Compounds and methods for the treatment or prevention of flavivirus infections

(57) Abrégé/Abstract:

the present invention provides novel compounds represented by formula I: or pharmaceutically acceptable salts thereof useful for treating Flaviviridae viral infection.

Canada http://opic.ic.gc.ca· Ottawa/Gatineau K1A0C9 · http://cipo.ic.gc.ca o PI C OPIC-CIPO 191

<img file="CA2449999C_D0001.tif" />

CIPO

CA 2449999 C 2012/07/31 (11)(21) 2 449 999 (13) C (51) Cl.lnt./lnt.CI. (suite/continued) C07D 211/58(2006.01 ), C07D 213/40(2006.01 ), C07D 2/5//2(2006.01),

C07D 231/20(2006.01), C07D 233/54(2006.01), C07D 257/04(2006.01), C07D 261/08(2006.01),

C07D 263/56(2006.01), C07D 263/57(2006.01), C07D 277/32(2006.01), C07D 277/42(2006.01),

C07D 277/58(2006.01), C07D 307/46(2006.01), C07D 307/52(2006.01), C07D 307/81 (2006.01),

C07D 333/20(2006.01 ), C07D 333/24(2006.01 ), C07D 333/28(2006.01 ), C07D 333/38(2006.01 ),

C07D 407/04(2006.01), C07D 409/04(2006.01), C07D 409/14(2006.01), C07D411/12(2006.01),

C07D 417/04(2006.01) (72) lnventeurs(suite)/lnventors(continued): SIDDIQUI, M. ARSHAD, US; WANG, WUYI, CA; NGUYEN-BA, NGHE, CA (73) Propriétaires(suite)/Owners(continued):VIROCHEM PHARMA INC., CA (74) Agent: NORTON ROSE CANADA S.E.N.C.R.L.,S.R.L./LLP

-2CA 02449999 2003-12-08

<img file="CA2449999C_D0002.tif" />

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization

International Bureau (43) International Publication Date 19 December 2002 (19.12.2002)

PCT (10) International Publication Number

WO 02/100846 Al

W0 02/100846 Al I lllllllllllll II llllllllllllllll II III lllllllllllllllllllllllllllllllllllllllllllllll (51) International Patent Classification⁷: C07D 277/28,

C07C 233/87, C07D 307/81, 333/24, C07C 311/29, 311/19, C07D 233/54, 261/08, 263/56, 307/52, 407/04, 417/04, 333/20, 409/04, 231/20 (21) International Application Number: PCT/CA02/00877 (22) International Filing Date: 11 June 2002 (11.06.2002) (25) Filing Language: English (26) Publication Language: English (30) Priority Data:

60/296,732 11 June 2001 (11.06.2001) US (71) Applicant (for all designated States except US): SHIRE BIOCHEM INC. [CA/CA]; 275 Armand-Frappier Blvd., Laval, Québec H7V 4A7 (CA).

(71) Applicant (for US only): NGUYEN BA, Nghe [CA/CA]; 175 Leotable Dubuc, LaPrairie, Québec J5R 5M5 (CA).

(72) Inventors; and (75) Inventors/Applicants (for US only): CHAN, Chun, Kong, Laval [CA/CA]; 27 Levere Street, Kirkland, Québec H9J 3X8 (CA). BEDARD, Jean [CA/CA]; 437 Lansdowne, Rosemère, Québec J7A 3G6 (CA). DAS, Sanjoy, Kumar [IN/CA]; 553, 2ième rue, Laval, Québec H7V 1H7 (CA). PEREIRA, Oswy, Z. [CA/CA]; 12 Daudelin, Kirkland, Québec H2J 1L8 (CA). SHUTTLEWORTH, Steve [CA/US]; 2 Corporate Drive, South San Francisco, CA 94080 (US). SIDDIQUI, M., Arshad [CA/US]; 840

Memorial Drive, Cambridge, MA 02139 (US). WANG, Wuyi [CA/CA]; 2297 Frenette, Ville St-Laurent, Québec H4R 1M3 (CA).

(74) Agents: OGILVY RENAULT et al.; Suite 1600, 1981 McGill College Avenue, Montreal, Québec H3A 2Y3 (CA).

(81) Designated States (national): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZM, ZW.

(84) Designated States (regional): ARIPO patent (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).

Published:

— with international search report — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments

For two-letter codes and other abbreviations, refer to the Guidance Notes on Codes and Abbreviations appearing at the beginning of each regular issue of the PCT Gazette.

(54) Title: COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS

Ri

R.1 R'

<img file="CA2449999C_D0003.tif" />

X, (I) (57) Abstract: the present invention provides novel compounds represented by formula I: or pharmaceutically acceptable salts thereof useful for treating Flaviviridae viral infection.

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

COMPOUNDS AND METHODS FOR THE TREATMENT . OR PREVENTION OF FLAVIVIRUS INFECTIONS

FIELD OF THE INVENTION

The present invention relates to biaryl compounds and a method for the treatment or prevention of Flavivirus infections using biaryl compounds .

BACKGROUND OF THE INVENTION

Hepatitis is a disease occurring throughout the world. It is generally of viral nature, although there are other causes known.

Viral hepatitis is by far the most common form of hepatitis.

Nearly 750,000 Americans are affected by hepatitis each year, and out of those, more than 150,000 are infected with the hepatitis C virus (HCV).

HCV is a positive-stranded RNA virus belonging to the Flaviviridae family and has closest relationship to the pestiviruses that include hog cholera virus and bovine viral diarrhea virus (BVDV). HCV is believed to replicate through the production of a complementary negative-strand RNA template. Due to the lack of efficient culture replication system for the virus, HCV particles were isolated from pooled human plasma and shown, by electron microscopy, to have a diameter of about 50-60 nm. The HCV genome is a single-stranded, positive-sense RNA of about 9,600 bp coding for a polyprotein of 3009-3030 amino-acids, which is cleaved co and post-translationally by cellular and two viral proteinases into mature viral proteins (core, El, E2, p7, NS2, NS3, NS4A,

NS4B, NS5A, NS5B). It is believed that the structural proteins,_xEl and E2, the major glycoproteins are embedded into a viral lipid envelope and form stable heterodimers. It is also believed that the structural core protein interacts with the viral RNA genome to form the nucleocapsid. The nonstructural proteins designated NS2 to NS5 include proteins with enzymatic functions involved in virus replication and protein processing including a polymerase, protease and helicase.

SUBSTITUTE SHEET (RULE 26)

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PCT/CA02/00877

The main source of contamination with HCV is blood. The magnitude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers in western countries are chronically infected with HCV. For intravenous drug abusers, the prevalence varies from about 28% to 70% depending on the population studied. The proportion of new HCV infections associated with post-transfusion has been markedly reduced lately due to advances in diagnostic tools used to screen blood donors .

The only treatment currently available for HCV infection is interferon-a (IFN-α). However, according to different clinical 15 studies, only 70% of treated patients normalize alanine aminotransferase (ALT) levels in the serum and after discontinuation of IFN, 35% to 45% of these responders relapse. In general, only 20% to 25% of patients have long-term responses to IFN. Clinical studies have shown that combination treatment with

IFN and ribavirin (RIBA) results in a superior clinical response than IFN alone. Different genotypes of HCV respond differently to IFN therapy, genotype lb is more resistant to IFN therapy than type 2 and 3.

There is therefore a great need for the development of anti-viral agents.

SUMMARY OF THE INVENTION

The present invention provides compound of formula I:

<img file="CA2449999C_D0004.tif" />

I

d) and pharmaceutically acceptable salts thereof,

<img file="CA2449999C_D0005.tif" />

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 wherein,

M is chosen from

PCT/CA02/00877

-S'

<img file="CA2449999C_D0006.tif" />

<img file="CA2449999C_D0007.tif" />

(II) (III) s (IV) (V)

<img file="CA2449999C_D0008.tif" />

/

<img file="CA2449999C_D0009.tif" />

0r₆

CH· a bond (VI) (VII) (VIII) (IX) wherein each R₆ is independently chosen from H or C_x_ alkyl;

A¹ is chosen from a bond, alkyl, C₂_₆ alkenyl or C₂_₆ alkynyl;

A is chosen from COOR₅, CO-COOR₅, PO₃R₅R₅, SO₃R₅, tetrazole, CON(R₅) CH(R₅) -COOR_s, CONR₅R₅, CONR₅OH, wherein each R_s is independently chosen from H or alkyl;

R_x, R₂ are independently chosen from H, C_x_₆ alkyl, C₆.₁₂aryl, C₃_₁₀heterocycle, C₆.₁₂ aralkyl or C₃.₁₀ heteroaralkyl;

R₃ is chosen from C₆_₁₂aryl, C₃.₁₀ heterocycle, C₆.₁₂ aralkyl or C₃.₁₀heteroaralkyl;

Y is chosen from:

<img file="CA2449999C_D0010.tif" />

a bond

O (XI)

O (XII) (XIII) (XIV)

Z is chosen from alkyl, C₂.₆ alkenyl, C₂„₆ alkynyl, C₆.₁₄aryl, C₃__xheterocycle;

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2010-10-29

R₄ is chosen from H, halogen, CN, NO₂, C_V6 alkyl, C_e_₁₂aryl, C₃_₁₀heterocycle, C₆_₃₂ aralkyl, C₃.₁₀ heteroaralkyl, NR_SR_S, SO₂CH₃, Ο-Ο₃.₆alkyl, O-C₆.₁₂ aryl, O-C₆_₁₂ aralkyl, COR,, wherein each R₅ is independently chosen from H or C_x„₆ alkyl, and R₇ is chosen from C₆.₁₂ aryl or C₃.₁₀ heterocycle,· with the proviso that compound of formula (I) is other than 3[3-(2,6-Dichloro-pyridin-4-yl)-1-(4-thiophen-2-yl-benzyl)ureido]-3-thiophen-2-yl-propionic acid; compound #1 .

The compounds of the present invention are useful in therapy, particularly as antivirals .

In another aspect,· there is provided a method of treating viral infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or composition of the invention.

In still another aspect, there there is provided a method of treating viral infections in a subject in need of such treatment comprising administering to the subject a combination comprising at least one compound of formula (I) and at least one further therapeutic agent.

In another aspect, there is provided a pharmaceutical formulation comprising the compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.

In another aspect of the invention is the use of a compound according to formula (I), for the manufacture of a medicament for the treatment of viral infections.

In another aspect of the invention is a pharmaceutical composition for treating or preventing a Flaviviridae viral infection comprising at least one compound according to formula (I) as defined herein

CA 02449999 2010-10-29 together with at least one pharmaceutically acceptable carrier or excipient.

In another aspect of the invention is the use of a compound of formula (I) as defined herein, or pharmaceutically acceptable salts thereof for the manufacture of a medicament for inhibiting or reducing the activity of viral polymerase in a host.

In another aspect of the invention is the use of a compound of formula (I) as defined herein or pharmaceutically acceptable salts thereof for the manufacture of a medicament for inhibiting or reducing the activity of viral helicase in a host.

In another aspect of the invention is a combination comprising a compound of formula (I) as defined herein or pharmaceutically acceptable salts thereof, and further comprising at least one additional agent chosen from viral serine protease inhibitor, viral polymerase inhibitor, viral helicase inhibitor, an immunomudulating agent, an antioxydant agent, an antibacterial agent and an antisense agent.

DETAILED DESCRIPTION OF THE INVENTION

Iii one embodiment, compounds of the present invention comprise those wherein the following embodiments are present, either independently or in combination.

In a further embodiment, M is

4a

CA 02449999 2003-12-08 (II

WO 02/100846

PCT/CA02/00877

-S

II

In an alternative embodiment, M is

In a further embodiment, M is

X

<img file="CA2449999C_D0011.tif" />

O (VI )

<td></td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> M is</td><td></td>

<td></td><td></td><td colspan="2"> -CH—</td><td></td><td></td><td></td>

<td> 10</td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> M is</td><td> a bond.</td>

<td></td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> A is )</td><td> chosen from</td>

<td></td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> A is</td><td> COOH.</td>

<td></td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> A is</td><td> COOCH₂CH₃.</td>

<td> 15</td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> A¹ is</td><td> chosen from</td>

<td></td><td colspan="2"> bond.</td><td></td><td></td><td></td><td></td>

<td></td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> A¹ is</td><td> a bond.</td>

<td></td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> A¹ is</td><td> ch₂.</td>

<td> 20</td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> R₂ is</td><td> H or methyl</td>

<td></td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> R₂ is</td><td> H.</td>

<td></td><td> In</td><td> a</td><td> further</td><td> embodiment,</td><td> R₂ is</td><td> methyl.</td>

SUBSTITUTE SHEET (RULE 26)

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WO 02/100846 PCT/CA02/00877

In one embodiment, R_x is chosen from benzyl, thiophene, CH₂thiophene, methyl, CH₂-imidazole, CH₂-cyclohexyl which can be unsubstituted or substituted by at least one substituent chosen from halogen, OH or benzyl.

<td> In</td><td> one</td><td> embodiment,</td><td>^Ri</td><td> is</td>

<td> In</td><td> one</td><td> embodiment,</td><td> Ri</td><td> is</td>

<td> In</td><td> one</td><td> embodiment,</td><td>^R1</td><td> is</td>

<td> In</td><td> one</td><td> embodiment,</td><td>^R1</td><td> is</td>

benzyl substituted with OH.

benzyl substituted with Br.

CH₂-thiophene substituted with Br.

CHj-cyclohexyl substituted with benzyl.

In a further embodiment, R₃ is heterocycle.

In a further embodiment, R₃ is chosen from a C₆.₁₂ aryl or C₃.₁₀ chosen from:

wherein :

<img file="CA2449999C_D0012.tif" />

<img file="CA2449999C_D0013.tif" />

SUBSTITUTE SHEET (RULE 26)

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WO 02/100846 PCT/CA02/00877

<td> Rw</td><td> is</td><td> H or methyl;</td>

<td> Ry</td><td> is</td><td> H or methyl;</td>

<td> Rw</td><td> is</td><td> H;</td>

<td> Rw</td><td> is</td><td> methyl;</td>

<td> Ry</td><td> is</td><td> H;</td>

<td> Ry</td><td> is</td><td> methyl;</td>

And wherein, Xa is S, N,0 or C.

In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, C^ alkyl, C₂_₆alkenyl, OC₁.₆ alkyl, CF₃, COOH, OH, COOC_X_₆ alkyl, CN, NH₂, NO₂, ΝΗ(Ο_Χ_₆ alkyl), Ν(Ο_Χ_₆ alkyl) ₂.

In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl, vinyl, CF₃, COOH, COOCH₃, OH, CN, NH₂, NO₂, NH(CH₃) or N(CH₃)₂.

In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl, CF₃, COOH, COOCH₃, OH, CN, NH₂, or NO₂

In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, methyl, O-methyl, CF₃, COOH, COOCH₃, CN, NH₂, or NO₂.

In a further embodiment, each of Ra, Rb, Rc, Rd, Re, and Rf are independently chosen from, H, Cl, F, methyl, OH, CF₃or O-methyl

In one embodiment, Rf is H or methyl.

In another embodiment, Rf is H.

In another embodiment, Rf is methyl.

In a further embodiment, each of Ra, Rb, Rc, Rd and Re is independently chosen from, H or Cl.

In a further embodiment, each of Ra, Rb, Rc, Rd and Re is H.

In one embodiment :

Ra is chosen from Cl, F, methyl or O-methyl;

. 7

SUBSTITUTE SHEET (RULE 26)

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WO 02/100846 PCT/CA02/00877

Rb is H;

Rc is chosen from Cl, F, methyl or O-methyl;

Rd is H;

Re is H.

In one embodiment:

Ra is Cl;

Rb is H;

Rc is Cl;

Rd is H;

Re is H.

In one embodiment:

Ra is methyl;

Rb is methyl;

Rc is O-methyl;

Rd is H;

Re is methyl.

In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, Br, I, F, alkyl, OC_X_₆ alkyl, CF₃, COOH,

COOC^ alkyl, CN, NH₂, NO₂, NH(C_X_₆ alkyl), N(C_X_₆ alkyl)₂.

In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl, CF₃, COOH, COOCH₃, CN, NH₂, NO₂, NH(CH₃) or N(CH₃)₂.

In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, Br, I, F, methyl, O-methyl, CF₃, COOH, COOCH₃, CN, NH₂, or NO₂

In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, methyl, O-methyl, CF₃, COOH, COOCH₃, CN, NH₂ or NO₂.

In a further embodiment, each of Rs, Rt, Ru, are independently chosen from, H, Cl, F, methyl, CF₃or O-methyl.

SUBSTITUTE SHEET (RULE 26)

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WO 02/100846

In a further embodiment, chosen from, H or Cl.

each of Rs,

Rt, Ru,

PCT/CA02/00877 are independently

In a further embodiment, each 5

In one embodiment:

Rs and Ru are Cl and Rt is H.

of Rs, Rt, Ru, are H.

<td></td><td> RS</td><td> is Cl, Rt</td><td> and Ru are</td><td> H.</td><td></td>

<td> 10</td><td> In</td><td> a further</td><td> embodiment,</td><td> Y</td><td> is</td>

<td></td><td colspan="2"> CH₃CH₂COO- .</td><td></td><td></td><td></td>

<td></td><td> In</td><td> a further</td><td> embodiment,</td><td> Y</td><td> is</td>

<td></td><td> In</td><td> a further</td><td> embodiment,</td><td> Y</td><td> is</td>

<td></td><td> In</td><td> a further</td><td> embodiment,</td><td> Y</td><td> is</td>

<td> 15</td><td> In</td><td> a further</td><td> embodiment,</td><td> Y</td><td> is</td>

chosen from a bond, -CH₂~, CO or a bond.

-CH₂.

-ch₂ch₂coo- .

co.

In one embodiment, Z is phenyl unsubstituted or substituted by at least one substituent chosen from halogen, C₃_₁₀ heterocycle, C₃_₁₀ heterocycle-COOCH₃, NO₂, CN, CO-C₆.₁₂ aralkyl, COOC^ alkyl, Ο₃.₆ alkyl, 0-C^ alkyl, C₆.₁₂ aryl, O-C₆_₁₂ aryl, C₆_₁₂ aralkyl, O-C₆_₁₂aralkyl.

In another embodiment, Z is phenyl unsubstituted or substituted by at least one substituent chosen from Br, I, F, Cl, thiophene, thiazole, benzofuran, benzooaxazole,,furan-COOCH₃, thiopheneCOOCH₃, NO₂, CN-phenyl, chloro-benzoyl, difluoro-benzoyl, COmethyl-isoxazole substituted with chlorophenyl, dichlorobenzoyl, CH₃, CF₃CH₂, SO₂CH₃, OCH₃, OCH₂-fluoro-phenyl, 0-chlorophenyl, OCH₂-phenyl, benzyloxi.

In one embodiment, Z is furan unsubstitutéd or substituted by at least one substituent chosen from halogen, C₆.₁₂ aryl, C₃_₁₀heterocycle.

In another embodiment, Z is furan unsubstituted or substituted by at least one substituent chosen from Br, Cl-phenyl, CF₃CH₂phenyl, Br-phenyl, Cl-phenyl-CH₂CF₃, NO₂-phenyl, Cl-phenyl-Cl, Cl phenyl-F, ethyl benzoate, benzoic acid, F-phenyl-F, tolyl, F9

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 phenyl, benzofuran, thiazole, Cl-thiophene, methoxy-furan, pyridine.

In one embodiment, Z is thiophene unsubstituted or substituted 5 by at least one substituent chosen from halogen, C₆_₁₂ aryl, C₃_₁₀ heterocycle, nitro.

In another embodiment, Z is thiophene unsubstituted or substituted by at least one substituent chosen from Br, benzoic acid, ethyl benzoate, methyl benzoate, Cl-phenyl-Cl, Cl-phenylF, F-phenyl-F, F-phenyl, methoxy phenyl, tolyl, CN-phenyl, methyloxi-phenyl, trifluoromethyloxi-phenyl, trifluoromethylphenyl, S-CH₃-phenyl, benzofuran, thiazole, thiphene, Clthiophene, pyridine, pyridinyl, N0₂.

In one embodiment, Z is thiazole unsubstituted or substituted by at least one substituent chosen from halogen, C^g alkyl, NR₅R₅,

C₃_₁₀ heterocycle.

In another embodiment, Z is thiazole unsubstituted or substituted by at least one substituent chosen from Cl, CF₃CH₂, diethylamino, piperidine, piperazine-phenyl, piperazine-benzyl.

In another embodiment, Z is a C₆_₁₂ aryl chosen from naphthalene, anthraquinonyl.

In another embodiment, Z is a C₃.₁₀ heterocycle chosen from benzofuran, pyrazole, methyl oxazole, pyrrolidine, piperidine, pyridine, pyrrole, quinolinyl unsubstituted or substituted by at least one substituent chosen from chlorophenyl-ketone, dichlorophenoxy, chlorophenoxy, dichlorophenyl, COO-t-butyl, tolyl-sulfonyl, COO-benzyl, CF₃.

In another embodiment, Z is chosen from C_x_₆ alkyl, C₂_₆ alkenyl,

C₂_₆ alkynyl chosen from vinyl, allyl, methyl, propyl, propynyl, thiazole unsubstituted or substituted by at least one substituent chosen from benzofuran.

SUBSTITUTE SHEET (RULE 26)

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In one embodiment, the viral infection is chosen from Flavivirus infections .

In one embodiment, the Flavivirus infection is chosen from

Hepatitis C virus (HCV), bovine viral diarrhea virus (BVDV), hog cholera virus and yellow fever virus .

In one embodiment, the Flavivirus infection is Hepatitis C virus (HCV).

In further embodiments, the present invention provides;

A method for treating or preventing a Flaviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula (I) ·

A method for treating or preventing a Flaviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula (XV) :

<img file="CA2449999C_D0014.tif" />

A method for treating or preventing Flaviridae infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula (I) and at least one further antiviral agent.

A method for treating or preventing Flaviridae infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula (XV) and at least one further antiviral agent.

In one embodiment, the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.

SUBSTITUTE SHEET (RULE 26)

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In one embodiment,

PCT/CA02/00877 the antiviral agent is chosen from interferon (X and ribavirin.

In one embodiment, said compound of formulae (I) or (XV) and 5 said antiviral agent are administered sequentially.

In a further embodiment, said compound of formulae (I) or (XV) and said antiviral agent are administered simultaneously.

&gt; In further embodiments, the present invention provides a method for treating or preventing a Flaviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula (I).further comprising at least one additional agent chosen from immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.

In one embodiment, the additional agent is chosen from silybum marianum,. interleukine-12, amantadine, ribozyme, thymosin, Nacetyl cysteine or cyclosporin.

In a further embodiment, the additionnai agent are administered sequentially.

In still a further embodiment, said compound and said additionnai agent are administered simultaneously.

In a further embodiment, the Flaviviridae infection is hepatitis C (HCV).

In further embodiments, the present invention provides;

A pharmaceutical composition for treating or preventing a

Flaviviridae. viral infection comprising administering at least one compound according to formula (I), together with at least one pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition, further comprising one or more additional agent chosen from antiviral agent, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

In one embodiment, the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.

In one embodiment, the antiviral agent is chosen from interferon a and ribavirin.

In one embodiment, the additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, Nacetyl cysteine or cyclosporin.

In one embodiment, the Flaviviridae viral infection is hepatitis C viral infection (HCV).

In one embodiment, the present invention provides the use of a compound according to formula (I) for the manufacture of a medicament for treating or preventing a viral Flaviviridae infection in a host.

In one embodiment, the Flaviviridae infection is hepatitis C viral infection (HCV).

In one embodiment, the invention provides the use of a compound according to formula (I) for use in therapy.

In one embodiment, the present invention provides the use of a compound according to formula (I) for treating or preventing Flaviviridae viral infection in a host.

In one embodiment, the invention provides the use of a compound according to formula (I) for treating or preventing Flaviviridae viral infection in a host, further comprising one or more additional agent chosen from antiviral agent, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.

In one embodiment the antiviral agent is chosen from a viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor.

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

In a further embodiment, the antiviral agent is chosen from interferon a and ribavirin.

In a further embodiment, the additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine or cyclosporin.

In still a further embodiment, the compound of formula (I) and said additionnai agent are administered sequentially.

In still a further embodiment, the compound of formula (I) and said additionnai agent are administered simultaneously.

In a further embodiment, the Flaviviridea viral infection is hepatitis C viral infection (HCV).

In one embodiment, there is provided a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound having the formula (I):

^Ri R, z

I

R, (I) and pharmaceutically acceptable salts thereof, wherein, M is chosen from:

II

-s · (II)

<img file="CA2449999C_D0015.tif" />

(III] ο(VII)

<img file="CA2449999C_D0016.tif" />

S (IV)

CH(VIII)

<img file="CA2449999C_D0017.tif" />

(V) a bond (IX)

<img file="CA2449999C_D0018.tif" />

<img file="CA2449999C_D0019.tif" />

(VI)

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 wherein each R₆ is independently chosen from H or Ο₂_₆ alkyl;

A¹ is chosen from a bond, 0_χ_₆ alkyl, C₂_₆ alkenyl or C₂_₆ alkynyl;

A is chosen from COOR₅, CO-COOR₅, PO₃R₅R₅, SO₃R₅, tetrazole, CON(R₅)CH(R₅) -COOR_s, CONR₅R₅, CONR₅OH, wherein each R₅ is independently chosen from H or alkyl;

R_x, R₂ are independently chosen from Η, (/.θ alkyl, C₆.₁₂aryl, C₃.₁₀heterocycle, C₆_₁₂ aralkyl or C₃_₁₀ heteroaralkyl;

R₃ is chosen from C₆_₁₂aryl, C₃.₁₀ heterocycle, C₆.₁₂ aralkyl or C₃_₁₀15 heteroaralkyl;

Y is selected from the group consisting of:

<img file="CA2449999C_D0020.tif" />

<img file="CA2449999C_D0021.tif" />

O ; a bond (xii:

(XIII) (XIV)

Z is chosen from C_X__G alkyl, C₂_₆ alkenyl, C₂_₅ alkynyl, C₆.₁₄aryl, C₃heterocycle;

R₄ is chosen from H, halogen, CN, NO₂, alkyl, C₅_₁₂aryl, C₃_₁₀heterocycle, C₆.₁₂ aralkyl, C₃_₁₀ heteroaralkyl y NR₅R₅, SO₂CH₃, O-C^g alkyl, O-C₆_₁₂aryl, O-C₆_₁₂ aralkyl, COR₇, wherein each R₅ is independently chosen from H or Ο_χ_₆ alkyl, and R₇ is chosen from C₆.₁₂ aryl or C₃_₁₀ heterocycle.

In one embodiment, there is provided a method for inhibiting or 30 reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound having the formula (XV):

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 OH

PCT/CA02/00877

<img file="CA2449999C_D0022.tif" />

In one embodiment, there is provided a method for inhibiting or reducing the activity of viral polymerase in a host comprising administering a therapeutically effective amount of a compound having the formulae (I) or (XV), further comprising one or more viral polymerase inhibitor.

In one embodiment, polymerase.

the viral polymerase is a Flaviviridae viral

In'one embodiment, polymerase.

In one embodiment, the viral polymerase is a RNA-dependant RNAthe viral polymerase is

HCV polymerase.

