C and Et2O (200 mL) was added. The resulting precipitate waS
suction filtered and washed with Et2O. The solid was further purified by flas~ chromatography, elution with ~ ~ d, S ,~
WO 95/09859 2 1 7 ~ 3 1 1 PCT/U594111049 1:1 Et20-hexanes gave (4S)-N-BOC-4-chloro-~1.)-prollne methyl ester (17.03 g) as an oil in 84~ yield. lH NMR
(300 MHz, CDC13) ~ 4.37 (m, 2H), 3.95 (m, lH), 3.75 (s, 3H~, 3.63 (m, lH), 2.63 (m, lH), 2.38 (m, lH), 1.45 (s, 5 9H) .
Part B: A solution of the product from Part A (17.03 q, 64.5 mmol) in trifluoroacetic acid (20 mL) and CH2C12 (20 mL) was stirred 18 hours. The reaction mixture was concentrated under reduced pressure to give (4S)-4-10 chloro-(L)-proline methyl ester (18.05 g) as an oil in quanitative yield. 1H NMR (300 MHz, CDC13) ~ 9 . 75 (comp, 2H), 3.87 (comp, 2H), 3.94 (s, 3H), 2.99 (rrl, lH), 2.77 (m, lH) .
Pa-~ C: A solution of the product from Parl B (30.28 1~ 9, 105 mmol) in CH2C12 (50 mL) was cooled to 0 C and Et3N (45 . 6 mL, 327 mmol) followed by hydrocinnamoyl chloride (17.8 mL, 120 mmol) were added slowly in order to maintain an internal temperature less than 10 C.
After stirring six hours, H2O (50 mL) was added to the 2C reaction mixture. The resulting solution was eY.tracted witr. CH2C1 2 (3 x 50 mL) . The organics were washed with r.2C (25 mL), dried with MgSO4 and concentrated under reduce~ ~pressure to give (4S) -N- (3-phenylpropioryl ) -4-ch~oro~ )-proline meth~l ester (17.44 g) GS c waxy so_ia in 54~ yield. LRMS 296.1 ~base, M+H) .
Part D: EtOH (50 mL) was cooled to 0 C and sodium (0.78 9, 33.8 mmol) was added. After the hydrogen evolution ceased, thiophenol (3.72 g, 33.8 mmol) was added and the reaction mixture stirred for 15 minutes at 0 C, and the product from Part C (5 g, 16. 9 mmol) was added. The stirring was continued for an additional 16 hours at room temperature. The mixture was concentrated under reduced pressure, diluted with water (20 mL) ano a idified with lN HCl to pH . `~ eous s~ ~ on was ~174311 Wo 9s~098sg ~ PcrnJS94/11049 extracted with EtOAc (3 x 30 mL), the organics dried with Na25O4 and concentrated under reduced pressure.
The residue was further purified by flash chromatosraphy, elution with chromatographed with 1:3 EtOAc-hexanes gave 2 . 06 9 of (9R) -N- (3-phenylpropionyl) -4- (phenyl) thio- (L) -proline in 25~ yield. LRMS 356.1 (M+H, base).
Part E: Using the method described above for the preparation of Example 7e, Part D, (lR) -5-bromo- [ (4R)-N-(3-phenylpropionyl) -4- (phenyl) thio- (L) -prolyl]aminopentane-l-boronic acid, (+)-pinanediol ester was isolated (2 . 43 g) as an oil in e5~ yield. LRM5 681.2 683.2 (M+H, base~.
Part F: Using the method described above for Example 7e, Part E, the intermediate (lR) -5-azido- [ (4R) -N- (3-phenylpropionyl ) -4- (phenyl ) thio- (L) -prolyl ] aminopentane-1-bo-onic acid, (+)-pir~anediol ester w2S isolated (2.42 g) as ar. oil in quantitative yield.
Part. G: A solution of the product from Part F (2.42 g, 2~ 3.76 mmol) in 1,3-p=opanedithiol (1.62 9, 15 mmol), trLethylamine (l . 52 g, 15 mmol) and methanol (20 mL~
was s; rred at 50 C for 24 hours. The reaction mixture wac concentra~ed unde- reduce pressure and purified b~
flash chromatoyraph; through florosil, eluting with 1:9 ~-, MeO:;.-CH2Cl2. ~he concentrated residue was dissolved in diethyl ethe- (10 mL), acidified with 1 equivalent of lN
HCl in Et2O and concentrated to give the title compound (0 73 5~ as a solid in 31% yield. LRMS 617 . 3 (M+H, base~ . HRMS Cacld for C3sH4OBN3O45: 617.34583. Found:
3C 617 . 14580 .
E.VRrn~1e 303 4_ WO 95/09859 2 ~ 7 ~ 311 PCT/US94/11049 Nl- [ ~ 4R) -N- ~3-Phenylpropionyl ) -9- ~benzyl ) oxy- (L~ -prolyl ] -R-borolysine, (+)-pinanediol ester Part A: A solution of the commercially available 5 starting material, (4R) -N-BOC-4- (benzyl) oxy- (L) -proline, previously reported by Smith et al., J. Med. Chem. 31, 875 (1988); (2.11 g, 6.57 mmol), in CH2C12 (27 mL) was treated with anhydrous hydrogen chloride in dioxanes (4 M, 6 . 60 mL) . The reaction mixture was stirred for 18 10 hours, during which time a white precipitate formed. The reaction was diluted with diethyl ether (Et2O, ca. 100 mL) and the solid material was collected by suction filtration to afford ~4R) -4- ~benzyl) oxy- (L) -proline hydrochloride ~1. 60 g) as a white powder in 95~ yield.
T NMR ~300 MHz, DMSO-d6~ ~ 10.2 ~br s, lH~, 7.36 (comp, SH), 4.52 (s, 2H), 4.37 (dd, J= 10.8,7.5 Hz, lH), 4.31 ~m, lH), 3.43 ~dd, J= 12.5,4.4 Hz, lH), 3.33 ~d, J= 12.5 Hz, lH), 2.48 ~m, lH), 2.1~ ~m, lH); LRMS 22Z ~M+H, base ) .
Part B: ~ suspension of the product from Part A ~1. 5C
g, 5.83 mmol) in CH2C12 (58 mL) at 0 C was treated witr 3-phenylpropionyl chloride (0. 95 mL, 6. 4; mmol) followec bi 4-methylmorpholine (1. 92 mL, 17 .5 mmol) . The 2_ reaction mixture was warmed to room temperature over 20 hours, treated with 2M aqueous hydrochloric acid ~HCl) until pH = 2, and added to EtOAc ~ca. 200 mL) . The organic layer was washed with H2O ~3 x 50 mL), sat. aq.
NaCl ~1 x 50 mL), dried ~MgSO4) and concentrated under a~ reduced pressure . The resulting solid was recrystallized from hexanes-EtOAc and gave a first crop ~1.33 g, mp 127-129 C) and a second crop ~0.37 g, mp 122-125 C) of ~4R) -N- ~3-phenylpropionyl) -4- ~benzyl) oxy-(L~-proline as co,lorless plates in a total of 82~ yield.
3~ ~monoclinic, P21, a - 6.196, b = 9.101, c = 16.477A, ~ =
98 . 98 ) lH NMR ~300 MHz, CDC13) ~ 7 .29 ~comp, lGH), 4~

~ W095/09859 ~174311 - X PCr/Uss4/ll049 q.95 (br s, lH~, 4.69 (dd, J= 8.1,6.2 Hz, lH), 4.50 (ABq, ~Cr.AB = 32.5 Hz, JAB= 11.7 H2, 2H~, 4.20 (quin, J=
4.8 Hz, lH), 3.46 (d, J= 4.8 Hz, 2H~, 2.98 (t, J= 7.7 Hz, 2H~, 2.59 (t, J= 7.4 Hz, 2H), 2.50 (m, lH), 2.23 (ddd, J= 13.5, 8.4, 5.0 Hz, lH)i LRMS 354 (M+H, base);
Anal. Calcd for C21H23NOg: %C, 71.37; %H, 6.56; 96N, 3.96.
Found: %C, 71.39; %H, 6.57; %N, 3.92.
Part C: Using the method described above for the preparation of Example 78, Part D, (lR) -5-bromo- [ (4R) -N-(3-phenylpropionyl) -4- (benzyl) oxy- (L) -prolyl]aminopentane-1-boronic acid ~+)-pinanediol ester was isolated (2 . 80 g) as an oil in 90~ yield. LRMS
67S, 681 (M+H, base) .
Part D: Using the method described above for Example 78, Par~ E, (lR) -5-azido- [ (4R) -N- (3-phenylpropionyl) -4-(benzyl)oxy-~L)-prolyl,aminopentane-l-boronic acid (+)-pinanediol ester was isolated (2.31 g) as an oil in 9g0 2G yieId. LRMS 642 (M+H, base).
Part E: A solution of product from Part D (2.24 g, 3.50 mmol) in MeOH (3~ mL) together with palladium on charcoal (225 mg) was stirred under hydrogen (1 atm) for _ 1 hour ~he reaction mixture was filtered through a pad of Celite with additional MeOH ~ca. 3G m~ ) and the filtrate was concentrated under reduced pressure to give a foam which contained a small amount of unreacted azide. ~his material ~as resubjected to the 3G hydrogenation conditions described above to afford the title compound (2.GG g) as a white foam in 93~ yield.
LRMS 616 (M+H, base) .
F~r~~le 303a q WO 95/09859 ~ 1 7 ~ 31 i PCT/US94/11049 N1- ~ ( 4R) -N- ~ 3-Phenylpropionyl ) -4- (benzyl ) oxy- (L) -prolyl ] -R-borolysine, (+)-pinanediol ester, benzenesulfonate A solution of Example 303 (2.00 g, 3.25 mmol) in 5 methanol (25 mL) was treated with a solution of benzenesulfonic acid (0.514 g, 3.25 mmol) in methanol (8 mL). The mixture was allowed to stand at room temperature for 15 minutes and concentrated under reduced pressure to give a foam. The residue was washed with Et2O (2 x 25 mL), which was decanted, then dissolved in EtOAc (ca. 20 mL) and triturated with Et2O
(ca. 75 mL) to afford an oily material which was washed with Et2O (2 x 25 mL). The excess solvent was removed in vacuo to give the title compound (2 . 00 g) as a powder ih 79~ yield. LRMS 616 (M+H, base); HRMS Calcd for C36H51BN3O5: 616.392,. Found: 616.3921.
Ex~le 375 Nl- [ (4R) -N- (3-Phenylpropionyl) -4- (benzyl) amino- (L~ -prolyl]-R-borolysine, (+)-pinanediol ester, hydrochloride Parr ~: A mixture of the product ~rom Example 302, Part ~ ~3.009, 10.1 mmol~ and NaN3 (3.30 9, 5C.7 mmol) in D~ (15 mL) was heated to 75 ~C for 18 hours. The reaction mixture was dissolved in H20 (25 mL) . The aqueous solution was extracted with Et20 (3 x 25 m.L), dried with MgSOg and concentrated to give (4R)-N- (3-phenylpropionyl)-4-aZido-(L)-proline methyl ester (2.13 3G g) as an oil in 83~ yield. 1H NMR (300 MHz, CDC13) ~ -7.25 (comp, 5H), 4.56 (m, lH), 4.26 (m, lH), 3.77 (s~
3H), 3.75 (m, lH), 3.40 (dd, J = 8, 2 Hz, lH), 2.97 (m, 2H), 2,60 (m, 2H), 2.32 (comp, 2H) . LRMS 303.1 (M+H, base ) .

wossl~)s859 ~ 1 7 4 3 ~ Pcr/us94/11049 Part B: Using the method described above for the preparation of Example 78, Part E`, (4R) -N- (3-phenylproplonyl)-4-amil~o-(L)-proline methyl ester was isolated (2.43 g) as an oil in 85~; yield. lH NMR (300 MHz, CDC13) ~ 7.24 (comp~ 5H), 4.58 (m, lH), 3.79 (m, 2H), 3.73 (s, 3H), 3.01 (m, 3H), 2.60 (m, 2H), 2.12 (m, lH), 1. 94 (m, lH) . LRMS 277 . 1 (M+H, base) .
Part C: A mixture of the product from Part B (l.S1 g, 5.46 mmol), benzaldehyde (0.58 g, 5.46 mmol), potassium acetate (0.54 g, 5.46 mmol) and 5% palladium on charcoal (0.21 g) was stirred ill MeOH (25 mL) under hydrogen (3 atm~ for 5 hours. The reaction mixture was filtered through a pad of Celite with additiona~ MeOH (ca. 10 mL
and the filtrate concentrated under reduced pressure to give (4R)-N-(3-phenylpropionyl)-4-(benzyl)amino-(L)-prol.ine methyl ester (2.00 g) as an oil in quantitative yield. lH NMR (300 MHz, CDC13) ~ 7.27 (comp, 10H), 4.58 (m, lH), 3.73 (comp, 4~1), 3.50 (m, lH), 3.44 (s, 3H), 3.15 (m, lH), 2.96 (t, J = 7 Hz, 2H), 2.55 (m, 2H), 2.09 2C (m, 2H) . LRMS 367.2 ~M+H, base) .
Part D: A solution oF the product from Part C (2.00 g, 5.46 mmol) methano (lS mL) and lN sodiu~. hydroxiQe ( 9 mL) was stirred for 24 hours . The pH of the solutior.
was adjusl:ed to 6 with lN HCl and a white precipitate 2- formeQ. The solid material was collected by suction filtration to give (9R) -N- (3-phenylpropionyl) -9-(benzyl)amino-~L)-prOline (1.31 g) as a white powder in 68~ yield. LRMS 353.2 (M+H, base) .
Part. E: Using the method described above for the 30 preparation of Example 78, Part D, (lR) -5-bromo- [ (9R)-N-( 3-phenylpropionyl ) -9- (benzyl ) amino- ~L) -prolyl]aminopen,tane-l-boronic acid, (+)-pinanediol este-was isolated (0.71 g) as an oil in 99~ yield. LRMS
678.3 680.3 (M+E~, base) .
~7 W0 95/098S9 ~ PCT/US94111049 2~74311 Part F: Using the method described above for Example 78, Part E, the intermediate (lR) -5-azido- [ (4R)-N- (3-phenylpropionyl) -4- (ben2yl) amino- (L) -prolyl ] aminopentane-l-boronic acid, (+) -pinanediol ester was isolated 10 . 45 9) as an oil in 67% yield.
Part G: A solution of the product from Part F ~0.45 g, 0.70 mmol) in MeOH (5 mL) together with 20% palladium hydroxide on charcoal (O . 04 g) was stirred under hydrogen (1 atm) for 4 hours. The reaction mixture was filtered through a pad of Celite with EtOAc (ca. 10 mL~ . -The filtrate was concentrated under reduce~i pressure and purified by flash chromatography through florosil, eluting with 1: 9 MeOH-CH2C12 . The concentrated residue ;~ was dissolved in Et20 (10 mL), acidified wit}~. 2 equivalents of lN HCl in Et20 and concentrated to ~ive the title compound (0.27 g) as a oil in 56~ yield.= LRMS
615.4 (M+H, base) .

~A~nle 1 64 1 N1- [ ( 4R) -N- (Benzyloxy) carbonyl-4- (benzyl ) ox~-- (L) -prolyl ] -R-borothioarginine, (+~-pinanediol ester =
2. Part }~ sing the method described above fo- Example 78, (lR) -4-bromo- [ ~4R) -N- ~benzyloxy) carbon~ l-4-(benzyl) oxy- (L) -prolyl] aminobutane-l-boronic acid, ~+) -pinanediol ester (370 mg) was prepared as an oil in 99 yield. LP~MS 667, 669 (M+H), 587 (base) .
Part fi: A mixture of the product from Part A ~365 mg, 0.55 mmol) and thiourea (83 mg, 1.10 mmol) in ethanol (EtOH, 10 mL) was heated at reflux for 16 hours and cooled to room temperature. The reaction was poured into Et20 ~ca. 120 mL) and concentrated under reduced ~ Wo 95l098s9 ~3 1 7 ~ 3 1 1 ~ Pcr/r~sg4lllo49 pressure. The residue W25 triturated with Et2O (ca. 50 mL), which was decanted. Purification of the residue by size exclusion chromatography on Sephadex LH-20, elution with MeOH, gave a glass which was dissolved in THF (1.5 5 mL) and treated with Et2O ~ca. 20 mL) to give a solid.
The solid was washed with Et2O (ca. 10 mL) and dried to afford the title compound (125 mg) as a white solid in 31% yield, mp 79-82 C. LP~MS 663 (M+H, base~; H~<MS
Calcd for C35HçgBN4O65: 663.3388. Found: 663.3374.