In one embodiment, the invention provides a method for inhibiting or reducing the activity of viral helicase in a host comprising administering a therapeutically effective amount of a compound having the formula (I):

Ri

IVL z

I

R, \ ^R2

A^a1

Y (I) and pharmaceutically acceptable salts thereof, wherein,

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

<img file="CA2449999C_D0023.tif" />

WO 02/100846

M is chosen from:

PCT/CA02/00877

II

-S'

<img file="CA2449999C_D0024.tif" />

(II) (III)

S (IV) (V)

<img file="CA2449999C_D0025.tif" />

/

<img file="CA2449999C_D0026.tif" />

or₆

CH· a bond (VI) (VII) (viii;

(IX) wherein each R is independently chosen from H or C_x_₆ alkyl;

A¹ is chosen from a bond, C., alkyl, C alkenyl or C₂_₆ alkynyl;

A is chosen from COOR₅, CO-COOR_S, PO₃R₅R₅, SO₃R₅, tetrazole,

CON (R₅) CH (R_s) -COOR_s, CONR₅R₅, CONR₅OH, wherein each R₅ is independently chosen from H or C^ alkyl;

R_lZ R₂ are independently chosen from H, C₃_₆ alkyl, C₆_₁₂ aryl, C₃_₁₀heterocycle, C₆_₁₂ aralkyl or C₃_₁₀ heteroaralkyl;

R₃ is chosen from C₆.₁₂aryl, C₃.₁₀ heterocycle, C₆_₁₂ aralkyl or C₃_₁₀15 heteroaralkyl;

Y is selected from the group consisting of:

<img file="CA2449999C_D0027.tif" />

; a bond

O (XII) (XIII) (XIV)

Z is chosen from C^₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₆.₁₄aryl, C₃_₁₀heterocycle;

R₄ is chosen from H, halogen, CN, NO₂, C^ alkyl, C₆_₁₂aryl, C₃_₁₀heterocycle, C₆_₁₂ aralkyl, C₃.₁₀ heteroaralkyl, NR₅R₅, SO₂CH₃, O-C^ alkyl, O-C₆_₁₂ aryl, O-C₆_₁₂ aralkyl, COR₇,

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 wherein each R₅ is independently' chosen from H or C_x_₆ alkyl, and R₇ is chosen from C_S__X2 aryl or C₃__X0 heterocycle.

In one embodiment, the invention provides a method for 5 inhibiting or reducing the activity of viral helicase in a host comprising administering a therapeutically effective amount of a compound having the formula (XV):

<img file="CA2449999C_D0028.tif" />

In further embodiments;

The viral helicase is a flaviviridea helicase. The viral helicase is a HCV helicase.

In one embodiment, the invention provides the use of a compound according to formula (I) for inhibiting or reducing the activity of viral polymerase in a host.

In a further embodiment, the invention provides the use of a compound according to formula (I) for inhibiting or reducing the activity of viral polymerase in a host, further comprising one or more viral polymerase inhibitor.

In one embodiment, polymerase.

the viral polymerase is

Flaviviridae viral

In one embodiment, polymerase.

In one embodiment, the viral polymerase is

RNA-dependant RNAthe viral polymerase is

HCV polymerase.

In one embodiment, the invention provides the use of a compound according to formula (I) for inhibiting or reducing the activity of viral helicase in a host.

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

In one embodiment, the invention provides the usë ot a compound according to formula (I) for inhibiting or reducing the activity of viral helicase in a host, further comprising one or more viral helicase inhibitor.

In one embodiment, helicase.

the viral helicase is Flaviviridae viral

In one embodiment, the viral helicase is HCV helicase.

In one embodiment, the invention provides a combination comprising a compound according to formula (I) and one or more additionnai agent chosen from viral serine protease inhibitor, viral polymerase inhibitor and viral helicase inhibitor, immunomudulating agent, antioxydant agent, antibacterial agent or antisense agent.

In further embodiments ;

The additional agent is chosen from silybum marianum, interleukine-12, amantadine, ribozyme, thymosin, N-acetyl cysteine, cyclosporin, interferon a and ribavirin.

The combination of said compound and said additionnai agent is administered sequentially.

The combination of said compound and said additionnai agent is administered simultaneously.

In another embodiment, the Flavivirus infection is Hepatitis C virus.

It will be appreciated by those skilled in the art that the compounds of formula (I) can contain a chiral centre on the general formula (I). The compounds of formula (I) thus exist in the form of two different optical isomers (i.e. (+) or (-) enantiomers). All such enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention. The single optical isomer or enantiomer can be

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 obtained by method well known m“ tne art, sucn as' cnrrai HPLC, enzymatic resolution and chiral auxiliary.

In accordance with the present invention, the compounds of 5 formula (I) include:

(2s)-2-[(2,4-Dichloro-benzoyl)-(4-thiazol-2-yl-benzyl)-amino]-3 phenyl-propionic acid, compound #2 (2s)-2-[(4-Bromo-benzyl)-(2,4-dichloro-benzoyl)-amino]-3-phenyl 10 propionic acid, compound #3 (2s)-2-[(4-Benzofuran-2-yl-benzyl)-(2,4-dichloro-benzoyl) amino]-3-phenyl-propionic acid, compound #4 (2s)-2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #5 (2s)-2-[(4-Benzofuran-2-yl-benzyl)- (4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #6 (2s)-2-[(3-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #7 3-[(4-Iodo-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl) 20 amino]-3-thiophen-2-yl-propionic acid ethyl ester, compound #8 (2s)-2-[(3-Bromo-benzyl)-(2,4-dichloro-benzoyl)-amino]-3-phenyl propionic acid, compound #9 (2s)-2-[(3-Bromo-benzyl)-(2-chloro-benzoyl)-amino]-3-phenylpropionic acid, compound #10 (2s)-2-[(3-Benzofuran-2-yl-benzyl)-(2,4-dichloro-benzoyl) amino]-3-phenyl-propionic acid, compound #11 (2s)-2-[(2,4-Dichloro-benzoyl)-(4-iodo-benzyl)-amino]-3-phenylpropionic acid, compound #12 (2s)-2-[(3-Iodo-benzyl)-(4-methoxy-2,3,6-trimethyl30 benzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #13 (2s)-2-[(4-Bromo-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #14 (2s)-2-[(3-Bromo-benzyl)-(4-chloro-benzoyl)-amino]-3-phenylpropionic acid, compound #15 (2s)-2-[(4-Iodo-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #16 (2s)-2-[(3-Bromo-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #17

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s)-5-(4-{[(ls-l-Carboxy-2-phenyl-ethyl)-(4-methoxy-2,3,6trimethyl-benzenesulfonyl)-amino]-methyl}-phenyl)-furan-2carboxylic acid methyl ester, compound #18 (2s)-2-[(3-Bromo-benzyl)-(3,4-dichloro-benzoyl)-amino]-3-phenyl 5 propionic acid, compound #19 (2s)-2-[(3-Bromo-benzyl)-(2,4-dichloro-benzenesulfonyl)-amino]3-phenyl-propionic acid, compound #20 (2s)-3-(l-Benzyl-lh-imidazol-4-yl)-2-[(3-bromo-benzyl)-(2,4dichloro-benzoyl)-amino]-propionic acid, compound # 21 (2s)-2-{(3-Bromo-benzyl)- [ (2,4-dichloro-phenyl)-acetyl]-amino}3-phenyl-propionic acid, compound #22 (2s)-5-(4-{ [(Is-1-Carboxy-2-phenyl-ethyl)-(4-methoxy-2,3,6trimethyl-benzenesulfonyl)-amino]-methyl}-phenyl) -thiophene-2carboxylic acid methyl ester, compound #23 (2s)-2-[(2-Bromo-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #24 (2s)-2-[(3-Bromo-benzyl)-(4-chloro-phenoxycarbonyl)-amino]-3phenyl-propionic acid, compound #25 (2s)-2-[(4-Benzoyl-benzyl) -(4-methoxy-2,3,6-trimethyl20 benzenesulfonyl)-amino]-3-phenyl-propionic acid (2s)-Triethyl-ammonium; 2-[(3-benzofuran-2-yl-benzyl)-(4methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenylpropionate, compound #26

2- [Allyl-(4-chloro-2-iodo-benzoyl)-amino]-3-phenyl-propionic acid, compound #27 (2s)-2-[(3-Bromo-benzyl)-(2,4-dimethyl-benzoyl)-amino]-3-phenyl propionic acid, compound #28

3- (4-Benzofuran-2-yl-phenyl)-2-[(2,4-dichloro-benzoyl)-methylamino] -propionic acid, compound #29 (2s)-2-[(3-Bromo-benzyl) -(2,4-dichloro-benzyl)-amino]-3-phenylpropionic acid, compound #30 (2s)-2-[(3-Benzofuran-2-yl-benzyl)-(2,4-dimethyl-benzoyl)amino]-3-phenyl-propionic acid, compound #31 (2s)-2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethyl35 benzenesulfonyl)-amino]-3-(4-hydroxy-phenyl)-propionic acid, compound #32 (2s)-2-[(4-Benzofuran-2-yl-benzyl)-(2,4-dichloro-benzoyl)amino]-3-(4-hydroxy-phenyl)-propionic acid, compound #33

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s)-2-[(3-Bromo-benzyl)- (4-chloro-2-methyl-benzoyl)-amino]-3phenyl-propionic acid, compound #34 (2s)-2-[(3-Bromo-benzyl)- (4-chloro-2-iodo-benzoyl)-amino]-3phenyl-propionic acid, compound #35 (2s)-2-[(3-Bromo-benzyl)-(2-bromo-4-chloro-benzoyl)-amino]-3phenyl-propionic acid, compound #36 (2s)-2-{(3-Benzofuran-2-yl-benzyl)-[(2,4-dichioro-phenyl) acetyl]-amino]-3-phenyl-propionic acid, compound #37 (2s)-2-[(4-Benzofuran-2-yl-benzyl)-(2,4-dichioro-phenyl)-amino]

3-phenyl-propionic acid, compound #38 (2s)-2-[(2,4-Dichloro-benzoyl)-naphthalen-2-ylmethyl-amino]-3phenyl-propionic acid, compound #39 (2s)-2-[(2,4-Dichloro-benzoyl)-(9,10-dioxo-9,10-dihydroanthracen-2-ylmethyl)-amino]-3-phenyl-propionic acid, compound #40 (2s)-2-[[3-(3-Chloro-benzoyl)-benzyl]-(2,4-dichloro-benzoyl)amino]-3-phenyl-propionic acid, compound #41 (2s)-2-{(2,4-Dichloro-benzoyl)-[3-(2,4-difluoro-benzoyl) benzyl]-amino]-3-phenyl-prop!onio acid, compound # 42 (2s)-2-[{3-[3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carbonyl]benzyl]-(2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound # 43 (2s)-2-{(2,4-Dichloro-benzoyl)-[3-(2,4-dichloro-benzoyl)benzyl]-amino]-3-phenyl-propionic acid, compound #44 (2s) -2-[(3-Benzooxazol-2-yl-benzyl)-(2,4-dichloro-benzoyl)amino]-3-phenyl-propionic acid, compound #45 (2s)-2-[(3-Bromo-benzyl)- (4-chloro-2-ethyl-benzoyl)-amino]-3phenyl-propionic acid, compound #46 (2s)-2-[(4-Benzofuran-2-yl-benzyl) -(2,4-dichloro-benzoyl)30 amino]-3-cyclohexyl-propionic acid, compound #47 (2s)-2-[(3-Benzofuran-2-yl-benzyl)-(4-chloro-2-methyl-benzoyl)amino]-3-phenyl-propionic acid, compound #48 (2s)-2-[(3-Benzofuran-2-yl-benzyl)- (2-bromo-4-chloro-benzoyl) amino]-3-phenyl-propionic acid, compound #49 (2s)-2-[(3-Bromo-benzyl)-(4-chloro-2-vinyl-benzoyl)-amino]-3phenyl-propionic acid, compound #50 (2s)-2-[(2,4-Dichloro-benzoyl)-(3-fluoro-benzyl)-amino]-3phenyl-propionic acid, compound #51

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s) -2- [ (3-Chloro-benzyl) -(2,4-dichloro-benzoyl) -amino] -3phenyl-propionic acid, compound #52 (2S)-2-[(2,4-Dichloro-benzoyl)-(3-nitro-benzyl)-amino]-3-phenylpropionic acid, Compound #53 (2S)-2-[(3-Cyano-benzyl)-(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid, compound #54 (2s)-2-{(2-Chloro-benzoyl)- [5-(3-chioro-phenyl)-furan-2ylmethyl]-amino]-3-phenyl-propionic acid, compound #55 (2s)-2-((2,4-Dichloro-benzoyl)-[5-(3-trifluoromethyl-phenyl)10 furan-2-ylmethyl]-amino]-3-phenyl-propionic acid, compound #56 (2s)-2-[(5-Bromo-furan-2-ylmethyl) -(2,4-dichloro-benzoyl)amino]-3-phenyl-propionic acid, compound #57 (2s)-2-[(5~Benzofuran-2-yl-furan-2-ylmethyl)-(2,4-dichlorobenzoyl) -amino] -3 -phenyl -propionic acid, compound #58 (2s)-2-[[5-(4-Bromo-phenyl)-furan-2-ylmethyl]-(2,4-dichlorobenzoyl) -amino] -3 -phenyl -propionic acid, compound #59 (2s)-2-[[5-(2-Chloro-phenyl)-furan-2-ylmethyl]-(2,4-dichlorobenzoyl ) -amino] -3 -phenyl -propionic acid, compound #60 (2s)-2-[[5-(2-Chloro-5-trifluoromethyl-phenyl)-furan-220 ylmethyl]-(2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #61 (2s)-2-((2,4-Dichloro-benzoyl) -[5-(2-nitro-phenyl)-furan-2ylmethyl]-amino]-3-phenyl-propionic acid, compound #62 (3s)-3-{(2,4-Dichloro-benzoyl)-[5-(3-trifluoromethyl-phenyl)25 furan-2-ylmethyl]-amino]-4-phenyl-butyric acid, compound #63

2-((2,4-Dichloro-benzoyl)-[2-(3-nitro-phenyl)-thiazol-5ylmethyl]-amino]-3-phenyl-propionic acid, compound #64 (2s)-2-((2,4-Dichloro-benzoyl) -[5-(3,4-dichloro-phenyl)-furan-230 ylmethyl]-amino]-3-phenyl-propionic acid, compound #65 (2s)-2-[Benzofuran-2-ylmethyl-(2,4-dichloro-benzyl)-amino]-3phenyl-propionic acid, compound #66 (2s)-2-((2,4-Dichloro-benzoyl) -[5-(2,4-dichloro-phenyl)-furan-2ylmethyl]-amino]-3-phenyl-propionic acid, compound #67 (2s)-2-[(2-Bromo-4-chloro-benzoyl)- (5-bromo-furan-2-ylmethyl) ' amino]-3-phenyl-propionic acid, compound #68 (2s)-2-[[5-(3-Chloro-4-fluoro-phenyl)-furan-2-ylmethyl]-(2,4dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #69

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s) -2-[ [5- (4-Chloro-3-fluoro-phênÿlV-'furan-2-yïmethÿl] -(2,4dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #70 (2s)-2-[(5-Bromo-furan-2-ylmethyl)-(4-chloro-2-iodo-benzoyl) amino]-3-phenyl-propionic acid, compound #71 (2s)-2-(5-{[(Is-l-Carboxy-2-phenyl-ethyl)-(2,4-dichlorobenzoyl)-amino]-methyl)-furan-2-yl)-benzoic acid ethyl ester, compound #72 (2s)-2-(5-{[(1-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)amino]-methyl)-furan-2-yl)-benzoic acid, compound #73 (2s)-2-[(2,4-Dichloro-benzoyl)-(5-thiazol-2-yl-furan-2ylmethyl)-amino]-3-phenyl-propionic acid, compound #74 (2s)-2-[(2,4-Dichloro-benzoyl)-furan-2-ylmethyl-amino]-3-phenyl propionic acid, compound #75 (2s)-3-(5-{ [ (Is-IrCarboxy-2-phenyl-ethyl)-(2,4-dichloro15 benzoyl)-amino]-methyl)-furan-2-yl)-benzoic acid, compound #76 (2s)-4-(5 — { [ (ls-l-Carboxy-2-phenyl-ethyl)-(2,4-dichlorobenzoyl)-amino]-methyl}-fur an-2-yl)-benzoic acid , compound #77 (2s)-2-{(2-Bromo-4-chloro-benzoyl) -[5-(3-trifluoromethylphenyl)-furan-2-ylmethyl]-amino)-3-phenyl-propionic acid, compound #78 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(3,5-difluoro-phenyl)-furan-2 ylmethyl]-amino)-3-phenyl-propionic acid, compound #79 (2s)-2-[(2,4-Dichloro-benzoyl)- (5-m-tolyl-furan-2-ylmethyl)amino]-3-phenyl-propionic acid, compound #80 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(3-fluoro-phenyl)-furan-2ylmethyl]-amino)-3-phenyl-propionic acid, compound #81 (2s) -2-[(5-Bromo-thiophen-2-ylmethyl)-(2,4-dichloro-benzoyl) amino]-3-phenyl-propionic acid, compound #82 (2s)-4-(5-{[(Is-l-Carboxy-2-phenyl-ethyl)-(2,4-dichloro30 benzoyl)-amino]-methyl)-thiophen-2-yl)-benzoic acid, compound #83 (2s)-4-(5-{[(l-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)amino]-methyl}-thiophen-2-yl)-benzoic acid methyl ester, compound #84 (2s)-2-[(5-Benzofuran-2-yl-thiophen-2-ylmethyl)-(2,4-dichlorobenzoyl) -amino] -3 -phenyl -propionic acid, compound #85 2-[(2-Benzofuran-2-yl-thiazol-5-ylmethyl)-(2,4-dichlorobenzoyl) -amino] -3 -phenyl -propionic acid, compound #86

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s) -2-{ (2,4-Di chloro-benz oyl) -'[4-’(3,4-di chi or o-phenyl ) thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #87 (2s)-2-[[4-(4-Chloro-3-fluoro-phenyl)-thiophen-2-ylmethyl]-(2,4 5 dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #88 (2s)-2-[[4-(3-Chloro-4-fluoro-phenyl)-thiophen-2-ylmethyl]-(2,4 dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #89 (2s)-2-{(2,4-Dichloro-benzoyl)-[4-(2,4-dichioro-phenyl) thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #90 (2s)-2-[[5-(3-Chloro-4-fluoro-phenyl)-thiophen-2-ylmethyl]-(2,4 dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #91 (2s)-2-[[5-(4-chloro-3-fluoro-phenyl)-thiophen-2-ylmethyl]-(2,4 dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #92 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(2,4-dichloro-phenyl)thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #93 (2s)-2-[(2,4-Dichloro-benzoyl)-(5-thiazol-2-yl-thiophen-2ylmethyl)-amino]-3-phenyl-propionic acid, compound #94 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(3,5-difluoro-phenyl) thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #95 (2s)-2-{ (2,4-Dichloro-benzoyl)-[5-(3-methoxy-phenyl)-thiophen-2 ylmethyl]-amino}-3-phenyl-propionic acid, compound #96 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(3-fluoro-phenyl)-thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid, compound #97 (2s)-2-[(2,4-Dichloro-benzoyl)-thiophen-2-ylmethyl-amino]-3phenyl-propionic acid, compound #98 (2s)-2-[(4-Bromo-thiophen-2-ylmethyl)-(2,4-dichloro-benzoyl) 30 amino]-3-phenyl-propionic acid, compound #99 (2s)-2-{(2,4-Dichloro-benzoyl)-[2-(4-phenyl-piperazin-1-yl) thiazol-5-ylmethyl]-amino}-3-phenyl-propionic acid, compound #100 (2s)-1-(5-{[(ls-l-Carboxy-2-phenyl-ethyl)-(2,4-dichloro35 benzoyl)-amino]-methyl}-thiazol-2-yl)-piperidine-4-carboxylic acid, compound #101 (2s)-2-[[2-(4-Benzyl-piperazin-l-yl)-thiazol-5-ylmethyl]-(2,4dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #102

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s)-2-[(2,4-Dichloro-benzoyl)-(2-piperidin-l-yl-thiazol-5ylmethyl)-amino]-3-phenyl-propionic acid, compound #103 (2s)-2-[(2,4-Dichloro-benzoyl) -(2-diethylamino-thiazol-5ylmethyl)-amino]-3-phenyl-propionic acid, compound #104 (2s)-2-[[2-(4-Chloro-benzoyl)-benzofuran-3-ylmethyl]-(4-methoxy2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid, compound #105 (2s)-2-[[5-(2,4-Dichloro-phenoxy)-l-methyl-3-trifluoromethyl-Ihpyrazol-4-ylmethyl]-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl) 10 amino]-3-phenyl-propionic acid, compound #106 (2s)-2-((2,4-Dichloro-benzoyl)-{2-[5-(2,4-dichloro-phenyl)furan-2-yl]-2-oxo-ethyl}-amino)-3-phenyl-propionic acid, compound #107 (2s)-2-Benzyl-4-(2,4-dichloro-phenyl)-3-[3-(2,6-dichloro15 phenyl)-5-methyl-isoxazol-4-ylmethyl]-4-oxo-butyric acid, compound #108 (2s)-2-[Allyl-(2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #109 (2s)-2-[(2,4-Dichloro-benzoyl)-methyl-amino]-3-phenyl-propionic acid, compound #110 (2s)-2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenylpropionic acid, compound #111 (2s)-2-[(2,4-Dichloro-benzoyl)-propyl-amino]-3-phenyl-propionic acid, compound #112 (2s)-2-[(3-Benzofuran-2-yl-prop-2-ynyl) -(2,4-dichloro-benzoyl)amino]-3-phenyl-propionic acid, compound #113 (2s)-2-[(4-Benzofuran-2-yl-phenyl)-(2,4-dichloro-benzoyl)amino]-3-phenyl-propionic acid, compound #114 (2s)-2-[(2,4-Dichloro-benzoyl)-(3-methyl-but-2-enyl)-amino]-330 phenyl-propionic acid, compound #115

2- [(2-Bromo-allyl)-(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid, compound #116

3- {[(l-Carboxy-2-phenyl-ethyl) -(2,4-dichloro-benzoyl)-amino]methyl]-benzoic acid methyl ester, compound #117

3-[[5-(3-Chloro-4-fluoro-phenyl)-thiophen-2-ylmethyl]-(2,4dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid, compound #118

2-[[5-(3-Cyano-phenyl)-furan-2-ylmethyl]-(2,4-dichloro-benzoyl)amino]-3-phenyl-propionic acid, compound #119

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s)-2-{(2,4-Dichloro-benzoyl)- [5-(2-trifluoromethyl-phenyl)furan-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #120 (2s)-2-(5-{[(Is-1-Carboxy-2-phenyl-ethyl)-(2,4-dichlorobenzoyl)-amino]-methyl}-thiophen-2-yl)-benzoic acid ethyl ester, compound #121

3—(5—{[(Is-1-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl) amino]-methyl}-thiophen-2-yl)-benzoic acid ethyl ester, compound #122 (2s)-2-[[5-(3-Chloro-phenyl)-furan-2-ylmethyl]-(2,4-dichloro10 benzoyl)-amino]-3-phenyl-propionic acid, compound #123 (2s)-2-[(4-Chloro-2-iodo-benzoyl)-(3,5-dibromo-thiophen-2ylmethyl)-amino]-3-phenyl-propionic acid, compound #124 (2s)-3-(5-{[(1-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)amino]-methyl}-thiophen-2-yl)-benzoic acid, compound #125 (2s)-2-[[5-(5-Chloro-thiophen-2-yl)-furan-2-ylmethyl]-(2,4dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #126 (2s)-2-[[2,2’]Bithiophenyl-5-ylmethyl-(2,4-dichloro-benzoyl) amino]-3-phenyl-propionic acid, compound #127 (2s)-2-[(5'-Chloro-[2,2']bithiophenyl-5-ylmethyl)-(2,4-dichloro20 benzoyl)-amino]-3-phenyl-propionic acid, compound #128 (2s)-2-{(2,4-Dichloro-benzoyl) -[4-(3,5-difluoro-phenyl) thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #129 (2s)-2-{(2,4-Dichloro-benzoyl)-[4-(3-fluoro-phenyl)-thiophen-225 ylmethyl]-amino}-3-phenyl-propionic acid, compound #130 (2s)-2-{(4-Chloro-2-iodo-benzoyl)-[5-(3-trifluoromethyl-phenyl)furan-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #131 (2s)-2-{(4-Chloro-2-methyl-benzoyl)-[5-(3-trifluoromethylphenyl)-furan-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #132 (2s)-2- [ (5-Chloro-[2,3']bithiophenyl-5'-ylmethyl)-(2,4-dichlorobenzoyl )-amino]-3-phenyl-propionic acid, compound #133 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(4-methoxy-phenyl)-furan-2ylmethyl]-amino}-3-phenyl-propionic acid, compound #134 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(4-methoxy-phenyl)-thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid, compound #135 (2s)-2-{(2,4-Dichloro-benzoyl)-[4-(4-methoxy-phenyl)-thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid, compound #136

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s)-2-[(2,4-Dichloro-benzoyl)-('5-pyridin-4-yl-furan-2ylmethyl)-amino]-3-phenyl-propionic acid, compound #137 (2s)-2-[(2,4-Dichloro-benzoyl)-(5-pyridin-4-yl-thiophen-2ylmethyl)-amino]-3-phenyl-propionic acid, compound #138 (2s)-2-[(2,4-Dichloro-benzoyl) -(4-pyridin-4-yl-thiophen-2ylmethyl)-amino]-3-phenyl-propionic acid, compound #139 (2s)-2-[(2-Chloro-thiazol-5-ylmethyl)-(2,4-dichloro-benzoyl)amino]-3-phenyl-propionic acid, compound #140 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(4-fluoro-phenyl)-thiophen-210 ylmethyl]-amino]-3-phenyl-propionic acid, compound #141 (2s)-2-[(2,4-Dichloro-benzoyl)-(3,5-dichloro-benzyl)-amino]-3phenyl-propionic acid, compound #142 (2s)-2-[(2,4-Dichloro-benzoyl)-thiophen-3-ylmethyl-amino]-3phenyl-propionic acid, compound #143 (2s)-2-[(2,4-Dichloro-benzoyl)-(3-trifluoromethyl-benzyl)amino]-3-phenyl-propionic acid, compound #144 (2s)-2-[[3-(3-ChlorO-4-fluoro-phenyl)-thiophen-2-ylmethyl]-(2,4 dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #145 (2s)-2-[(3-Bromo-thiophen-2-ylmethyl)-(2,4-dichloro-benzoyl)20 amino]-3-phenyl-propionic acid, compound #146 (2s)-2-{(2,4-Dichloro-benzoyl)-[5-(3-trifluoromethyl-phenyl) furan-2-ylmethyl]-amino]-2-methyl-propionic acid, compound #147 (2s)-2-{(2,4-Dichloro-benzoyl) -[2-(3-trifluoromethyl-phenyl)thiazol-5-ylmethyl]-amino]-3-phenyl-propionic acid, compound #148 (2s)-2-[(2,4-Dichloro-benzoyl)- (5-nitro-thiophen-3-ylmethyl) amino]-3-phenyl-propionic acid, compound #149 (2s)-2-[(2,4-Dichloro-benzoyl)- (4-methanesulfonyl-benzyl) amino]-3-phenyl-propionic acid, compound #150 (2s)-2-[(2,4-Dichloro-benzoyl)-(3-methoxy-benzyl)-amino]-3phenyl-propionic acid, compound #151 (2s)-2-[(2,4-Dichloro-benzoyl) -(3-methyl-benzyl)-amino]-3phenyl-propionic acid, compound #152 (2s)-2-[[5-(3-Chloro-phenoxy)-l-methyl-3-trifluoromethyl-lh35 pyrazol-4-ylmethyl]-(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid, compound #153 (2s)-2-{(2,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl) thiophen-2-ylmethyl]-amino]-3-phenyl-propionic acid, compound #154