Based on the representative e~amples detailed --above, the following compounds of tT~e invention can be 15 prepareQ, as shown in Tables 1-20 .

~c W0 95/09859 2 1 7 4 3 1 1: ~ PCTIUS94/11049 ' ~h~L
OH
N l~ ~B~
OH
0~, N H
RA O ~N--Z--R10 4~(CR8CR9)U--W--(CR6CR7)tJ~O

Ex.No RA R6 R7 R8 R9 R~0 W Z I u Da~
H - _ _ _ CH3 _ C0 0 0 2 H ~ ~ ~ ~ CH3 CH2 C0 0 0 3 H H H ~ -- CH3 CH2 C0 1 0 HCH3 CH3 ~ ~ CH3 CH2 C0 I 0
6 H - - CH3 CH3 CH3 CH2 C0 0
7 H _ _ Ph H CH3 C0 0
8 H H H - - CH3 0 C0 1 0
9 HCH3 CH3 _ _ CH3 0 C0 1 0
10 H H H ~ ~ CH3 S07 C0 1 0 1 i2-CH3 H H ~ ~ CH3 CH2 C0 1 0 123-CH3 H H ~ ~ CH3 CH2 C0 ~ 0 ]32, 3-diCH3 H H ~ ~ CH3 CH2 C0 1 0 142-F H H ~ ~ CH3 CH2 C0 1 0 1~3-F H H ~ ~ CH3 CH2 C0 1 0 164-F H H ~ ~ CH3 CH2 C0 ~ 0 172-NH2 H H ~ ~ CH3 CH2 C0 1 0 183-NH2 H H ~ ~ CH3 CH2 C0 ] 0 192-N02 H H ~ ~ CH3 CH2 C0 1 0 203-N02 H~ H ~ ~ CH3 CH2 C0 ~ I 0 212-N H H ~ ~ CH3 CH2 C0 ] () Sr ~,17~311 223-N H H - - CH3 CH2 CO l 0 234-N H H - - CH3 CH2 CO l 0 24 H H H _ _ (CH2)2Ph O CO l 0 25 HCH3 CH3 _ (CH2)2ph O CO 0 26 H H H _ _ (CH2)2ph S2 CO l 0 27 H H H _ _ (cH2)2ph CH2 CO l 0 28 HCH3 CH3 _ _ (CH2)2ph CH2 CO l 0 29 H _ _ ~CH3 CH3 (CH2)2Ph CH2 CO 0 302-CH3 H H - _ (CH2)2ph CH2 CO l 0 313-CH3 H H - _ (CH2)2ph CH2 CO l 0 322, 3-diCH3 H H - _ (CH2)2ph CH2 CO I O
332-F H H - _ (CH2)2ph CH2 CO l 0 3~3-F H H - - (CH2)2Ph CH2 CO l 0 354-F H H - - (CH2)2Ph CH2 CO l 0 362-NH2 H H - - (CH2)2ph CH2 CO l 0 373-NH2 H H - - (CH2)2ph CH2 CO I 0 3g2-No2 H H - _ (CH2)2ph CH2 CO l 0 393-NO2 H H - - (CH2)2ph CH2 CO l 0 402-N H H - - (CH2)2ph CH2 CO l 0 413-N H H - _ (CH2)2Ph CH2 CO l 0 424-N H H - _ (CH2)2Ph CH2 CO l 0 43 H H H - - CH2Ph CH2 C(O)O I
4~ HCH3 CH3 _ _ CH7Ph CH2 C(O)O l 0 45 H _ _ CH3 CH3 CH2Ph CH2 C(O)O 0 462-CH3 H H - - CH2Ph CH2 C(O)O l 0 473-CH3 H H _ _ CH2Ph CH2 C(O)O l 0 48'', 3-diCH3 H H - - CH2Ph CH2 C(O)O I O
492-F H H - - CH2Ph CH2 C(O)O I
503-F H H - - CH2Ph CH2 C(O)O l 0 514-F H H - - CH2Ph CH2 C(O)O I
5'2-NH2 H H - - CH2Ph CH2 C(O)O l 0 533-NH2 H H _ _ CH2Ph CH2 C(O)O I
542-NO2 H H - - CH2Ph CH2 C(O)O I
553-NO2 H~ H .- _ CH2Ph CH2 C(O)O I
562-N H H - - CH~)Ph CH2 C(O)O I O

W095109859 2?~4~l~ PCTIUS94/11049 573-N H H _ _ CH2Ph CH2 C(O)O ] 0 584-N H H _ _ CH2Ph CH2 C(O)O I O
59 H H H _ _ CH2Ph CH2 C(O)NH ] 0 60 H CH3 CH3 _ CH2Ph CH2 C(O)NH l 0 61 H _ _ CH3 CH3 CH2Ph CH2 C(O)NH 0 622-CH3 H H - = -- CH2Ph CH2 C(O)NH l 0 633-CH3 H H _ = _ CH2Ph CH2 C(O)NH l 0 642, 3-diCH3 H H _ _ CH2Ph CH2 C(O)NH I O
652-F H H _ _ CH2Ph CH2 C(O)NH I
663-F H H _ _ CH2Ph CH2 C(O)NH l 0 674-F H H - - ~ CH2Ph CH2 C(O)NH I
682-NH2 H H -- - CH2Ph CH2 C(O)NH 1 0 693-NH2 H H -- - CH2Ph CH2 C(O)NH I () 702-N02 H H - - CH2Ph CH2 C(O)N7H I O
7]3-NO2 H H - - CH2Ph CH2 C(O)NH l 0 722-N H H - - CH2Ph CH2 C(O)NH l 0 733-N H H - - CH2Ph CH2 C(O)NH l 0 744-N H H - - CH2Ph CH2 C(O)NH 3 0 75 H H H - - CH2OPh CH2 CO 1 0 WO 95109859 2 1 7 ~ 3 1 1 PCT/US94/11049 Ta~le 2 ~0 ~
N ~--~B~o Oq~NH CH3 ~ L (CR8CR8)U--W--(CR6CR7)J~O
s 6 E~NoF~A R6 ~7 R8 R9 R10 W Z I u Da~
76 H _ _ _ _ CH3 -- CO 0 0 A
77 H ~ ~ ~ ~ CH3 CH I CO 0 0 B
78 H H H ~ . ~ CH3 CH2 CO I 0 C

80 HCH3 CH3 ~ ~ CH3 CH2 CO 1 0 E
8I H _ _ ~H3 CH3 CH3 CH2 CO 0 I F
8~ H _ _ Ph H CH3 CO 0 1 G
83 H H H _ _ CH3 O CO 1 0 H
8~ HCH3 CH3 _ _ CH3 o CO l 0 85 H H H ~ ~ CH3 52 CO l 0 862 CH3 H H ~ ~ CH3 CH2 CO ~ 0 873-CH3 H H ~ ~ CH3 CH2 CO ~ 0 882, 3-diC~3 H H ~ ~ CH3 CH2 CO I O
892-F H H ~ ~ CH3 CH2 CO l 0 903-F H H ~ ~ CH3 CH2 CO I 0 914-F H H ~ ~ CH3 CH2 CO 1 0 9'2-NH2 H H ~ CH3 CH 2 CO 1 0 -933-NH2 H H ~ ~ CH3 CH2 CO l 0 9~,~-N02 H H ~ ~ CH3 CH2 CO I O
953-NO2 H' H ~ ~ CH3 CH2 CO ~ 0 962-N H H ~ - CH3 CH~ CO l 0 _ _ WO 95/09859 21 7. 4,~1 1 PCT/US94/11049 984-N H H - - CH3 CH2 CO l 0 99 H H H - _ (CH2)2Ph o CO l 0 100 HCH3 CH3 _ (CH2)2Ph O CO 0 101 H H H _ _ (cH2)2ph S2 CO l 0 102 H H H _ _ (CH2)2ph CH2 CO I 0 L
103 HCH3 CH3 _ _ (CH2)2ph CH2 CO l 0 114 H _ _ CH3 CH3 (CH2)2Ph CH2 CO 0 1052-CH3 H H - - (CH2)2ph CH2 CO l 0 1063-CH3 H H - - (CH2)2ph CH2 CO l 0 1072, 3-diCH3 H H - - (cH2)2ph CH2 CO I O
1082-F H H - _ (CH2)2ph CH2 CO l 0 1093-F H H - - (cH2)2ph CH2 CO l 0 1104-F H H - - (CH2)2ph CH2 CO l 0 1112-NH2 H H - - (cH2)2ph CH2 CO . I 0 1123-NH2 H H - _ (CH2)2ph CH2 CO l 0 1132-NO2 H H - _ (cH2)2ph CH2 CO l 0 1143-N2 H H - - (cH2)2ph CH2 CO l 0 1152-N H H - - (CH2)2ph CH2 CO l 0 1163-N H H - -- (cH2)2ph CH2 CO l 0 1~74-N H H - - (cH2)2ph CH2 CO l 0 118 H, H H - - CH2Ph CH~ C(O)O l 0 119 HCH3 CH3 _ CH2Ph CH2 C(O)O ~
120 H _ _ CH3 CH3 CH2Ph CH~ C(O~O
1212-CH3 H H - - CH2Ph CH7 C(O)O I
12~3-CH3 H H - - CH2Ph CH2 C(O)O I
1232, 3-diCH3 H H _ _ CH2Ph CH2 C(O)O I O
1242-F H H - - CH2Ph CH2 C(O)O l 0 1253-F H H - - CH2Ph CH2 C(O)O 1 1264-F H H - - CH2Ph CH2 C(O)O I
1272-NH2 H H - - CH2Ph CH2 C(O)O 1 0 1283-NH2 H H - - CH2Ph CH2 C(O)O I
1292-NO2 H H - - CH2Ph CH2 C(O)O I
1303-NO2 H H _ _ CH2Ph CH2 C(O)O l 0 1312-N H H - - CH2Ph CH2 C(O)O I
5~

WO 95/098S9 2 1 7 4 ~ 1 i PCT/US94/11049 1323-N H H _ _ CH2Ph CH2 C(O)O l 0 1334-N H H _ _ CH2Ph CH2 C(O)O I
131 H H H _ _ CH2Ph CH2 C(O)NH I
135 H CH3 CH3 _ _ CH2Ph CH2 C(O)NH l 0 136 H _ _ CH3 CH3 CH2Ph CH2 C(O)NH 0 1372-CH3 H H _ _ CH2Ph CH2 C(O)NH l 0 1383-CH3 H H _ _ CH2Ph CH2 C(O)NH I
1392, 3-diCH3 H H _ _ CH2Ph CH2 C(O)NH I O
1402-F H H - -- CH2Ph CH2 C(O)NH 1 0 1413-F H H - - CH2Ph CH2 C(O)NH l 0 1424-F H H _ _ CH2Ph CH2 C(O)NH l 0 1432-NH2 H H _ _ CH2Ph CH2 C(O)NH l 0 1~3-NH2 H H _ _ CH2Ph CH2 C(O)NH l 0 1452 NO2 H H - - CH2Ph CH2 C(O)NH l 0 1463-NO~ H H _ _ CH2Ph CH~ C(O)NH I O
1472-N H H - - CH2Ph CH2 C(O)NH l 0 1483-N H H _ _ CH2Ph CH2 C(O)NH l 0 1494-N H H - - CH2Ph CH2 C(O)NH l 0 150 H H H - - CH2oph CH~ CO l O

~5 WO 95/09859 2 ~ 7 4; 3 f ~: PCT/US94111049 Table 3 ,OH
H 2 N B~
OH
Oq~ N H
4~(CH ) `~ R6 R7 ~RB
s 6 E7uNo RA RB R6 R7 z V W u Da~
151 H H H H C(O)O O - I
15' H H H H CO O CH2 0 153 H H CH3 CH3 CO S =CH2 o~
15~ H H H H CO CH2 1 ~3SA
sal~,M
155 H 2'- CH3 H H CO CH2 156 H 3'-CH3 H H CO O CH2 I N
157 H 2, 3-diCH3 H H CO CH2 158 H 2'-F H H CO O CH2 159 H 3'-F H H CO o , CH2 160 H 2'-N H H CO O CH2 16~ H 3'-1~ H H CO O CH, ~673-CH3 H H H CO O CH2 1633-CH3 2~-CH3 H H CO O CH2 16~3-CH3 3 CH3 H H CO O CH2 1653-CH3 2', 3'-diCH3 H H CO CH2 1663-CH3 2'-F H H CO CH2 1673-CH3 3'-F H H CO O CH2 1683-CH3 2'-1~ H H CO CH2 1693-CH3 3'-N H H CO O CH2 1712-F ~-CH3 H H CO CH2 5~

WO95109859 2i74~ PCT/US94/11049 172 2-F 3~-CH3 H H CO CH2 173 2-F 2', 3'-diCH3 H H CO O CH2 174 2-F 2'-F H H CO CH2 175 2-F 3'-F H H CO O CH2 176 2-F 2'-N H H CO CH2 177 2-F 3:N H H CO CH2 179 3-F 2~-CH3 H H CO CH2 170 3-F 3~-CH3 H H CO CH2 181 3-F 2', 3'-diCH3 H H CO CH2 182 3-F 2'-F H H CO CH2 183 3-F 3'-F H H CO CH2 181 3-F 2'-N H H CO CH2 185 3-F 3'-N H H CO O CH2 187 3-NH2 2~-CH3 H H CO CH2 188 3-NH2 3~-CH3 H H CO CH2 189 3-NH2 2', 3'-diCH3 H H CO O CH2 19O 3-NH2 2'-F H H CO CH2 191 3-NH2 3'-F H H CO CH2 192 3-NH2 2'-N H H CO CH2 193 3-NH2 3'-N H H CO O CH2 19~ 3-NO2 H H H CO CH2 195 3-NO2 2~-CH3 H H CO CH2 196 3-NO2 3~-CH3 H H CO O CH2 3 197 3-NO2 2', 3-diCH3 H H CO O CH2 198 3-NO2 2'-F H H CO O CH2 199 3-NO2 3'-F H H CO CH2 2CO 3-NO2 2'-N H H CO O CH2 201 3-N2 3'-N H H CO CH2 203 2-N 2~-CH3 1 i H CO CH2 204 2-N 3'-CH3 } i H CO O CH2 205 2-N 2', 3'.diCH3 1~ H CO CH2 206 2-N 2'-F ~; H CO O CH2 WO 95/09859 2 ~ 7 g~l PCTII~S94/11049 2072-N 3'-F H H CO O CH2 2082-N 2'-N H H CO O CH2 2092-N 3'-N H H CO O CH2 2103-N' H H H CO o CH2 2113-N 2'-CH3 H H CO CH2 2123-N 3~-CH3 H H CO CH2 2133-N 2', 3'-diCH3 H H CO O CH2 2143-N 2'-F H H CO O CH2 2153-N 3'-F H H CO O CH2 2163-N 2'-N H H CO CH2 2~73-N 3'-N H H CO CH2 2194-N' 2'-CH3 H H CO CH2 2204-1`.' 3~-CH3 H H CO O CH2 2714-1`: 2', 3'-diCH3 H H CO O CH2 2224_1~: 2'-F H H CO O CH2 2234-N' 3'-F H H CO CH2 22~4-N' 2'-N H H CO O CH2 2254-N 3'-N H H CO O CH~ I

229 H 2'- CH3 H H CO O O
230 H 3'-CH3 H H CO O O
231 H 2'~ 3'-diCH3 H H CO O O
23 H2'-F H H CO O O
233 H 3'-F H H CO O O
234 H 2'-N H H CO O O
235 H 3'-N H H CO O O
2363-CH3 H H H CO O O I ~ -2373-CH3 2'-CH3 H H CO O O 1, 2383-CH3 3~-CH3 H H CO O O
2393-CH3 2', 3-diCH3 H H CO O O I
2403-CH3 ~'-F H H CO O O
2413-CH3 3'-F H H CO O O

WO 95109859 2 1 7 4 3:1 ~ PCT/US94/11049 o 242 3-CH3 2'-N H H CO O O
243 3-CH3 3'-N H H CO O O

245 2-F 2'-CH3 H H CO O O

247 2-F 2', 3'-diCH3 H H CO O O
248 2-F 2'-F H H CO O O
249 2-F 3'-F H H CO O O
250 2-F 2'-N H H CO O O
251 2-F 3'-N H H CO O O

253 3-F 2'-CH3 H H CO O O
25, 3-F 3~-CH3 H H CO O O
255 3-F 2', 3'-diCH3 H H CO O O
256 3-F 2'-F H H CO O O
257 3-F 3'-F H H CO O O
258 3-F 2:N H H CO O O
259 3-F 3'-N H H CO O O

261 3-NH2 2~-CH3 H H CO O O
26'' 3-NH2 3~-CH3 H H CO O O
263 3-NH2 2, 3-diCH3 H H CO O O
26~ 3-NH2 Z-F H H CO O O
265 3-NH2 3'-F H H CO O O
266 3-NH2 2'-N H H CO O O
267 3-NH2 3'-N H H CO O O

269 3-NO2 2~-CH3 H H CO O O
270 3-NO2 3~-CH3 H H CO O O
27i 3-N2 2, 3-diCH3 H H CO O O
272 3-NO2 2'-F H H CO O O
273 3-NO2 3'-F H H CO O O
27~ 3-NO2 2'-N H H CO O O
275 3-NO2 '3:~' H H CO O O

5~

W095/09859 21~5~i3~ i PCr/lJS94/11049 2772-N 2'-CH3 H H C0 0 0 2782-N 3~-CH3 H H C0 0 0 2792-N 2', 3'-diCH3 H H C0 0 0 2802-N 2'-F H H C0 0 0 2812-N 3'-F H H C0 0 0 2822-N 2'-N H H C0 0 0 2832-N 3'-N H H C0 0 0 2853-N 2~-CH3 H H C0 0 0 2863-N 3~-CH3 H H C0 0 0 2873-N 2', 3'-diCH3 H H C0 0 0 2883-N 2'-F H H C0 0 0 2893-N 3'-F H H C0 0 0 2903-N 2'-N H H C0 0 0 2913-N 3'-N H H C0 0 0 2934-N' 2~-CH3 H H C0 0 0 2914-N 3~-CH3 H H C0 0 0 2954-N 2', 3'-diCH3 H H C0 0 0 2964-N 2'-F H H C0 0 0 2974-N 3'-F H H C0 0 0 2984-N , 2'-N H H C0 0 0 2994-N' 3'-N H H C0 0 0 Table 9 w~gsl098s9 S~174311 PCT~7S94/11049 i O ~
H2N ~ ,~B, O~,NH r H3 ~ N--Z~,W~_ E~.No RA RB R6 R7 z V W u Da~
300 H H H H C(O)O O - I

302 H H H H CO S CH2 o P

303a H H H H CO O CH2 I BSA
sal~
30~ H 2~- CH3 H H CO O CH2 305 H 3'-CH3 H H CO O CH2 I R
306 H 2, 3-diCH3 H H CO O CH2 307 H 2'-F H H CO O CH2 308 H 3'-F H H CO O CH2 309 H 2'-~' H H CO O CH2 310 H 3'-N H H CO O CH2 I S
3~ i 3-CH3 H H H CO O CH2 312 3-CH3 2~-CH3 H H CO O CH2 313 3-CH3 3~-CH3 H H CO CH2 314 3-CH3 2, 3-diCH3 H H CO O CH2 315 3-CH3 2'-F H H CO O CH2 316 3-CH3 3'-F H H CO O CH2 317 3-CH3 2'-N H H CO O CH2 318 3-CH3 ,3~ H H CO O CH2 . I

WO 95/09859 ;~ ~ 7 4 3 ~ i PCT/llS94/11049 320 2-F 2'-CH3 H H CO CH2 321 2-F 3~-CH3 H H CO CH2 322 2-F 2', 3'-diCH3 H H CO O CH2 323 2-F 2'-F H H CO CH2 324 2-F 3'-F H H CO CH2 325 2-F 2'-N H H CO o CH2 326 2-F 3'-N H H CO O CH2 328 3-F 2'-CH3 H H CO o CH2 329 3-F 3~-CH3 H H CO O CH2 330 3-F 2'~ 3'-diCH3 H H CO CH2 331 3-F 2'-F H H CO CH2 332 3-F 3'-F H H CO O CH2 333 3-F 2'-N H H CO CH2 334 3-F 3'-N H H CO O CH2 336 3-NH2 2~-CH3 H H CO CH2 337 3-NH2 3~-CH3 H H CO CH2 338 3-NH2 2', 3-diCH3 H H CO O CH2 339 3-NH2 2'-F H H CO O CH2 340 3-NH2 3'-F H H CO O CH, I
343 3-NH2 2'-N H H CO O CH2 ]
34'2 3-NH2 3'-N~ H H CO CH2 343 3-NO2 H H H CO O CH ~ I
34~ 3-NO2 2'-CH3 H H CO CH2 345 3-NO2 3~-CH3 H H CO O CH2 346 3-N2 2', 3-diCH3 H H CO O CH2 347 3-NO2 2'-F H H CO O CH2 348 3-N2 3'-F H H CO O CH2 345 3-N02 2'-N H H CO CH2 350 3-NO2 3'-N H H CO CH2 352 2-N 2'-CH3 H H CO O CH2 353 2-N 3~-CH3 H H CO CH2 35~ 2-N 2', 3'-diCH3 H H CO CH2 WO95/09859 ~ 43~ PCTIUS94J11049 355 2-N 2'-F H H CO O CH2 356 2-N 3'-F H H CO O CH2 357 2-N 2'-N H H CO O CH2 358 2-N 3'-N H H CO CH2 360 3-N 2'-CH3 H H CO O CH2 361 3-N 3~-CH3 H H CO CH2 362 3-N 2', 3'-diCH3 H H CO O CH2 363 3-N 2'-F H H CO CH2 364 3-N 3'-F H H CO CH2 365 3-N 2'-N H H CO O CH2 366 3-N 3'-N H H CO O CH2 36~ 4~N 2~-CH3 H H CO O CH~ I
369 4-N 3~-CH3 H H CO CH2 370 4-N 2', 3'-diCH3 H H CO O CH~ I
37~ 4-N 2'-F H H CO O CH2 372 4-N 3'-F H ' H CO CH2 373 4-N 2'-N H H CO O CH2 374 4-N 3'-N H H CO CH2 376 H H H H CO O (cH2 I K
CH2) 377 H H H H CO O O I ~' 37~ H 2: CH3 H H CO O O
379 H 3~-CH3 H H CO O O ] ~;
380 H 2', 3'-diCH3 H H CO O O
38~ H 2'-F H H CO O O
38' H 3'-F H H CO O O I W~' 383 H 2'-N H H CO O O
384 H 3'-N H H CO O O

386 3-CH3 2~-CH3 H H CO O O
387 3-CH3 3,-CH3 H H CO O O
39~ 3-CH3 2', 3'-diCH3 H H CO O O

WO 95/09859 .~ PC'r/llS94/11049 399 3-CH3 2'-F H H CO O O
390 3-CH3 3'-F H H CO O O
391 3-CH3 2'-N H H CO O O
392 3-CH3 3'-N H H CO O O

394 2-F 2'-CH3 H H CO O O
395 2-F 3~-CH3 H H CO O O
396 2-F 2', 3'~iCH3 H H CO O O
397 2-F 2'-F H H CO 0 O
398 2-F 3'-F H H CO O O
399 2-F 2'-N H H CO 0 O
400 2-F 3'-N H H CO 0 O

40'' 3-F 2'-CH3 H H CO 0 O
403 3-F 3~-CH3 H H CO 0 O
40~ 3-F 2', 3'-diCH3 H H CO 0 O
405 3-F 2'-F H H CO O O
40~ 3-F 3'-F H H CO 0 O
407 3-F 2'-N H H CO O 0 408 3-F 3'-N H H CO 0 O

410 3-NH~ 2'-CH3 H H CO 0 0 411 3-l`.H . 3~-CH3 H H CO 0 O
412 3-NH2 2', 3-diCH3 H H CO 0 O
413 3-NH2 2'-F H H CO 0 0 414 3-NH2 3'-F H H CO 0 0 415 3-NH2 2'-N H H CO 0 O
416 3-NH2 3'-N H H C0 0 O

418 3-NO2 2'-CH3 H H C0 0 0 419 3-NO2 3~-CH3 H H CO 0 O

420 3-NO2 2', 3-diCH3 H H C0 0 O
421 3-N2 2'-F H H C0 0 O
422 3-NO2 '3'-F H H C0 0 O
423 3-NO2 2'-N H H C0 0 O

Wo 9St09859 217 ~ 311 PCr/U594/lla49 424 3-No2 3'-N H H CO O O

426 2-N 2'~CH3 H H CO O O
427 2-N 3~-CH3 H H CO O O
428 2-N 2', 3'~iCH3 H H CO O O
429 2-N 2'-F H H CO O O
430 2-N 3'-F H H CO O O
431 2-N 2'-N H H CO O O
432 2-N 3'-N H H CO O O

434 3-N 2~-CH3 H H CO O O
435 3-N 3~-CH3 H H CO O O
436 3-~' '', 3'-diCH3 H H CO O O
437 3-18' 2'-F H H CO O O
438 3-N 3'-F H H CO O O
439 3-N 2'-N H H CO O O
440 3-N 3'-N H H CO O O
441 4-~' H H H CO O O
442 4-N 2:CH3 H H CO O O
443 4-N' 3~-CH3 H H CO O O
444 4-N 2, 3-diCH3 H H CO O O
445 4-N 2'-F H H CO O O
446 4-N 3'-F H H CO O O
447 4-~ 2'-N H H CO O O
448 4-~' 3'-N H H CO O O
Table 5 5~

~1 74 ~. i NH pH
RX J~ N ~\I~B~o H
Oq~ N H
RA o ~N--Z--R10 4~ 3~(CR8CR7u--W--(CR6CR7)~ ~O
s 6 Ex.No RA R6 R7 R8 R9 R10 W Z ~ u RX Da~a 449 H H H ~ ~ CH3 CH~ CO I 0 H
450 H CH3 CH3 ~ ~ ~ CH3 CH2 CO l 0 H
45~ H _ _ CH3 CH3 CH3 CH2 CO 0 l H
452 H H H _ _ CH3 O CO l 0 H
453 H CH3 CH3 - -.. CH3 O CO l 0 H
45~ H H H ~ ~ CH3 SO2 CO l 0 H
4553-CH3 H H ~ -- CH3 CH2 CO ~ 0 H
4563-F H H ~ ~ CH3 CH2 CO I 0 H
4573-NH2 H H ~ ~ CH3 CH2 CO l 0 H
4532-N H H ~ ~ CH3 CH2 CO l 0 H
4593-CH3 H H - - (CH2)2Ph CH2 CO l 0 H
4603-F H H - - (CH2)2Ph CH2 CO l 0 H
4613-NH2 H H - - (CH2)2Ph CH~ CO l 0 H
46"2-N H H - - (CH2)2Ph CH2 CO I O H
4633-CH3 H H - - CH2Ph CH2 C(O)O 1 ~ H
46~3-F H H - - CH2Ph CH2 C(O)O l 0 H
4653-NH2 H H - - CH2Ph CH2 C(O)O l 0 H
4662-N H H - - CH2Ph CH2 C(O)O 1 0 H
4673-CH3 H H - - CH2Ph CH2 C(O)NH I 0 H
4683-F H H - -= CH2Ph CH2 C(O)NH I 0 H
4693-NH2 H H - -- CH2Ph CH2 C(O)NH I 0 H
4702-N H ~ H - -- CH2Ph CH2 C(O)NH I 0 H
471 H H H ~ ~ CH3 CH, CO l H2N

21743~
WO 95/098S9 - - = = PCT/[IS94111049 473 H _ _ CH3 CH3 CH3 CH2 CO I H2N

475 H CH3 CH3 _ _ CH3 O CO ] H2N

4813-CH3 H H - -- (CH2)2Ph CH2 CO I H2N
4823-F H H - - (CH2)2Ph CH2 CO I H2N
4833-NH2 H H - - (CH2)2Ph CH2 CO I H2N
4842-N H H - - (CH2)2Ph CH2 CO I H2N
4853-CH3 H H - - CH2Ph CH2 C(O)O I H2N
4863-F H H - - CH2Ph CH2 C(O)O I H2N
4873-NH2 H H - - CH2Ph CH2 C(O)O I H2N
4882-N H H - - CH2Ph CH2 C(O)O I H2N
4893-CH3 H H - - CH2Ph CH2 C(O)NH I H2N
4903-F H H - - CH2Ph CH2 C(O)NH I H2~
4913-NH2 H H - - CH2Ph CH2 C(O)NH I H2N
4922-N H H - - CH2Ph CH2 C(O)NH I H2N
493 H H H - - CH3 CH2 CO I o CH3NH
49~ H CH3 CH3 - - CH3 CH~ CO I 0 CH3NH
495 H _ _ CH3 CH3 CH3 CH- CO o I CH3NH
496 H H H _ _ CH3 O CO I o CH3NH
497 H CH3 CH3 _ _ _CH3 O CO I o CH3NH

4993-CH3 H H - - CH3 CH2 CO I o CH3NH
5003-F H H - - CH3 CH2 CO I o CH3NH
5013-NH2 H H - - CH3 CH2 CO l 0 CH3NH
5022-N H H - - CH3 CH2 CO I o CH3NH
5033-CH3 H H - - (CH2)2Ph CH2 CO I o CH3NH
50~3-F H H - - (CH2)2Ph CH2 CO I o CH3NH

5053-NH2 H ' H - - (CH2)2Ph CH2 CO l 0 CH3NH
5062-N' H H - - (CH2)2Ph CH2 CO I 0 CH3NH
6~

Wo 95/09859 217 4 3 11 PCrNS94/11049 5073-CH3 H H - _ CH2Ph CH2 C(O~O I 1~ CH3NH
5083-F H H - - CH2Ph CH2 C(O)O I o CH3NH
5093-NH2 H H ~ ~ ~ CH2Ph CH2 C(O)O I 0 CH3NH
5102-N H H - - CH2Ph CH2 C(O)O I o CH3NH
5113-CH3 H H - -- CH2Ph CHz C(O)NH 1 o CH3NH
5123-F H H - - CH2Ph CH2 C(O)NH I o CH3NH
5133-NH2 H H - - CH2Ph CH2 C(O)NH I o CH3NH
5142-N H H - - CH2Ph CH2 C(O)NH I o CH3NH
Table 6 N H B, ~3 Oq~NH CH, RA o ~N--Z--R10 4~ (CR8CR9)U--W--(CR6CR7)J~O
s 6 Ex.No RA R6 R7 RR R9 R10 W Z ~ u i~; Da~
515 H H H ~ -- CH3 CH~ CO i 0 H
516 H CH3 CH3 ~ CH3 CH~ ~o I 0 H
517 H - _ CH3 CH3 CH3 CH2 CO 0 1 H
51~ H H H _ _ CH3 O CO ~ 0 H
519 H CH3 CH3 _ _ CH3 O CO ] 0 H
520 H H H ~ ~ CH3 SO2 CO I 0 H
5213-CH3 H H ~ ~ CH3 CH2 CO I 0 H
5Z3-F H H ~ ~ CH3 CH2 CO I 0 H
5233-NH2 H H ~ ~ CH3 CH2 CO I 0 H
5242-N H H ~ ~ CH3 CH, CO I 0 H
5253-CH3 H H - -- (CH2)2Ph CH2 CO I 0 H
6~3 21~4311 WO 95109859 . . ~ PCT/US94/11049 ~ . . ~ ,.
526 3-F H H - - (CH2)2Ph CH2 CO I 0 H
527 3-NH2 H H - - (CH2)2Ph CH2 CO I 0 H
528 2-N H H - - (CH2)2Ph CH2 CO I 0 H
529 3-CH3 H H - - CH2Ph CH2 C(O)O I 0 H
530 3-F H H - - CH2Ph CH2 C(O)O I H
531 3-NH2 H H _ _ CH2Ph CH2 C(O)O I 0 H
532 2-N H H - - CH2Ph CH2 C(O)O I 0 H
533 3-CH3 H H - - CH2Ph CH2 C(O)NH I 0 H
534 3-F H H - - CH2Ph CH2 C(O)NH l 0 H
535 3-NH2 H H - - CH2Ph CH2 C(O)NH I 0 H
536 2-N H H - - CH2Ph CH2 C(O)NH i 0 H
537 H H H - - CH3 CH2 CO I H21~' 539 H _ _ CH3 CH3 CH3 CH~ CO I H2N
540 H H H - - CH3 O CO I H2~
541 H CH3 CH3 _ _ CH3 O CO I H2N
542 H H H - - CH3 SO~ CO ] H2N