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 (2s)-2-{(2,4-Dichloro-benzoyl)-[3-(3,4-dichioro-phenyl) thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #155 (2s)-2-[[3-(4-Chloro-3-fluoro-phenyl)-thiophen-2-ylmethyl]-(2,45 dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #156 (2s)-2-{(2,4-Dichloro-benzoyl)-[3-(2,4-dichloro-phenyl)thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #157 (2s)-2-[(2,4-Dichloro-benzoyl)-(3-m-tolyl-thiophen-2-ylmethyl)10 amino]-3-phenyl-propionic acid, compound #158 (2s)-2-(2-{[(Is-l-Carboxy-2-phenyl-ethyl)-(2,4-dichlorobenzoyl) -amino]-methyl}-thiophen-3-yl)-benzoic acid ethyl ester, compound #159 (2s)-4-(2-{[(Is-1-Carboxy-2-phenyl-ethyl) -(2,4-dichloro15 benzoyl)-amino]-methyl}-thiophen-3-yl)-benzoic acid ethyl ester, compound #160 (2s ) -2.-{ (2,4-Dichloro-benzoyl ) - [3- ( 3-f luoro-phenyl ) - thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid, compound #161 ¹(2s)-2-[[3-(3-Cyano-phenyl)-thiophen-2-ylmethyl]-(2,4-dichloro20 benzoyl)-amino]-3-phenyl-propionic acid, compound #162 {(2,4-Dichloro-benzoyl)-[5-(3-trifluoromethyl-phenyl)-furan-2ylmethyl]-amino}-thiophen-2-yl-acetic acid, compound #163 L-2-{[(l-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)-amino]methyl}-pyrrolidine-l-carboxylic acid #tert!-butyl ester, compound #164 d-2 - {[(l-carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)-amino]methyl}-pyrrolidine-l-carboxylic acid #tert!-butyl ester, compound #165

4-[(l-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)-amino]30 piperidine-l-carboxylic acid benzyl ester, compound #166

1- 2-[(2,4-Dichloro-benzoyl)-pyrrolidin-2-ylmethyl-amino]-3phenyl-propionic acid, compound #167 d-2-[(2,4-Dichloro-benzoyl)-pyrrolidin-2-ylmethyl-amino]-3phenyl-propionic acid, compound #168

3-(5-Bromo-thiophen-2-yl)-2-[(2,4-dichloro-benzoyl)-methylamino] -propionic acid, compound #169

2- [(2,4-Dichloro-benzoyl)-pyridin-3-ylmethyl-amino]-3-phenylpropionic acid, compound #170

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

2-[(2,4-Dichloro-benzoyl)-(4-trifluoromethyl-benzyl)-amino]-3phenyl-propionic acid, compound #171

2-((2,4-Dichloro-benzoylA [4-(4-fluoro-benzyloxy)-benzyl]amino}-3-phenyl-propionic acid, compound #172

2-[(2,4-Dichloro-benzoyl)- (4-fluoro-3-trifluoromethyl-benzyl) amino]-3-phenyl-propionic acid, compound #173 2-[(l-Benzenesulfonyl-lh-pyrrol-2-ylmethyl) -(2,4-dichlorobenzoyl)-amino]-3-phenyl-propionic acid, compound #174 2 — [ [3 — (4-Chloro-phenoxy) -benzyl] -(2,4-dichloro-benzoyl) '-amino] 10 3-phenyl-propionic acid, compound #175

2-[(5-Chloro-2-chloromethyl-hepta-2,4,6-trienoyl)-quinolin-3ylmethyl-amino]-3-phenyl-propionic acid, compound #176 2-[(2-Benzyloxy-benzyl)-(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid, compound #177

2-((2,4-Dichloro-benzoyl)-[3-(5-isopropyl-2-methoxy-phenyl)thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #178

2-((2,4-Dichloro-benzoyl) -(3-(4-trifluoromethoxy-phenyl) thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #179

2-((2,4-Dichloro-benzoyl)-[3-(3-trifluoromethyl-phenyl) thiophen-2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #180

2-[[3-(3,5-Bis-trifluoromethyl-phenyl)-thiophen-2-ylmethyl]25 (2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid, compound #181

2-[(2,4-Dichloro-benzoyl) - (3-pyridin-4-yl-thiophen-2-ylmethyl)amino]-3-phenyl-propionic acid, compound #182

2-((2,4-Dichloro-benzoyl) -[3-(4-methylsulfanyl-phenyl)-thiophen

2-ylmethyl]-amino}-3-phenyl-propionic acid, compound #183

2-((2,4-Dichloro-benzoyl) -[3-(4-fluoro-phenyl)-thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid, compound #184 2-[(2,4-Dichloro-benzoyl)- (3-pyridin-3-yl-thiophen-2-ylmethyl)amino]-3-phenyl-propionic acid, compound #185

2-((2,4-Dichloro-benzoyl) -[1-(toluene-2-sulfonyl)-pyrrolidin-2ylmethyl]-amino}-3-phenyl-propionic acid, compound #186 2-[(2-Bromo-benzyl) -(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid, compound #187

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

3-(2-Bromo-phenyl)-2-[(2,4-dichloro-benzoyl)-methyl-amino]propionic acid, compound #188

3-(4-Bromo-phenyl)-2-[(2,4-dichloro-benzoyl)-methyl-amino]propionic acid, compound #189

2-[(3-Bromo-phenyl) -(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid, compound #190

2-[(4-Bromo-phenyl)-(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid, compound #191

2- [[4-(3-Chloro-4-fluoro-phenyl)-thiophen-2-ylmethyl]-(2,410 dimethyl-benzoyl)-amino]-3-phenyl-propionic acid, compound #192

3- {[(l-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)-amino]methyl}-benzoic acid, compound #193

2-[(3-Amino-benzyl)-(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid, compound #194

3-Phenyl-2-{(2-trifluoromethyl-benzoyl) -[5-(2-trifluoromethylphenyl)-furan-2-ylmethyl]-amino}-propionic acid, Compound #195 2-{(3-Cyano-benzoyl)-[5-(2-trifluoromethyl-phenyl)-furan-2ylmethyl]-amino}-3-phenyl-propionic acid, Compound #196 2-{(4-Nitro-benzoyl)-[5-(2-trifluoromethyl-phenyl)-furan-220 ylmethyl]-amino}-3-phenyl-propionic acid, Compound #197

2-{(2-Fluoro-benzoyl)-[5-(2-trifluoromethyl-phenyl)-furan-2ylmethyl]-amino}-3-phenyl-propionic acid, Compound #198

2-[Benzyl-(2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid

Compound #199

2- {(2,4-DICHLORO-BENZOYL) -[3- (2H-TETRAZOL-5-YL)-BENZYL]-AMINO}3- PHENYL-PROPIONIC ACID Compound #200

2-[(2,4-DICHLORO-BENZOYL)-(2-NITRO-BENZYL)-AMINO]-3-PHENYLPROPIONIC ACID Compound #201

2-[(2,4-DICHLORO-BENZOYL)-(4-NITRO-BENZYL)-AMINO]-3-PHENYLPROPIONIC Compound #202 ³⁵

2-[(2-CYANO-BENZYL)-(2,4-DICHLORO-BENZOYL)-AMINO]-3-PHENYLPROPIONIC ACID Compound #203

2-[(4-CYANO-BENZYL)-(2,4-DICHLORO-BENZOYL)-AMINO]-3-PHENYL40 PROPIONIC ACID Compound #204

SUBSTITUTE SHEET (RULE 26)

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WO 02/100846 PCT/CA02/00877

2- [[1-(3-CYANO-PHENYL)-ETHYL]-(2,4-DICHLORO-BENZOYL)-AMINO]-3PHENYL-PROPIONIC ACID Compound #205

3-{[(l-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)-amino]methyl]-benzoic acid methyl ester Compound #206

3- {[(l-Carboxy-2-phenyl-ethyl)-(2,4-dichloro-benzoyl)-amino]methyl]-benzoic acid Compound #207

2-[(2,4-DICHLORO-BENZOYL)- (3-METHANESULFONYL-BENZYL)-AMINO]-3PHENYL-PROPIONIC ACID Compound #208

2-[(3-ACETYL-BENZYL)-(2,4-DICHLORO-BENZOYL)-AMINO]-3-PHENYL15 PROPIONIC ACID Compound #209

2-[(2,4-DICHLORO-BENZOYL)- (1-OXY-PYRIDIN-3-YLMETHYL)-AMINO]-3PHENYL-PROPIONIC ACID Compound #210

2 — &lt;(2_z4-Dichloro-benzoyl) -[5-(3-trifluoromethyl-phenyl)thiophen-2-ylmethyl]-amino]-3-phenyl-propionic acid Compound #211.

Preferably, the compounds of the present invention are provided in the form of a single enantiomer at least 95%, more preferrably at least 97% and most preferably at least 99% free of the corresponding enantiomer.

More preferably the compound of the present invention is in the form of the (+) enantiomer at least 95% free of the corresponding (-) enantiomer.

More preferably the compound of the present invention is in the form of the (+) enantiomer at least 97% free of the corresponding (-) enantiomer.

More preferably the compound of the present invention is in the form of the (+) enantiomer at least 99% free of the corresponding (-) enantiomer.

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2010-10-29

In a more preferred embodiment, the compound of the present invention is in the form of the (-) enantiomer at least 95% free of the corresponding (+) enantiomer.

Most preferably the compound of the present invention is in the form of the (-) enantiomer at least 97% free of the corresponding (+) enantiomer.

More preferably the compound of the present invention is in the form of the (-) enantiomer at least 99% free of the corresponding (+) enantiomer.

There is also provided a pharmaceutically acceptable salts of the present invention. By the term pharmaceutically acceptable salts of compounds of general formula (I) are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR-4+ (where R is C]__4 alkyl) salts.

Reference hereinafter to a compound according to the invention includes compounds of the general formula (I) and their pharmaceutically acceptable salts.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

CA 02449999 2010-10-29

In case of conflict, the present specification, including definition, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

As used in this application, the term alkyl represents an unsubstituted or substituted (by a halogen, nitro, SO₃R₄, PO₃R₄R₄, CONH₂, COOH, SR₅, 0-C_x_₆ alkyl, O-C₂_₆ alkenyl, O-C₂_₆ alkynyl, C_s.₁₂aryl, C₃_₁₀ heterocycle, hydroxyl, amino, NR₄R₄, or COOQ, wherein Q is Ο₃_₆ alkyl; C₂_₆ alkenyl; C₂.₆ alkynyl, C ₆_₁₂ aryl and R₄ is H, C _x._salkyl) straight chain, branched chain or cyclic hydrocarbon moiety (e.g. isopropyl, ethyl, fluorohexyl or cyclopropyl). The term alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an halogen, more preferably , the halogen is fluoro (e.g. CF₃- or CF₃CH₂-).

The terms alkenyl and alkynyl represent an alkyl containing at least one unsaturated group (e.g. allyl, acetylene, ethylene).

The term aryl represents a carbocyclic moiety which may be substituted (by Η, Ο₃.₆ alkyl, C₂._s alkenyl, C₂_₆ alkynyl, C₃.₈heterocycle, halogen, nitro, aminoamidino, amidino, guanido,

CONH₂, COOH, O-C_w alkyl, O-C₂.₆ alkenyl, O-C₂_₆ alkynyl, SCH₃, SO₂CH₃, amino, NR₄R₄, hydroxyl or COOQ, wherein Q is C_x_₆ alkyl, C₂_₆alkenyl, a C₂.₆ alkynyl) and containing at least one benzenoidtype ring (e.g., phenyl, naphthyl and anthraquinonyl).

The term aralkyl represents an aryl group attached to the adjacent atom by a C^alkyl, C^alkenyl, or C^alkynyl ( e. g. , benzyl).

The term heterocycle represents a mono or di-substituted (e.g. by a C_x_₆ alkyl,Ο- C_x_₆ alkyl, O-C₆__l2 aryl, C_s„₁₂ aryl, C₆.₁₂ aralkyl, C₃_ ₁₀ heterocycle,, halogen, amino, COOH, COOR_S or N0₂ ; wherein R_s is a C_x_₆ alkyl) , or unsubstituted, saturated or unsaturated, cyclic moiety wherein said cyclic moeity is interrupted by at least one heteroatom, e.g. oxygen, sulfur or· nitrogen. It is. understood that the term heterocyclic ring represents a mono or polycyclic (e.g., bicyclic) ring. Examples of heterocyclic rings include

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 but are not limited to epoxide; furan; benzofuran; isobenzofuran; oxathiolane; dithiolane; dioxolane; pyrrole; pyrrolidine; imidazole; pyridine; pyrimidine; indole; piperidine; morpholine; thiophene and thiomorpholine.

The term heteroaralkyl represents an heterocycle group attached to the adjacent atom by a C_x_₆ alkyl, C_x.₆ alkenyl, or C_x_₆alkynyl(e.g., thiophenyl) .

When there is a sulfur atom present, the sulfur atom can be at different oxidation levels, ie. S, SO, or SO₂. All such oxidation levels are within the scope of the present invention.

The term independently means that a substituent can be the same or different definition for each item.

It will be appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition for which treatment is required and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, preferably in the range of 0.5 to 60 mg/kg/day, most preferably in the range of 1 to 20 mg/kg/day.

The desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.

The compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.

Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75μΜ, preferably about 2 to 50 μΜ, most preferably

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 about 3 to about 30 μΜ. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution’of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 500 mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.

While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), ¹ transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Pharmaceutical formulation suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion. The active ingredient may also be

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form .of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, nonaqueous vehicles (which may include edible oils), or preservatives .

The compounds according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain' formulatory agents such as suspending, stabilizing an/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

For topical administration to the epidermis, the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Such transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents .

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier..

Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops. Drops may be formulated with an aqueous or nonaqueous base also comprising one more dispersing agents, solubilising agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs .

For administration by inhalation the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of'a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

When desired the above described formulations adapted to give sustained release of the active ingredient may be employed.

The compounds of the invention may also be used in combination with other antiviral agents.

In one aspect of the invention, the compounds of the invention 15 may be employed together with at least one other antiviral agent chosen from protease inhibitors, polymerase inhibitors, and helicase inhibitors .

In another aspect of the invention, the compounds of the 20 invention may be employed together with at least one other antiviral agent chosen from Interferon-α and Ribavirin.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier therefore comprise a further aspect of the invention.

The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When the compound (I) or a pharmaceutically acceptable salts thereof is used in combination with a second therapeutic agent active against the same virus the dose of each compound may be either the same as or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

The following general schemes and examples are provided to illustrate various embodiments of the present invention and shall not be considered as limiting in scope.

General scheme 1 for the preparation of biaryl carboxamide analogs with a five membered ring

<img file="CA2449999C_D0029.tif" />

Legend:

X=0, S, N

Y=N

X1=N, O or S for five-membered heterocycles L=CI, Br, I, NR1R2

A1 ,A2=substituents, F, Cl, OMe, CH3, CN M=Zn, B, Sn

The following compounds were prepared in a similar manner as described in general scheme 1:

compound #38 Compound #59 15 compound #64 Compound #69 compound #74 compound #79 compound #84 20 #compound #90 #94 compound #99 compound compound #104 #113 compound 25 compound #124 #128 compound compound #133 #137 compound compound #142 30 compound #146 compound #55 compound #56 Compound #57 Compound #58 compound #60 compound #61 compound #62 compound #63 compound #65 compound #66 compound #67 compound #68

Compound #70 Compound #71 compound #72 compound #73

Compound #75 Compound #76 compound #77 compound #78 compound #compound #81 compound #82 compound #83 compound #85 compound #87 compound #88 compound compound #91 compound #92 compound #93 compound #95 compound #96 compound #compound #98 compound #100 compound #101 compound #102 compound #103 compound #105 compound #106 compound #107 compound #120 compound #121 compound #122 compound #123 compound #125 compound #126 compound #127 compound #129 compound #130 compound #131 compound #132 compound #134 compound #135 compound #136 compound #138 compound #139 compound #140 compound #141 Bcompound #143 compound #144 compound #145 compound #147 compound #148 compound #149 compound

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 #150 compound #151 compound #152 compound #153 compound #154 compound #155 compound #156 compound #157 compound #158 compound #159 compound #160 compound #161 compound #162 compound #163 compound #164 compound #165 compound #166 compound #167 compound #168 compound #169 compound #170 compound #171 compound #172 compound #173 compound #174 compound #175 compound #176 compound #177 compound #178 compound #179 compound #180 compound #181 compound #182 compound #183 compound #184 compound #185 compound #186 compound #187 compound #188 compound #189 compound #190 compound #191

Example 1

2-{(2 ,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl)-thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid compound #154

STEP I

2-[(3-Bromo-thiophen-2-ylmethyl)-amino]-3-phenyl-propionic acid tent-butyl ester

<img file="CA2449999C_D0030.tif" />

To a stirred solution of 2-Amino-3-phenyl-propionic acid tentbutyl ester (50.6mg, 0.229 mmol) in ethanol (1 mL·), were added 3-Bromo-thiophene-2-carbaldehyde (50mg, 0.208mmol.) and acetic acid (21 μΒ). The reaction mixture was stirred at room temperature under nitrogen for 2 hrs as the progress of imine formation was monitored by TLC. Then, sodium cyanoborohydride (20mg, 0.312 mmol) was added. The mixture was acidified with sodium bicarbonate and then extracted with dichloromethane.

After removal of the solvent, the crude product was purified by silica plate (hexane/ethylacetate 90%:10%) to give 2-[(3-Bromo30 thiophen-2-ylmethyl)-amino]-3-phenyl-propionic acid tent-butyl ester in 80% yield : ^XH NMR (Varian 400MHz, CDC1₃) δ7.23 (m, 6H, ArH), 6.90 (d, 1H, J=5.3Hz, thiophenH), 4.00 (d, 1H, J=14.6Hz, NCH₂) , 3.85 (d, 1H, J=14.6Hz, NCH₂) , 3.48 (m, 1H, CHCH₂) , 3.00 (m, 2H, CHCHJ, 1.37 (s, 9H, tBu) .

STEP II

2- [(3-Bromo-thiophen-2-ylmethyl)-(2,4-dichloro-benzoyl)-amino]3- phenyl-propionic acid tent-butyl ester

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846

<img file="CA2449999C_D0031.tif" />

<img file="CA2449999C_D0032.tif" />

To a stirred solution of 2-[(3-Bromo-thiophen-2-ylmethyl) 5 amino]-3-phenyl-propionic acid tert-butyl ester (91.6mg, 0.231mmol) in dichloromethane (3.3ml) and N,Ndiisopropylethylamine (44μ1) was added a solution of 2,4Dichloro-benzoyl chloride (34μ1, 0.243 mmol) in dichloromethane (1.3ml). The reaction mixture was stirred at room temperature under nitrogen overnight. Then, the mixture was extracted with sodium bicarbonate/dichloromethane. The extract was dried (sodium sulfate) and evaporated' under reduced pressure to yield

2- [(3-Bromo-thiophen-2-ylmethyl)-(2,4-dichloro-benzoyl)-amino]3- phenyl-propionic acid tert-butyl ester with 92% yield. ^XH

NMR(Varian 400MHz, CDC1₃) δ (ppm) presence of rotomers 8.08 (d, 0.5H, J=8.7Hz, ArH), 7.56 (d, 0.5H, J=2.0Hz, ArH), 7.40 (m, 2H, ArH), 7.23 (m, 2.5H, ArH), 6.99 (d, 0.5H, J=5.4Hz, ArH), 6.92 (m, 2H, ArH), 6.83 (d, 0.5H, J=5.0Hz, ArH), 6.54 (d, 1H,

J=7.lHz, ArH), 5.78, (d, 0.5H, J=8.0Hz, ArH), 5.20 (m, lH, NCH₂) ,

4.85 (m, 1H, NCH₂) , 4.16 (m, 1H, CHCH₂) , 3.10 (m, 2H, CHCH₂) , 1.47 (s, 9H, tBu).

STEP III

2-((2,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl)-thiophen-225 ylmethyl]-amino}-3-phenyl-propionic acid tert-butyl ester

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

<img file="CA2449999C_D0033.tif" />

PCT/CA02/00877

<img file="CA2449999C_D0034.tif" />

To 3 mL of THF solution of 2-[(3-Bromo-thiophen-2-ylmethyl)(2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid tert-butyl ester (50 mg, 0.0879mmol) was sequentially added tetrakis (triphenylphosphine)palladium(O) (lOmg, 0.00878 mmol). To the resulting brown solution was added a THF solution of 3, 5difluorozinc bromide ( 0.5M, 1.06 mL). The reaction was stirred and heated to reflux overnight. TLC showed complete conversion of the starting material to a less polar product. A few drop of acetic acid was added before complete removal of the solvent using a rotavap. The crude product was chromatographed to give 2-{(2,4-Dichloro-benzoyl) -[3-(3,5-difluoro-phenyl) -thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid tert-butyl ester, 37 mg, in 72% yield. ¹H NMR(Varian 400 MHz, CDC1₃) , ô(ppm), presence of rotomers, 7.45 (m, &lt;1H), 7.36 (s, &lt;1H), 7.20 (m, ~8H), 7.05 (m, &lt;1H) , 6.98 (m, 1H) , 6.90 (m, 4H) , 6.82 (m, &lt;1H) , 6.51 (m, &lt;1H), 5.80 (m, &lt;1H) , 5.20 (m, &lt;1H), 4.84 (m, &lt;1H), 4.18 (m, 2H),

3.38 (m, 2H), 2.90 (m, 1H), 1.33, 1.42, 1.44 (s, 9H).

STEP IV

2-{(2,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl) -thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid

<img file="CA2449999C_D0035.tif" />

<img file="CA2449999C_D0036.tif" />

To a stirred solution of 2-{(2,4-Dichloro-benzoyl)-[3-(3,5difluoro-phenyl)-thiophen-2-ylmethyl]-amino}-3-phenyl-propionic

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 acid tert-butyl ester (37.63 mg, 0.0625mmol.) in dichloromethane (lml.), was added trifluoroacetic acid (1ml.). The reaction mixture was stirred at room temperature during 1 hr. TLC monitored the progress of the reaction. When the reaction was completed, the mixture was concentrated under reduced pressure on a rotary evaporator, followed by silica chromatography using 90% ethylacetate, 10% methanol and 1 drop of acetic acid, afforded 2{(2,4-Dichloro-benzoyl)-[3-(3,5-difluoro-phenyl)-thiophen-2ylmethyl]-amino}-3-phenyl-propionic acid in 85% yield. ¹H NMR (Varian 400MHz, CDC1₃) ô(ppm), 7.22 (m, 8H, ArH) , 7.00 (m, 2H,

ArH), 6.82 (m, 2H, ArH), 6.50 (m, 1H, ArH), 4.95 (m, 0.5H, NCH₂) ,

4.65 (m, 0.5H, NCH₂) , 4.10 (m, 1H, NCH₂) , 3.60 (m, 1H, CHCH₂) , 3.20 (m, 1H, CHCH,), 3.05 (m, 1H, CHCH,) . MS, 546.00 found.

General scheme 2 for the preparation of biaryl carboxamide analogs with six membered aromatic ring

<img file="CA2449999C_D0037.tif" />

The following compounds were prepared in a similar manner as described in general scheme 2:

compound #2 , compound #, compound #4 , compound #9 , Compound #10 , Compound #11 , Compound #12 Compound#15, Compound #19 , compound #21 , compound #22 , compound #25 , compound #28 , Compound #, Compound #34 , Compound #35 , compound #37 , compound #39 , compound #, compound # 42 , compound # 43 , compound #44 , compound #31 compound #36 compound #41

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 compound #45 Compound #49

PCT/CA02/00877 compound #46 , compound #47 Compound #48 , compound #50 ,

General scheme 3 for the preparation of biaryl sulfonamide analogs with six membered aromatic ring spacer

Example 2

2-[(4-Benzofuran-2-yl-benzyl) -(4-methoxy-2,3,6-trimethylbenzenesulf onyl) -amino]-3--phenyl-propionic acid Compound #5

STEP I

2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-phenylpropionic acid methyl ester

<img file="CA2449999C_D0038.tif" />

A solution of L-phenylalanine methyl ester (300 mg, 1.68 mmol) in anhydrous CH₂C1₂ (10 mL) was cooled to 0°C in .an ice bath, then triethylamine (0.35 mL), 4-methoxy-2,3,6-trimethylbenzenesulf onyl chloride (438 mg, 1.76 mmol) and catalytic amount of DMAP (25 mg) were added under a N₂ atmosphere. The reaction mixture was stirred at room temperature'for 12h. After that period of time, the mixture was partitioned between water and CH₂C1₂, the organic layer was. separated, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3phenyl-propionic acid methyl ester as a white solid, 500 mg

<td> (77%;</td><td> 1 .</td><td> NMR</td><td> (CDC1₃, 400</td><td> MHz): δ7.26-7.18 (m, 3H), 7.02-6.99</td>

<td> 2H) ,</td><td> 6.53</td><td> (s,</td><td> 1H), 5.12</td><td> (d, 1H), 4.09-4.04 (m, 1H), 3.84 (s,</td>

<td> 3H) ,</td><td> 3.55</td><td> (S,</td><td> 3H), 3.05</td><td> (dd, 1H), 3.03 (dd, 1H), 2.64, 2.38,</td>

<td> 2.08</td><td> (3s,</td><td> 9H)</td><td> •</td><td></td>

<td> STEP</td><td> II</td><td></td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 • 2-[(4-Iodo-benzyl)-(4-methoxy-2,3,6-trimethyi-benzenesulfonyT) amino]-3-phenyl-propionic acid methyl ester

<img file="CA2449999C_D0039.tif" />

To a solution of 2-(4-Methoxy-2,3,6-trimethyl5 benzenesulfonylamino)-3-phenyl-propionic acid methyl ester (50 mg 0.129 mmol) in anhydrous DMF (1 mL), 4-iodobenzyl bromide (46 mg, 0.154 mmol) and cesium carbonate (50 mg, 0.154 mmol) were added and the reaction mixture was stirred at room temperature under a N₂ atmosphere for 12 h. The reaction mixture was partitioned between water and ether. The ether layer was separated, dried (Na₂SO₄) , concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(4-Iodo-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl) -amino]-3-phenyl-propionic acid methyl ester (68 mg, 90%) as a foam. ^XH NMR (CDC1₃, 400 MHz): 67.48 (d, 2H) , 7.21 (m, 3H), 7.09 (d, 2H), 6.91(d, 2H), 6.45 (s, 1H), 4.60 (m, 3H),

3.81 (s, 3H), 3.38 (s, 3H), 3.17 (dd, 1H), 2.81 (dd, 1H), 2.63, 2.44, 2.14 (3s, 9H).

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

PCT/CA02/00877

WO 02/100846

STEP III

2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl) -amino] -3-phenyl-propionic acid methyl ester.

<img file="CA2449999C_D0040.tif" />

<img file="CA2449999C_D0041.tif" />

To a degassed solution of 2-[(4-Iodo-benzyl) -(4-methoxy-2,3,6trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (40 mg, 0.068 mmol) and benzofuran-2-boronic acid (20 mg, 0.124 mmol) in a mixture of DME (3 mL) and 2M aqueous Na₂CO₃ (1.5 mL) , Pd(PPh₃)₄ (4 mg) was added and the reaction mixture was stirred at 65°C for 2h under a N₂ atmosphere. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (Na₂SO₄) , concentrated. The residue was purified by column chromatography using ethyl acetate and hexane (1:9) to obtain 2-[(4-Bénzofuran-2-yl-benzyl)-(4-methoxy15 2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (39 mg, 100%) as a thick syrup. ^ΧΗ NMR (af-2783) (CDC1₃, 400 MHz): δ7.2 (d, 2H) , 7.62 (d, 1H) , 7.55 (d, 1H) , 7.307.15 (m, 7H), 7.12 (d, 2H), 6.96 (s, 1H), 6.51 (s, 1H), 4.72 (m, 3H) , 3.80, 3.40 (2s, 6H), 3.28 (dd, 1H), 3.02 (dd, 1H) , 2.71,

2.58 , 2.12 ( 3s, 9H) .

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

PCT/CA02/00877

WO 02/100846

STEP IV

2-[(4-Benzofuran-2-yl-benzyl)~(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid.

’—o

<img file="CA2449999C_D0042.tif" />

2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (40 mg, 0.067 mmol) was taken in a mixture of THF:MeOH:H₂O (3:2:1) and then added IN aqueous solution of LiOH.H₂0 (0.40 mL·, 0.40 mmol). The reaction mixture was stirred at room temperature for

12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10 % KHSO₄ solution. The organic layer was separated, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and methanol (9:1) to obtain 2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-3-phenyl-propionic acid. (29 mg, 75%) as a white solid. lH NMR (CDC1₃, 400 MHz): δ7.59 (d, 2H) , 7.48 (d,

2H), 7.42 (d, 2H), 7.19 (m, 4H), 7.06, 6.88 (2m, 6H), 6.37 (s,

1H), 4.55 (m, 3H), 3.70 (s, 3H), 2.00, 1.98 (3s, 9H). ESI- (M-H):

3.19, 582 .

2.85 (2m, 2H), 2.56,

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

STEP V

2-[(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-(4tributylstannanyl-benzyl)-amino]-3-phenyl-propionic acid methyl ester,.

<img file="CA2449999C_D0043.tif" />

To a stirred solution of 2-[(4-Iodo-benzyl)-(4-methoxy-2,3,6trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (lg. 1.65mmol.) in toluene (100ml.) were added P(Ph₃)₄Pd (123 mg., 0.107mmol.) and 1,1,1,2,2,2-Hexabutyl-distannane (1.7ml. 3.3mmol.) under nitrogen. The reaction mixture was stirred and heated to 115²C during 8 hrs. The progress of the reaction was monitored by TLC. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by flash column chromatographic purification using 5% of EtOAc in hexane, afforded 2-[(4-Methoxy-2,3,6-trimethylbenzenesulfonyl)-(4-tributylstannanyl-benzyl)-amino]-3-phenylpropionic acid methyl ester in 50% yield: ¹HNMR (Varian 400MHz,

CDC1₃) d 7.30 (d, 2H, J=7.9Hz, HPhSn), 7.26 (m, 3H, HPh), 7.18 (d, 2H, J=7.0Hz, HPh), 7.14 (d, 2H, J=8.lHz, HPhI), 6.53 (s, 1H, MTRH) , 4.59 (m, 2H, NCH₂Ph) , 3.83 (s, 3H, OCH₃) , 3.26 (s, 3H, COOCH₃) , 3.18(dd, 1H, J=10.5 and 13.3Hz, CHCH₂) , 2.92 (dd, 1H, J=4.3 and 13.3Hz, CHCH₂) , 2.69 (s, 3H, ArCH₃) , 2.51 (s, 3H,

ArCH₃) , 2.11 (s, 3H, ArCH₃) , 1.00 (m, 27H, SnBu₃) ppm.

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

PCT/CA02/00877

WO 02/100846

STEP VI

5-(4-{[(l-Methoxycarbonyl-2-phenyl-ethyl)-(4-methoxy-2,3,6trimethyl-benzenesulfonyl)-amino]-methyl}-phenyl)-thiophene-2carboxylic acid methyl ester

<img file="CA2449999C_D0044.tif" />

To a stirred solution of 2-[(4-Methoxy-2,3,6-trimethylbenzenesulf onyl) -(4-tributylstannanyl-benzyl)-amino]-3-phenylpropionic acid methyl ester (lOOmg. 0.13mmol.) in toluene (3ml.) were added P(Ph₃)₄Pd (6mg. 0.039eq.), CuBr (2mg.) and 5-Bromothiophene-2-carboxylic acid methyl ester (26.5mg, 0.12mmol.) under nitrogen. The reaction mixture was stirred and heated to reflux during 5 hrs. The progress of the reaction was monitored by TLC. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by silica plate for purification using 80% hexane 20% EtOAc afforded 5-'(4—{[(l — Methoxycarbonyl-2-phenyl-ethyl)-(4-methoxy-2,3,6-trimethylbenzenesulf onyl ) -amino]-methyl}-phenyl)-thiophene-2-carboxylic acid methyl ester in 41% yield: ¹HNMR(Varian 400MHz, CDC1₃) d 8.67(d, 1H, HPh), 8.35 (d, 2H, thiopheneH),8.10(m, 6H, HPh) , 8.00(d, 2H, thiopheneH), 7.38 (s, 1H, MTRH), 5.72(m, 3H, NCH₂Ph, CHCH₂) , 4.82 (s, 3H, OCH₃) , 4.68(s, 3H, COOCH₃) , 4.29 (s, 3H,

COOCH₃) , 4.10 (m, 1H, CHCH₂) , 3.85 (m, 1H, CHCH₂) , 3.57 (s, 3H, ArCH₃) , 3.40(s, 3H, ArCH₃) , 3.0(s, 3H, ArCH₃) ppm. MS 622.6 (M⁺) .

STEP VII

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

5-(4-{[(1-Carboxy-2-phenyl-ethyl) -(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-amino]-methyl}-phenyl)-furan-2-carboxylic acid

<img file="CA2449999C_D0045.tif" />

<img file="CA2449999C_D0046.tif" />

To a stirred solution of 5-(4—{[(1-Methoxycarbonyl-2-phenyl5 ethyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]methyl}-phenyl)-furan-2-carboxylic acid methyl ester (16 mg, 0.026mmol.) in THF: H₂O : MeOH (3:1:2) (1ml.), was added LiOH in water (IN) (0.2ml. 0.26mmol.). The reaction mixture was stirred at room temperature during 1 hr. TLC monitored the progress of the reaction. When the reaction was completed, the mixture was concentrated under reduced pressure on a rotary evaporator. The residue was treated with a solution 20% of KHSO₄ and extracted in EtOAc. The EtOAc layer was dried over Na₂SO₄. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by silica chromatography using 90% EtOAc,

10% MeOH and 1 drop of AcOH, afforded 5-(4-{[(l-Carboxy-2phenyl-ethyl) -(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)amino]-methyl}-phenyl)-furan-2-carboxylic acid. ¹HNMR (Varian 400MHz, DMSO) d 7.37 (d, 2H, J=8.5Hz, HPh), 7.27 (d, 2H,

J=8.3Hz, HPh), 7.13 (m, 6H, HPh), 6.69 (d, 1H, J=3.2Hz, furanH),

6.58 (d, 1H, J=3.2Hz, furanH), 6.50 (s, 1H, MTRH), 4.81 (d, 1H, J=15.5Hz, NCH₂Ph) , 4.41 (d, 1H, J=15.9Hz, NCH₂Ph) , 4.06 (dd, 1H, J=3.5 and 9.5Hz, CHCH₂) , 3.64 (s, 3H, OCH₃) , 3.10 (dd, 1H, J=9.5 and 12.6Hz, CHCH₂) , 2.65 (dd, 1H, J=3.8 and 12.6 Hz, CHCH₂) , 2.49 (s, 3H, ArCH₃) , 2.38 (s, 3H, ArCH₃) , 1.92 (s, 3H, ArCH₃) ppm. MS

576.5 (M“) .

The following compounds were prepared in a similar manner as described in example 2 :

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 compound #5 compound #6 Compound #7 compound #8 Compound #13 Compound #14 Compound #16 Compound #17 BCH-19067

Compound #18 Compound #20 compound #23 compound #24 compound #26 compound #27 compound #29 compound #32 compound #192 compound #193 compound #194

Example 3

2-((2,4-dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic 10 acid compound #111

<img file="CA2449999C_D0047.tif" />

STEP I

2-( (4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-prop-2-ynylamino]-3-phenyl-propionic acid methyl ester

<img file="CA2449999C_D0048.tif" />

A DMF (8 mL) solution of 2-(4-Methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-phenyl-propionic acid methyl ester (prepared according to example 2, step I) (200 mg) was cooled to 0°C and then propargyl bromide (80%, 0.07 mL·, 0.61 mmol) and Cs₂CO₃(200 mg, 0.61 mmol) were added under an atmosphere of N₂. The ice bath was removed and the reaction mixture was stirred at room temperature for 12h. The mixture was partitioned between ether and

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 water, the ether layer was separacea, ariea u\ia₂su₄j ana . concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-prop-2-ynyl amino]-3-phenyl-propionic acid methyl ester ( 185 mg, 85%) as a solid. Ti NMR (CDC1₃, 400 MHz): δ7.20-7.17 (m, 3H) , 7.10-7.08 (m, 2H), 6.56 (s,\lH), 4.42-4.29 (m, 3H), 3.86 (s, 3H), 3.56 (s, 3H), 3.32 (dd, 1H), 3.26 (dd, 1H), 2.66, 2.35 (2s, 6H), 2.21 (t, 1H), 2.08(s, 3H).

STEP II

3-Phenyl-2-prop-2-ynylamino-propionic acid methyl ester

<img file="CA2449999C_D0049.tif" />

<img file="CA2449999C_D0050.tif" />

To a solution of 2-[(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl) 15 prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (150 mg, 0.349 mmol) in anhydrous dichloroethane (1.5 mL), trifluoroacetic acid (3.5 mL) and ethyl methyl sulfide (0.16 mL, 1.75 mmol) were added. The reaction mixture was stirred at room temperature under a N₂ atmosphere for 12h.. Excess of solvents were removed under reduced pressure and the residue was extracted between saturated NaHCO₃ solution and ethyl acetate. The organic layer was separated, dried (Na₂SO₄) , concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 3-Phenyl-2-prop-2-ynylamino25 propionic acid methyl ester as a thick syrup, 70 mg (92%). NMR (CDC1₃, 400 MHz):δ 7.32-7.19 (m, 5H) , 3.78 (t, 1H) , 3.68 (s, 3H) ,

3.40 (ABq, 2H), 3.03 (dd, 1H), 2.98 (dd, 1H), 1.99 (t, 1H).

SUBSTITUTE SHEET (RULE 26)

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WO 02/100846 PCT/CA02/00877

STEP III

2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester

<img file="CA2449999C_D0051.tif" />

A solution of 3-Phenyl-2-prop-2-ynylamino-propionic acid methyl ester (75 mg, 0.346 mmol) in anhydrous CH₂C1₂ (2 mL) was cooled to 0°C in an ice bath, then triethylamine (0.1 mL) and 2,4dichlorobenzoyl chloride (0.06 mL, 0.45 mmol) were added. The mixture was stirred at room temperature for 3h. Excess of benzoyl chloride was quenched by adding ice-cold water and then the reaction mixture was partitioned between water and CH₂C1₂. The organic layer was separated, dried (Na₂SO₄) , and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2—[(2,4— Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester as a syrup, 125 mg (93%).

STEP IV

2-[ (2,4-Dichloro-benzoyl) -prop-2-ynyl-amino] -3-phenyl-propionic acid

<img file="CA2449999C_D0052.tif" />

To a THF:MeOH:H₂O (3:2:1) (3 mL) solution of 2-[ (2,4-Dichlorobenzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (30 mg, 0.076 mmol), IN aqueous solution of lithium hydroxide (0.46 mL, 0.46 mmol) was added and the reaction mixture was stirred at room temperature for 6h. Solvents were removed under

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 reduced pressure and the residue Mtfas’partitioned“between ethyl acetate and water. The water layer, was acidified using 10% KHSO₄solution and then the organic layer was separated, dried (Na₂SO₄) , concentrated. The residue was purified by column chromatography (ethyl acetate:hexane 1:1 to ethyl acetate) to obtain 2-[(2,4dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid, 23 mg (81%) as a white solid. The compound contains two other minor rotamers. Y NMR (CDC1₃, 400 MHz): δ7.45-7.05 (m, 8H) , 6.77 (dd, minor rotamer), 5.70 (d, minor rotamer), 4.99 (bs, minor rotamer),

4.64-4.59 (m, minor rotamer), 4.28 (d, minor rotamer), 4.29-4.18 (m, minor rotamer), 3.79-3.09 (m, 5H), 2.37 (t, minor rotamer), 2.31 (t, minor rotamer), 2.17 (t, 1H) . ESI (M-H): 375.

The following compounds were prepared in a similar manner as described in example 3 :

compound #109 compound #110 compound #111 compound #112 compound #115 compound #116

Example 4

2- [ (3-Benzofuran-2-yl-prop-2-ynyl) -(2,4-dichloro-benzoyl) -amino] 3-phenyl-propionic acid.compound #113

<img file="CA2449999C_D0053.tif" />

To a solution of 2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3phenyl-propionic acid methyl ester (prepared according to example

9) (50 mg, 0.128 mmol) and 2-iodobenzofuran (41 mg, 0.166 mmol) in

DMF (2 mb), triethylamine (2 mL) and tetrakis(triphenylphosphine)palladium(O) (15 mg, 0.01 mmol) were added and the reaction mixture was stirred under reflux conditions

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877 for 4h under a N₂ atmosphere. DMP and triethylamine were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried (Na₂SO₄) , concentrated and the residue was purified by column chromatography using ethyl acetate and hexane (1:4) as eluent to obtain 2-[(3-Benzofuran-2-yl-prop-2-ynyl)-(2,4-dichloro-benzoyl)amino]-3-phenyl-propionic acid methyl ester as a thick syrup, 50 mg (76%). The compound contains two other rotamers. ¹H-NMR (CDC1₃, 300 MHz): δ7.58-7.09 (m, 12H), 6.98 (s, minor rotamer), 6.97 (d, minor rotamer), 6.85 (dd, minor rotamer), 6.83 (s, 1H), 5.82 (d, minor rotamer), 5.25 (bs, minor rotamer), 5.10 (bs, minor rotamer), 4.88-4.52 (m, minor rotamer), 4.35-3.21 (m, 5H), 3.78 (s, 3H) , 3.76, 3.65 (2s, minor rotamer).

A procedure similar to step IV (example 9) was used for the hydrolysis of 2-[(3-Benzofuran-2-yl-prop-2-ynyl)-(2,4-dichlorobenzoyl) -amino]-3-phenyl-propionic acid methyl ester. 2-[(3Benzofuran-2-yl-prop-2-ynyl)-(2,4-dichloro-benzoyl)-amino]-3phenyl-propionic acid was isolated after silica gel column chromatography using ethyl acetate :hexane (1:1) to ethyl acetate as eluent as a solid, 20 mg (69%). The compound contains two other

<td> rotamers</td><td> . ’'H-NMR (CDC1₃,</td><td> 400 MHz): ? 7.82 (d,</td><td> minor rotamer), 7.53·</td>

<td> 7.05 (m,</td><td> 12H), 6.93 (s,</td><td> minor rotamer), 6.89</td><td> (d, minor rotamer),</td>

<td> 6.81 (s,</td><td> 1H), 6.80 (dd,</td><td> minor rotamer), 6.49</td><td> (m, minor rotamer),</td>

<td> 25 6.26 (d,</td><td> minor rotamer)</td><td colspan="2"> , 5.73 (d, minor rotamer), 5.22 (bs, minor</td>

rotamer), 5.09-4.45 (m, minor rotamers), 4.36-3.11 (m, 5H). ESI (M-H): 491.

SUBSTITUTE SHEET (RULE 26)

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Example 5

2-[(4-Benzofuran-2-yl-phenyl)-(2,4-dichloro-benzoyl)-amino]-3phenyl-propionic acid compound #114

<img file="CA2449999C_D0054.tif" />

<img file="CA2449999C_D0055.tif" />

<img file="CA2449999C_D0056.tif" />

STEP I

2-(4-Bromo-phenylamino)-3-phenyl-propionic acid tert-butyl ester

<img file="CA2449999C_D0057.tif" />

<img file="CA2449999C_D0058.tif" />

<img file="CA2449999C_D0059.tif" />

A mixture of L-phenylalanine tert-butyl ester (1.47 g, 6.64 mmol), 4-bromophenylboronic acid (2.67 g, 13.28 mmol), triethylamine (1.9 mL, 13.28 mmol) and copper (II) acetate (1.21 g, 6.64 mmol) in di chloromethane (50 mL) was stirred at room temperature for 24 h. The solids were removed by filtration through a pad of silica gel and the desired product was obtained by chromatography eluting with 5% ethyl acetate in hexanes, h NMR (CDC1₃)7.2 (m, 8 H) , 6.48 (d, 2 H) , 4.18 (t, 2 H, H-2 and NH), 3.08 (d, 2 H), 1.35 (s, 9 H)

SUBSTITUTE SHEET (RULE 26)

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WO 02/100846 PCT/CA02/00877

STEP II

2-[(4-Bromo-phenyl)-(2,4-dichloro-benzoyl)-amino]-3-phenylpropionic acid tert-butyl ester

<img file="CA2449999C_D0060.tif" />

<img file="CA2449999C_D0061.tif" />

<img file="CA2449999C_D0062.tif" />

This compound was prepared in a similar manner as for step I in example 1. ^XH NMR (CDC13) 7.2 (m, )7.2 (d), 7.0 (d, 6.93 (d) , 6.4 br s), 4.62 (t, 1 H) , 3.4 9m, 2 H), 1.3 (s, 9 H)

STEP III

2-[(4-Benzofuran-2-yl-phenyl)-(2,4-dichloro-benzoyl)-amino]-3phenyl-propionic acid tert-butyl ester

<img file="CA2449999C_D0063.tif" />

This compound was prepared in a similar manner as for step III in example 2. ^XH NMR (CDC1₃) 7.6 (m) , 7.3 (m) , 6.9 (m) , 6.7 (m) , 4.8 (m) , 4.2 (m), 3.5 (m)

STEP IV

2-[(4-Benzofuran-2-yl-phenyl)-(2,4-dichloro-benzoyl)-amino]-320 phenyl-propionic acid

<img file="CA2449999C_D0064.tif" />

<img file="CA2449999C_D0065.tif" />

SUBSTITUTE SHEET (RULE 26)

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WO 02/100846 PCT/CA02/00877

This compound was prepared in a similar manner as for step IV in example 1. ^XH NMR (DMSO) 13.1 (hrs, 1 H), 7.6 (m, 5 H) , 7.3 (m, 9 H) , 7'.01 (d, 2 H) , 6.72 (d, 2 H) , 4.95 (dd, 1 H) , 3.39 (2

H)

The following compounds were prepared in a similar manner as described in example 5 :

Compound 190 Compound 191

Example 5 The following compound was obtained from Oxford Diversity:

Compound #1,

The following compounds were prepared as listed in Table 1 and Table 2.

TABLE 1. LIST OFCOMPOUNDS HAVING POLYMERASE ACTIVITY

<td> Compound #</td><td> Compound Name</td><td> Structure</td><td> RNA pol Assay 1 IC„ dim)</td><td> RNA pol Assay 2 dim)</td>

<td> compound #1</td><td> 3 - L3 - (2,6-Dichloro- pyridin-4-yl)-1-(4thi ophen-2-ylbenzyl)-ureido]-3thiophen-2-yl- . propionic acid</td><td> OH _C| *γΑ Tx</td><td> ++</td><td></td>

<td> compound #2</td><td> (2s“F2-L (2,4- Dichloro-benzoyl)(4-thiazol-2-ylbenzyl)-amino]-3phenyl-propi oni c acid,</td><td> ΓΓ-Ά .sAJ Λ ^L-A</td><td> +++</td><td></td>

<td> compound #3</td><td> (2s)-2-L(4-Bromo- benzyl) -(2,4dichloro-benzoyl) amino]-3-phenylpropionic acid,</td><td> r=\ o ci MZXnXA ^hoA</td><td> +++</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="4"> Compound #</td><td rowspan="4"> Compound Name</td><td rowspan="4"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC„ (um)</td><td> RNA pol</td>

<td> Assay 2</td>

<td rowspan="2"> T&amp;o (dm)</td>

<td></td>

<td> compound #4</td><td> (2s)-2~L(4- Benzofuran-2-ylbenzyl)-(2,4dichloro-benzoyl)amino]-3-phenylpropionic acid,</td><td></td><td> +++</td><td></td>

<td> compound #5</td><td> (2s)-2-L(4- Benzofuran-2-ylbenzyl)-(4-methoxy2,3,6-trimethylbenzenesulfonyl) amino]-3-phenylpropionic acid,</td><td> s ^N\ TL ¹ O Η</td><td> ++ +</td><td></td>

<td> compound #6</td><td> (2s)-2-[(4- Benzofuran-2-ylbenzyl)-(4-methoxy2,3,6-trimethylbenzenesulfonyl) amino]-3-phenylpropionic acid,</td><td> /θ'^Χνθ Q / p^Nptet_0H Λα</td><td> ++ +</td><td></td>

<td> compound #7</td><td> (2s)-2-L(3- Benz o furan-2-ylbenzyl)-(4-methoxy2,3,6-trimethylbenzenesulfonyl) amino]-3-phenylpropionic acid, compound #7</td><td> L / / O</td><td> + + +</td><td></td>

<td> compound #8</td><td> 3-L(4-Iodo-benzyl) - (4-methoxy-2,3,6trimethylbenzenesulfonyl)amino]-3-thiophen2-yl-propionic acid ethyl ester,</td><td> , te —o</td><td> ++</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound #</td><td> Compound Name</td><td> Structure</td><td> RNA pol Assay 1 IC_S„ (urn)</td><td> RNA pol Assay 2 (Urn)</td>

<td> compound #9</td><td> (2s)-2-L(3-Bromo- benzyl)-(2,4dichloro-benzoyl) amino]-3-phenylpropionic acid,</td><td> M ,-¼⁰ I \ OH ' b</td><td> +++</td><td></td>

<td> compound #10</td><td> (2s)-2-L(3-Bromo- benzyl)-(2-chlorobenzoyl)-amino]-3phenyl-propionic acid,</td><td> U ,¼⁰ T 1 °^H ' b</td><td> +</td><td></td>

<td> compound #11</td><td> (2s)-2-L(3- Benzofuran-2-ylbenzyl)-(2,4dichloro-benzoyl) aminq]-3-phenylpropionic acid,</td><td> xx</td><td> ++</td><td></td>

<td> compound #12</td><td> (2s)-2-[(2,4- Dichloro-benzoyl)(4-iodo-benzyl) amino]-3-phenylpropionic acid,</td><td> Chiral UL°o ÂAh ¢3 b I</td><td> + +</td><td></td>

<td> compound #13</td><td> (2s)-2-L(3-Iodo- benzyl)-(4-methoxy2,3,6-trimethylbenzenesulfonyl)amino]-3-phenylpropionic acid,</td><td> / ’ r/ ο bX ÔÇÛ</td><td> ++</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="3"> Compound #</td><td rowspan="3"> Compound Name</td><td rowspan="3"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC_c„ (Urn)</td><td> RNA pol</td>

<td> Assay 2</td>

<td> I+o dim)</td>

<td> compound. #14</td><td> (2s)-2-L(4-Bromo- benzyl)-(4-methoxy2,3,6-trimethylbenzenesulfonyl) amino]-3-phenylpropionic acid,</td><td> _^Ο_χ / mS / ₀*r fî &lt;ⁿ-Aoh φΌ Br</td><td> + +</td><td></td>

<td> compound. #15</td><td> (2s)-2-L(3-Bromo- benzyl)-(4-chlorobenzoyl)-amino]-3phenyl-propi oni c acid,'</td><td> Chiral UÇ°o A + oh</td><td> ++</td><td></td>

<td> compound #16</td><td> (2s)-2-L(4-Iodo- benzyl)- (4-methoxy2,3,6-trimethylbenzenesulfonyl)amino]-3-phenylpropionic acid</td><td> I Chiral φΌ 1</td><td> + +</td><td></td>

<td> compound #17</td><td> (2s)-2-L(3-Bromo-i benzyl)- (4-methoxy2,3,6-trimethylhenzenesulfonyl)amino]-3-phenylpropionic acid</td><td> I Chiral ^/0 ιϊ% .+ +</td><td> ++</td><td> &lt;</td>

<td> compound #18</td><td> (2s) -5- (4-T'['(ls-l- Carboxy-2-phenylethyl)-(4-methoxy2,3,6-trimethylbenzenesulfonyl) amino]-methyl}phenyl)-furan-2carboxylic acid methyl ester</td><td>⁰ ++ 0-/ &lt;y °\</td><td> +</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> Compound Name</td><td> Structure</td><td> RNA pol</td><td> TINA pol</td>

<td rowspan="3"> #</td><td rowspan="3"></td><td rowspan="3"></td><td rowspan="2"> Assay 1 IC,„ (Jim)</td><td> Assay 2</td>

<td rowspan="2"> ÎÇ50 (Urn)</td>

<td></td>

<td> compound #19 ·</td><td> (2s)-2-L(3-Bromo- benzyl)-(3,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td>^c'xx jo'o</td><td> +</td><td></td>

<td> compound #20</td><td> (2s)-2-[(3-Bromo- benzyl)-(2,4dichlorobenzenesulfonyl)amino]-3-phenylpropionic acid</td><td> Chiral J'Ti Ό</td><td> +</td><td></td>

<td> compound' # 21</td><td> (2s)-3-(1-Benzyl- lh-imidazol-4-yl)2-[(3-bromobenzyl) -(2,4di chloro-benzoyl)amino]-propionic acid</td><td> O_vo₀_Br_O M &amp;</td><td> ++</td><td></td>

<td> compound #22</td><td> (2s)-2-((3-Bromo- benzyl)-[(2,4dichloro-phenyl)acetyl]-amino}-3pheny1-propionic acid</td><td> ci Chiral</td><td> + +</td><td></td>

<td> compound #23</td><td> T2's)-3-(4-( L (ls-1- Carboxy-2-phenylethyl) - (4-methoxy2,3,6-trimethylbenzenesulfonyl)amino]-methyl}phenyl)-thiophene2-carhoxylic acid methyl ester</td><td> ° ^s \ λ~Ο o^z \</td><td> +</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="3"> Compound #</td><td rowspan="3"> Compound Name</td><td rowspan="3"> Structure</td><td rowspan="2"> RNA pol Assay 1 IC„ (Um)</td><td> RNA pol Assay 2</td>

<td rowspan="2"> iÇgo (Ltm)</td>

<td></td>

<td> compound #24</td><td> (2s)-2-L(2-Bromo- benzyl)- (4-methoxy2,3,6-trimethylbenzenesulfonyl) amino]-3-phenylpropionic acid</td><td> d-*</td><td> ++</td><td></td>

<td> compound #25</td><td> (2s)-2-L(3-Bromo- benzyl)-(4-chlorophenoxycarbonyl ) amino]-3-phenylpropionic acid</td><td> Chiral Χα,η jib</td><td> +</td><td></td>

<td> compound #26</td><td> (2s)-Triethyl- ammonium; 2- [ (3benzofuran-2-ylbenzyl)-(4-methoxy2,3,6-trimethylbenzenesulfonyl ) amino]-3-phenylpropionate</td><td></td><td> +++</td><td></td>