544 3-F H H - - CH3 CH, CO ~ H2N
545 3-NH2 H H - - CH3 CH2 CO I H2~

547 3-CH3 H H - - (CH2)2Ph CH2 CO I H2r~
548 3-F H H - - (CH2)2Ph CH2 CO I H2N
549 3-NH2 H H - - (CH2)2Ph CH7 CO I O H~18 550 2-N H H - _ (CH2)2Ph CH2 CO I O H7!~
551 3-CH3 H H - - CH2Ph CH2 C(O)O I H21 552 3-F H H - - CH2Ph CH2 C(O)O I H2r~
553 3-NH2 H H - - CH2Ph CH7 C(O)O I O H7N
554 2-N H H - - CH2Ph CH2 C(O)O I O H7N
555 . 3-CH3 H H - - CH2Ph CH2 C(O)NH I H2N
556 3-F H H - - CH2Ph CH2 C(O)NH I O H7N
557 3-NH2 H H - - CH2Ph CH2 C(O)NH I H2N
558 2-N H H - - CH2Ph CH2 C(O)NH I O H7N
559 H H ~ H - - CH3 CH2 CO ] o CH3NH
560 H CH3 CH3 - CH3 CH2 CO l 0 CH3NH

W0 9S/098~9 ~ PCT/US94/11049 561. H _ _ CH3 CH3 CH3 CH2 CO o I CH3NH
562 H H H - _ CH3 O CO I 0 CH3NH
563 H CH3 CH3 _ CH3 O CO I 0 CH3NH
56~ H H H ~ ~ CH3 SO2 CO I 0 CH3NH
5653-CH3 H H ~ ~ CH3 CH2 CO 1 0 CH3NH
5663-F H H ~ ~ CH3 CH2 CO I 0 CH3NH
5673-NH2 H H ~ - CH3 CH2 CO I o CH3NH
5682-N H H ~ ~ CH3 CH2 CO 1 0 CH3NH
5693-CH3 H H - - (CH2)2Ph CH2 CO I 0 CH3NH
5703-F H H - - (CH2)2Ph CH2 CO 1 0 CH3NH
5713-NH2 H H - - (CH2)2Ph CH2 CO I o CH3NH
5722-N H H - - (CH2)2Ph CH2 CO I 0 CH3NH
5733-CH3 H H - - CH2Ph CH2 C(O)O I o CH3NH
5743-F H H - - CH2Ph CH2 C(O)O I o CH3NH
5753-NH~ H H - - CH2Ph CH2 C(O)O I 0 CH3NH
5762-N H H - - CH2Ph CH2 C(O)O I 0 CH3NH
5773-CH3 H H - - CH2Ph CH2 C(O)NH I o CH3NH
5783-F H H - - CH2Ph CH2 C(O)NH I 0 CH3NH
5793-NH2 H H - - CH2Ph CH2 C(O)NH I o CH3NH
5802-N H H - - CH2Ph CH2 C(O)NH I o CH3NH
Table 7 ,O H
H2N /\~B~
OH
0~, N H
4 ~ ( C H2)U--V
55~ 6 ~WO 95/09859 217 4 31~ PCT/US94/11049 Ex No. RA R10 z V 11 D~a 58g3-N2 c]~3 CO O 0 5904-NO2 C] i3 C0 0 0 5913-N C1~3 C0 O 0 5924-N C1~3 C0 0 0 593 H C~3 CO S 0 5943-CH3 C}~3 C0 S 0 5954-CH3 C~3 CO S 0 5962-F C~3 CO S 0 5984-F C1~3 CO S 0 5993-NH2 C~13 CO S 0 6004-NH2 c~l3 CO S (]
6013-N02 C~13 CO S () 60"4-N2 C~3 C0 S 0 6033-N CH3 CO S () 60~4-N CH3 CO S () 605 H CH(CH3)2 C0 O 0 6063-CH3 CH(CH3)2 C0 0 0 6074-CH3 CH(CH3)2 CO O 0 6082-F CH(CH3)2 C0 O 0 60g3-F CH(CH3)2 CO O 0 6104-F CH(C1~3)2 CO O 0 6113-NH2 CH(C3~3)2 CO O 0 6124-NH2 CHlcl~3)2 CO O 0 6133-NO2 . CH(Cl~3)2 CO O 0 6144-NO2 CH(C1i3)2 CO O 0 WO 95/09859 217 4 ~ PCT/US94/11049 615 3-N CH(CH3)2 CO O 0 616 4-N CH(CH3)2 CO O O
617 H CH(CH3)2 CO S O
618 3-CH3 CH(CH3)2 CO S 0 619 4-CH3 CH(cH3)2 CO S O
620 2-F CH(CH3)2 CO S O
621 3-F CH(CH3)2 CO S 0 622 4-F CH(cH3)2 CO S 0 623 3-NH2 CH(CH3)2 CO S O
624 4-NH2 CH(CH3)2 CO S 0 625 3-N2 CH(cH3)2 CO S 0 626 4-N2 CH(cH3)2 CO S U
677 3-N CH(CH3)2 CO S O
6'8 4-18 CH(cH3)2 CO S O
629 H CH2CH2CH(CH3)2 CO O 0 630 3-CH3 CH2CH2CH(cH3)2 CO O 0 631 4-CH3 CH2CH2CH(CH3)2 CO O O
632 2-F CH2CH2CH(cH3)2 CO O O
633 3-F CH2CH2CH(CH3)2 CO O 0 634 4-F CH2CH2CH(CH3)2 CO O 0 635 3-NH2 CH2CH2CH(CH3)2 CO O 0 636 4-NH2 CH2CH2CH(CH3)2 CO O O
637 3-N2 CH2CH2CH(cH3)2 CO O 0 638 4-N2 CH2CH2CH(CH3)2 CO O 0 639 3-N CH2CH2CH(CH3)2 CO O O
640 4-N CH2CH2CH(CH3)2 CO O 0 641 H CH2CH2CH(CH3)2 CO S 0 642 3-CH3 CH2CH2CH(cH3)2 CO S O
643 4~CH3 CH2CH2CH(CH3)2 CO S 0 644 2-F CH2CH2CH(cH3)2 CO S 0 645 3-F CH2CH2CH(CH3)2 CO S 0 646 4-F CH2CH2CH(CH3)2 CO S O
647 3-NH2 CH2CH2CH(CH3)2 CO S 0 648 4-NH2 , CH2CH2CH(CH3)2 CO S 0 649 3-N2 CH2CH2CH(CH3)2 CO S O

,317~3~1 WC~ 95109859 ~ ~ ~ PCT/US94/11049 650 4-NO2 CH2CH2CH(CH3)2 CO S 0 65~ 3-N CH2CH2CH(cH3~2 CO S 0 652 4-N CH2CH2CH(CH3)2 CO S 0 65g 4-F CH3 CO O

663 3-N c~3 CO O
66`l 4-N C~3 CO O
665 H C1~3 CO S
666 3 CH3 Cli3 CO S
667 4 CH3 C1~3 CO S
668 2-F Cli3 CO S
669 3-F C]~3 CO S
670 4-F C1~3 CO S
671 3-NH2 C~i3 CO S
67' 4-NH2 C~3 CO S
673 3-NO2 C~i3 CO S
674 4-N2 C~3 CO S
675 3-N C~3 CO S
676 4-N C~3 CO= S
677 H C~13 CO NH
678 3-CH3 C~3 CO NH

680 2-F C~13 CO NH

681 3-F C~13 CO NH
682 4-F C}13 CO NH
683 3-NH2 C}13 CO NH
68~ 4-NH2 CH3 CO N'H
.

WO 95/09859 21 7 ~ 3 1 1 PCT/US94/11049 689 H CH(CH3)2 CO O
690 3-CH3 CH(CH3)2 CO O
691 4-CH3 CH(cH3)2 CO O
692 2-F CH(CH3)2 CO O
693 3-F CH(cH3)2 CO O
694 4-F CH(cH3)2 CO O
695 3-NH2 CH(CH3)2 CO O
696 4-NH2 CH(cH3)2 CO O
697 3-NO2 CH(CH3)2 CO O
698 4-NO2 CH(CH3)2 CO O
699 3-N CH(CH3)2 CO O
700 4-N CH(cH3)2 CO O
701 H CH(cH3)2 CO S 3 70'' 3-CH3 CH(CH3)2- CO S
703 4-CH3 CH(cH3)2 CO S
704 2-F CH(CH3)2 CO S
705 3-F CH(CH3)2 CO S
706 4-F CH(CH3)2 CO S
707 3-NH2 CH(cH3)2 CO S
708 4-NH2 CH(CH3)2 CO S
709 3-NO2 CH(cH3)2 CO S
710 4-NO2 CH(cH3)2 CO S
711 3-N CH(cH3)2 CO S
712 4-N CH(cH3)2 CO S
713 H CH(CH3)2 CO NH
714 3-CH3 CH(cH3)2 CO NH
715 4-CH3 CH(cH3)2 CO NH
716 2-F CH(CH3)2 CO NH
717 3-F CH(cH3)2 CO NH
718 4-F CH(CH3)2 CO NH
719 3-NH2 CH(CH3)2 CO NH
7~

~17~
WO 95/09859 - ' - PC'r/US9411 1049 1~ ~ "~
720 4-NH2 CHl,CH3)2 C0 NH
721 3 N2 CH~CH3)2 CO NH
7Z 4-NO2 CH~CH3)2 CO NH
723 3-N CH(CH3)2 CO NH
724 4-N CH(cH3)2 CO NH
725 H CH2CH2CH(CH3)2 CO O
726 3-CH3 CH2CH2CH(CH3)2 C0 0 727 4-CH3 CH2CH2CH(CH3)2 CO O
728 2-F CH2CH2CH(cH3)2 CO O
729 3-F CH2CH2CH(CH3)2 CO O
730 4-F CH2CH2CH(cH3)2 CO O
731 3-NH2 CH2CH2CH(cH3)2 CO O
732 4.NH2 CH2CH2CH(cH3)2 CO O
733 3-N02 CH2CH2CH(CH3)2 C0 O
7~ 4-NO2 CH2CH2CH(CH3)2 CO 0 735 3-N CH~CH2CH(CH3)2 CO O
736 4-N CH2CH2CH(CH3)2 C0 0 3 737 H CH2CH2~H(CHi)2 CO S
738 3-CH3 CH2CH2CH(CH3)2 C0 S
739 4-CH3 CH7CH2CH(CH3)2 CO S
740 2-F CH2CH2CH(CH3)2 CO S
741 3-F CH2CH2CH(CH3)2 CO S 3 74q 4-F CH2CH~CH(CH3)7 CO S
743 3-NH2 CH2CH2CH(cH3)2 CO S
744 4-NH~ CH2CH2CH(CH3)2 CO S 3 745 3-NO2 CH2CH2CH(CH3)2 CO S
746 4 N2 CH2CH2CH(CH3)2 CO S
747 3-N CH2CH2CH(CH3)2 CO S
748 4-N CH2CH2CH(cH3)2 CO . S
749 H CH2CH2CH(cH3)2 C0 NH
750 3-CH3 CH2CH2CH(cH3)2 CO NH
751 4-CH3 CH2CH2CH(CH3)2 C0 NH
752 2-F CH2CH2CH(cH3)2 CO NH
753 3-F , CH2CH2CH(CH3)2 CO NH

75~ 4-F CH~CH2CH(cH3)2 C0 NH
7 '-WO95/09859 ~1 7~3~ii ;` ' PCr~S94/11049 755 3-NH2 CH2CH2CH(CH3)2 CO NH
756 4-NH2 CH2CH2CH(CH3)2 CO NH
757 3-NO2 CH2CH2CH(cH3)2 CO NH
758 4-No2 CH2CH2CH(cH3)2 CO NH
759 3-N CH2CH2CH(CH3)2 CO NH
760 4-N CH2CH2CH(cH3)2 CO NH
761 H cH2NH(cH3) CO O
762 H CH2N(CH3)CO2C(CH3)3 CO O
~able 8 0 ~1 H2N ~
0~, N H C 113 RA < N--Z--R10 ,=1~
4 ~ ( C H2)u--V
s 6 Ex. No. RA R10 z ~, u Da~a 764 3~CH3 CH3 CO O 0 767 3-F CH3 CO O 0 ~: ~

771 3-NO~ ' CH3 CO O 0 772 4-NO2 CH3 CO O . 0 ,~17~311~
WO 95/09859 ~ - PCI'117594/11049 787 H CH(CH3)2 CO O 0 78g 3-CH3 CH(CH3)2 CO O 0 789 4-CH3 CH(CH3)2 CO O 0 790 2-F CH(CH3)2 CO O 0 791 3-F CH(CH3)2 CO O 0 792 4-F CH(CH3)2 CO O 0 793 3-NH2 CH~CH3)2 CO O 0 79~ 4-NH2 CH(CH3)2 CO O 0 795 3-NO2 CH(CH3)2 CO O 0 796 4-N2 CH(CH3)~ CO O 0 797 348 CH(cH3)~ CO O 0 798 4-N CH(I_H3 ~ CO~ O 0 799 H CH(CH3)2 CO S 0 800 3-CH3 CH(I-H3)2 CO S 0 80~ 4-CH3 CH(I-H3)2 CO S 0 802 2-F CH(CH3)2 CO S 0 803 3-F CH(CH3)2 CO S 0 804 4-F CH(I~H3)2 CO S 0 805 3-NH2 CH(CH3)2 CO S 0 806 4-NH2 . CH(CH3)2 CO S 0 807 3-N02 CH(CH3);~ CO S O
_ 7 ~, WO 95/09859 æ~ S i PCTNS94/11049 80~ 4 N2 CH(CH3)2 CO S 0 809 3-N CH(CH3)2 CO S 0 810 4-N CH(CH3)2 CO S 0 81~ H CH2CH2CH(CH3)2 CO O 0 812 3-CH3 CH2CH2CH(CH3)2 CO O 0 813 4-CH3 C~2CH2CH(cH3)2 CO O 0 t 814 2-F CH2CH2CH(CH3)2 CO O 0 815 3-F CH2CH2CH(CH3)2 CO O 0 816 4-F CH2CH2CH(CH3)2 CO O 0 817 3-NH2 CH2CH2CH(CH3)2 CO O 0 818 4-NH2 CH2CH2CH(CH3)2 CO O 0 819 3 N2 CH2CH2CH(CH3)2 CO O 0 820 4 N2 CH2CH2CH(CH332 CO O 0 8~1 3-N CH2CH2CH(CH3)2 CO O 0 822 4-N CH2CH2CH(CH3)2 CO O 0 823 H CH2CH2CH(CH3)2 CO S 0 82~ 3-CH3 CH2CH2CH(CH3 j2 CO S 0 875 4-CH3 CH2CH2CH(CH3)2 CO S 0 826 2-F CH2CH2CH(CH3)2 CO S 0 877 3 F CH2CH2CH(CH3)2 CO S 0 828 4-F CH2CH2CH(CH3)2 CO S 0 829 3-NH2 CH2CH2CH(CH3)2 CO S 0 830 4-NH2 CH2CH2CH(CH3)7 CO S 0 831 3 N2 CH2CH2CH(CH3~2 CO S 0 83~ 4-N02 CH2CH2CH(CH3j2 CO S 0 833 3-N CH2CH2CH(CH3)2 CO S 0 834 4-N CH2CH2CH(CH3)2 CO S 0 835 H CH3 CO O l Z

84' 4-NH2 CH3 CO O

wogs/ogXs9 217~311 P~US94n}049 856 4-NO~ CH3 CO S
857 3-N' CH3 CO S
858 4-~' Cli3 CO S
859 H C1~3 CO NH
860 3-CH3 cl~3 CO NH
86l 4-CH3 C~3 CO NH
862 2-F C}~3 CO NH
863 3-F C~3 CO NH
86~ 4-F C~13 CO NH
865 3-NH~ C~3 CO NH
866 4-NH2 C~13 CO NH
867 3-N'O~ C~3 CO NH
868 4-N2 C~13 CO NH

870 4-N C~13 CO NH
871 H CH(CH3)2 CO O I CC
872 3-CH3 CH(CH3)2 CO O
873 4-CH3 CH(CH3)2 CO O
874 2-F CH(C1~3)2 CO O
875 3-F CH(Cli3)2 CO O
876 4-F . CH(C1l3)2 CO O
877 3-NH2 CH(Cli3)2 CO O