<td> Compound #27</td><td> 2-[Allyl-(4-ch±oro- 2-iodo-benzoyl) amino]-3-phenylpropionic acid</td><td></td><td> ++</td><td></td>

<td> compound #28</td><td> (2s)-2-[(3-Bromo- benzyl)-(2,4dimethyl-benzoyl)amino]-3-phenylpropionic acid</td><td> chiral XÇ. AA» .Λό</td><td> +++</td><td></td>

<td> Compound #29</td><td> 3-(4-Benzofuran-2- yl-phenyl)-2-[(2,4dichloro-benzoyl)methyl-amino]propionic acid</td><td> TÇo Αγ+οΗ</td><td></td><td> + +</td>

SUBSTITUTE SHEET (RULE 26)

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<td rowspan="4"> Compound #</td><td rowspan="4"> Compound Name</td><td rowspan="4"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC_e„ (Urn)</td><td> RNA pol</td>

<td> Assay 2</td>

<td rowspan="2"> ÎÇso (llm)</td>

<td></td>

<td> compound #30</td><td> (2s)-2-L(3-Bromo- benzyl)-(2,4dichloro-benzyl) amino]-3-phenylpropionic acid</td><td> Chiral _rVo„</td><td> +++</td><td></td>

<td> compound #31</td><td> T2s)-2-L(3- Benz o furan-2-y1benzyl)-(2,4dimethyl-benzoyl)amino]-3-phenylpropionic acid</td><td> Chiral o n °^H</td><td> + + +</td><td></td>

<td> compound #32</td><td> (2s)-2-L(4- Benzofuran-2-ylbenzyl)-(4-methoxy2,3,6-trimethylbenzenesulfonyl ) amino]-3-(4hydroxy-phenyl) propionic acid</td><td> Ο γΊ</td><td> +++</td><td></td>

<td> compound #33</td><td> (2s)-2-L(4- Benzofuran-2-ylbenzyl)-(2,4dichloro-benzoyl) amino]-3-(4hydroxy-phenyl) propionic acid</td><td>^Cl ο (Ί</td><td> +++</td><td></td>

<td> compound #34</td><td> (2s)-2-[(3-Bromo- benzyl)-(4-chloro2-methyl-benzoyl)amino]-3-phenylpropionic acid</td><td> Chiral XÇ. AA. ./)‘Ό</td><td> +++</td><td></td>

SUBSTITUTE SHEET (RULE 26)

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<td rowspan="2"> Compound #</td><td rowspan="2"> Compound Name</td><td rowspan="2"> Structure</td><td> RNA pol Assay 1 IC,„ (Urn)</td><td rowspan="2"> RNA pol Assay 2 (pm)</td>

<td></td>

<td> compound. #35</td><td> (2s)-2-L(3-Bromo- benzyl) -(4-chloro2-iodo-benzoyl)amino]-3-phenylpropionic acid</td><td> CI.^/1 Chiral uç°° φΛοΗ .15 0</td><td> ++ +</td><td></td>

<td> compound #36</td><td> (2s)-2-[(3-Bromo- benzyl) - (2-bromo-4chloro-benzoyl)amino]-3-phenylpropionic acid</td><td>^Clx^/^Br Chiral X&gt; ‘Ό</td><td> + + +</td><td></td>

<td> compound #37</td><td> (2s)-2-{(3- Benzofuran-2-ylbenzyl)-((2,4dichloro-phenyl)acetyl]-amino)-3phenyl-propionic acid</td><td> Cl Chiral ,ΛΧ», ru</td><td> + + +</td><td></td>

<td> compound #38</td><td> (2s)-2-L(4- Benzofuran-2-ylbenzyl)-(2,4dichloro-phenyl) amino]-3-phenylpropionic acid</td><td>₀_Γ-^Ν'η-Ü—Ο H</td><td> +++</td><td></td>

<td> compound #39</td><td> (2s)-2-L(2,4- Dichloro-benzoyl) naphthalen-2ylmethyl-amino]-3pheny1-propionic acid</td><td> CL 05 °^H</td><td> +++</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> Compound Name</td><td> Structure</td><td> RNA pbt</td><td> RNA pol</td>

<td> #</td><td></td><td></td><td> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td> IC„ (Urn)</td><td></td>

<td></td><td></td><td></td><td></td><td> (llm)</td>

<td> compound #40</td><td> (2s)-2-L(2,4- Dichloro-benzoyl) (9,10-dioxo-9,10-</td><td> Ck Ao</td><td> ++ +</td><td></td>

<td></td><td> dihydro-anthracen-</td><td> o</td><td></td><td></td>

<td></td><td> 2-ylmethyl)-amino]-</td><td></td><td></td><td></td>

<td></td><td> 3-phenyl-propionic acid</td><td> AT</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> O* °</td><td></td><td></td>

<td> compound</td><td> (2s)-2-L(3-(3-</td><td> Cl</td><td> +++</td><td></td>

<td> #41</td><td> Chloro-benzoyl) benzyl]-(2,4-</td><td> Ok 0l_c1</td><td></td><td></td>

<td></td><td> dichloro-benzoyl) -</td><td> HO -</td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td> ÇAx¹ ct</td><td></td><td></td>

<td rowspan="2"> compound #42</td><td> (2s)-2-t(2,4- Dichloro-benzoyl)-</td><td> r-τ, A</td><td> +++</td><td></td>

<td rowspan="2"> [3-(2,4-difluorobenzoyl) -benzyl]-</td><td rowspan="2"> TJ TT,</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> amino]-3-phenylpropionic acid</td><td>^ΗΟγθΑθ</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-L[3-[3-(2-</td><td> Cl</td><td> +++</td><td></td>

<td> #43</td><td> Chloro-phenyl)-5methyl-isoxazole-4-</td><td> Ok Ol</td><td></td><td></td>

<td></td><td> carbonyl]-benzyl}-</td><td></td><td></td><td></td>

<td></td><td> (2,4-dichloro-</td><td></td><td></td><td></td>

<td></td><td> benzoyl)-amino]-3pheny1-propi oni c acid</td><td></td><td></td><td></td>

<td></td><td></td><td>ⁿuO°</td><td></td><td></td>

<td rowspan="2"> compound #44</td><td> (2s)-2-((2,4- Dichloro-benzoyl)-</td><td> A</td><td> +++</td><td></td>

<td rowspan="2"> [3-(2,4-dichlorobenzoyl) -benzyl]-</td><td rowspan="2"> TJ Ça a</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> amino}-3-phenylpropionic acid</td><td> θ</td><td></td><td></td>

<td></td><td></td><td>_c,</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="2"> Compound #</td><td rowspan="2"> Compound Name</td><td rowspan="2"> Structure</td><td rowspan="2"> RNA pol Assay 1 IC₅₀ (Pm)_</td><td> RNA pol Assay 2</td>

<td> ÎÇ50 (Um)</td>

<td> compound #45</td><td> (2s)-2~L(3- Benzooxazol-2-ylbenzyl)-(2,4dichloro-benzoyl)- . amino]-3-phenylpropionic acid</td><td> οςφχ ώ t/</td><td> +++</td><td></td>

<td> compound #46</td><td> (2s)-2-L(3-Bromo- benzyl)-(4-chloro2-ethyl-benzoyl) amino]-3-phenylpropionic acid</td><td> Chiral ÀA»</td><td> + + +</td><td></td>

<td> compound #47</td><td> (2s)-2-L(4- Benzofuran-2-ylbenzyl)-(2,4dichloro-benzoyl)amino]-3cyclohexylpropionic acid</td><td></td><td> +++</td><td></td>

<td> compound #48</td><td> (2s)-2-L(3- . Benzofuran-2-ylbenzyl)-(4-chloro2-methyl-benzoyl)amino]-3-phenylpropionic acid</td><td>^COÇ% JX zryv jj</td><td> +++</td><td></td>

<td> compound #49</td><td> (2s)-2-L(3- Benzofuran-2-ylbenzyl)-(2-bromo-4chloro-benzoyl)amino]-3-phenylpropionic acid</td><td>^cl\/V^Br QyOt</td><td> + + +</td><td></td>

<td> compound #50</td><td> (2s)-2-((3-Bromo- benzyl)-(4-chloro2-vinyl-benzoyl)amino]-3-phenylpropionic acid</td><td> XÇo AAh</td><td> +++</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="2"> Compound #</td><td rowspan="2"> Compound Name</td><td colspan="3" rowspan="2"> Structure</td><td rowspan="2"> RNA pol Assay 1 IC„ (lim)</td><td> RNA pol</td>

<td> Assay 2 I&amp;o (Um)</td>

<td> compound #51</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)(3-fluoro-benzyl)amino]-3-phenylpropionic acid</td><td>^CIY</td><td> 3 (</td><td> .Cl Y° o U</td><td> ++ +</td><td></td>

<td></td><td></td><td></td><td> Γ</td><td> II Yl</td><td></td><td></td>

<td></td><td></td><td> F^x</td><td> -V</td><td> J u</td><td></td><td></td>

<td> compound #52</td><td> (2s)-2-L(3-Cbloro- benzyl)-(2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td> °'I</td><td> 5 γ</td><td> .CI Y° o Μ»</td><td> ++ +</td><td></td>

<td></td><td></td><td></td><td> r</td><td> Il YlY</td><td></td><td></td>

<td></td><td></td><td> cr</td><td> V</td><td> J u</td><td></td><td></td>

<td> Compound #53</td><td> (2S)-2-L(2,4- Dichloro-benzoyl)(3-nitro-benzyl)amino]-3-phenylpropionic acid,</td><td>^Clk</td><td> I r</td><td> .Cl Υ o Aon</td><td></td><td> ++ +</td>

<td></td><td></td><td></td><td> Γ</td><td> 11 Vi</td><td></td><td></td>

<td></td><td></td><td> °V</td><td> Lx</td><td> J U</td><td></td><td></td>

<td></td><td></td><td> II o</td><td></td><td></td><td></td><td></td>

<td> compound #54</td><td> (2S)-2-L(3-Cyano- benzyl)-(2,4dichloro-benzoyl ) amino]-3-phenylpropionic acid</td><td> A</td><td> I</td><td> ,CI r°j Mm</td><td></td><td> +++</td>

<td></td><td></td><td></td><td></td><td> Il Yl</td><td></td><td></td>

<td></td><td></td><td> nA</td><td></td><td> J U</td><td></td><td></td>

<td> compound #55</td><td> (2s) -2-{ ('Z-Chioro- benzoyl)-[5-(3chloro-phenyl) furan-2-ylmethyl]amino}-3-phenylpropionic acid</td><td> ci O-</td><td> U</td><td> o ^Clv Ap fV Λ^OH</td><td> + +</td><td></td>

<td></td><td></td><td></td><td></td><td> V</td><td></td><td></td>

<td> compound #56</td><td> (2s)-2-{(2,4- Dichloro-benzoyl)- [5-(3- trifluoromethylphenyl)-furan-2ylmethyl]-amino}-3pheny1-propionic acid</td><td> C'x F F+- F</td><td> c o^x 0</td><td> Y</td><td> +++</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound #</td><td> Compound Name</td><td colspan="2"> Structure</td><td> RNA pol Assay 1 IC_5I1 (pm).</td><td> RNA pol Assay 2 ÎÇ50 (Um)</td>

<td rowspan="2"> compound #57</td><td> (2s)-2-L(5-Bromo- furan-2-ylmethyl)-</td><td></td><td> A'</td><td> ++</td><td></td>

<td> (2,4-dichloro-</td><td> L Jl</td><td> - /0</td><td></td><td></td>

<td></td><td> benzoyl)-amino]-3-</td><td></td><td> T o</td><td></td><td></td>

<td></td><td> phenyl-propionic acid</td><td> Br^/°k</td><td> 1 p v_OH</td><td></td><td></td>

<td></td><td></td><td rowspan="2"> O</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> u</td><td></td><td></td>

<td rowspan="2"> compound #58</td><td> (2s)-2-[(5- Benzofuran-2-yl-</td><td> CI</td><td> VV^C|</td><td> +++</td><td></td>

<td> furan-2-ylmethyl)-</td><td></td><td></td><td></td><td></td>

<td></td><td> (2,4-dichloro-</td><td></td><td></td><td></td><td></td>

<td></td><td> benzoyl)-amino]-3-</td><td></td><td> /-.Γ o</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td> .°. /°</td><td></td><td></td><td></td>

<td></td><td> acid</td><td> yyjk</td><td> Jl i OH</td><td></td><td></td>

<td></td><td></td><td></td><td> b</td><td></td><td></td>

<td> compound #59</td><td> '(Ts')-2-L L5-(4- Bromo-phenyl) furan-2-ylmethyl]-</td><td></td><td> qx</td><td> ++ +</td><td></td>

<td></td><td> (2,4-dichloro-</td><td></td><td> ko</td><td></td><td></td>

<td></td><td> benzoyl)-amino]-3phenyl-propionic</td><td rowspan="2"></td><td> 0 γ ΟΗ</td><td></td><td></td>

<td></td><td> acid</td><td> kk</td><td></td><td></td>

<td></td><td></td><td></td><td> u</td><td></td><td></td>

<td rowspan="2"> compound #60</td><td> (2s)-2-[[5-(2- Chloro-phenyl)-</td><td> Cl.</td><td></td><td> ++ +</td><td></td>

<td> furan-2-ylmethyl]-</td><td colspan="2"> X /</td><td></td><td></td>

<td></td><td> (2,4-dichloro-</td><td></td><td></td><td></td><td></td>

<td></td><td> benzoyl)-amino]-3pheny1-propi oni c</td><td rowspan="2"> Cl ok</td><td> _ / 0 kk</td><td></td><td></td>

<td></td><td> acid</td><td> -- OH \</td><td></td><td></td>

<td></td><td></td><td></td><td> b</td><td></td><td></td>

<td> compound</td><td> (2s)-2-LL5-(2-</td><td colspan="2"> ci.</td><td> +++</td><td></td>

<td> #61</td><td> Chloro-5- trifluoromethyl- phenyl) -furan-2-</td><td></td><td> Q^c'</td><td></td><td></td>

<td></td><td> ylmethyl]- (2,4-</td><td> Cl</td><td> r°_o</td><td></td><td></td>

<td></td><td> dichloro-benzoyl)amino]-3-phenyl-</td><td> d-c</td><td> I o Ok JJ ί OH</td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> b</td><td></td><td></td>

<td> compound</td><td> (2s) -2-{ (2,4-</td><td></td><td></td><td> +++</td><td></td>

<td> #62</td><td> Dichloro-benzoyl)[5-(2-nitro-</td><td> V</td><td> CO</td><td></td><td></td>

<td></td><td> phenyl)-furan-2-</td><td rowspan="3"> Ok</td><td> kT o</td><td></td><td></td>

<td></td><td> ylmethyl]-amino}-3-</td><td> ►KA</td><td></td><td></td>

<td></td><td> phenyl-propi oni c</td><td> f OH</td><td></td><td></td>

<td></td><td> acid</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> b</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="2"> Compound. #</td><td rowspan="2"> Compound Name</td><td colspan="4" rowspan="2"> Structure</td><td rowspan="2"> RNA poi Assay 1</td><td> RNA pol</td>

<td> Assay 2</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> IC_sn (|Um)</td><td> SI U H</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> (llm)</td>

<td> compound</td><td> (3s)-3-{(2,4-</td><td></td><td></td><td colspan="2"> Cl.</td><td> +++</td><td></td>

<td> #63</td><td> Dichloro-benzoyl)[5-(3- trifluoromethyl-</td><td> F F</td><td> F</td><td></td><td> CA¹</td><td></td><td></td>

<td></td><td> phenyl) -furan-2-</td><td rowspan="2"> f</td><td rowspan="2"> Λ</td><td></td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-amino}-4-</td><td> o.</td><td> /N ,OH</td><td></td><td></td>

<td></td><td> phenyl-butyric acid</td><td colspan="2"></td><td> Ό</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> Ό</td><td></td><td></td>

<td rowspan="2"> compound #64</td><td> 2-{(2,4-Dichloro- benzoyl)-[2-(3-</td><td></td><td> Cl·</td><td> Y</td><td> r</td><td></td><td> ++ +</td>

<td> nitro-phenyl)-</td><td></td><td></td><td> ¥</td><td> /ri^o</td><td></td><td></td>

<td></td><td> thiazol-5-</td><td></td><td></td><td></td><td> i 9</td><td></td><td></td>

<td></td><td> ylmethyl]-amino}-3-</td><td></td><td></td><td></td><td> /'/OH</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td> ο</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> acid</td><td> π₊ Ο-Ν,</td><td> c</td><td> L</td><td> &gt; Ό</td><td></td><td></td>

<td></td><td></td><td></td><td> ri^</td><td></td><td></td><td></td><td></td>

<td> compound</td><td> ( 2s)-2-'Π2,4-</td><td></td><td></td><td></td><td>^ci\/ri/^cl</td><td> +++</td><td></td>

<td rowspan="2"> #65</td><td> Dichloro-benzoyl)-</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> [5-(3,4-dichloro-</td><td></td><td></td><td></td><td> °A//</td><td></td><td></td>

<td></td><td> phenyl)-furan-2ylmethyl]-amino}-3phenyl-propi oni c</td><td> Ck 1</td><td> ri/</td><td> O 0</td><td> | OH</td><td></td><td></td>

<td></td><td> acid</td><td rowspan="2"> cr</td><td> A</td><td></td><td> Il ύ</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> M</td><td></td><td></td>

<td> compound</td><td> (2s)-2-LBenzoturan-</td><td></td><td></td><td> Cl</td><td></td><td> + + +</td><td></td>

<td> #66</td><td> 2-ylmethyl-(2,4— dichloro-benzyl)-</td><td rowspan="2"> Cl-</td><td> -f</td><td> v</td><td> A o</td><td></td><td></td>

<td></td><td> amino]-3-phenylpropionic acid</td><td> \=</td><td> -J</td><td> MoH</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> &lt; U</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> \_</td><td> /</td><td></td><td></td>

<td> compound #67</td><td rowspan="2"> (2s)-2-{ (2,4- Dichloro-benzoyl)[5-(2,4-dichlorophenyl) -furan-2-</td><td rowspan="2"></td><td rowspan="2"> Cl</td><td rowspan="3"> o 0</td><td rowspan="3"> A = OH</td><td rowspan="2"> + + +</td><td rowspan="2"></td>

<td></td>

<td></td><td> ylmethyl]-amino}-3phenyl-propionic</td><td> if</td><td> A/</td><td></td><td></td>

<td></td><td> acid</td><td rowspan="2"> cr</td><td> A</td><td></td><td> t ύ</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> k/</td><td></td><td></td>

<td rowspan="2"> compound #68</td><td> (2s)-2-[(2-Bromo-4- chloro-benzoyl)-(5-</td><td> Cl</td><td> v</td><td> v</td><td> Br</td><td> +++</td><td></td>

<td rowspan="3"> bromo-furan-2ylmethyl)-amino]-3phenyl-propi oni c acid</td><td rowspan="3"></td><td rowspan="3"> k 0</td><td rowspan="3"> À</td><td rowspan="3"> Τ° î ,^ν-/Όη</td><td rowspan="3"></td><td rowspan="3"></td>

<td></td>

<td></td>

<td></td><td></td><td> Br^z</td><td> rio</td><td> (f</td><td></td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> Compound Name</td><td colspan="2"> Structure</td><td> RNA pdl</td><td> 'RNA pol</td>

<td> #</td><td></td><td></td><td></td><td> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td></td><td> IC„ (Him)</td><td> ÎÇ.50</td>

<td></td><td></td><td></td><td></td><td></td><td> (Um)</td>

<td> compound</td><td> (2s)-2-L LB-(3-</td><td></td><td>_XCI</td><td> +++</td><td></td>

<td> #69</td><td rowspan="3"> Chloro-4-fluorophenyl) -furan-2ylmethyl)-(2,4dichloro-benzoyl)-</td><td rowspan="3"> /</td><td rowspan="3"> Y° o /□„</td><td rowspan="3"></td><td rowspan="3"></td>

<td></td>

<td></td>

<td></td><td> amino]-3-phenyl-</td><td></td><td> s ⁼\</td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td> &lt; xs</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> //0,</td><td></td><td></td>

<td></td><td></td><td></td><td> F</td><td></td><td></td>

<td> compound</td><td> (2s)-2-t L5-(4-</td><td> Cl\</td><td> xCI</td><td> +++</td><td></td>

<td rowspan="2"> #70</td><td> Chloro-3-fluoro-</td><td></td><td></td><td></td><td></td>

<td> phenyl)-furan-2-</td><td></td><td> Ύ·° o</td><td></td><td></td>

<td></td><td> ylmethyl]- (2,4dichloro-benzoyl)-</td><td></td><td> X/,</td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td rowspan="2"></td><td> = _</td><td></td><td></td>

<td></td><td> propionic acid</td><td> SfS</td><td></td><td></td>

<td></td><td></td><td></td><td> Λ XY</td><td></td><td></td>

<td></td><td></td><td></td><td> a-f ’</td><td></td><td></td>

<td></td><td></td><td></td><td> CI</td><td></td><td></td>

<td rowspan="2"> compound #71</td><td> (2s)-2-[(5-Bromo- furan-2-ylmethyl)-</td><td> /</td><td></td><td> + + +</td><td></td>

<td rowspan="2"> (4-chloro-2-iodobenzoyl) -amino]-3-</td><td rowspan="2"> M</td><td rowspan="2"> o</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> phenyl-propi oni c</td><td></td><td> X ft</td><td></td><td></td>

<td></td><td> acid</td><td></td><td> N A,</td><td></td><td></td>

<td></td><td></td><td></td><td> γ ΟΗ</td><td></td><td></td>

<td></td><td></td><td> Ço</td><td></td><td></td><td></td>

<td></td><td></td><td> Br</td><td> u</td><td></td><td></td>

<td rowspan="2"> compound #72</td><td> (2s)-2-(5-{L(ls-l- Carboxy-2 -phenyl- ·</td><td> Ck</td><td></td><td> +++</td><td></td>

<td> ethyl)-(2,4-</td><td colspan="2"></td><td></td><td></td>

<td></td><td> dichloro-benzoyl)amino]-methyl}furan-2-yl)-benzoic</td><td> ,0</td><td> γ^υο y~^NYOH</td><td></td><td></td>

<td></td><td> acid ethyl ester</td><td> Y o</td><td> Λ s/</td><td></td><td></td>

<td></td><td></td><td></td><td> u</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2"> compound #73</td><td> (2s)-2-(5-(L (1- Carboxy-2-phenyl-</td><td></td><td> \^CI //</td><td> +++</td><td></td>

<td rowspan="2"> ethyl)-(2,4dichloro-benzoyl)-</td><td rowspan="2"> S</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> amino]-methyl}furan-2-yl)-benzoic</td><td> HO q</td><td> Xh,</td><td></td><td></td>

<td></td><td> acid</td><td> γ</td><td> &gt; Si/</td><td></td><td></td>

<td></td><td></td><td> Γί</td><td>² u</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound #</td><td> Compound Name</td><td colspan="4"> Structure</td><td> RNA pol Assay 1 IC₅&lt;, (pm)</td><td> RNA pol Assay 2 îÇa. (Hm)</td>

<td rowspan="2"> compound #74</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)-</td><td></td><td></td><td></td><td></td><td> ++ +</td><td></td>

<td rowspan="2"> (5-thiazol-2-ylfuran-2-ylmethyl)-</td><td rowspan="2"></td><td rowspan="2"> Cl I</td><td rowspan="2"> o</td><td rowspan="2"> Y</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> amino]-3-phenylpropionic acid</td><td> Ii</td><td> s</td><td></td><td> V^H</td><td></td><td></td>

<td></td><td></td><td> cr</td><td> Y</td><td> s</td><td> Y N.</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-[(2,4-</td><td></td><td colspan="2"> Cl</td><td></td><td> ++</td><td></td>

<td> #75</td><td rowspan="2"> Dichloro-benzoyl) furan-2-ylmethylamino]-3-phenyl-</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"> jO</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> propionic acid</td><td> cr</td><td> X</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> 0</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> o</td><td></td><td></td><td></td>

<td rowspan="2"> compound #76</td><td> (2s)-3-(5-&lt; L(ls-1- Carboxy-2-phenyl-</td><td></td><td> Ck</td><td rowspan="2"> 0</td><td> Cl</td><td> + + +</td><td></td>

<td rowspan="3"> ethyl)-(2,4dichloro-benzoyl) amino]-methyl}furan-2-yl)-benzoic acid</td><td rowspan="3"> 0</td><td rowspan="3"></td><td rowspan="3"> Y o Ξ OH &gt;</td><td rowspan="3"></td><td rowspan="3"></td>

<td></td><td></td>

<td></td><td></td>

<td></td><td></td><td> HO^</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-4-(b-{L(ls-1-</td><td></td><td></td><td colspan="2"> Cl</td><td> +++</td><td></td>

<td> #77</td><td rowspan="3"> Carboxy-2-phenylethyl )- (2,4dichloro-benzoyl ) amino]-methyl}-</td><td rowspan="3"></td><td rowspan="3"> Cl-^</td><td> σ</td><td rowspan="3"> OH</td><td rowspan="3"></td><td rowspan="3"></td>

<td></td><td></td>

<td></td><td></td>

<td></td><td> furan-2-yl)-benzoic</td><td></td><td></td><td> ? A</td><td></td><td></td><td></td>

<td></td><td> acid</td><td></td><td> A</td><td></td><td> o</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> HO</td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2"> compound #78</td><td> (2s)-2-{(2-Bromo-4- chloro-benzoyl) -[5-</td><td> Cl·</td><td></td><td>^Br</td><td></td><td> +++</td><td></td>

<td> (3-trifluoromethyl-</td><td></td><td></td><td></td><td> -° O</td><td></td><td></td>

<td></td><td> phenyl) -furan-2-</td><td></td><td></td><td colspan="2"> N—-T</td><td></td><td></td>

<td></td><td> ylmethyl]-amino}-3-</td><td></td><td></td><td></td><td> = UH</td><td></td><td></td>

<td></td><td> phenyl-propionic acid</td><td></td><td></td><td> Jo</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> c</td><td></td><td> ,F</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> F</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound #</td><td> Compound Name</td><td colspan="5"> Structure</td><td> RNA pol Assay 1 IC₅₀_LUmi</td><td> *κΝΆ pol Assay 2 I&amp;o (pm)</td>

<td> compound #79</td><td rowspan="2"> (2s)-2-{(2,4- Dichloro-benzoyl)[5-(3,5-difluorophenyl) -furan-2-</td><td rowspan="2"></td><td rowspan="2"> Cl 1</td><td rowspan="2"> o</td><td rowspan="2"></td><td rowspan="3"> OH</td><td rowspan="2"> +++</td><td rowspan="2"></td>

<td></td>

<td></td><td> ylmethyl]-amino}-3-</td><td> r</td><td></td><td> Y</td><td> If</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td rowspan="2"> cX</td><td> Y</td><td></td><td> 11</td><td> F</td><td></td><td></td>

<td></td><td> acid</td><td></td><td rowspan="2"></td><td> -0</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> F</td><td></td><td></td>

<td rowspan="2"> compound #80</td><td> (2s)-2-[(2,4- — Dichloro-benzoyl)-</td><td></td><td></td><td></td><td> Ii</td><td></td><td> + + +</td><td></td>

<td> (5-m-tolyl-furan-2-</td><td></td><td rowspan="2"></td><td></td><td> Y</td><td></td><td></td><td></td>