WO9~i/098~9 ii " ~ PCT/US94/11049 878 4-NH2 CH(cH3)2 CO O
879 3-N2 CH(cH3)2 CO O
880 4-N2 CH(CH3k CO O
881 3-N CH(CH3k CO O
882 4-N CH(CH3k CO O
883 H CH(CH3k CO S
884 3-CH3 CH(CH3k CO S
885 4-CH3 CH(CH3k CO S
886 2-F CH(CH3k CO S
887 3-F CH(CH3)2 CO S
888 4-F CH(cH3)2 CO S
889 3-NH2 CH(CH3)2 CO S
890 4-NH2 CH(CH3)2 CO S
891 3-N2 CH(CH3)~ CO . S . I
892 4-N2 CH(CH3)2 CO S
893 3-N CH(cH3)2 CO S
89~ 4-N CH(cH3)2 CO S
895 H CH(CH3)2 CO NH
896 3-CH3 CH(cH3)2 CO NH
897 4-CH3 CH(CH3)2 CO NH
898 2-F CH(cH3)2 CO NH
899 3-F CH(cH3)2 CO NH
900 4-F CH(CH3k CO NH
901 3-NH2 CH(CH3) ~ CO NH
90~ 4-NH2 CH(CH3 H CO .. NH
903 3-NO2 CH(cH3)2 CO NH
904 4-NO2 CH(CH3)2 CO NH
90~ 3-N CH(cH3)2 CO NH
906 4-N CH(CH3k CO NH
907 H CH2CH2CH(CH3)2 CO O I DD
908 3-CH3 CH2CH2CH(cH3)2 CO O
909 4-CH3 CH2CH2CH(CH3)2 CO O
910 2-F CH2CH2CH(CH3)2 CO O
911 3-F CH2CH2CH(cH3)2 CO O
912 4-F CH~CH2CH(cH3)2 CO O
&Q

~ ~17~311 Wo 9s/09859 ~ ' PCT/US94/11049 9l3 3-NH2 CH2C~H2CH(CH3)2 CO O
914 4-NH2 CH2CIi2CH(cH3)2 CO O
915 3-NO2 CH2C112CH(CH3)2 CO O
9 l 6 4-NO2 CH2C}~2CH(CH3)2 CO O
9l7 3-N CH2C~2CH(cH3)2 CO O
9l8 4-N CH2C~2CH(CH3)2 CO O
9l9 H CH2C~I2CH(CH3)2 CO S
920 3-CH3 CH2CH2CH(CH3)2 CO S
921 4-CH3 CH2CH2CH(CH3)2 CO S
922 2-F CH2CH:2CH(CH3)2 CO S
923 3-F CH2CH2CH(cH3)2 CO S
924 4-F CH2CH2CH(CH3)2 CO S
925 3-NH2 CH2CH2CH(CH3)2 CO S
926 4-NH2 CH2CH2CH(cH3)2 CO S
927 3-NO2 CH2CH2CH(cH3)2 CO S
928 4-N2 CH2CH 2CH(CH3)2 CO S
929 3-N CH2CH2CH(CH3)2 CO S
930 4-N CH2CHCH(cH3)2 CO S
931 H CH2CH2CH(cH3)2 CO NH
932 3-CH3 CH2CH2CH(CH3)2 CO NH
933 4-CH3 CH2CH2CH(CH3)2 CO NH
934 2-F CH2CH2CH(CH3)2 - CO NH
935 3-F CH2CH2CH(CH3)2 CO NH
936 4-F CH2CH2CH(CH3)2 CO NH
937 3-NH2 CH2CH2~H(CH3)2 CO NH
938 4-NH2 CH2CH2CH(cH3)2 CO NH
939 3-NO2 CH2CH2CH(cH3)2 CO NH
940 4-NO2 CH2CH2CH(CH3)2 CO NH
941 3-N CH2CH2CH(cH3)2 CO NH
94' 4-N CH2CH2CH(cH3)2 CO NH
943 H CH2NI~(CH3) CO O I EE

94~ H CH2N(CH3)CO2c(cH3)3 CO O I FF
Table 5 W095/09859 ~t ~i?ti3~' pCT/US94111049 OH
H 2 N ~ O H
0~, N H
~N-- --R10 o R3--O~`
E~ No. R3 R10 Da~a 946 (H3C)3c CH3 9~7 CH3 Q~ , 949 CH3 CH2CH2Ph 950 ~H3C~3C CH2CH2Ph C ~ CH2CH2Ph 95- C H2 CH2CH2Ph W09sl098s9 2 17 ~ 3 1 I PCI/US94~11049 ~able 10 ,0 H2N-- ~B~
Oq~N H CH3 ~N ~ R 1 0 ~

Ex No. R3 R10 Da~a 954 (H3C~3C CH3 GG

I ~ CH3 HH

C ~ CH3 957 CH3 CH2CH2Ph 958 (H3C)3C CH2CH2Ph 11 C ~ CH2CH2Ph JJ
960 C ~ CH~CH2Ph 8 _ WO95/09859 ~ ~17~ `; PCT/US94/11049 Table 11 N H O H
RX~ N --B`o H
O~, N H
4 ~ ( C H2) `~ R6 R7 ~ RB

RX = H2N
ExNo. RA RB R6 R7 z V W u Daa 961 H H H H C(O)O O - I

96~ H H H H CO O CH2 965 H 2~- CH3 H H CO O CH2 966 H 3' CH3 H H CO O CH2 967 H .2', 3'-diCH3 H H CO O CH2 968 H 2'-F H H CO O CH2 969 H 3'-F H H CO O CH2 ]
970 H 2'-N H H CO O CH2 971 H 3'-N H H CO O CH~ I

973 3~CH3 2'-CH3 H H CO O CH2 974 3-CH3 3~-CH3 H H CO O CH2 975 3-CH3 2, 3-diCH3 H H CO o CH2 976 3-CH3 2'-F H H CO O CH2 977 3-CH3 3'-F H H CO o CH2 978 3-CH3 2'-N H H CO O CH2 979 3-CH3 3~ ~ H H CO O CH- I

WO95109859 ~ 743~1 : PCT~'US94/11049 ~ ;
981 2-F 2'-CH3 H H CO CH2 982 2-F 3~-CH3 H H CO CH2 983 2-F 2', 3'-diCH3 H H CO O CH2 984 2-F 2'-F H H CO O CH2 985 2-F 3'-F H H CO O CH2 986 2-F 2'-N H H CO O CH2 987 2-F 3'-N H H CO O CH2 988 3-F H H H CO O CH2 ] KK
989 3-F 2~-CH3 H H CO O CH2 990 3-F 3.-CH3 H H CO O CH2 991 3-F 2', 3'-diCH3 H H CO O CH2 992 3-F 2'-F H H CO CH2 993 3-F 3'-F H H CO O CH2 99~ 3-F 2'-N H H CO O CH2 995 3-F 3'-N' H H CO O CH2 997 3-NH2 2'-CH3 H H CO CH2 998 3-NH2 3~-CH3 H H CO O CH2 999 3-NH2 2, 3 -diCH3 H H CO CH2 1000 3-NH2 2'-F H H CO O CH2 lool 3-NH2 3'-F H H CO O CH2 1002 3-NH2 2'-N H H CO O CH2 1003 3-NH2 3'-N' H H CO o CH2 . I
100l 3-NO2 H H H CO CH2 1005 3-NO2 2~-CH3 H H CO CH2 1006 3-N2 3~-CH3 H H CO CH2 1007 3-NO2 2', 3'-diCH3 H H CO CH2 1008 3-NO2 2'-F H H CO O CH2 1009 3-NO2 3'-F H H CO CH2 1010 3-NO2 2'-N H H CO CH2 1011 3-N2 3'-N H H CO CH2 1013 2-N 2~-CH3 H H CO CH2 1014 2-N' 3~-CH3 H H CO CH2 1015 2-N' 2', 3'-diCH3 H H CO O CH, I

WO 95/098S9 2 1 7~ 31 i ~ ~ t . PCT/US94/11049 1016 2-N 2'-F H H CO O CH
1017 2-N 3'-F H H CO CH
1018 2-N 2'-N H H CO CH
1019 2N 3'-N H H CO CH

1021 3-N 2'-CH3 H H CO o CH
1022 3-N 3~-CH3 H H CO O CH
1023 3-N 2', 3'-diCH3 H H CO O CH
1024 3-N 2'-F H H CO CH
1025 3-N 3'-F H H CO O CH
1026 3-N 2'-N H H CO O CH
1027 3-N 3'-N H H CO CH

10~9 4-N 2'-CH3 H H CO CH
1030 4-N 3~-CH3 H H CO CH
1031 4-N 2', 3'-diCH3 H H CO CH
103' 4-N 2'-F H H CO CH
1033 4-N 3'-F H H CO O CH
103~ 4-N 2'-1`: H H CO O CH
1035 4-N 3'-1~ H H CO CH

1039 H 2'- CH3 H H CO O O
1040 H 3'-CH3 H H CO O O
1041 H 2', 3'-diCH3 H H CO O O
1042 H 2'-F H H CO O O
1043 H 3'-F H H CO O O
1044 H 2'-N H H CO O O
1045 H 3'-N H H CO O O

1047 3-CH3 2'-CH3 H H CO O O
1048 3-CH3 3~-CH3 H H CO O O
1049 3-CH3 2', 3',diCH3 H H CO O O
1050 3-CH3 2'-F H H CO O O
1~6 -- wo 9S/09859 ' PCIrUS94rllO49 1051 3-CH3 3'-F H H CO O O
10S2 3-CH3 2'-N H H CO O O
1053 3-CH3 3'-N H H CO O O
105~ 2-F H H H CO O O
1055 2-F 2~-CH3 H H CO O O
1056 2-F 3r-CH3 H H CO O O
1057 2-F 2', 3'-diCH3 H H CO O O
1058 2-F 2'-F H H CO O O
1059 2-F 3'-F H H CO O O
1060 2-F 2'-N H H CO O O
1061 2-F 3:N H H CO O O
106' 3-F H H H CO O O
1063 3-F 2~-CH3 H H CO O O
106~ 3-F 3 CH3 H H CO O O
1065 3-F 2', 3'-diCH3 H H CO O O
1066 3-F 2'-F H H CO O O
1067 3-F 3'-F H H CO O O
1068 3-F 2'-N H ' H CO O O
1069 3-F 3'-N' H H CO O O

1071 3-NH2 2'-CH3 H H CO O O
107' 3-NH2 3~-CH3 H H CO O O
1073 3-NH2 2, 3 -diCH3 H H CO O O
107~ 3-NH2 2'-F H H CO O O
1075 3-NH2 3'-F H H CO O O
1076 3-NH2 2'-N H H CO O O
1077 3-NH2 3'-N H H CO O O

1079 3-NO2 2'-CH3 H H CO O O

1081 3-N2 2, 3-diCH3 H H CO O O

108q 3-NO2 2'-F H H CO O O
1083 3-NO2 3'-F H H CO O O
108~ 3'N2 2'-N H H CO O O
1085 3-N02 3:N H H CO O O
~7 W0 95/09859 ' i~ é PCT/US94/11049 1087 2-N 2~-CH3 H H CO O O
1088 2-N 3~-CH3 H H CO O O
~089 2-N 2', 3'-diCH3 H H CO O O
1090 2-N 2'-F H H CO O O
1091 2-N 3'-F H H CO O O
1092 2-N 2'-N H H CO O O
1093 2-N 3'-N H H CO O O
1094 3-N ~ H H H CO O O
1095 3-N 2'-CH3 H H CO O O
1096 3-N 3~-CH3 H H CO O O
1097 3-N 2', 3'-diCH3 H H CO O O
1098 3-N 2'-F H H CO O O
1099 3-N 3'-F H H CO O O
]100 3-~ 2'-N H H CO O O I
1101 3-N 3'-N H H CO O o 1102 4-N' H H H CO O O
1103 4-N 2'-CH3 H ~ H CO O O
110~ 4-N 3~-CH3 H H CO O O
1105 4-N' 2', 3'-diCH3 H H CO O O
1106 4-N 2'-F H H CO O O
1107 4-N 3'-F H H CO O O
1108 4-N 2'-N H H CO O O
1109 4-~ 3'-N H H CO O O
Table 12 1i8 Wo 95~9859 ~17 ~ 311 Pcr/Uss4nl04s N H ,0 Oq~ N H C 1-13 RA ~ R6 R7 ~R
s RX = H21`1 E~No, RA RB R6 R7 z V W u Da a 1110 H H H H C(O)O O - - I

1il3 H H H H CO CH2 1 1 l ~
1114 H 2'- CH3 H H CO O CH2 1115 H 3'-CH3 IB H CO CH2 1116 H 2 . 3-diCH3 H H CO CH2 1117 H 2'-F 1~ H CO O CH7 1118 H . 3'-F 1~ H CO CH2 1119 H 2'-N }i H CO CH2 1120 H 3'-N ~ H CO CH2 1]21 3-CH3 H ~I H CO CH2 1122 3-CH3 2'-CH3 ~I H CO O CH2 1123 3-CH3 3~-CH3 ~! H CO CH2 1124 3-CH3 2',3'-diCH3 ~I H CO CH2 1125 3-CH3 2'-F H H CO CH2 1126 3-CH3 3'-F H H CO O CH7 1127 3-CH3 2'~N H' H CO CH2 -1128 3-CH3 3'-N H H CO CH2 1130 2-F 2~-CH3 H H CO CH2 1131 2-F 3~-CH3 H H CO CH2 WO95/09859 1 7,~3~1 PCT/I~S94/11049 L J
1132 2-F 2', 3'-diCH3 H H CO O CH2 1133 2-F 2'-F H H CO O CH2 1134 2-F 3'-F H H CO O CH2 1135 2-F 2'-N H H CO CH2 1136 2-F 3'-N H H CO CH2 1138 3-F 2'-CH3 H H CO O CH2 1139 3-F 3~-CH3 H H CO O CH2 1140 3-F 2', 3'-diCH3 H H CO O CH2 1141 3-F 2'-F H H CO CH2 1142 3-F 3'-F H H CO O CH2 1143 3-F 2'-N H H CO O CH2 1144 3-F 3'-N H H CO CH2 1146 3-NH2 2'-CH3 H H CO CH2 1147 3-NH2 3~-CH3 H H CO CH2 1148 3-NH2 2, 3-diCH3 H H CO o CH2 1149 3-NH2 2'-F H H CO CH2 1150 3-NH2 3'-F H H CO o CH2 1151 3-NH2 2'-N H H CO CH2 115'' 3-NH2 3'-N H H CO CH2 115~ 3-N2 2'-CH3 H H CO O CH2 1155 3-NO2 2',3'-diCH3 H H CO CH2 1156 3-N2 2'-F H H CO O CH2 ]
1157 3-N2 3'-F H H CO CH2 1158 3-N2 2'-N H H CO O CH2 59 3-NO2 3~-N H H CO O CH2 1161 2-N 2'-CH3 H H CO O CH2 1162 2-N 3~-CH3 H H CO O CH2 1163 2-N 2', 3'-diCH3 H H CO O CH2 1164 2-N 2'-F H H CO CH2 1165 2-N 3'-F H H CO O CH2 W095109859 21 7~3~1 PcrNsg4/ll049 1166 2-N 2'-N H H C0 0 CH
1167 2-N 3'-N H H C0 0 CH

1169 3-N 2~-CH3 H H C0 0 CH
1170 3-N 3~-CH3 H H C0 CH
1171 3-N 2', 3'-diCH3 H H C0 CH
1172 3-N 2'-F H H C0 CH
1173 3-N 3'-F H H C0 0 CH
1174 3-N 2'-N H H C0 0 CH
1175 3-N 3'-N H H CO CH

1177 4-N 2'-CH3 H H C0 0 CH7 1178 4-N 3~-CH3 H H C0 0 CH
1179 4-N 2',3'-diCH3 H H C0 0 CH
1180 4-N 2'-F H H C0 0 CH
1181 4-N 3'-F H H C0 CH
118' 4-N 2'-N H H C0 0 CH
1183 4-N 3'-N H H C0 0 CH
118~ H H H H C0 0 0 1187 H 2'- CH3 H H C0 0 0 ~188 H 3'-CH3 H H C0 0 0 1189 H 2',3'-dicH3 H H CO O O
1190 H 2'-F H H C0 0 0 1191 H 3'-F H H CO O O
1192 H 2'-N H H C0 0 0 1193 H 3'-N H H C0 0 0 1195 3-CH3 2~-CH3 H H C0 0 0 1196 3-CH3 3~-CH3 H H C0 0 0 1197 3-CH3 2, 3-diCH3 H H C0 0 0 1198 3-CH3 2'-F H H C0 0 0 WO 9510g859 21 7 4 3 il PCT/US94/11049 1199 3-CH3 3'-F H H CO O O
1200 3-CH3 2'-N H H CO O O
]201 3-CH3 3'-N H H CO O O

1203 2-F 2'-CH3 H H CO O O
1204 2-F 3'-CH3 H H CO O O
1205 2-F 2', 3'-diCH3 H H CO O O
1206 2-F 2'-F H H CO O O
1207 2-F 3'-F H H CO O O
1208 2-F 2'-N H H CO O O
1209 2-F 3'-N H H CO O O