<td rowspan="2"></td><td rowspan="2"> ylmethyl)-amino]-3pheny1-propi oni c acid</td><td rowspan="2"> J</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"> .OH</td><td rowspan="2"></td><td rowspan="2"></td>

<td> y</td>

<td></td><td></td><td> cr'</td><td></td><td></td><td> '1°</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> (/</td><td></td><td> w</td><td></td><td></td>

<td rowspan="2"> compound #81</td><td> (2s)-2-&lt;(2,4- Dichloro-benzoyl)-</td><td></td><td></td><td></td><td> II</td><td></td><td> +++</td><td> l</td>

<td> [5-(3-fluoro-</td><td></td><td rowspan="2"></td><td></td><td> /A</td><td> Y</td><td></td><td></td>

<td rowspan="2"></td><td rowspan="2"> phenyl)-furan-2ylmethyl]-amino}-3phenyl-propi onic</td><td rowspan="2"></td><td rowspan="2"> I</td><td rowspan="3"> Ar -1°</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td>

<td> V</td>

<td></td><td> acid</td><td> cY</td><td> A</td><td></td><td> F</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> J</td><td></td><td> ~~0</td><td></td><td></td>

<td rowspan="2"> compound #82</td><td> (2s)-2-L(5-Bromo- thiophen-2-</td><td> Cl</td><td> V</td><td> Y</td><td> Cl</td><td></td><td> +++</td><td></td>

<td rowspan="2"> ylmethyl)-(2,4dichloro-benzoyl) -</td><td rowspan="2"></td><td rowspan="2"> k</td><td rowspan="2"> A</td><td rowspan="2"> X</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> amino]-3-phenylpropionic acid</td><td> Br—</td><td> x^s&gt;</td><td> r</td><td colspan="2">^NAo„</td><td></td><td></td>

<td></td><td></td><td></td><td> o</td><td></td><td></td><td> Ά</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> υ</td><td></td><td></td>

<td rowspan="2"> compound #83</td><td> (2s)-4-(5-([(Ts'-l- Carboxy-2-phenyl-</td><td></td><td></td><td> Cl,</td><td rowspan="2"> Q</td><td> /Cl</td><td> + + +</td><td></td>

<td rowspan="2"> ethyl)-(2,4dichloro-benzoyl)-</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td>

<td></td><td></td>

<td></td><td> amino]-methyl}-</td><td> o</td><td rowspan="2"> ry</td><td> s-</td><td colspan="2"> II</td><td></td><td></td>

<td></td><td> thiophen-2-yl)-</td><td></td><td rowspan="2"> Y</td><td> J]</td><td> ΞΌΗ</td><td></td><td></td>

<td></td><td> benzoic acid</td><td> HO⁷</td><td></td><td></td><td> Y</td><td></td><td></td>

<td rowspan="2"> compound #84</td><td> (2s)-4-(5-{L(1- Carboxy-2-phenyl-</td><td></td><td></td><td>^Cl\</td><td rowspan="2"> Q</td><td> -Cl</td><td> + + +</td><td></td>

<td rowspan="3"> ethyl)-(2,4dichloro-benzoyl)amino]-methyl}thïophen-2-yl)-</td><td rowspan="3"> Ο</td><td rowspan="3"></td><td rowspan="4"> s Y</td><td rowspan="3"> A o X</td><td rowspan="3"></td><td rowspan="3"></td>

<td></td><td></td>

<td></td><td> J</td>

<td rowspan="2"></td><td rowspan="3"> benzoic acid methyl ester</td><td rowspan="2"> —O</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td></td><td></td><td></td><td></td><td> M</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> Compound Name</td><td colspan="4"> Structure</td><td> RNA</td><td> pol</td><td> RNA pol</td>

<td> #</td><td></td><td></td><td></td><td></td><td></td><td colspan="2"> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> IC__Rn</td><td> (Um)</td><td> ÎÇ50</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td colspan="2"></td><td> (μπι)</td>

<td> compound</td><td> (2s)-2-L(5-</td><td></td><td></td><td> Ck</td><td></td><td> +++</td><td></td><td></td>

<td> #85</td><td rowspan="2"> Benzofuran-2-ylthiophen-2ylmethyl)-(2,4-</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="3"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> dichloro-benzoyl)-</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td> XX</td><td> X</td><td></td><td> Jl j OH</td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> compound</td><td> 2-[(2-Benzofuran-2-</td><td></td><td></td><td rowspan="2"> CI_X</td><td></td><td></td><td></td><td> +++</td>

<td rowspan="3"> #86</td><td rowspan="3"> yl-thiazol-5ylmethyl)-(2,4dichloro-benzoyl)-</td><td rowspan="3"></td><td rowspan="3"></td><td rowspan="3"> X</td><td rowspan="3"></td><td rowspan="3"></td><td rowspan="3"></td>

<td></td>

<td></td>

<td></td><td> amino]-3-phenyl-</td><td></td><td></td><td></td><td> r %</td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> / ί OH</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> s</td><td> Λ χ</td><td></td><td></td><td></td>

<td></td><td></td><td> XX</td><td>_xo</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> XX</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-{(2,4-</td><td> Cl</td><td></td><td></td><td> -Ci</td><td> +++</td><td></td><td></td>

<td rowspan="2"> #87</td><td> Dichloro-benzoyl)-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2"> [4-(3,4-dichlorophenyl) -thiophen-2-</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"> 0 ΧΛοη</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> ylmethyl]-amino}-3-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td rowspan="2"> phenyl-propi oni c acid</td><td></td><td></td><td></td><td> 7 0</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2"> cr</td><td> CI</td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-L[4-(4-</td><td> CK</td><td></td><td></td><td> -Cl</td><td> + + +</td><td></td><td></td>

<td> #88</td><td> Chioro-3-fluorophenyl ) -thi ophen-2-</td><td></td><td> T</td><td> JC</td><td> y° o</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]- (2,4-</td><td></td><td></td><td></td><td> '^νΓ^^οη</td><td></td><td></td><td></td>

<td></td><td> dichloro-benzoyl)-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> X</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2"> Cl·</td><td> F</td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-[[4-(3-</td><td> Cl</td><td colspan="2"></td><td> -Cl</td><td> +++</td><td></td><td></td>

<td> #89</td><td> Chloro-4-fluorophenyl) -thiophen-2-</td><td></td><td></td><td></td><td> Y° ft</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]- (2,4-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> dichloro-benzoyl)-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td></td><td></td><td> V</td><td></td><td></td><td></td><td></td>

<td></td><td> propionic acid,</td><td></td><td> f</td><td> A</td><td>⁷</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> Cl</td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2 s)—2—1 (2,4-</td><td> CK</td><td colspan="2"></td><td> -Cl</td><td> + + +</td><td></td><td></td>

<td rowspan="2"> #90</td><td> Dichloro-benzoyl)-</td><td></td><td colspan="2"> l T</td><td></td><td></td><td></td><td></td>

<td> [4-(2,4-dichloro-</td><td></td><td></td><td></td><td> +° Ο</td><td></td><td></td><td></td>

<td></td><td> phenyl)-thiophen-2ylmethyl]-amino}-3-</td><td></td><td></td><td></td><td> ΧχΛοκ</td><td></td><td></td><td></td>

<td></td><td> phenyl-propionic acid</td><td></td><td></td><td></td><td> 7‘Ο</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> Γ</td><td></td><td> Cl</td><td></td><td></td><td></td>

<td></td><td></td><td> c</td><td></td><td></td><td></td><td></td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="4"> Compound #</td><td rowspan="4"> Compound Name</td><td rowspan="4"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC_B„ (Um)</td><td> RNA pol</td>

<td> Assay 2</td>

<td rowspan="2"> 1C,, (Um)</td>

<td></td>

<td> compound #91</td><td> (2sT-2- [ [5-(3- Chloro-4-fluorophenyl) -thiophen-2ylmethyl]- (2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td> -OÇ Γ^Ν ι ^0H éfO \ y^ci F</td><td> ++ +</td><td></td>

<td> compound #92</td><td> (2s)-2-L L5-(4- chloro-3-fluorophenyl) -thiophen-2ylmethyl]- (2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td> o Cl</td><td> + + +</td><td></td>

<td> compound #93</td><td> (23)-2-((2,4- Dichloro-benzoyl)[5-(2,4-dichlorophenyl)-thiophen-2ylmethyl]-amino}-3phenyl-propionic acid</td><td> Χ^θο ^C|-M Cl</td><td> + + +</td><td></td>

<td> compound #94</td><td> (2s)-2-[(2,4- Dichloro-benzoyl) (5-thiazol-2-ylthiophen-2ylmethyl)-amino]-3phenyl-propi oni c acid</td><td> s-^</td><td> ++ +</td><td></td>

<td> compound #95</td><td> (2s)-2-((2,4- Dichloro-benzoyl)[5-(3,5-difluorophenyl)-thiophen-2ylmethyl]-amino}-3phenyl-propionic acid</td><td> h°^h ciA F</td><td> +++</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound. #</td><td> Compound Name</td><td> Structure</td><td> RNA pol Assay 1 IC_sn (dm)</td><td> RNA pol Assay 2 TC ..50 (Um)</td>

<td> compound #96</td><td> (2s)-2-{(2,4- Dichloro-benzoyl)[5-(3-methoxyphenyl) -thiophen-2ylmethyl]-amino)-3phenyl-propionic acid</td><td> ,,. ,0 rSA^N if^0H</td><td> ++ +</td><td></td>

<td> compound #97</td><td> (2s)-2-((2,4- Dichloro-benzoyl)[5-(3-fluorophenyl)-thiophen-2ylmethyl]-amino)-3phenyl-propionic acid</td><td> ,. fi jfj? if^0H</td><td> + + +</td><td></td>

<td> compound #98</td><td> (2s) -2- L (2,,4- Dichloro-benzoyl)thiophen-2ylmethyl-amino]-3pheny1-propi oni c acid</td><td> .,+ X» °</td><td> + + +</td><td></td>

<td> compound #99</td><td> (2s)-2-L(4-Bromo- thiophen-2ylmethyl) -(2,4dichloro-benzoyl) amino]-3-phenylpropionic acid</td><td> + ,0 AV /=^ ° Br^V^S</td><td> +++</td><td></td>

<td> compound #100</td><td> (2s)-2-((2,4- Dichloro-benzoyl)[2-(4-phenylpiperazin-l-yl)thiazol-5ylmethyl]-amino)-3phenyl-propionic acid</td><td> CL V b</td><td> ++</td><td></td>

<td> compound #101</td><td> (2s)-l-(5-{L(ls-1- Carboxy-2-phenylethyl)-(2,4dichloro-benzoyl) amino]-methyl}thiazol-2-yl)piperidine-4carboxylic acid</td><td> b</td><td> + +</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="2"> Compound. #</td><td rowspan="2"> Compound Name</td><td colspan="2" rowspan="2"> Structure -</td><td rowspan="2"> RNA pol Assay 1 IC„ (lim)</td><td> RNA pol</td>

<td> Assay 2 IÇ50 (Wm)</td>

<td rowspan="2"> compound #102</td><td> (2s)-2-[L2-(4- Benzyl-piperazin-1-</td><td> Ck</td><td> tr</td><td> +++</td><td></td>

<td rowspan="3"> yl)-thiazol-5ylmethyl]-(2,4dichloro-benzoyl) amino]-3-phenylpropionic acid</td><td rowspan="3"> fk Y^xn^/</td><td rowspan="3"> XL cfA ⁿ b</td><td rowspan="3"></td><td rowspan="3"></td>

<td></td>

<td></td>

<td rowspan="2"> compound #103</td><td> (2s,-2-((2,4- Dichloro-benzoyl) -</td><td> °k</td><td> =y^c|</td><td> +++</td><td></td>

<td> (2-piperidin-l-yl-</td><td rowspan="2"> %</td><td> J</td><td></td><td></td>

<td></td><td> thiazol-5-</td><td> X=o</td><td></td><td></td>

<td></td><td> ylmethyl)-amino]-3phenyl-propi oni c acid</td><td> X</td><td> r°</td><td></td><td></td>

<td></td><td></td><td> 0</td><td> o</td><td></td><td></td>

<td rowspan="2"> compound #104</td><td rowspan="5"> (2s)-2-[ (2,4- Dichloro-benzoyl)(2-diethylaminothiazol-5ylmethyl)-amino]-3phenyl-propi oni c acid</td><td rowspan="3">^CIO</td><td> /Cl</td><td rowspan="5"> +++</td><td rowspan="5"></td>

<td rowspan="4"> x° /? OH vx</td>

<td rowspan="2"></td>

<td> y</td>

<td></td><td> /V</td>

<td></td><td></td><td> J</td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-L[2-(4-</td><td></td><td></td><td> + +</td><td></td>

<td> #105</td><td> Chloro-benzoyl)benzofuran-3-</td><td> '”?T</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-(4-</td><td colspan="2"> YnT 9</td><td></td><td></td>

<td></td><td> methoxy-2,3,6-</td><td></td><td> -ⁿ-Y&lt;oh</td><td></td><td></td>

<td></td><td> trimethyl-</td><td rowspan="2"> Ori</td><td></td><td></td><td></td>

<td></td><td> benzenesulfonyl)-</td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenylpropionic acid</td><td> 0</td><td> X Cl</td><td></td><td></td>

<td rowspan="2"> compound #106</td><td> (2s)-2-L L5-(2,4- Dichloro-phenoxy)-</td><td></td><td></td><td> ++</td><td></td>

<td rowspan="2"> 1-methyl-3- trifluoromethyl-Ih-</td><td rowspan="2"> XX</td><td rowspan="3"> r°_o Ah</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> pyrazol-4-</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-(4-</td><td>^fW</td><td> OH</td><td></td><td></td>

<td></td><td> methoxy-2,3,6-</td><td></td><td> ) 'kkk</td><td></td><td></td>

<td></td><td> trimethyl-</td><td> 'N ¹</td><td> WyU</td><td></td><td></td>

<td></td><td> benzenesulfonyl)-</td><td> Cl—</td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td></td><td> V</td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td> Cl</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="4"> Compound #</td><td rowspan="4"> Compound Name</td><td rowspan="4"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC_sn (urn)</td><td> RNA pol</td>

<td> Assay 2</td>

<td rowspan="2"> (pm)</td>

<td></td>

<td> compound #107</td><td> (2s)-2-((2,4- Dichloro-benzoyl ) {2-(.5-(2,4dichloro-phenyl) furan-2-yl]-2-oxoethyl} -amino) -3phenyl-propionic acid</td><td> •v&gt;“ ,4+0</td><td> ++.+</td><td></td>

<td> compound #108</td><td> (2s)-2-Benzyl-4- (2,4-dichlorophenyl)-3-[3-(2,6dichloro-phenyl)-5methyl-isoxazol-4ylmethyl]-4-oxobutyric acid</td><td> ‘TÇ„ _|/^Ν'Ύ^ΟΗ 'ci ^N-°</td><td> ++ +</td><td></td>

<td> compound #109</td><td> (2s)-2-LAllyl-(2,4- dichloro-benzoyl) amino]-3-phenylpropionic acid</td><td> CIv^^.CI Chiral .N^GOjH</td><td> ++</td><td></td>

<td> compound #110</td><td> (2s)-2-[(2,4- Dichloro-benzoyl)methyl-amino]-3phenyl-propionic acid</td><td>^ci_ \=/ /N CO₂H</td><td> ++</td><td></td>

<td> compound #111</td><td> TO)-2-'TO, 4- Dichloro-benzoyl)prop-2-ynyl-amino]3-phenyl-propionic acid</td><td> TjÇ% ÂA, ¹¹ 4</td><td> ++</td><td></td>

<td> compound #112</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)propyl-amino]-3phenyl-propi oni c acid</td><td>^cl^yK° ^x=^/ .N_vCO₂H</td><td> +</td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="2"> Compound #</td><td rowspan="2"> Compound Name</td><td rowspan="2"> Structure</td><td> RNA pol' Assay 1 IC„ (pm)</td><td rowspan="2"> RNA pol Assay 2 ÎÇ50 (Um)</td>

<td></td>

<td> compound #113</td><td> (2s)-2-L (3- Benzofuran-2-ylprop-2-ynyl)-(2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td>^Cl\</td><td> +++</td><td></td>

<td> compound #114</td><td> (2s)-2-L(4- Benzofuran-2-ylphenyl) -(2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td> crA Cl</td><td> +++</td><td></td>

<td> compound #115</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)(3-methyl-but-2enyl)-amino]-3phenyl-propionic acid</td><td> \—/ ?N^CO₂H</td><td> ++</td><td></td>

<td> compound #116</td><td> 2-L(2-Bromo-aliyi)- (2,4-dichlorobenzoyl) -amino]-3pheny1-propi oni c acid</td><td> 'XXOt.. X'O</td><td> ++</td><td></td>

<td> Compound #117</td><td> 3-(L(l-Carboxy-2- phenyl-ethyl)-(2,4dichloro-benzoyl)amino]-methyl}benzoic acid methyl ester</td><td> Αχ™ ço'o 0</td><td></td><td> +++</td>

<td> Compound #118</td><td> 3-L L5-(3-Chioro-4- fluoro-phenyl)thiophen-2ylmethyl]- (2,4dichloro-benzoyl)amino]-5-phenylthiophene-2carboxylic acid</td><td>^cyyci f/</td><td></td><td> + + +</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound #</td><td> Compound Name</td><td colspan="3"> Structure</td><td> RNA pol Assay 1 IC₅₀ (Mm).</td><td> RNA pol Assay 2 Z&amp;o (Um)</td>

<td> Compound</td><td> 2 - [L 5-(3-Cyano-</td><td></td><td> IT</td><td></td><td></td><td> +++</td>

<td> #119</td><td> phenyl)-furan-2ylmethyl)-(2,4-</td><td>_CN</td><td> oY</td><td></td><td></td><td></td>

<td></td><td> dichloro-benzoyl)amino]-3-phenyl-</td><td> I</td><td> J</td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td rowspan="2"> Cl-s</td><td> I =</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> y u</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> ï,</td><td></td><td></td>

<td> compound</td><td> (2s)-2-((2,4-</td><td> F F</td><td></td><td> Cl Chiral</td><td> +++</td><td></td>

<td rowspan="2"> #120</td><td> Dichloro-benzoyl) -</td><td> H</td><td> TV-</td><td> o \=,</td><td></td><td></td>

<td> [5-(2-</td><td> Ar</td><td></td><td rowspan="2"> 'TT^CI γ™</td><td></td><td></td>

<td></td><td> tri fluoromethylphenyl) -furan-2-</td><td> U</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-amino)-3-</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td></td><td> C</td><td> )</td><td></td><td></td>

<td></td><td> acid,</td><td></td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-(5-(L(ls-1-</td><td></td><td></td><td>^c,\_</td><td> +++</td><td></td>

<td> #121</td><td> Carboxy-2-phenylethyl)-(2,4dichloro-benzoyl) -</td><td></td><td></td><td> T^CI</td><td></td><td></td>

<td></td><td> amino]-methyl)-</td><td></td><td></td><td> Γ°ο</td><td></td><td></td>

<td></td><td> thiophen-2-yl)-</td><td colspan="2"></td><td rowspan="2"> V il</td><td></td><td></td>

<td></td><td> benzoic acid ethyl ester</td><td></td><td> liY</td><td></td><td></td>

<td></td><td></td><td></td><td> u</td><td> b</td><td></td><td></td>

<td> compound</td><td> 3-(5-(L(ls-1-</td><td></td><td> Cl-</td><td></td><td> +++</td><td></td>

<td rowspan="2"> #122</td><td> Carboxy-2-phenyl-</td><td></td><td></td><td> TT _</td><td></td><td></td>

<td rowspan="3"> ethyl)-(2,4dichloro-benzoyl) amino]-methyl)-</td><td rowspan="3"></td><td rowspan="3"></td><td rowspan="3"> ,o „ J OH</td><td rowspan="3"></td><td rowspan="3"></td>

<td></td>

<td></td>

<td></td><td> thiophen-2-yl)-</td><td></td><td> □</td><td></td><td></td><td></td>

<td></td><td> benzoic acid ethyl</td><td> O''</td><td></td><td> AA ÏJ</td><td></td><td></td>

<td></td><td> ester</td><td> _/</td><td> u</td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-L[5-(3-</td><td> Cl</td><td></td><td> Cl</td><td> +++</td><td></td>

<td> #123</td><td> Chloro-phenyl)furan-2-ylmethyl]-</td><td> 0</td><td> Λ</td><td rowspan="2"></td><td> l</td><td></td>

<td rowspan="2"></td><td rowspan="2"> (2,4-dichlorobenzoyl) -amino]-3phenyl-propionic acid</td><td rowspan="2"></td><td rowspan="2"> \J</td><td rowspan="2"></td><td rowspan="2"></td>

<td> ί °^h</td>

<td></td><td></td><td></td><td></td><td> O</td><td></td><td></td>

<td rowspan="2"> compound #124</td><td> (2s)-2-L(4-Chloro- 2-iodo-benzoyl) -</td><td> CI-</td><td></td><td></td><td> ++ +</td><td></td>

<td> (3,5-dibromo-</td><td></td><td rowspan="2"></td><td> i n</td><td></td><td></td>

<td></td><td> thiophen-2-</td><td></td><td> Τα° o</td><td></td><td></td>

<td></td><td> ylmethyl)-amino]-3-</td><td></td><td colspan="2"> . A</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td></td><td> // V</td><td> 'oh</td><td></td><td></td>

<td></td><td> acid</td><td> Br</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> u</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> Compound Name</td><td colspan="4"> ° Structure</td><td> RNÀ</td><td> RNA pol</td>

<td> #</td><td></td><td></td><td></td><td></td><td></td><td> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> IC_sn (urn)</td><td> ÎÇao</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> (Llm)</td>

<td> compound</td><td> (2s) -3-(5-( L d-</td><td></td><td> Cl-</td><td></td><td> zCl</td><td> ++ +</td><td></td>

<td rowspan="2"> #125</td><td> Carboxy-2-phenyl-</td><td></td><td></td><td> L</td><td></td><td></td><td></td>

<td rowspan="3"> ethyl)-(2,4dichloro-benzoyl)amino]-methyl}-</td><td rowspan="3"></td><td rowspan="3"></td><td rowspan="3"> V</td><td rowspan="3"> V 0</td><td rowspan="3"></td><td rowspan="3"></td>

<td></td>

<td></td>

<td></td><td> thiophen-2-yl)-</td><td> o</td><td></td><td rowspan="2"> Xj</td><td> = OH</td><td></td><td></td>

<td></td><td> benzoic acid</td><td> HO^</td><td> Or</td><td> Ό</td><td></td><td></td>

<td></td><td></td><td></td><td> V</td><td></td><td></td><td></td><td></td>

<td> compound</td><td> (2s)-2-[[5-(5-</td><td></td><td></td><td></td><td> Chiral</td><td> +++</td><td></td>

<td> #126</td><td> Chloro-thiophen-2yl)-furan-2-</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> ylmethyl]- (2,4-</td><td></td><td></td><td colspan="2"> V ,^0H</td><td></td><td></td>

<td></td><td> dichloro-benzoyl)amino]-3-phenyl-</td><td rowspan="2"></td><td> /(</td><td></td><td rowspan="2"> A S Cl</td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td> O</td><td></td><td></td>

<td rowspan="2"> compound #127</td><td> (2s)-2- [[2,2 ' ]Bithiophenyl</td><td></td><td></td><td></td><td></td><td> +++</td><td></td>

<td rowspan="2"> -5-ylmethyl-(2,4dichloro-benzoyl)-</td><td rowspan="2"></td><td rowspan="2"> Cl I</td><td rowspan="2"> O</td><td rowspan="2"> A</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> amino]-3-phenylpropionic acid</td><td></td><td> 6</td><td> Ά</td><td></td><td></td><td></td>

<td></td><td></td><td> cK</td><td></td><td></td><td> o -s</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> (Γ</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2"> compound #128</td><td> (2s)-2-((5'-Chioro- [2,2']bithi opheny1-</td><td></td><td></td><td></td><td></td><td> +++</td><td></td>

<td> 5-ylmethyl)-(2,4-</td><td></td><td rowspan="2"> Cl I</td><td></td><td> AA</td><td></td><td></td>

<td></td><td> dichloro-benzoyl)-</td><td></td><td> II</td><td rowspan="2"> xz^0H</td><td></td><td></td>

<td rowspan="2"></td><td rowspan="3"> amino]-3-phenylpropionic acid</td><td rowspan="2"> ~ I</td><td rowspan="2"> Æ</td><td rowspan="2"> A</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> cr</td><td></td><td colspan="2"> \ t»</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td colspan="2"> LAO?</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> s-Λ</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> Cl</td><td></td><td></td>

<td> compound #129</td><td> (2s)-)^-( (2,4- Dichloro-benzoyl)[4-(3,5-difluoro-</td><td></td><td> Cl</td><td> 9</td><td> A</td><td> +++</td><td></td>

<td></td><td> phenyl)-thiophen-2-</td><td></td><td> A</td><td rowspan="2"> An</td><td> .OH</td><td></td><td></td>

<td></td><td> ylmethyl]-amino)-3-</td><td rowspan="2"> ci-</td><td></td><td> o</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td></td><td> /7</td><td> -s</td><td></td><td></td>

<td></td><td> acid</td><td></td><td></td><td> If</td><td> A</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> A F</td><td></td><td></td>

<td> compound</td><td> (2s,-2-((2,4-</td><td></td><td></td><td></td><td></td><td> +++</td><td></td>

<td> #130</td><td> Dichloro-benzoyl)[4-(3-fluoro-</td><td></td><td> Cl</td><td> g</td><td> jO</td><td></td><td></td>

<td></td><td> phenyl)-thiophen-2-</td><td></td><td> A</td><td> An</td><td> O°^H</td><td></td><td></td>

<td></td><td> ylmethyl]-amino)-3-</td><td></td><td> A</td><td></td><td> if</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td> Cl</td><td></td><td></td><td> -s</td><td></td><td></td>

<td></td><td> acid</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td colspan="2"> A</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> Compound Name</td><td colspan="2"> Structure</td><td> RNA pol</td><td> RNA pol</td>

<td> #</td><td></td><td></td><td></td><td> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td></td><td> IC,„ (Mm)</td><td> IÇ50</td>

<td></td><td></td><td></td><td></td><td></td><td> (Mm)</td>

<td rowspan="2"> compound #131</td><td> (2s)-2-((4-Chloro- 2-iodo-benzoyl)-[5-</td><td> Y</td><td> OC</td><td> +++</td><td></td>

<td rowspan="2"> (3-trifluoromethylphenyl ) -furan-2-</td><td rowspan="2"></td><td rowspan="2"> i?</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> ylmethyl]-amino}-3-</td><td></td><td></td><td></td><td></td>

<td></td><td rowspan="2"> phenyl-propionic acid</td><td></td><td> Υο</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> F _&lt;/^=X/ F</td><td></td><td></td>

<td rowspan="2"> compound #132</td><td> (2s)-2-((4-Chloro- 2-methyl-benzoyl)-</td><td> Ck</td><td> OCo</td><td> ++ +</td><td></td>

<td> [5-(3- tri fluoromethyl-</td><td></td><td></td><td></td><td></td>

<td></td><td> phenyl) -furan-2-</td><td></td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-amino}-3phenyl-propi oni c acid</td><td></td><td> Fv / F-\ F</td><td></td><td></td>

<td> compound</td><td> (2s)—2—[(5-Chioro-</td><td></td><td></td><td> +++</td><td></td>

<td> #133</td><td> [2,3']hithiophenyl5'-ylmethyl)-(2,4-</td><td></td><td> ί' fi</td><td></td><td></td>

<td></td><td> dichloro-benzoyl)-</td><td> r</td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenylpropionic acid</td><td> cC</td><td> Y s0</td><td></td><td></td>

<td></td><td></td><td></td><td> Ci</td><td></td><td></td>

<td> compound</td><td> l(2s)-2-{ (2,4-</td><td> Clx</td><td></td><td> +++</td><td></td>

<td rowspan="2"> #134</td><td> Dichloro-benzoyl)-</td><td></td><td> dCo</td><td></td><td></td>

<td> [5-(4-methoxy-</td><td></td><td></td><td></td><td></td>

<td></td><td> phenyl)-furan-2ylmethyl]-amino}-3-</td><td></td><td> f^N0^OH</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td></td><td></td><td></td><td></td>

<td></td><td> acid</td><td></td><td> OO</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 0 /</td><td></td><td></td>

<td> compound</td><td> (2s)-2-{(2,4-</td><td> Clx</td><td></td><td> + + +</td><td></td>

<td rowspan="2"> #135</td><td> Dichloro-benzoyl)-</td><td></td><td> OCo</td><td></td><td></td>

<td> [5-(4-methoxy-</td><td></td><td></td><td></td><td></td>

<td></td><td> phenyl) -thi ophen-2ylmethyl]-amino}-3-</td><td></td><td> ^^Νγ-ΟΗ</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td></td><td> γ's Ίί 0</td><td></td><td></td>

<td></td><td> acid</td><td></td><td> ^=\ oo</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 0 /</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="3"> Compound #</td><td rowspan="3"> Compound Name</td><td rowspan="3"> (Structure</td><td rowspan="2"> SNA pôi⁸ Assay 1 IC„ (Um)</td><td> RNA pol</td>

<td rowspan="2"> Assay 2 IÇso (Um)</td>

<td></td>

<td> compound #136</td><td> (2^)-2-((2,4- Dichloro-benzoyl)[4-(4-methoxyphenyl) -thiophen-2ylmethyl]-amino}-3phenyl-propionic acid</td><td> XXpo Λα.» Çy — ο</td><td> + + +</td><td></td>

<td> compound #137</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)(5-pyridin-4-ylfuran-2-ylmethyl)amino]-3-phenylpropionic acid</td><td> ci^c' Xç°„ Αά„ \=N</td><td> +++</td><td></td>

<td> compound #138</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)(5-pyri din-4-ylthiophen-2ylmethyl)-amino]-3phenyl-propi oni c acid</td><td> H ^0 \=N</td><td> +++</td><td></td>

<td> compound #139</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)- (4-pyridin-4-yl- thiophen-2- ylmethyl)-amino]-3- phenyl-propionic acid</td><td> TÇ, AA„ O</td><td> + + +</td><td></td>

<td> compound #140</td><td> (2s)-2-L(2-Chioro- thiazol-5ylmethyl)-(2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td> N-^J î OH h</td><td></td><td> + + +</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="4"> Compound #</td><td rowspan="4"> Compound Name</td><td rowspan="4"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC_sn (pm)</td><td> RNA pol</td>

<td> Assay 2</td>

<td rowspan="2"> îGso dim)</td>

<td></td>

<td> compound #141</td><td> (2s)-2-{(2,4- Dichloro-benzoyl)[5-(4-fluoropheny1) -thi ophen-2ylmethyl]-amino}-3phenyl-propionic acid</td><td> ÇI O iSfS i^0H Vs°</td><td></td><td> +++</td>

<td> compound #142</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)(3,5-dichlorobenzyl)-amino]-3phenyl-propi oni c acid</td><td> OXh</td><td></td><td> +++</td>

<td> compound #143</td><td> (2sT^LT(2,4- Dichloro-benzoyl) thiophen-3ylmethyl-amino]-3pheny1-propionic acid</td><td>_οοφσ⁰¹ ηΛΑ cyo</td><td></td><td> +++</td>

<td> compound #144</td><td> (2s')-2-q.72,4- Dichloro-benzoyl)(3-trifluoromethylbenzyl)-amino]-3phenyl-propionic acid</td><td> c'yyc. ₀°γΜ</td><td></td><td> + + +</td>

<td> compound #145</td><td> (2s)-2-[[3-(3- Chloro-4-fluorophenyl )-thiophen-2ylmethyl]- (2,4dichloro-benzoyl) amino]-3-phenylpropionic acid</td><td> aô+y ^hoXAC+ç, S-#</td><td></td><td> + +</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="4"> Compound #</td><td rowspan="4"> Compound Name</td><td rowspan="4"> Structure</td><td rowspan="3"> RNA pol Assay 1 ICY (pm)</td><td> RNA pol</td>

<td> Assay 2</td>

<td rowspan="2"> IC -=^50 (mn)</td>

<td></td>

<td> compound #146</td><td> (2s)-2-L(3-Bromo- thiophen-2ylmethyl)-(2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td> O, A ° ύ</td><td></td><td> + + +</td>

<td> compound #147</td><td> (2s)-2-{(2,4- Dichloro-benzoyl) - [5-(3- trifluoromethylphenyl) -furan-2ylmethyl]-amino}-2methyl-propionic acid</td><td> Ob</td><td></td><td> ++</td>

<td> compound #148</td><td> (2s)-2-{(2,4- Dichloro-benzoyl)[2-(3- trifluoromethylphenyl) -thiazol-5ylmethyl]-amino}-3pheny1-propi onic acid</td><td>^c'OÇo _F aⁿA°h T b</td><td></td><td> + + +</td>

<td> compound #149</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)(5-nitro-thiophen3-ylmethyl)-amino]3-phenyl-prop i oni c acid</td><td>^CI\Y^^CI ob N=O 0</td><td></td><td> +++</td>

<td> compound #150</td><td> (2s)-2-L(2,4- Dichloro-benzoyl)(4-methanesulfonylbenzyl)-amino]-3phenyl-propionic acid</td><td> /0 o=s=o</td><td></td><td> +++</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> Compound Name</td><td colspan="3"> Structure</td><td> RNA poi</td><td> RNA pol</td>

<td> #</td><td></td><td></td><td></td><td></td><td> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td></td><td></td><td> IC„ (Um)</td><td> IÇso</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> (dm)</td>

<td> compound</td><td> (2s)-2-((2,4-</td><td></td><td rowspan="2"> Cl</td><td></td><td></td><td> +++</td>

<td rowspan="2"> #151</td><td> Dichloro-benzoyl)-</td><td> w</td><td></td><td></td><td></td>

<td> (3-methoxy-benzyl) -</td><td> LA</td><td> .O</td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td></td><td> A 9</td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td> r</td><td> kA</td><td> OH</td><td></td><td></td>

<td></td><td></td><td> r</td><td> Sr</td><td> γ</td><td></td><td></td>

<td></td><td></td><td> X</td><td> a l</td><td> Y</td><td></td><td></td>

<td> compound</td><td> (2 s)-2-[(2,4-</td><td></td><td rowspan="2"> Cl</td><td></td><td></td><td> +++</td>

<td rowspan="2"> #152</td><td> Dichloro-benzoyl)-</td><td> w</td><td></td><td></td><td></td>

<td> (3-methyl-benzyl)-</td><td> LA</td><td></td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td> γχ</td><td> r 9</td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td> (</td><td> %A</td><td> OH</td><td></td><td></td>

<td></td><td></td><td> r</td><td> Sr</td><td> Y</td><td></td><td></td>

<td></td><td></td><td> xX</td><td> ί L</td><td> Y</td><td></td><td></td>

<td> compound</td><td> (2s)-2-L L5-(3-</td><td> Ck .</td><td> .Cl</td><td></td><td></td><td> + +</td>

<td rowspan="2"> #153</td><td> Chloro-phenoxy)-1-</td><td colspan="2"> τ T</td><td></td><td></td><td></td>

<td> methyl-3-</td><td colspan="2"></td><td></td><td></td><td></td>

<td></td><td> trifluoromethyl-lh-</td><td> U X</td><td></td><td></td><td></td><td></td>

<td></td><td> pyrazol-4-</td><td> À .N. HO a</td><td></td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-(2,4-</td><td> P \</td><td> Π s</td><td> .Cl</td><td></td><td></td>

<td></td><td> dichloro-benzoyl)-</td><td colspan="2"> AAX/ /V Ύ</td><td> Ύ</td><td></td><td></td>

<td></td><td> amino]-3-phenylpropionic acid</td><td> U^FF^Z Si</td><td></td><td> A</td><td></td><td></td>

<td> compound #154</td><td rowspan="2"> (2s)-2-((2,4- Dichloro-benzoyl)[3-(3,5-difluorophenyl)-thiophen-2-</td><td rowspan="2"> ex</td><td rowspan="2"> A</td><td rowspan="2"> Cl</td><td rowspan="2"></td><td rowspan="2"> + + +</td>

<td></td>

<td></td><td> ylmethyl]-amino)-3-</td><td>^HOY</td><td> N'^^‘0</td><td></td><td></td><td></td>

<td></td><td> phenyl-propi oni c</td><td>⁰ \</td><td></td><td> Y</td><td></td><td></td>

<td></td><td> acid</td><td> s</td><td></td><td> F</td><td></td><td></td>

<td rowspan="2"> compound #155</td><td> (2s)-2-{(2,4- Dichloro-benzoyl) -</td><td></td><td> Cl 1</td><td></td><td></td><td> + + +</td>

<td> [3-(3,4-dichloro-</td><td> AY</td><td></td><td></td><td></td><td></td>

<td></td><td> phenyl) -thi ophen-2-</td><td> UL</td><td> LA</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-amino)-3-</td><td> XX &gt;</td><td></td><td></td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td> HO. X</td><td> A</td><td></td><td></td><td></td>

<td></td><td> acid</td><td colspan="2"> Π / ⁰ o &lt; AY</td><td> -Cl</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> s</td><td> V</td><td> Cl</td><td></td><td></td>

<td> compound</td><td> (2s)-2-[[3-(4-</td><td></td><td> Cl</td><td></td><td></td><td> ++</td>

<td> #156</td><td> Chloro-3-fluorophenyl) -thiophen-2-</td><td></td><td> A</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]- (2,4-</td><td> LX</td><td> LA</td><td></td><td></td><td></td>

<td></td><td> dichloro-benzoyl) -</td><td> XX &gt;</td><td> Y^ci</td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td> HO. X</td><td> A</td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td colspan="2"> Y 7 X o ( rY</td><td> .Cl</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> s</td><td> x</td><td> F</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="4"> Compound #</td><td rowspan="4"> Compound Name</td><td rowspan="4"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC„ (um)</td><td> RNA pol</td>

<td> Assay 2</td>

<td rowspan="2"> (Um)</td>

<td></td>

<td> compound #157</td><td> (2s)-2-((2,4- Dichloro-benzoyl)[3-(2,4-dichlorophenyl )-thiophen-2ylmethyl]-amino]-3phenyl-propi oni c acid</td><td> OÂ ° \ ΛΪΓ ^SA Cl</td><td></td><td> + +</td>

<td> compound #158</td><td> (2s)'-T- [ (2/3- Dichloro-benzoyl)(3-m~tolylthiophen-2ylmethyl)-amino]-3phenyl-propionic acid</td><td>^HOySÀ&gt;</td><td></td><td> +++</td>

<td> compound #159</td><td> (2s)-2-(2-(L(ls-1- Carboxy-2-phenylethyl)-(2,4dichloro-benzoyl) amino]-methyl}thiophen-3-yl)benzoic acid ethyl ester</td><td> Cl Ck (A ^ΗγΥ c</td><td></td><td> + +</td>

<td> compound #160</td><td> (2s)-4-(2-(((ls-1- Carboxy-2-phenylethyl)-(2,4dichloro-benzoyl) amino]-methyl}thiophen-3-yl)benzoic acid ethyl ester</td><td> 0, ¢, HO. X. o</td><td></td><td> + + +</td>

<td> compound #161</td><td> (2sT-/-{ (2,4- Dichloro-benzoyl)[3-(3-fluorophenyl)-thiophen-2ylmethyl]-amino}-3pheny1-propi oni c acid</td><td> oA _s^Q_F</td><td></td><td> + +</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="2"> Compound #</td><td rowspan="2"> Compound Name</td><td rowspan="2"> Structure</td><td> RNA pol Assay 1 IC,_n (pm)</td><td rowspan="2"> RNA pol Assay 2 IC (Urn)</td>

<td></td>

<td> compound #162</td><td> (2s)-2-L L3-(3- Cyano-phenyl) thiophen-2ylmethyl]- (2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td> α,ά, ^ΗΟγ/Α&gt;</td><td></td><td> + + +</td>

<td> compound #163</td><td> { (2,4-Dichloro- benzoyl)-[5-(3tri fluoromethylphenyl)-furan-2ylmethyl]-amino}thi ophen-2-y1acetic acid</td><td> ci ci °T”, OO Ο-Λ F</td><td></td><td> ++</td>

<td> compound #164 1</td><td> L-2-{L(l-Carboxy-2- phenyl-ethyl)-(2,4dichloro-benzoyl)amino]-methyl}pyrrolidine-1carboxylic acid #tert!-butyl ester</td><td> Οχ/χΛΙΙ Chiral ςώΧ Y Y</td><td></td><td> + +</td>

<td> compound #165</td><td> d-2-{L(l-carboxy-2- phenyl-ethyl)-(2,4dichloro-benzoyl) amino]-methyl}pyrrolidine-1carboxylic acid #tert!-butyl ester</td><td> θΙγΥγ/θ' Chiral çÛX s 'ό</td><td></td><td> ++</td>

<td> compound #166</td><td> 4-L(l-Carboxy-2- phenyl-ethyl)-(2,4di chloro-benzoyl)amino]-piperidine1-carboxylic acid benzyl ester</td><td> Chiral υφ °Υ^Ν\Υ 0</td><td></td><td> + +</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="3"> Compound #</td><td rowspan="3"> Compound Name</td><td rowspan="3"> Structure</td><td rowspan="3"> RNA pol Assay 1 ic₅o._Oi).·</td><td> RNA pol</td>

<td> Assay 2</td>

<td> (pm)</td>

<td> compound #167</td><td> 1-2-[(2,4-Dichloro- benzoyl) pyrrolidin-2ylmethyl-amino]-3phenyl-propionic acid</td><td> Chiral ςώχ ^H</td><td></td><td> ++</td>

<td> compound #168</td><td> d-2-[(2,4-Dichioro- benzoyl) pyrrolidin-2ylmethyl-amino]-3pheny1-propionic acid</td><td> CI\z/\/CI Chiral O/,% ^H Lk</td><td></td><td> ++</td>

<td> compound #169</td><td> 3-(5-Bromo- thiophen-2-yl)-2[(2,4-dichlorobenzoyl) -methylamino] -propionic acid</td><td> Br</td><td></td><td> ++ +</td>

<td> compound #170</td><td> 2-[(2,4-Dichloro- benzoyl)-pyridin-3ylmethyl-amino]-3phenyl-propionic acid</td><td> k/o AA„</td><td></td><td> + +</td>

<td> compound #171</td><td> 2-L(2,4-Dichloro- benzoyl)-(4trifluoromethylbenzyl)-amino]-3phenyl-propionic acid</td><td>^Clri/ri/^CI «A AÂ σό F-J p/rip</td><td></td><td> + +</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> Compound Name</td><td colspan="2"> Structure</td><td> RNA pol</td><td> RNA pol</td>

<td> #</td><td></td><td></td><td></td><td> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td></td><td> IC_B„ (dm)</td><td> ÎÇgo</td>

<td></td><td></td><td></td><td></td><td></td><td> (dm)</td>

<td> compound</td><td> 2-{(2,4-Dichioro-</td><td></td><td></td><td></td><td> + +</td>

<td></td><td> benzoyl)-(4-(4-</td><td></td><td> n 1 Y</td><td></td><td></td>

<td></td><td> fluoro-benzyloxy)-</td><td> 0</td><td></td><td></td><td></td>

<td></td><td> benzyl]-amino}-3-</td><td> 1</td><td> J</td><td></td><td></td>

<td></td><td> phenyl-propi oni c</td><td> HO^</td><td> γΝ</td><td></td><td></td>

<td></td><td> acid</td><td></td><td> ) X</td><td></td><td></td>

<td></td><td></td><td></td><td> rrii</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> ri</td><td></td><td></td>

<td></td><td></td><td></td><td> A</td><td></td><td></td>

<td></td><td></td><td></td><td> Y F</td><td></td><td></td>

<td> compound</td><td> 2-((2,4-Dichloro-</td><td></td><td> Ck XI</td><td></td><td> ++</td>

<td> Ü1 77</td><td> benzoyl)-(4-fluoro-</td><td></td><td> w</td><td></td><td></td>

<td></td><td> 3-trifluoromethyl-</td><td></td><td> As. J</td><td></td><td></td>

<td></td><td> benzyl)-amino]-3-</td><td> 0</td><td> XY YY</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td> A</td><td></td><td></td><td></td>

<td></td><td> acid</td><td> Her</td><td></td><td></td><td></td>

<td></td><td></td><td> Ax</td><td>^J Λ</td><td></td><td></td>

<td></td><td></td><td> u</td><td> UX</td><td></td><td></td>

<td></td><td></td><td></td><td> Tri</td><td></td><td></td>

<td> compound</td><td> 2-((1-</td><td colspan="2"> Ck χ-s XI</td><td></td><td> ++</td>

<td> 7 Δ.</td><td> Benzenesulfonyl-lh-</td><td></td><td> T ï</td><td></td><td></td>

<td></td><td> pyrrol-2-ylmethyl)-</td><td> 0.</td><td> XX</td><td></td><td></td>

<td></td><td> (2,4-dichloro-</td><td> 0 ^x</td><td> &lt;X YY</td><td></td><td></td>

<td></td><td> benzoyl)-amino]-3-</td><td></td><td></td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td> ho^Y</td><td> ri 0</td><td></td><td></td>

<td></td><td> acid</td><td></td><td> À //</td><td></td><td></td>

<td></td><td></td><td> (ΙΊ</td><td> A-fV</td><td></td><td></td>

<td></td><td></td><td></td><td> \=/ 0</td><td></td><td></td>

<td> compound</td><td> 2-((3-(4-Chloro-</td><td></td><td> Ck XI</td><td></td><td> ++</td>

<td> #1 7R</td><td> phenoxy)-benzyl]-</td><td></td><td> YY</td><td></td><td></td>

<td></td><td> (2,4-dichloro-</td><td></td><td></td><td></td><td></td>

<td></td><td> benzoyl)-amino]-3-</td><td> 0 II</td><td> XX XX</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td> Λ</td><td></td><td></td><td></td>

<td></td><td> acid</td><td> HO</td><td> TA</td><td></td><td></td>

<td></td><td></td><td></td><td>^J Λ</td><td></td><td></td>

<td></td><td></td><td> U</td><td> TT</td><td></td><td></td>

<td></td><td></td><td></td><td> A</td><td></td><td></td>

<td></td><td></td><td></td><td> A</td><td></td><td></td>

<td></td><td></td><td></td><td> Cl</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="2"> Compound #</td><td rowspan="2"> Compound Name</td><td rowspan="2"> Structure</td><td rowspan="2"> RNA pol Assay 1 IC_cn (Um)</td><td> RNA pol</td>

<td> Assay 2 ÎÇ50 (Um)</td>

<td> compound #176</td><td> 2-L(5-Chioro-2- chloromethyl-hepta2,4,6-trienoyl) guinolin-3ylmethyl-amino]-3pheny1-propionic acid</td><td> „οσ xl ho γ X σά</td><td></td><td> ++</td>

<td> compound #177</td><td> 2-L(2-Benzyloxy- benzyl)-(2,4dichloro-benzoyl)amino]-3-phenyl- propionic acid</td><td>^ci^Y^ci 0°γΤ kk</td><td></td><td> ++</td>

<td> compound #178</td><td> 2-((2,4-Dichioro- benzoyl)-[3-(5isopropyl-2methoxy-phenyl) thiophen-2ylmethyl]-amino}-3phenyl-propionic acid</td><td> Cl αΦ = Th₃cTch₃ HO. z\ T. T ¥&gt; °Λ ° XT</td><td></td><td> ++</td>

<td> compound #179</td><td> 2-((2,4-Dichloro- benzoyl) -[3- (4trifluoromethoxyphenyl)-thiophen-2ylmethyl]-amino}-3phenyl-propionic acid</td><td> ok HO. /C F ΥφπΎ ° kk F ^sk</td><td></td><td> ++</td>

<td> compound #180</td><td> 2-((2,4-Dichloro- benzoyl)-[3-(3trifluoromethylphenyl) -thi ophen-2ylmethyl]-amino} - 3 phenyl-propionic acid</td><td> ok ^Sk ^F F</td><td></td><td> + +</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound.</td><td> Compound Name</td><td colspan="2"> Structure</td><td> RNA pol</td><td> RNA pol</td>

<td> #</td><td></td><td></td><td></td><td> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td></td><td> IC„ (dm)</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> (dm)</td>

<td rowspan="2"> compound #181</td><td> 2-'L L3- (3, b-Bis- trifluoromethyl-</td><td></td><td> Cl 1</td><td></td><td> ++</td>

<td> phenyl)-thiophen-2-</td><td> XXi rf</td><td rowspan="2"> S</td><td></td><td></td>

<td></td><td> ylmethyl]- (2,4-</td><td> Γ H \</td><td></td><td></td>

<td></td><td> dichloro-benzoyl)-</td><td></td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td></td><td> ι ^fA^f</td><td></td><td></td>

<td></td><td> propionic acid</td><td> HO. .</td><td> A r^F</td><td></td><td></td>

<td></td><td></td><td> x</td><td> n</td><td></td><td></td>

<td></td><td></td><td>⁰ \_</td><td></td><td></td><td></td>

<td></td><td></td><td> s_x</td><td> A ^FF</td><td></td><td></td>

<td> compound</td><td> 2-((2,4-Dichloro-</td><td></td><td rowspan="2"> Cl 1</td><td></td><td> ++</td>

<td rowspan="2"> #182</td><td> benzoyl)-(3-</td><td></td><td></td><td></td>

<td> pyridin-4-yl-</td><td></td><td></td><td></td><td></td>

<td></td><td> thiophen-2-</td><td> 1 H</td><td> ί ι</td><td></td><td></td>

<td></td><td> ylmethyl)-amino]-3-</td><td></td><td> VA ,</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td></td><td> X XI</td><td></td><td></td>

<td></td><td> acid</td><td> V;</td><td> An</td><td></td><td></td>

<td></td><td></td><td> o \</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td> compound</td><td> 2-((2,4-Dichloro-</td><td colspan="2"> Cl</td><td></td><td> + +</td>

<td> #183</td><td> benzoyl)-[3-(4methylsulfanyl-</td><td></td><td> A</td><td></td><td></td>

<td></td><td> phenyl)-thiophen-2ylmethyl]-amino]-3-</td><td> CA t</td><td rowspan="2"> Ac</td><td></td><td></td>

<td></td><td> phenyl-propi oni c</td><td> =</td><td></td><td></td>

<td></td><td> acid</td><td> X</td><td> r A ^ch3</td><td></td><td></td>

<td></td><td></td><td> O</td><td> AX</td><td></td><td></td>

<td></td><td></td><td colspan="2">^sV</td><td></td><td></td>

<td rowspan="2"> compound #184</td><td> 2-((2,4-Dichloro- benzoyl) - [3- (4-</td><td></td><td> Cl A</td><td></td><td> +++</td>

<td rowspan="2"> fluoro-phenyl)thiophen-2-</td><td rowspan="2"> ÛL ί</td><td rowspan="2"> 1</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> ylmethyl]-amino}-3-</td><td></td><td rowspan="2"> γχ,</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td></td><td></td><td></td>

<td></td><td> acid</td><td> V?</td><td> Χγ Γ H</td><td></td><td></td>

<td></td><td></td><td>⁰ \</td><td> AJ)</td><td></td><td></td>

<td></td><td></td><td> s\</td><td> X</td><td></td><td></td>

<td rowspan="2"> compound #185</td><td> 2-L(2,4-Dichloro- benzoyl)-(3-</td><td></td><td> Cl 1</td><td></td><td> +++</td>

<td> pyridin-3-yl-</td><td></td><td> A,</td><td></td><td></td>

<td></td><td> thiophen-2ylmethyl)-amino]-3-</td><td> kA</td><td rowspan="2"> a,</td><td></td><td></td>

<td></td><td> phenyl-propionic</td><td></td><td></td><td></td>

<td></td><td> acid</td><td>^H0X</td><td></td><td></td><td></td>

<td></td><td></td><td> 0 \</td><td> \ AX</td><td></td><td></td>

<td></td><td></td><td> c</td><td> A</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="3"> Compound #</td><td rowspan="3"> Compound Name</td><td rowspan="3"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC„ (um)</td><td> RNA pol</td>

<td> Assay 2</td>

<td> I&amp;o (Um)</td>

<td> compound #186</td><td> 2-( (2 ,4-Dichloro- benzoyl)-[1(toluene-2sulfonyl)pyrr olidin-2ylmethyl]-amino}-3pheny1-propi oni c acid</td><td> Cl Chiral c,^p _oçuX Qf° γ Y AA</td><td></td><td></td>

<td> compound #187</td><td> 2-L(2-Bromo- benzyl) -(2,4dichloro-benzoyl)amino]-3-phenylpropionic acid</td><td>^cly/y/^cl Ik</td><td></td><td> + +</td>

<td> compound #188</td><td> 3-(2-Bromo-phenyl)- 2- [ (2,4-dichlorobenzoyl)-methylamino] -propionic acid</td><td> Ύ Xa H,C ^V OH io</td><td></td><td> ++</td>

<td> compound #189</td><td> 3-(4-Bromo-phenyl)- 2-((2,4-dichlorobenzoyl) -methylamino] -propionic acid</td><td> Όγθο Ià H,C Y 1)H A</td><td></td><td> + + +</td>

<td> compound #190</td><td> 2-[(3-Bromo- phenyl)-(2,4dichloro-benzoyl) amino]-3-phenylpropionic acid</td><td> Μγ°₀ Y</td><td></td><td> ++ flashpl ate</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="2"> Compound #</td><td rowspan="2"> Compound Name</td><td colspan="4" rowspan="2"> Structure</td><td rowspan="2"> RNA pol Assay 1 IC.„ (um)</td><td> RNA pol Assay 2</td>

<td> i&amp;o (Um)</td>

<td> compound</td><td> 2-[(4-Bromo-</td><td></td><td></td><td rowspan="2"> ?</td><td></td><td></td><td> +</td>

<td> #191</td><td> phenyl)-(2,4dichloro-benzoyl) -</td><td colspan="2"> fV</td><td> OH</td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td colspan="2"> IL J</td><td rowspan="2"></td><td rowspan="2"> sO</td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td> /=7</td><td></td><td></td>

<td></td><td></td><td></td><td> M</td><td> z</td><td>^Cl</td><td></td><td></td>

<td></td><td></td><td> bZ</td><td></td><td> T</td><td> β</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> Cl</td><td></td><td></td><td></td>

<td rowspan="2"> Compound #192</td><td> 2- [T4~-(3-Chloro-4- fluoro-phenyl) -</td><td></td><td></td><td></td><td></td><td></td><td> + + +</td>

<td> thiophen-2-</td><td> rA</td><td colspan="2"> (ι Ί</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]- (2,4-</td><td> LZL</td><td colspan="2"></td><td></td><td></td><td></td>

<td></td><td> dimethyl-benzoyl)-</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td> HO. &gt;</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td colspan="2"> IT 1</td><td> O</td><td></td><td></td><td></td>