1211 3-F 2'-CH3 H H CO O O 3 1212 3-F 3~-CH3 H H CO O O
1213 3-F 2', 3'-diCH3 H H CO O O
1214 3-F 2'-F H H CO O O
1215 3-F 3'-F H H CO O O
1216 3-F 2'-N' H H CO O O
1217 3-F 3'-N H H CO O O

1219 3-NH2 2~-CH3 H H CO O O
1220 3-NH2 3~-CH3 H H CO O O ]~
12'1 3-NH7 ' 2', 3'-diCH3 H H CO O O
12" 3-NH, 2'-F H H CO O O
1223 3-NH~ 3'-F H H CO O O
122~ 3-~'H2 2'-N' H H CO O O
1225 3-NH2 3'-N H H CO O O

1227 3-N2 2'-CH3 H H CO O O
1228 3-NO2 3~-CH3 H H CO O O
1229 3-N2 2', 3'-diCH3 H H CO O O
1230 3-N2 2'-F H H CO O O :1=
1231 3-NO2 3'-F H H CO O O ' I
~232 3-N2 ,2'-N H H CO O O
1233 3-N2 3'-N H H CO O O

W09sl098S9 Xl PCr/USs4/11049 ~J , 1235 2-N 2'-CH3 H H CO 0 O
1236 2-N 3~-CH3 H H CO O 0 1237 2-N 2', 3'-diCH3 H H CO O O
1238 2-N 2'-F H H CO O O
1239 2-N 3'-F H H CO O O
1240 2-N 2'-N H H CO O O
1241 2-N 3'-N H H CO O O

1243 3-N 2~-CH3 H H C0 O O
1244 3-N 3~-CH3 H H C0 O O
1245 3-N 2', 3'-diCH3 H H C0 O O
1246 3-N 2'-F H H CO O O
1247 3-N 3'-F H H CO O O
1248 3-N 2'-N H H CO O O
1249 3-N 3'-N H H C0 O O

1251 4-N 2~-CH3 H H CO O 0 125'2 4-N 3~-CH3 H H CO O O
1253 4-N 2', 3'-diCH3 H H CO 0 O
1254 4-N 2'-F H H CO O O
1255 4-N 3'-F H H CO O O
1256 4-N' 2'-N H H C0 O O
1257 4-N 3'-N H H CO O 0 Table 13 311 ~i ~
WO 95/09859 ' i - i - . PCI/~S94/11049 NH OH
RXJ~N ~ OH
0~, N H

RA ~N--Z--R10 3 2 \J
/= =\ i.~
4~(CHz)u--V

RX = H2N
E~ No. RA R10 z V u Dala 126~ 3-NH2 CH3 CO O 0 1266 3-NOi CH3 CO O 0 1269 4-1~ CH3 CO O 0 : :

1278 34~l02 CH3 CO S O

WO 95/09859 ~ ' ' PCT/~Sg4~11049 1282 H CH(CH3k CO O 0 1283 3-CH3 CHl(CH3k CO O 0 1284 4-CH3 CH(CH3)2 CO O 0 1285 2-F CH(CH3)2 CO O 0 1286 3-F CH(CH3k CO O 0 1287 4-F CH(CH3k CO O 0 1288 3-NH2 CH(CH3k CO O 0 1289 4-NH2 CH~C~3k CO O 0 1290 3-NO2 CH~CH3)2 CO O 0 1291 4-N2 CH~CH3k CO O 0 129' 3-N CH(CH3)2 CO O 0 1293 4-N CH(CH3)2 CO O 0 129l H CH(CH3k CO S O
1295 3~CH3 CH(CH3)2 CO S 0 1296 4-CH3 CH(I'`H3)2- CO S O
1297 2-F CH(CH3)2 CO S 0 1298 3-F CH(CH3)2 CO S 0 1299 4-F CH(CH3k CO S 0 1300 3-NH2 CH(CH3)2 CO S 0 1301 4-NH2 CH(CH3)2 CO S 0 130' 3-N2 CH(CH3k CO S 0 1303 4-NO2 CH(CH3)2 CO S 0 130~ 3-N CH(CH3k CO S 0 1305 4-N CH(CH3)2 CO S 0 1306 H CH2CH2CH(CH3)2 CO O 0 1307 3-CH3 CH2CH2CH(CH3)2 CO O 0 1308 4-CH3 CH2CH2CH(CH3)2 CO O 0 1309 2-F CH2CH2CH(cH3)2 CO O 0 1310 3-F CH2CH2CH(CH3)2 CO O 0 1311 4-F CH2CH2CH(CH3)2 CO O 0 1312 3-NH2 , CH2CH2CH(CH3)2 CO O 0 1313 4-NH2 CH2CH2CH(cH3)2 CO O 0 ' ~ ' t. ~ } .
WO 95/09859 PCT/I~S94/1 1049 ~7~31~
1314 3-N2 CH2CH2CH(cH3)2 CO O 0 1315 4-N2 CH2CH2CH(CH3)2 CO O 0 1316 3-N CH2CH2CH(CH3)2 CO O 0 1317 4-N CH2CH2CH(CH3)2 CO O 0 1318 H CH2CH2CH(CH3)2 CO S 0 1319 3-CH3 CH2CH2CH(cH3)2 CO S 0 1320 4-CH3 CH2CH2CHtcH3)2 CO S 0 1321 2-F CH2CH2CH(CH3)2 CO S 0 1322 3-F CH2CH2CH~CH3)2 CO S 0 1323 4-F CH2CH2CH(CH3)2 CO S 0 1324 3-NH2 CH2CH2CH(cH3)2 CO S 0 1325 4-NH2 CH2CH2CH(CH3)2 CO S 0 1326 3-NO2 CH2CH2CH(CH3)2 CO S 0 1327 4-N2 CH2CH2CH(CH3)2 CO S 0 1328 3-N CH2CH2CH(CH3)2 CO S 0 1329 4-N CH2CH2CH(CH3)2 CO S 0 i335 4-F CH3 CO O

134~ 4-~ CH3 CO O

1347 4-F ~ CH3 CO S
1348 3-NH~ CH3 CO S
5~:

~43~1 1361 4-NH2 CH3 CO ~'H
136' 3-N2 CHj CO NH

136~ 3-N CH3 CO NH

1366 H CH(CH3)2 CO: O
1367 3-CH3 CH(CH3~2 CO O
1368 4-CH3 CH(CH3)~ CO O
1369 2-F CH(CH3)2 CO. O
1370 3-F CH(CH3)2 CO O
1371 4-F CH(cH3)2 CO O
137' 3-NH2 CH(CH3)2 CO O
1373 4-NH2 CH(cH3)2 CO O
137~ 3-NO2 CH(cH3)2 CO O
1375 4-N2 CH(CH3)2 CO O
1376 3-N CH(cH3)2 CO O
1377 4-N CH(CH3)2 CO O
1378 H CH(CH3)2 CO S
1379 3-CH3 CH(CH3)2 CO S
1380 4-CH3 CH(CH3)2 CO S
1381 2-F CH(cH3)2 CO S
1387 3-F , CH(CH3)2 CO S
1383 4-F CH(CH3)2 CO S
g _ W0 95/09859 ~ , PCTIUS94111049 ~17~31~
~384 3-NH2 CH(cH3)2 CO S
1385 4-NH2 CH(cH3)2 CO S
1386 3-N2 CH(cH3)2 CO S
1387 4-N2 CH(cH3)2 CO S
1388 3-N CH(CH3)2 CO S
1389 4-N CH(cH3)2 CO S
1390 H CH(CH3)2 CO NH
1391 3-CH3 CH(cH3)2 CO NH
1392 4-CH3 CH(CH3k CO NH
1393 2-F CH(cH3)2 CO NH
1394 3-F CH(CH3)2 CO NH
1395 4-F CH(cH3)2 CO NH
1396 3-NH2 CH(cH3)2 CO NH
1397 4-NH2 CH(CH3)2 CO NH
1398 3-N02 CH(cH3)2 CO NIH
1399 4-N2 CH(cH3)2 CO NH
1400 3-N CH(cH3)2 CO NH
1401 4-N CH(CH3)2 CO NH
140' H CH2CH2CH(CH3)2 CO O
1403 3-CH3 CH2CH2CH(CH3)2 CO O
140~ 4-CH3 CH2CH2CH(CH3)2 CO O
1405 2-F CH2CH2CH(CH3)2 CO O
1406 3-F CH2CH2CH(CH3)2 CO O
1407 4-F CH2CH2CH(cH3)2 CO O
1408 3-NH2 CH2CH2CH(CH3)2 CO O
1409 4-NH2 CH2CH2CH(cH3)2 CO O
1410 3-NO2 CH2CH2CH(cH3)2 CO O
1411 4-NO2 CH2CH2CH(CH3)2 CO O
1412 3-N CH2CH2CH(cH3)2 CO O
1413 4-N CH2CH2CH(CH3)2 CO O
1414 H CH2CH2CH(CH3)2 CO S
1415 3-CH3 CH2CH2CH(cH3)2 CO S
1416 4-CH3 CH2CH2CH(cH3)2 CO S
1417 2-F , CH2CH2CH(cH3)2 CO S
1418 3-F CH2CH7CH(CH3)2 CO S
CC

WO95109859 21~43~1 PCr/US94/11049 1419 4-F CH2CH2CH(cH3)2 CO S
1420 3-NH2 CH2CH2CH(cH3)2 CO S
1421 4-NH2 CH2CH2CH(cH3)2 CO S
1422 3-N2 CH2C1~2CH(cH3)2 CO S
1423 4-N2 CH2C1~2CH(cH3)2 CO S
1424 3-N CH2C1~2CH(CH3)2 CO S
1425 4-N CH2C}~2CH(cH3)2 CO S
1426 H CH2C~2CH(CH3)2 CO NH
1427 3-CH3 CH2C}~2CH(cH3)2 CO NH
428 4 CH3 CH2C~12CH(CH3)2 CO NH
~429 2-F CH2C~12CH(CH3)2 CO NH
1430 3-F CH2C~12CH(cH3)2 CO NH
~431 4-F CH~C~12CH(CH3)~ CO NH
1432 3-NH2 CH2CH2CH(cH3)2 CO ~'H
1433 4-NH2 CH-~CH2CH(CH3)2 CO NH
43~ 3-NO2 CH2CH2CH(CH3)2 CO NH
1435 4-NO2 CH2CH2CH(CH3)2 CO NH
1436 3-N CH2CH2CH(CH3)2 CO NH
1437 4-N CH2CH2CH(cH3)2 CO NH
1438 H CH2l~H(cH3) CO O
1439 H CH2N(CH3)CO2C(CH3)3 CO O
TA~3~ 14 R~J~N ' o--Oq~ N H C H3 RA /~N--Z--R10 3,=l=~2 V
/ \
4~(CH2)L--V
~i 6 ~, A I ^ ' WO 95/098S9 2~ 1 7 ~ 3 1 1 PCTIUS94111049 ~
`` RX = H2N
Ex No. RA R10 z V u Dala 1451 4-N' CH3 CO O 0 145'' H CH3 CO S O

146~ 4-NO~ CH3 CO S 0 146'' 3-N CH3 CO S () 1464 H CH(CH3)2 CO O 0 1465 3-CH3 CH(CH3)2 CO O 0 1466 4-CH3 CH(CH3)2 CO O 0 1467 2-F CH(cH3)2 CO O 0 ~468 3-F CH(CH3)2 CO O 0 1469 4-F CH(cH3)2 CO O 0 1470 3-NH2 CH(CH3)2 CO O 0 1471 4-NH2 CH(CH3)2 CO O 0 C_ 217~311 WO95/09859 PCr~US94~11049 1472 3-NO2 CH(CH3)2 CO O 0 1473 4-N2 CH~(CH3)2 CO O 0 1474 3-N CH(CH3)2 CO O 0 1475 4-N CH(CH3)2 CO O 0 1476 H CH(CH3)2 CO S 0 1477 3-CH3 CH(CH3)2 CO S 0 1478 4-CH3 CH(CH3k CO S 0 1479 2-F CH(CH3)2 : CO S 0 1480 3-F CH(CH3)2 CO S 0 1481 4-F CHI~CH3)2 CO S 0 1482 3-NH2 CH(CH3)2 CO S 0 1483 4-NH2 CH(CH3)2 CO S 0 1484 3-NO2 CH(cH3)7 CO S 0 1485 4-NO2 CH(CH3)2 CO S 0 1486 3-N CH(CH3)~ CO S () ~487 4-N CH(CH3)2 CO S 0 1488 H CH2cH2cH(cH3)7 CO O () 1489 3-CH3 CH2CH2CH(CH3)2 CO O () 1490 4-CH3 CH2CH2CH(CH3)2 CO O 0 149~ 2-F CH2CH2CH(CH3)2 CO O 0 ~492 3-F CH2CH2CH(CH3)2 CO O 0 1493 4-F CH2CH2CH(CH3)2 CO O 0 149~ 3-NH2 CH2CH2CH(CH3)2 CO O 0 1495 4-NH2 CH2CH2CH(CH3)7 CO O () 1496 3-N2 CH2CH2CH(cH3)2 CO O () 1497 4-N02 CH2CH21`-H(CH3)2 CO O 0 1498 3-N CH2CH21-H(CH3)2 CO O 0 1499 4-N CH2CH2CH(CH3)2 CO O 0 1500 H CH2CH2CH(CH3)2 CO S 0 1501 3-CH3 CH2CH2CH(CH3)2 CO~ S 0 1502 4-CH3 CH2CH2CH(CH3)2 CO S 0 1503 2-F CH2CH2CH(CH3)2 CO S 0 1504 3-F CH2CH2CH(CH3)2 CO S 0 1505 4-F CH2CH2CH(CH3)2 CO S 0 1506 3-NH2 CH2CH2CH(cH3)2 CO ~ S 0 ~174311 " . i .
WO 95/09859 { ~ PCTIUS94/11049 1507 4-NH2 CH2CH2CH(cH3)2 CO S 0 1508 3-NO2 CH2CH2CH(CH3)2 CO S 0 1509 4-N2 CH2CH2CH(CH3)2 CO S 0 1510 3-N CH2CH2CH(CH3)2 CO S 0 1511 4-N CH2CH2CH(CH3)2 CO S 0 1518 3-NH2 CH3 CO O ]

15 ~ 4-NO2 CH3 CO O

152~ H CH3 CO S

~523 3-F CH3 CO S

153~ 4-NH~ CH3 CO S

~539 2-F CH3 CO NH

154~ 4-F CH3 CO NH

wo gslog8~9 2 17 43~ PCT/U594/11049 .
1542 3-NH2 C~i3 CO NH
1543 4-NH2 C~13 CO NH
1544 3-N2 c~l3 CO NH
1545 4-N2 C~13 CO NH
1546 3-N C~13 CO NH
1547 4-N C~13 CO NH
1548 H CH(CH3)2 CO O
1549 3-CH3 CH(CH332 CO O
1550 4-CH3 CH(cH332 CO O
1551 2-F CH(CH332 CO O
~552 3-F CH(cH3)2 CO O
1553 4-F CH(cH3)2 CO O
155~ 3-NH2 CH(CH3k CO O
1555 4-NH2 CH(cH3)2 CO O
1556 3-NO2 CH(cH3)2 CO O
1557 4-N2 CH(CH332 CO O
1558 3-N CH(CH332 CO O
1559 4-N CH(CH3)2 CO O
156(3 H CH(cH3)2 CO S
1561 3-CH3 CH(cH3)2 CO S
156'2 4-CH3 CH(cH3)2 CO S
1563 2-F CH(cH3)2 CO S
156~ 3-F CH(CH3)~ CO S
1565 4-F - CH(CH3) CO S
1566 3-NH2 CH(cH3)2 CO S
1567 4-NH2 CH(cH3)2 CO S
1568 3-N2 CH(CH3)~ CO S
1569 4-N2 CH(CH3)2 CO S
1570 3-N CH(CH3)2 CO S
1571 4-N CH(CH3k CO S
1572 H CH(CH3k CO NH
1573 3-CH3 CH(CH3)2 CO NH
1574 4-CH3 CH(CH3k CO NH
1575 2-F CH(cH3)2 CO NH
1576 3-F CH(CH3)2 CO NH
10?