<td></td><td></td><td> o</td><td colspan="2"></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td colspan="2"> sX</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> Cl</td><td></td><td></td>

<td rowspan="2"> Compound #193</td><td> 3—{L(l-Carboxy-2- phenyl-ethyl)-(2,4-</td><td>^Cki</td><td></td><td> .Cl</td><td></td><td></td><td> +++</td>

<td> dichloro-benzoyl)-</td><td></td><td rowspan="2"> X</td><td></td><td></td><td></td><td></td>

<td></td><td> amino]-methyl}-</td><td></td><td></td><td> o</td><td></td><td></td>

<td></td><td> benzoic acid</td><td></td><td> r</td><td colspan="2"> Άοη</td><td></td><td></td>

<td></td><td></td><td></td><td> r</td><td> Ϊ]^K</td><td></td><td></td><td></td>

<td></td><td></td><td>^HO</td><td> X</td><td> β</td><td> U</td><td></td><td></td>

<td></td><td></td><td> II 0</td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2"> Compound #194</td><td> 2-[(3-Amino- benzyl)-(2,4-</td><td>^Cl\/</td><td></td><td> Cl</td><td></td><td></td><td> + +</td>

<td rowspan="2"> dichloro-benzoyl)amino]-3-phenyl-</td><td rowspan="2"> I</td><td rowspan="2"> J</td><td rowspan="2"></td><td rowspan="2"> n</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td>

<td></td><td> propionic acid</td><td></td><td> r</td><td colspan="2"> A°h</td><td></td><td></td>

<td></td><td></td><td></td><td> r</td><td></td><td> Χί</td><td></td><td></td>

<td></td><td></td><td> Η,Ν''</td><td> X</td><td> !l</td><td> u</td><td></td><td></td>

<td> Compound</td><td> 2-[Benzyl-(2,4-</td><td></td><td></td><td rowspan="2"> Cl &gt;</td><td></td><td></td><td> + +</td>

<td> #199</td><td> dichloro-benzoyl)amino]-3-phenyl-</td><td></td><td> 0</td><td> A</td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td> X</td><td> -&lt;</td><td></td><td></td><td></td>

<td></td><td></td><td> U.</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> β</td><td colspan="2"> s. OH</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846

PCT/CA02/00877

<td> Compound</td><td rowspan="2"> Compound Name</td><td></td><td></td><td> Structure</td><td></td><td> RNA pol</td><td> RNA pol</td>

<td> #</td><td></td><td></td><td></td><td></td><td> Assay 1</td><td> Assay 2</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> IC„ (Urn)</td><td> I&amp;o</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> (Urn)</td>

<td> Compound #200</td><td> 2-((2,4-DICHLORO- BENZOYL)-[3-(2HTETRAZOL-5-YL)BENZYL]-AMINO}-3PHENYL-PROPIONIC ACID</td><td></td><td> ck</td><td> TO Y</td><td> OH</td><td></td><td> + + +</td>

<td></td><td></td><td></td><td></td><td> A Sr</td><td></td><td></td><td></td>

<td></td><td></td><td colspan="3"> N If n-n H</td><td> TO¹</td><td></td><td></td>

<td> Compound #201</td><td> 2-L(2,4-DICHLORO- BENZOYL)-(2-NITROBENZYL) -AMINO]-3PHENYL-PROPIONIC ACID</td><td> Ί</td><td> 0</td><td>_XCI V° o Yoh</td><td></td><td></td><td> ++</td>

<td></td><td></td><td> no₂</td><td> A</td><td> Ί TOi</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> s</td><td> F U</td><td></td><td></td><td></td>

<td> Compound #202</td><td> 2-L(2,4-DICHLORO- BENZOYL)-(4-NITROBENZYL) -AMINO]-3PHENYL-PROPIONIC ACID</td><td>^c't</td><td> TC r</td><td> Cl +° O TO°h</td><td></td><td></td><td> ++</td>

<td></td><td></td><td></td><td> r</td><td> ί SA</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> V</td><td> J U</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td colspan="2"> no₂</td><td></td><td></td><td></td>

<td> Compound #203</td><td> 2-L(2-CYANO- BENZYL)-(2,4DICHLORO-BENZOYL)AMINO]-3-PHENYLPROPIONIC ACID</td><td>^C'T</td><td> y r</td><td> XI γ° o '^NASh</td><td></td><td></td><td> + +</td>

<td></td><td></td><td> CN.</td><td></td><td> Il Sa</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> r to</td><td> u</td><td></td><td></td><td></td>

<td> Compound #204</td><td> 2- I (4-CYANO- BENZYL)-(2,4DICHLORO-BENZOYL)AMINO]-3-PHENYLPROPIONIC ACID</td><td>^C'T</td><td> r</td><td> Cl +° O TOo„</td><td></td><td></td><td> ++</td>

<td></td><td></td><td></td><td> r</td><td> ii sa</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td colspan="2"> CN</td><td></td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td rowspan="4"> Compound #</td><td rowspan="4"> Compound Name</td><td rowspan="4"> Structure</td><td rowspan="3"> RNA pol Assay 1 IC_sn (dm)</td><td> RNA pol</td>

<td> Assay 2</td>

<td rowspan="2"> I&amp;o (dm)</td>

<td></td>

<td> Compound #205</td><td> 2-L[1-(3-CYANO- PHENYL)-ETHYL](2,4-DICHLOROBENZOYL) -AMINO]-3PHENYL-PROPIONIC ACID</td><td> γχ% ^h3Cx^.N_x_JL_0H .,0 'Ό</td><td></td><td> ++</td>

<td> Compound #206</td><td> 3-( [ (1-Carboxy-2- phenyl-ethyl)-(2,4dichloro-benzoyl ) amino]-methyl}benzoic acid methyl ester</td><td> xc₀_ru„ œO 0</td><td></td><td> ++ +</td>

<td> Compound #207</td><td> 3-(L(l-Carboxy-2- phenyl-ethyl)-(2,4dichloro-benzoyl)amino]-methyl}benzoic acid</td><td> Μ» 0</td><td></td><td> +++</td>

<td> Compound #208</td><td> 2- [ (2,4-DICHLORO- BENZOYL)-(3METHANESULFONYLBENZYL)-AMINO]-3PHENYL-PROPIONIC ACID</td><td> fY°H γθ Ό II Ο</td><td></td><td> ++</td>

<td> Compound #209</td><td> 2-L(3-ACETYL- BENZYL)-(2,4DICHLORO-BENZOYL)AMINO]-3-PHENYLPROPIONIC ACID</td><td>^α\/θΥΙ OÇo_o y^N&gt;XoH ch₃</td><td></td><td> +++</td>

<td> Compound #210</td><td> 2-L(2,4-DICHLORÔ- BENZOYL)-(1-OXYPYRIDIN-3YLMETHYL)-AMINO]-3PHENYL-PROPIONIC ACID</td><td> Wo M» Χό</td><td></td><td> + + +</td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound #</td><td> Compound Name</td><td> Structure</td><td> RNA pol Assay 1 lC₅o. (Mm)</td><td> RNA pol Assay 2 IGso (Um)</td>

<td> Compound #211</td><td> 2-{(2,4-Dichloro- benzoyl)-[5-(3trifluoromethylphenyl)-thiophen-2ylmethyl]-amino}-3phenyl-propionic acid</td><td> TÇ F _F S-Λ ; OH TT b</td><td></td><td> ++</td>

* : +++ IC₅₀ &lt;5μΜ ++ IC₅₀ 5μΜ-20μΜ + IC₅₀ &gt;20μΜ

TABLE 2. LIST OF COMPOUNDS HAVING ANTI-HELICASE ACTIVITY

<td> Compound.</td><td> Compound name</td><td colspan="2"> Structure</td><td> Anti-</td><td> Anti-</td>

<td> #</td><td></td><td></td><td></td><td> ATPase</td><td> ATPase</td>

<td></td><td></td><td></td><td></td><td> activity</td><td> activity</td>

<td></td><td></td><td></td><td></td><td> (Malachite</td><td> (HPLC</td>

<td></td><td></td><td></td><td></td><td> Green</td><td> method)</td>

<td></td><td></td><td></td><td></td><td> assay) EC₅₀</td><td> ec₅₀</td>

<td></td><td></td><td></td><td></td><td> (gm)</td><td> (gm)</td>

<td> Compound</td><td> (2s)-2-L(4-</td><td colspan="2"></td><td> + +</td><td> ++</td>

<td></td><td> Benzofuran-2-yl-</td><td></td><td> T Γ</td><td></td><td></td>

<td></td><td> benzyl)-(2,4-</td><td></td><td> TT</td><td></td><td></td>

<td></td><td> dichloro-</td><td></td><td> M ⁰</td><td></td><td></td>

<td></td><td> benzoyl)-amino]-</td><td></td><td> N ii</td><td></td><td></td>

<td></td><td> 3-phenyl-</td><td></td><td> j| OH</td><td></td><td></td>

<td></td><td> propionic acid,</td><td> U-b</td><td> γγ</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td> Compound</td><td> (2s)— 2 —L(2 —</td><td>^CIMV^CI</td><td></td><td> ++ +</td><td> + +</td>

<td> #1 1</td><td> Benzofuran-2-yl-</td><td> TT</td><td></td><td></td><td></td>

<td> Hl</td><td> benzyl)-(2,4-</td><td> W_o</td><td></td><td></td><td></td>

<td></td><td> dichloro-</td><td> I i</td><td></td><td></td><td></td>

<td></td><td> benzoyl)-amino]-</td><td> Fy&gt;oh</td><td></td><td></td><td></td>

<td></td><td> 3-phenyl-</td><td> .A ΎΊ</td><td></td><td></td><td></td>

<td></td><td> propionic acid,</td><td> UTU</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td> Compound</td><td> 2-((5-</td><td>^Cl\^\</td><td> /^C|</td><td> + +</td><td> + +</td>

<td></td><td> Benzofuran-2-yl-</td><td> π</td><td></td><td></td><td></td>

<td> ffOJ</td><td> thiophen-2-</td><td> V</td><td> v°</td><td></td><td></td>

<td></td><td> ylmethyl)-(2,4-</td><td></td><td> T /?</td><td></td><td></td>

<td></td><td> dichloro-</td><td> \ If &gt;_Z ||</td><td></td><td></td><td></td>

<td></td><td> benzoyl)-amino]-</td><td></td><td> ; OH</td><td></td><td></td>

<td></td><td> 3-phenyl-</td><td></td><td> TT</td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td> u</td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2003-12-08

WO 02/100846 PCT/CA02/00877

<td> Compound</td><td> (2s)-2-L(4-</td><td colspan="3"> // X</td><td> ++</td><td> + +</td>

<td rowspan="2"> #5</td><td> Benzofuran-2-yl-</td><td></td><td> x_7</td><td></td><td></td><td></td>

<td rowspan="3"> benzyl)-(4methoxy-2,3,6trimethylbenzenesulfonyl)</td><td rowspan="3"> X</td><td rowspan="3"> V $</td><td rowspan="3"></td><td rowspan="3"></td><td rowspan="3"></td>

<td></td>

<td></td>

<td></td><td> -amino]-3-</td><td> L</td><td></td><td></td><td></td><td></td>

<td></td><td rowspan="2"> phenyl-propi oni c acid,</td><td></td><td colspan="2"> T nN. U ¹ o h</td><td></td><td></td>

<td></td><td></td><td> o</td><td></td><td></td><td></td>

<td> Compound</td><td> (2s)-2-L(3-</td><td> !</td><td></td><td></td><td> ++</td><td> +</td>

<td> #7</td><td> Benzofuran-2-ylbenzyl)-(4-</td><td colspan="2"> ο Z Lu</td><td></td><td></td><td></td>

<td></td><td> methoxy-2,3,6trimethylbenzenesulfonyl)</td><td></td><td>₀₌=S^° ⁰</td><td></td><td></td><td></td>

<td></td><td> -amino]-3phenyl-propionic</td><td></td><td> o±p</td><td></td><td></td><td></td>

<td></td><td> acid, compound #7</td><td> ··</td><td></td><td></td><td></td><td></td>

<td rowspan="2"> Compound #195</td><td> 3-Phenyl-2-{. (2- tri fluoromethyl-</td><td></td><td></td><td></td><td> + +</td><td> ++</td>

<td> benzoyl)-[5-(2-</td><td></td><td> J</td><td></td><td></td><td></td>

<td></td><td> trifluoromethyl-</td><td></td><td> !</td><td></td><td></td><td></td>

<td></td><td> phenyl)-furan-2ylmethyl]-</td><td></td><td> X/</td><td></td><td></td><td></td>

<td></td><td> amino}-propi oni c acid</td><td> Ç</td><td> T</td><td></td><td></td><td></td>

<td></td><td></td><td>^f&gt;L</td><td> o LZ</td><td></td><td></td><td></td>

<td></td><td></td><td> F</td><td> F 0</td><td></td><td></td><td></td>

<td> Compound</td><td> 2-{(3-Cyano-</td><td></td><td> F Fi</td><td rowspan="2"> Λ</td><td> +++</td><td> +++</td>

<td rowspan="2"> #196</td><td> benzoyl)-[5-(2-</td><td></td><td> F-y-Z</td><td></td><td></td>

<td> tri fluoromethyl-</td><td></td><td> / \</td><td></td><td></td><td></td>

<td></td><td> phenyl) -furan-2-</td><td></td><td> F /</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> amino] - 3-phenyl-</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td></td><td> r il</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> °οΛ</td><td> 0</td><td></td><td></td>

<td> Compound</td><td> 2-{(4-Nitro~</td><td></td><td> F ΓΓ</td><td rowspan="2"> A</td><td> +++</td><td> +++</td>

<td rowspan="2"> #197</td><td> benzoyl)-[5-(2-</td><td></td><td>_FS__Z</td><td></td><td></td>

<td> trifluoromethyl-</td><td></td><td>^Γ / Y</td><td></td><td></td><td></td>

<td></td><td> phenyl) -furan-2-</td><td rowspan="2"> A</td><td> F Γ</td><td></td><td></td><td></td>

<td></td><td> ylmethyl]-</td><td rowspan="2"> Η 7^./</td><td></td><td></td><td></td>

<td></td><td> amino]-3-phenyl-</td><td> nA</td><td></td><td></td><td></td>

<td></td><td> propionic acid</td><td> 0</td><td> χχ</td><td> χ</td><td></td><td></td>

<td></td><td></td><td></td><td> 0 À</td><td> J-</td><td></td><td></td>

<td></td><td></td><td></td><td> 0 X</td><td></td><td></td><td></td>

SUBSTITUTE SHEET (RULE 26)

CA 02449999 2011-05-03

Compound #198

2-((2-Piuorobenzoyl)-(5-(2tri fluoromethylphenyl)- furan-2ylmethylJ amino)-3-phenylpropionic acid

<img file="CA2449999C_D0066.tif" />

* : +++ IC₅₀ &lt;5μΜ ++ IC₅₀ 5μΜ-20μΜ + ICso &gt;2O|1M

Example 6 Evaluation of Biaryl Analogues in The HCV RNADependent RNA Polymerase Assay

1. Behrens, S., Tomei, L., De Francesco, R. (1996) EMBO 15, 1222

2. Harlow, E, and Lane, D. (1988) Antibodies: A LaboratoryManual. Cold Spring Harbord Laboratory. Cold Spring Harbord. NY.

3.. Lohmann, V., Kômer, F., Herian, U., and Bartenschlager, R. (1997, J. Virol. 71, 8416-8428

4. Tomei, L., Faille, C., Santolini, E., De Francesco, R., and La Monica, N. (1993, J Virol 67, 4017-4026

Compounds were evaluated using an in vitro . polymerase assay containing purified recombinant HCV RNA-dependent RNA polymerase (NS5B protein) . HCV NS5B was expressed in sf9 insect cells using a recombinant baculovirus as vector. The experimental procedures used for the cloning, expression and purification of the HCV NS5B protein are described below. Follows, are details of the RNA-dependent RNA polymerase assays used to test the compounds.

The cDNA encoding the entire NS5B protein of HCV-Bk strain, genotype lb, was amplified by PCR using the primers NS5Nhe5' (5'GÇÎ^σQςIAGCTCAAT^IΌCΠACΆCAT3G-3^, ; SEQ ID NO:1) and XhcNS53' (5'CTŒ^ÇTQ^Œ7IXXATOGGTTGGGGAG-3' SEQ ID NO: 2) and the plasmid pCD 3.

8-9.4 as template (Tomei et al., 1993). NS5Nhe5' and XhoNS53' contain 100

CA 02449999 2011-05-03 two Nhel and Xhol sites (underlined sequences,, respectively, at their 5' end. The amplified DNA fragment was cloned in the bacterial expression plasmid pET-21b (Novagen, between the restriction sites Nhel and Xhol, to generate the plasmid pET/NS5B. This plasmid was later used as template to PCRamplify the NS5B coding region, using the primers NS5B-H9 {5'ATACAlATOGCIAGŒlUrcAAT^ 3';^SEQ ID NO:3) and NS5B-R4 (5' GGATCCXjGATCCCGTTCATCX3GTTGGGGAG-3 ' ; SEQ ID No:4) . NS5B-H9 spans a region of 15 nucleotides in the plasmid pET-21b followed by the translation initiation codon (ATG) and 8 nucleotides corresponding to the 5' end of the NS5B coding region (nt. 75907607 in the HCV sequence with the accession number M58335, . NS5B-R4 contains two BairiHI sites (underlined, followed by 18 nucleotides corresponding to the region around the stop codon in the HCV genome (nt. 9365-9347,. The amplified sequence, of 1.8 kb, was digested with Nhel and BamH.1 and ligated to a predigested pBlueBaclI plasmid (Invitrogen, . The resulting recombinant plasmid was designated pBac/NS5B. Sf9 cells were co-transfected with 3 μg of pBac/NS5B, together with 1 gg of linearized baculovirus DNA (Invitrogen) , as described in the manufacturer's protocol. Following two rounds of plaque purification, an NS5B-recombinant baculovirus, BacNS5B, was isolated: The presence of the recombinant NS5B protein was determined by western blot analysis (Harlow and Lane, 1988) of BacNS5B-infected Sf9 cells, using a rabbit polyclonal antiserum (anti-NS5B, raised against a His-tagged version of the NS5B protein expressed in E. coli. Infections of Sf9 cells with this plaque purified virus were performed in one-liter spinner flasks at a cell density of 1.2 x 10’ cells/ml and a multiplicity of infection of 5.

Sf9 cells were infected as described above. Sixty hours postinfection, cells were harvested then washed twice with phosphate buffer saline (PBS,. Total proteins were solubilized as described in Lohmann et al. (1997, with some modifications. In brief, proteins were extracted in three steps, SI, S2, S3, using lysis buffers (LB, X, LB II and LB III (Lohmann et al, 1997). The composition of LBII was modified to contain 0.1 % triton X100 and 150 mM NaCl to reduce the amount of solubilized NS5B

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WO 02/100846 PCT/CA02/00877 protein at this step. In addition, sonication of cell extracts was avoided throughout the protocol to preserve the integrity of the protein structure.

Purification of recombinant NS5B using fast protein liquid chromatography (FPLC):

Soluble NS5B protein in the S3 fraction was diluted to lower the NaCl concentration to 3 00 mM, then it incubated batchwise with DEAE sepharose beads (Amersham-Pharmacia) for 2 hrs at 4°C, as described by Behrens et al. (1996). Unbound material was cleared by centrifugation for 15 min at 4°C, at 25 000 rpm using a SW41 rotor (Beckman). The supernatant was further diluted to lower the NaCl concentration to 2 00 mM and subsequently loaded, with a flow rate of 1 ml/min, on a 5 ml HiTrap® heparin column (Amersham-Pharmacia) connected to an FPLC® system (AmershamPharmacia). Bound proteins were eluted in 1 ml fractions, using a continuous NaCl gradient of 0.2 to 1 M, over a 25 ml volume. NS5B-containing fractions were identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), followed by western blotting using the anti-NS5B antiserum at a dilution of 1:2000. Positive fractions were pooled and the elution buffer was exchanged against a 50 mM NaPO₄ pH 7.0, 20 % glycerol, 0.5 % triton X-100 and 10 mM DTT, using a PD-10 column (Amersham-Pharmacia) . The sample was then loaded onto a 1 ml

HiTrap® SP column (Amersham-Pharmacia) , with a flow rate of 0.1 ml/min. Bound proteins were eluted using a continuous 0 to 1 M NaCl gradient over a 15 ml volume. Eluted fractions were analyzed by SDS-PAGE and western blotting. Alternatively, proteins were visualized, following SDS-PAGE, by silver staining using the Silver Stain Plus kit (BioRad) as described by the manufacturer. Positive fractions were tested for RdRp activity (see below) and the most active ones were pooled, and stored as a 40 % glycerol solution at -70°C.

In vitro RNA-dependent RNA polymerase assays used to evaluate biaryl analogues (Assay 1):

RdRp assays were conducted using the homopolymeric template/primer polyA/oligo dT. All RdRp reactions were

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WO 02/100846 PCT/CA02/00877 performed in a total volume of 50 μΐ, and in a basic buffer consisting of 20 mM Tris-HCl pH 7.5, ImM DTT, 50 mM NaCl, 5 mM

MgCl₂, 0.5 gCi [y²P]-UTP (3000 Ci/mmol) , 15 μΜ cold UTP and 20 U

RNasin (Promega). Standard HCV RdRp reactions contained 200 ng of purified NS5B protein. PolyA RNAs (Amersham-Pharmacia) was resuspended at 400 ng/μΐ. The primer oligodT₁₅ (Canadian life technologies) was diluted to a concentration of 20 pmol/ml (7.6 ng/μΐ). Templates and primers were mixed volume to volume, denatured at 95°C for 5 min and annealed at 37°C for 10 min.

Following a two hour incubation at 22°C, reactions were stopped by the addition of 100 μg of sonicated salmon sperm DNA (Life Technologies) and 1 ml of 10 % trichloroacetic acid-0.5 % tetrasodium pyrophosphate (TCA-PPi). Nucleic acids were precipitated at 4°C for 30 min after which samples were filtered on GF/C glass microfiber filters (Millipore). Membranes were subsequently washed with 25 ml of a 1% TCA-0.1 % PPi solution, then air dried. Incorporated radioactivity was quantified using a liquid scintillation counter (1450-Microbeta, Wallac). Results are shown in Table 1, in the column indicated as Assay 1..

In vitro HCV RdRp Flashplate scintillation proximity assay (Strep-Flash assay) used to evaluate analogues:

This assay consists on measuring the incorporation of [³H] radiolabelled UTP in a polyrA/ biotinylated-oligo dT templateprimer, captured on the surface of streptavidin-coated microtiter flashplates (NEN SMP 103A). In brief, a 400 ng/μΐ polyrA solution (Amersham Pharmacia Biotech) was mixed volumeto-volume with 5' biotin-oligo dT₁₂ at 20 pmol/μΐ. The template and primers were denatured at 95 C for 5 minutes then incubated at 37 C for 10 minutes. Annealed -template-primers were subsequently diluted in a Tris-HCl containing buffer and allowed to bind to streptavidin-coated flashplates overnight. Unbound material was discarded, compounds were added in a 10 μΐ solution followed by a 10 μΐ of a solution containing 100 mM MgCl₂, 200 mM Tris-HCl pH 7.5, 500 mM NaCl and 10 mM DTT. The enzymatic reaction .was initiated upon addition of a 30 μΐ solution containing the enzyme and substrate to obtain the following

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WO 02/100846 PCT/CA02/00877 concentrations: 25 μΜ UTP, 1 pCi [³H] γ-UTP and 100 nM recombinant HCV NS5B. RdRp reactions were allowed to proceed for 2 hrs at ro.om temperature after which wells were washed three times with a 0.15 M NaCl solution, air dried at 37 C, and counted -in a Microbeta 1450 counter (Wallac). Results are shown in Table 1, in the column indicated as Assay 2.

Example 7 Evaluation of Biaryl Analogues for measurement of ATPase activity of HCV NS3 helicase

Measurement of ATPase activity for HCV NS3 helicase using the Malachite Green method:

The measurement of ATPase activity was performed by measuring 15 the amount of free inorganic phosphate released during the conversion of ATP to ADP by the HCV NS3 ATPase activity. The assay is as follows: In a 96-well microtiter-plate, compounds were dissolved at various concentrations in a final volume of 25 gL of ATPase buffer containing 400 μΜ ATP. The enzymatic reaction was initiated by the addition of 25 μΐ of ATPase buffer containing 6 nM of HCV NS3 enzyme without ATP to the wells followed by an incubation of 3 0 min. at 37 C. Essentially, the final concentration of the ATPase buffer components are as follows: 44 mM MOPS pH 7.0, 8.8 mM NaCl, 2.2 mM MgCl₂, 125 μρ/ιηΐ poly A, 1% DMSO, 200 μΜ ATP, and 3 nM HCV NS3 enzyme. The reaction was stopped by the addition of 100 μΐ of Biomol Green™ reagent (BIOMOL® Research Laboratories Inc., Plymouth Meeting, PA) . In order to allow the development of the green color, the plate was incubated for 15 min. at room temperature. Then the plate was read on a micro-plate reader at 620 nm. The 50% inhibitory concentration ‘ (IC₅₀) for anti-ATPase activity was defined as the concentration of compound that resulted in a 50 % reduction of the signal compared to the signal observed in control sample without compound. The signal recorded was also corrected from the background signal obtained with control samples with compound only. The IC₅₀ was determined from doseresponse curves using six to eight concentrations per compound.

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Curves were fitted to data points using a non-linear regression analysis, and IC₅₀s were interpolated from the resulting curves using GraphPad Prism software, version 2.0 (GraphPad Software Inc, San Diego, CA).

Measurement of ATPase activity of HCV NS3 helicase using the HPLC method:

The measurement of HCV NS3 ATPase activity was performed by measuring the amount of ADP produced during the conversion of ATP to ADP by the HCV NS3 enzyme using paired-ion HPLC on a reverse phase column. The assay is as follows: The same protocol as mentioned above was used except that the final concentration of HCV NS3 enzyme was reduced to 1 nM in a 50 μΐ reaction mixture and that the ATPase reaction was stopped by the

M EDTA. A modular liquid Spectrasystern®, ThermoQuest using a ChromQuest™ software

USA) controlled the The mobile phase was column.

addition of 12.5 ' μΐ of 0.5 chromatography system (TSP

Corporation, San Diego, USA) (ThermoQuest Corporation, San Diego, autosampling of 25 μΐ from each reaction an isocratic solution of 0.15 M triethylamine, 6% methanol, and phosphoric acid to pH 5.5. ADP and ATP peaks were resolved using the Aqua 5 μ, C18, 125 Â, (150 X 4.6 mm) reverse phase The extent of ATP conversion to ADP was evaluated by measuring the area under the ADP peak produced which was detected at 259 nm. The amount of ADP was corrected for the presence of ADP contaminant in the original ATP solution. The 50% inhibitory concentration (IC₅₀) for anti-ATPase activity was defined as the concentration of compound that resulted in a 50 % reduction of the ADP peak area compared to the ADP peak area observed in control sample without compound. The IC₅₀ was determined from dose-response curves using six to eight concentrations per compound. Curves were fitted to data points using a non-linear regression analysis, and IC₅₀s were interpolated from the resulting curves using GraphPad Prism software, version 2.0 (GraphPad Software Inc, San Diego, CA).

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Results of the ATPase activity for HCV NS3 helicase are shown in Table 2.

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CA 02449999 2010-10-29