~ r ~
.,. 1 ~ . ~ ..
WO 95/09859 ~ PCT/T~S94/11049 15774-F CH(CH3)2 CO NH
15783-NH2 CH(cH3)2 CO NH
15794-NH2 CH(CH3)2 CO NH
15803-NO2 CH(cH3)2 CO NH
15814-NO2 CH(cH3~2 CO NH
15823-N CH(cH3)2 CO NH
15834-N CH(cH3~2 CO NH
1584 H CH2CH2CH(CH3k CO O
15853-CH3 CH2CH2CH(CH3)2 CO O
15864-CH3 CH2CH2CH(cH3)2 CO O
15872-F CH2CH2CH(CH3)2 CO O
15883-F CH2CH2CH(CH3)2 CO O
15894-F CH2CH2CH(cH3)2 CO O .
15903-NH2 CH2CH2CH(CH3)2 CO O
15914-NH2 CH2CH2CH(CH3)2 CO O
159'2 3-NO~ CH2CH2CH(CH3)2 CO O
15934-NO2 CH2CH2CH(c.H3)2 CO O
159~3-N CH2CH2CH(CH3)2 CO O
15954-N CH2CH2CH(CH3)2 CO O
1596 H CH2CH2CH(CH3)2 CO S
15973-CH3 CH2CH2CH(CH3)2 CO S
15984-CH3 CH2CH2CH(cH3)2 CO S
15992-F CH2CH2CH(CH3)2 CO S
16003-F CH2CH2CH(CH3)2 CO S
16014-F CH2CH2CH(cH3)2 CO S
16023-NH2 CH2CH2CH(CH3)2 CO S
16034-NH2 CH2CH2CH(CH3)2 CO S
16(~3-N2 CH2CH2CH(CH3)2 CO S
16054-No2 CH2CH2CH(CH3)2 CO S
16063-N CH2CH2CH(CH3)2 CO S 1 r 16074-N CH2CH2CH(cH332 CO S
1608 H CH2CH2CH(CH3)2 CO NH
16093-CH3 CH2CH2CH(CH3)2 CO NH
16104-CH3 CH~CH2CH(CH3)2 CO Nll 161~2-F CH~CH2CH(cH3)2 CO NH
;0~

~17~311 WO 95/098sg PCT~Uss4/1 1049 1612 3 ~ CH2CH2CH(CH3)2 CO NH
1613 4-F CH2CH2CH(CH3)2 CO NH
1614 3-NH2 CH2CH2CH(cH3)2 CO NH
1615 4-NH2 CH2CH2CH(cH3)2 CO NH
1616 3-NO2 CH2CH2CH(cH3)2 CO NH
1617 4-NO2 CH2CH2CH(CH3)2 CO NH
1618 3-N CH2CH2CH(cH3)2 CO NH
1619 4-N CH2CH2CH(CH3)2 CO NH
1620 H CH2NH(CH3) CO O
1621 H CH2N(cH3)co2c(cH3)3 CO O
Table 15 NH OH
RXJ~ H ~B~o H
Oq~ N H
~N--Z---Rl ~X = ~21~, Z=C~=O) Ex No. R3 R10 Da~a 1623 (H3c)3c CH3 C ~ CH3 WogS/098S9 21~3~ pCrNS94/11049 1 625 - : -~o~C Hz CH3 16~6 CH3 t,'H2CH2Ph 1627 (H3C)3C CH2CH2Ph f ~ CH2CH~Ph 0~

~,C H2 CH2CH2Ph Ta~le 1 6 RXJ~ N ,B ~3 O~,NH C~
<~N--Z--R 10 RX = ~2N, Z=C~=O) No. R3 R10 Da~a ~630 CH3 CH3 1631 (H3c)3c C~3 ~1743~1 `

d~ CH3 C,C 1~2 CH3 1634 CH3 CH2CH2Ph 1635 (H3C)3C CH2CH2Ph C ~ CH2CH2Ph CC

CC~ H2 ' CH2CH2Ph ~able 17 H N~S~ ~
0~ N H C H3 O

Wo 95/098S9 3~ PCT/US94/11049 Ex No. R3 Rll R10 z Da;
163B H H CH2Ph C(O)O NN
163 9 PhCH2 H C(CH3)3 C(O)O OO
1640 PhCH2 H CH3 CO PP
16 41 PhCH2 H CH2Ph C(O)O OO
Table 18 O ~
H2N~ B` ~3 Oq~NH CH3 ~N--Z--R10 R
S R3--g Ex No. R3 R l l R 1 0 z Dala singlc bond CH2CH2Ph CO . RR
TABLE l 5 u N H B~ ~3 Oq~ N H C H3 ~N--Z--Rl WO95109859 æ~3ll PCr/US94/11049 Ex No. R3 R10 z R~
1643 CH2Ph CH2CH2Ph CO NHCH3 SS
1644 CH2Ph CH2CH2Ph CO H lT
Table 20 NH OH
RXJ~1 ' OH
0~ N H
~N--Z--R10 Ex No. R3 R10 Z Rx Da~a 1645 CH2Ph CH2CH2Ph CO NHCH3 Ul I
1646 CH2Ph CH2CH2Ph CO H VV
O ~
HR~S Calcd for C29H4.B~3O6: 540.3245. Found:
540 .3248 .
B HRMS Calcd for C30H44BN3O6: 554.3401. Found:
55~.3404.
C HR~S Calcd for C31H47BN3O6: 568.3558. Found:
5 68 . 3558 .
D HRMS Calcd for C29H42BN3O6: 540.3245. Found:
540 . 3248 .
20 ~ HRMS Calcd for C33~51BN3O6: 596.3871. Found:
596 . 3870 .

WO 95/09859 ~ PCr/U594/11049 F HRMS Calcd ~or C33H51BN3O6: 596.3871. Founà:
596 .3857 .
G HRMS Calcd for C36H48BN306: 630.3714. Found:
630 .3709 .
5 H HRMS Calcd for C30H44BN3O7: 570.3351. Found:
570 . 3353 .
I LF~MS Calcd for C3~H45BN3O8S: 618.3. Found: 618.q.
J HRMS Calcd for C31H468FN3O6: 586.3464. Found:
586. 3456 .
10 K HRMS Calcd for C30H46BN4O6: 569.3510. Found:
569 . 3501 .
L HRMS Calcd for C3~H52BN3O6: 6sa . 4027 . Found:
658 . 4036.
M HRMS Calcd for C28H39BN3O5 (ethylene glycol ester):
508.2983. Found: 508.2999.
N HRMS Calcd for C27H39BN3O5 (ethylene glycol ester~:
522.3139. Found: 522.3123.
O LRMS Calcd for C26H36BFN3O5 (ethylene glycol ester~:
526. Found: 526.
20 P HP~qS Calcd for C35H49BN3045: 618.3537. Founa:
61 8 . 3537 .
HRMS Calcd for C36H51BN3O5: 616.3922. Found:
616.3910. : :
R HRMS Calcd for C37H~3BN305: 630.4078. Found:
630 . 4060 .
S HR~.S Calcd for C35H50BN4O5: 617.3874. Found:
617 . 387 6 .
T LRMS Calcd for C36H50BFN3Os: 634. Found: 634.5.
U LRMS Calcd for C36H52BN4O5: 631. Found: 631.3.
30 V HRMS Calcd for C37H53BN305: 630 . qO78 . Found:
630 . 4071 .
W HRMS Calcd for C36H48BN3O6: 618.3714. Found:
618 . 3713 .
X HRMS Calcd for C36H51BN3O6: 632.3871. Found:
3~ 632.3857.
llr wo gs~og~sg ~ 1 7 4 3 1 I PCI/lJS94/11049 Y LFcMS Calcd for C36H51BN4O4: 615. Found: 615.5.
Z HRMS Calcd for CzgH~4BN405: 526.3452. Found:
526.3460.
AA HRMS Calcd for C30H46BN305: 540.3609. Found:
540 . 3604 .
BB HRMS Calcd for C30E~q7BN3O5: 540.3609. Found:
540.3620 .
CC HRMS Calcd for C31E~4gBN3Os: 554.3765. Found:
554 . 37 69 .
DD HRMS Calcd for C33El53BN407: 582.4078. Found:
582 . 4 071 .
EE ~EcMS Calcd for C30P.48BNgO5: 555.3718. Found:
555 . 3735 .
FF HE`cMS Calcd for C35E156BN4O7: 655.4242. Found:
655 . 4234 .
GG HRMS Calcd for C26H47BN3O5: 492.3609. Found:
4 5~ . 3600 .
Hl'. HRMS Calcd for C33Ei47BN305: 576.3609. Found:
576 . 3593 .
II HRMS Calcd for C33H53BN305: 582.4078. Found:
582 . 4092 .
JJ HFcMS Calcd for C40Hs3BN3Os: 666.4078. Found:
666 . 408~ .
~E' LRMS Calcd for C26H36BFN505: 528.3. Found: 528.3.
2_ , L HRMS Calcd for C36HslBNsos: 64~ .39~,. Found:
6~ ~ . 3 977 .
MM LRMS Calcd for C36H50BFN5O5: 662. Found: 662.
NN HRMS Calcd for C28H~l2BN4O6S: 573.2918. Found:
573 . 2919 . '~
OO HFcMS Calcd for C32HsoBN4O6S: 629.3544. Found:
62 9 . 3524 .
PP HR~IS Calcd for C29H42BN3O5S: 571.3126. Found:
571 . 3138 .
QQ HRMS Calcd for C35Ei48BN4O6S: 663.3388. Found:
663.3374.
i ~ 1 WO 95/09859 ~ PCTIUS94/1 l049 RR HRMS Calcd for C29H43BN3O5: 524.3300. Found:
524 . 3305 .
SS LRMS Calcd for C37Hs3BNsOs: 653. Found: 658 TT LRMS Calcd for C36Hs~BN4Os: 629. Found: 629 5 UU LRMS Calcd for C27H3gBNsOs: S24. Found: S~4 W LRMS Calcd for C26H36BN4Os: 495. Found: 49S
WW HRMS Calcd for C3sH4~BFN3O6: 636.3620. Found:
63 6 . 3612 .
Ut; lity The compounds of formula (I) are useful as inhibitors of serine proteases and notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indic~ted for use in the preYention or treatment of physiologica' , reactions, blood coagulatiQn and inflammatior., calalyzed b~ the aforesaid class of er.zymes.
Inhibition constants were determined by the melhod described by Kettner et al. in J. ~iol. ~hem. 265, 18289-18297 (1990~, herein incorporated by reference.
In these assays, thrombin-mediated hydrolysis cf the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX) was monitored spectrophotometrically.
Aad~ tion of an inhibitor to the assay miY.Iure resul~s lr ~- decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Il~ al a concentratior.
of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.S, 0.20 ~ NaCl, and 0 S'i polyethylene glycol 6000, was ~0 incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minuteS of ~
incubation, thrombin activity was assayed by moni1:0rins the rate of increase in absorbance at 9405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of tbe 1 ~

~ WO9~1098S9 21 7~31`~. PCr/U594/11049 re~ction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk.
Using the methodology described above, 5 representative compounds of this invention were evaluated and found to exhib t a Ki of less than l mM, thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors.
The ability of the compounds to inhibit coagulation lO was assayed in normal rabbit piasma which was prepared by diluting blood l:lO with 3.2~ aqueous citric acid followed by centrifugation. Bovine thrombin was obtained from Sigma and diluted to 2~ NIH units/mL.
Plasma ( 0.2 mL) and buffe~ (0.05 m~, O.lO M
l~ ~ris[hydroxymethyl~-aminomethane hydrochloride, pH 7.4, o . 9~ (w/v) sodium chloride, and 2 . 5 mg/mL bovine serum albumin) containing inhibitor were incubated 3 min at 37 C in a fibrameter. Reactions were ~initiated by adding thrombin (0.05 mL) T:O achieve a final concentration of 4 20 NIH units/mL. ~he effectiveness of compounds as antiGoagulants is reported as the level of inhibitor req~ired to prolong clotting to that observed for 2 NIH
units/mL of .thrombin in the absence of inhibitor. In this assay then, better inhibitors req~ire lower 2~ concentrations to dela~ clot formatlon. Representative compounds of this invention were evaluated and found to be active.
Since the ~ :~.pounds of formula (I) have anti-thromoogeniC proper~ies, they may be employed when an 30 anti-thrombogenic agent is indicated, such as for the control of the coagulation of the fibrinolysis system in mammals or they may be added to blood for the purpose of preventing coagulation of the blood due to contact with blood collecting or distribution 3' containers, tubing or apparatus.

WO9S/09859 ~ 3 1~.; PCr/US94111049 Generally, these compounds may be administered orally, parenterally or intravenousl ~ to a host to obtain an anti-thrombogenic effect. The dosage of the active compound depends on the mammalian species, body 5 weight, age, and mode of administration as determined by one skilled in the art. In the case of large mammals such as humans, the compounds may be administered alone or in combination with pharmaceutical carriers or diluents at a dose of from l0 0.02 to 15 mg/kg to obtain the anti-thrombogenic effect, and may be given as a single dose or in divided doses or as a sustained release formulation.
Pharmaceutical carriers or diluents are well known and include sugars, s~arches and water, which may be used to 15 make tablets, capsules, injectable solutions or the like which can serve as suitable dosage forms for administration of the compounds of this invention.
Rem;nqton's Pharmaceutlcal Sciences, A. Osol, is a standard reference teY.t which discloses sui~able 20 pharmaceutical carriers and dosage forms. The disclosure of this text is hereby incorporated by reference for a more complete teaching of suit:able dosage forms for administration of the compounds of this invention .
11

Claims (7)

    WHAT IS CLAIMED IS:
    1. A compound of formula (I):
    (I) or a pharmaceutically acceptable sall or prodrug thereof wherein:
    R1 is a) -(C1-C12 alkyl)-X, or b) -(C2-C12 alkenyl)-X, or c) X is a) halogen, b) -CN, c) -NO2, d) -CF3 e) -S(O)pR2, f) -NHR2, g) -NHS(O)pR2, h) -NHC(=NH)H, i) -NHC(=NH)NHOH, j) -NHC(=NH)NHCN, k) -NHC(=NH)NHR2, l) -NHC(=NH)NHC(=O)R2, m) -C(=NH)H, n) -C(=NH)NHR2, o) -C(=NH)NHC(=O)R2, p) -C(=O)NHR2, q) -C(50)NHC(=O)R2, r) -C (=O) oR2, s) -OR2, t) -OC(=O)R2, u) -OC(=O)OR2, v) -OC(=O)NHR2, w) -OC(=O)NHC(=O)R2, x) -SC(=NH)NHR2;
    R2 is a) hydrogen, b) -CF3 c) C1-C4 alkyl, d) -(CH2)q-aryl;
    R3 and R10 are independently selected at each occurrence from the group consisting of:
    a) hydrogen, b) halogen, c) -(CR6R7)tW(CR8R9)u-R9, d) -(CR6R7)tW(CR8R9)u-aryl, e) -(CR6R7)tW(CR8R9)u-heteroaryl, f) -(CR6R7)tW(CR8R9)u-heterocycle, g) -(CR6R7)tW(CR8R9)u-adamantyl, h) -(CR6R7)tW(CR8R9)u(C5-C7)cycloalkyl, i) , j) , k) , l) , m) , n) , o) , p) , q) , r) , s) , R3 and R10 when taken together form a ring such as:
    a) -(CR6R7)t(CR8R9)u-W-(CR8R9)u(CR6R7)t;
    b) -(CR6R7)tW(CR8R9)u-aryl-(CR8R9)uW(CR6R7)t-;
    c) -(CR6R7)tW(CR8R9)u-heteroaryl-(CR8R9)uW(CR6R7)t-;
    d) -(CR6R7)tW(CR8R9)u-heterocycle-(CR8R9)uW(CR6R7)t-;
    e) -(CR6R7)tW(CR8R9)U-W-(CR8R9)uW(CR6R7)t-;
    R4 and R5 are independently selected at each occurrence from the group consisting of:
    a) hydrogen, b) C1-C4 alkyl, c) C1-C4 alkoxy, d) C5-C7 cycloalkyl, e) phenyl, f) benzyl;
    R6, R7, R8 and R9 are independently selected at each occurrence from the group consisting of:
    a) hydrogen, b) C1-C6 alkyl, c) C1-C6 alkoxy, d) C3-C8 cycloalkyl, e) aryl, f) heterocycle, g) heteroaryl, h) -W-aryl, i) -(CH2)wC(=O)OR4, j) R6 or R7 can alternatively be taken together with R6 or R7 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons, or k) R8 or R9 can alternatively be taken together with R8 or R9 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons;
    R11 is a) hydrogen, b) C1-C4 alkyl, c) C1-C4 thioalkyl, d) -(CR6R7)tW(CR8R9)u-aryl, e) -(CR6R7)tW(CR8R9)u-heteroaryl, f) -(CR6R7)tW(CR8R9)u-heterocycle, or g) -(CR6R7)tW(CR8R9)u-R9;
    R11 and V, when taken together, can also be:
    a) keto, b) =NR10, c) =C[(CR6R7)tW(CR8R9)uR2]2, or d) -(CR6R7)tW(CR8R9)u-W-(CR6R7)tW(CR8R9)u-A is a) -Byly2 b) -C(=O)CF3, c) -C(=O)CF2CF3, d) -PO3H2 d) -C(=O)H, e) -C(=O)-1-piperdinyl, f) -C(=O)CH2OCH2CF3, g) CH2Cl h) SO2F;
    Y1 and Y2 are a) -OH, b) -F, c) -NR4R5-, d) -C1-C8 alkoxy, or;
    when taken together Y1 and Y2 form.:

    e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
    W can be independently selected at each occurence from the group consisting of:
    a) -(CH2)x-, b) -C(=O)-, c) -C(=O)O-, d) -C(=O)NR4-, e) -O-, f) -OC(=O)-, g) -OC(=O)O-, h) -OC(=O)NR4-, i) -NR4-, j) -NR4C(=O)-, k) -NR4C(=O)O-, l) -NR4C(=O)NR5-, m) -NR4S(O)p-n) -S(O)p-, o) -S(O)pO-, p) -S(O)pNR4-, q) -S(O)pNR4C(=O)-, r) -S(O)pNR4C(=O)NR5-;
    V s selected from the group consisting of:
    a) -(CH2)x-, b) - (CH2)xC(=O)-, c) - (CH2)xC(=O)O-, d) -C(=O)(CH2)x-, e) -O-(CH2)x-, f) -O(CH2)xC(=O)-, g) -O(CH2)xC(=O)O-, h) -O(CH2)xC(=O)NR4-, i) -O(CH2)xS(O)p-, j) -(CH2)xS(O)p-, k) -(CH2)xS(O)pO-, l) -(CH2)xS(O)pNR4-, m) -(CH2)xS(O)pNR4C(=O)-, n) -(CH2)xS(O)pNR4C(=O)NR5-, o) -(CH2)XNR4-, p) -(CH2)XNR4C(=O)-, q) -(CH2)XNR4C(=O)O-, r) -(CH2)XNR4C(=O)NR5-, s) -(CH2)XNR45(O)p-;
    Z is selected from the group consisiting of:
    a) -(CH2)x-, b) -(CH2)xC(=O)-, c) -C(=O)(CH2)x-, d) -(CH2)xC(=O)O-, e) -(CH2)xC(=O)NR4-, f) -(Cr2)xNR4-, g) -(CH2)xNR4C(=O)-, h) -(CH2)xNR4C(=O)O-, i) -(CH2)xNR4C(=O)NR5-, j) -(CH2)xNR4S(O)p-, k) -(CH2)xS(O)p-, l) -(CH2)xS(O)pNR4-, m can be 0 to 4, n can be 0 to 4;
    p can be 0 to 2 q can be 0 to 4;
    r, s, t, u, and v are independently selected at each occurrence from 0 to 6, w and x are independently selected at each occurence from 0 to 4;
    with the following provisos:
    (a) when V is (CH2)x, x cannot be 0 when R3 is hydrogen;
    (b) when Z is -(CH2)xC(=O)- and -C(=O)(CH2)x and x is C, R10 cannot be halogen;
    wherein aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents;
    heteroaryl is 2-, or 3-, or 4-pyridyl; 2-or 3-furyl; 2-or 3-benzofuranyi; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3-indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl; 2-or 4- or 5-imidazolyl.; 1- or 2- benzimidazolyl; 2- or 4-or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4-cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl ring; said ring (s) may be unsubstitued or include optional substitution with one to three substituents;
    heterocycle is 2- or 3-pyrrolidinyl, a 2-, 3-, or 4-piperidinyl, or a 1-, 3-, or 4-tetrahdroisoquinolinyl, 1-, 2-, or 4-tetrahydroquinoiinyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothiophene, 1-, 2-, 3-, or 4-piperazinyl, and 1-, 2-, 3-, or 4-morpholino;
    said ring(s) which may be unsubstituted or include ?
    optional substitution with one to three substituents;
    cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl;
    the substituents which may be attached to the ring(s) above may be independently selected at each occurrence from the group selected from:
    halogen, -CF3, C1-C4 alkyl,nitro, phenyl, -(CH2)rR4, -(CH2)rC(=O)(CH2)5R4, -(CH2)rC(=O)O(CH2)sR4, -(CH2)rC(=O)N[(CH2)sR4][(CH2)sR5], methylenedioxy, C1-C4 alkoxy, -CH2)rO(CH2)sR4, -(CH2)rOC(=O)(CH2)sR4, -(CH2)rOC(=O)O(CH2)sR4, -(CH2)rOC(=O)N[(CH2)sR4][(CH2)sR5], -(CH2)rOC(=O)N[(CH2)sR4, [C(=O)(CH2)sR5], -(CH2)rS(O)p(CH2)sR4, -(CH2)rS(O)p(CH2)sC(=O)R4, -(CH2)rS(O)p(CH2)sC(=O)OR4, -(CH2)rS(O)pN[(CH2)sR4][(CH2)sR5], -(CH2)rS(O)pN[(CH2)9R4][C(=O)(CH2)sR5], -(CH2)rN[(CH2)sR4][(CH2)sR5], -(CH2)rN[(CH2)sR4][C(=O)(CH2)sR5], -(CH2)rN[(CH2)sR4][C(=O)O(CH2)sR5], -(CH2)rN[(CH2)sR4]CON[(CH2)sR4][(CH2)sR5], -(CH2)rN[(CH2)sR4]C(=O)-N[(CH2)sR4][C(=O)(CH2)sR5], -(CH2)rN[(CH2)sR4][S(O)p(CH2)sR5], 2. A compound of claim 1 wherein:
    R1 is (C3-C4 alkyl);
    X is selected from the group consisting of:
    -NHC(=NH)H, -NHC(=NH)NHR2, -NH2 or -SC(=NH)NHR2;
    R2 is hydrogen or C1-C4 alkyl.
    3. A compound of claim 2 having formula (Ia) wherein:
    (Ia) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    R1 is (C3-C4 alkyl);
    X is selected from the group consisting of:
    -NHC(=NH)H, -NHC(=NH)NHR2, -NH2 or -SC(=NH)NHR2;
    R2 is hydrogen or C1-C4 alkyl;
    R3 and R10 are independently selected at each occurrence from the group consisting of:
    a) hydrogen, b) halogen, c) - (CR6R7)tW(CR8R9)u-R9 d) - (CR6R7)tW(CR8R9)u-aryl e) - (CR6R7)tW(CR8R9)u-heteroaryl;
    R4 and R5 are independently selected at each occurrence from the group consisting of:
    a) hydrogen, b) C1-C4 alkyl, c) C1-C4 alkoxy, d) phenyl, or e) benzyl;
    R6, R7, R8, R9 are independently selected at each occurrence from, the group consisting of:
    a) hydrogen b) C1-C6 alkyl, c) aryl, d) -(CH2)wC(=O)OR4, or;
    Y1 and Y2 are a) -OH, b) -F, c) -NR4R5 -, d) -C1-C8 alkoxy, or;
    when taken together Y1 and Y2 form:
    e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, f) a cyclic boron amide where sald chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;
    W can be independently selected at each occurrence from the group consisting of:
    a) -(CH2)x-, b) -O-, c) -S(O)p-, d) -NR4-, e) -NR4C(=O)-, f) -NR4C(=O)O-, V is selected from the group consisting of:
    a) -(CH2)x-, b) -O(CH2)x-, c) -O(CH2)x(C=O)-, d) -(CH2)xS(O)p-, e) -(CH2)xNR4-f) -(CH2)xNR4C(=O)-, g) -(CH2)xNR4C(=O)O-;
    Z is selected from the group consisiting of:
    a) -(CH2)xC(=O)-, b) -C(=O)(CH2)x-, c) -(CH2)xC(=O)O-, p can be 0 or 2;
    r can be independently selected at each occurrence from 0 to 3;
    s can be independently selected at each occurrence from 0 to 3;
    t can be independently selected at each occurrence from 0 to 2;

    u can be independently selected at each occurrence from 0 to 2;
    w can be independently selected at each occurrence from 0 to 2;
    x can be independently selected at each occurrence from 0 to 3;
    with the following provisos:
    (a) when V is (CH2)x, x can not be 0 when R3 is hydrogen;
    (b) when Z is -(CH2)xC(=O)- and -C(=O)(CH2)x and x is 0, R10 can not be halogen, wherein aryl is phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents;
    heteroaryl is 2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl, which may be unsubstitued or include optional substitution with one to three substituents;
    heterocycle is 1-, 3-, or 4-tetrahdroisoquinolinyl, 2-or 3-pyrrolidinyl, and 2-, 3- or 4-piperidinyl, which may be unsubstituted or include optional substitution with one to three substituents;
    cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl;

    the substituents which may be ettached to the aryl, heteroaryl and heterocycle ring(s) may be independently selected at each occurrence from the group selected from:
    halogen, -CF3, C1-C4 alkyl,nitro, phenyl, -(CH2)rR4, -(CH2)rC(=O)(CH2)sR4, -(CH2)rC(=O)O(CH2)sR4, -(CH2)rC(=O)N[(CH2)sR4][(CH2)sR5], methylenedioxy, C1-C4 alkoxy, -CH2) rO(CH2)sR4, -(CH2)rOC(=O)(CH2)sR4, -(CH2)rOC (=O)O(CH2)sR4, -(CH2)rOC(=O)N[(CH2)sR4][(CH2)sR5], -(CH2)rOC(=O)N[(CH2)sR4][C(=O)(CH2)sR5], -(CH2)rS(O)p(CH2)sR4, -(CH2)rS(O)p(CH2)sC(=O)R4, -(CH2)rS(O)p(CH2)sC(=O)OR4, -(CH2)rS(O)pN[(CH2)sR4][(CH2)sR5], -(CH2)rS(O)pN[(CH2)sR4][C(=O)(CH2)sR5], -(CH2)rN[(CH2)sR4][(CH2)sR5], -(CH2)rN[(CH2)sR4][C(=O)(CH2)sR5], -(CH2)rN[(CH2)sR4][C(=O)O(CH2)sR5], -(CH2)rN[(CH2)sR4]CON[(CH2)sR4][(CH2)sR5], -(CH2)rN[(CH2)sR4]C(=O)-N[(CH2)sR4][C(=O)(CH2)sR5], -(CH2)rN[(CH2)sR4][S(O)p(CH2)sR5].
    4. A compound of claim 3 wherein:
    R3 is independently selected from the group consisting of:
    benzyl, phenyl, phenethyl, (3-phenyl)prop-1-yl, (2-methyl-1-phenyl)prop-2-yl, (2-methyl-2-phenyl)prop-1-yl, 1,1-diphenylmethyl, phenoxymethyl, phenylsulfonylmethyl, 2- (m-fluorophenyl) ethyl,, 2-(3-pyridyl)ethyl, (m-aminophenyl)methyl, (m-methylphenyl)methyl, (p-methylphenyl)methyl, 1-naphthylmethyl;

    R10 is independently selected from the group consisting of:
    methyl, t-butoxy, benzyloxy, phenethyl, benzyl, phenoxymethyl, isopropyl, isoamyl, N-methyl-N-t-butoxycarbonylaminomethyl, N-methylaminomethyl, (m-methyl)phenethyl, (m-fluoro)phenethyl, (m-methyl)phenoxymethyl, (3-pyridyl)ethyl;
    R11 is hydrogen;
    V is independently selected from the group consisting of:
    O, -OC(=O)-, S, -NH-;
    Z is -C(=O)-.
    5. A compound of claim 4 of the formula (Ib) selected from the group consisting of:
    (Ib) selected from the list consisting of:
    the compound of formula (Ib) wherein R3 is phenyl and R10 is methyl;

    the compound of formula (Ib) wherein R3 is phenylmethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is phenethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is 3-phenylprop-1-yl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is 1,1-dimethyl-2-phenylethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is 2, 2-dimethyl-2-phenylethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is diphenylmethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is phenoxymethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is phenylsulfonylmethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is (m-fluorophenyl)ethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is (3-pyridyl)ethyl and R10 is methyl;
    the compound of formula (Ib) wherein R3 is phenylethyl and R10 is phenethyl.
    6. A compound of claim 4 of the formula (Ic) selected from the group consisting of:

    (Ic) selected from the list consisting of:
    the compound of formula (Ic) wherein V is sulfur, R3 is phenyl and R10 is phenethyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is phenethyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is 3-phenylpropyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is (m-methyl ) phenoxymethyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is (m-fluoro) phenoxymethyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is (m-methylphenyl)ethyl;

    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is (m-fluorophenyl) ethyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is phenoxymethyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is (m-fluorophenyl)methyl and R10 is phenethyl;
    the compound of formula (Ic) wherein V is amino, R3 is phenylmethyl and R10 is phenethyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is methyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is 2-propyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is isoamyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is (m-methylphenyl)methyl and R10 is methyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is (p-methylphenyl)methyl and R10 is methyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is (1-naphthyl)methyl and R10 is methyl;
    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is N-methyl-N-t-butoxycarbonylaminomethyl;

    the compound of formula (Ic) wherein V is oxygen, R3 is phenylmethyl and R10 is N-methylaminomethyl.
    7. A compound of claim 4 of the formula (Id) selected from the group consisting of:
    (Ic) selected from the list consisting of:
    the compound of formula (Id) wherein V is oxygen, R3 is phenylmethyl and R10 is phenethyl;
    the compound of formula (Id) wherein V is oxygen, R3 is (m-fluorophenyl)methyl and R10 is phenethyl.
    the compound of formula (Id) wherein V is oxygen, R3 is phenylmethyl and R10 is (m-methyl)phenethyl;
    8. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 1.
    9. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim, 2.

    10. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 3.
    11. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 4.
    12. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 5.
    13. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 6.
    14. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 7.
    15. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of
  1. claim 1.
    16. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of
  2. claim 2.

    17. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of:
  3. claim 3.
    18. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of
  4. claim 4.
    19. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of
  5. claim 5.
    20. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comrpising administering to an animal in need of such treatment an effective amount of a compound of
  6. claim 6.
    21. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of
  7. claim 7.
CA002174311A 1993-10-07 1994-10-06 Boropeptide inhibitors of thrombin which contain a substituted pyrrolidine ring Abandoned CA2174311A1 (en)

Applications Claiming Priority (4)

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US08/133,250 1993-10-07
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US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
US5726159A (en) * 1994-03-04 1998-03-10 Eli Lilly And Company Antithrombotic agents
CA2143533A1 (en) * 1994-03-04 1995-09-05 Kenneth D. Kurz Antithrombotic agents
US5885967A (en) * 1994-03-04 1999-03-23 Eli Lilly And Company Antithrombotic agents
ZA951618B (en) * 1994-03-04 1996-08-27 Lilly Co Eli Antithrombotic agents
US5705487A (en) * 1994-03-04 1998-01-06 Eli Lilly And Company Antithrombotic agents
US5602101A (en) * 1994-03-04 1997-02-11 Eli Lilly And Company Antithrombotic agents
US5914319A (en) * 1995-02-27 1999-06-22 Eli Lilly And Company Antithrombotic agents
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
AU2001268607A1 (en) 2000-06-21 2002-01-02 Bristol-Myers Squibb Company Piperidine amides as modulators of chemokine receptor activity
EP1561466A3 (en) * 2002-09-09 2006-08-23 Trigen Limited Boronic acid salts and use thereof in the preparation of medicaments for treating thrombosis
US7371729B2 (en) 2002-09-09 2008-05-13 Trigen Limited Boronic acid salts useful in parenteral formulations
ES2802251T3 (en) * 2012-01-06 2021-01-18 Novartis Ag Heterocyclic compounds and methods for their use
WO2014058538A1 (en) * 2012-08-27 2014-04-17 Merck Sharp & Dohme Corp. Substituted pyrrolidine thrombin inhibitors
US10590084B2 (en) 2016-03-09 2020-03-17 Blade Therapeutics, Inc. Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof
WO2018009417A1 (en) 2016-07-05 2018-01-11 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
CA3038331A1 (en) 2016-09-28 2018-04-05 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof

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US5187157A (en) * 1987-06-05 1993-02-16 Du Pont Merck Pharmaceutical Company Peptide boronic acid inhibitors of trypsin-like proteases
GB9017694D0 (en) * 1990-08-13 1990-09-26 Sandoz Ltd Improvements in or relating to organic chemistry
GB9024129D0 (en) * 1990-11-06 1990-12-19 Thrombosis Research Trust Inhibitors and substrates of thrombin
EP0503203A1 (en) * 1991-03-15 1992-09-16 Merrell Dow Pharmaceuticals Inc. Novel thrombin inhibitors

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