AU743901B2 - Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloprote inase and tace inhibitors - Google Patents

Description

WO 98/16514 PCT/US97/18281 ORTHO-SULFONAMIDO BICYCLIC HETEROARYL HYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASE AND TACE INHIBITORS Background of the Invention The present invention relates to the discovery of novel, low molecular weight, nonpeptide inhibitors of matrix metalloproteinases gelatinases, stromelysins and collagenases) and TNF-a converting enzyme (TACE, tumor necrosis factor-a converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system and HIV infection.

Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes [Woessner, Jr. FASEB J. 1991, 5, 2145; Birkedal-Hansen, Moore, W.G.I.; Bodden, Windsor, Birkedal-Hansen, DeCarlo, Engler, J.A. Crit. Rev.

Oral Biol. Med. 1993,4, 197; Cawston, T.E. Pharmacol. Ther. 1996, 70, 163; Powell, Matrisian, L.M. Cur. Top. Microbiol. and Immunol. 1996, 213, These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of osteoarthritis [Howell, D.S.; Pelletier, In Arthritis and Allied Conditions; McCarthy, Koopman, Eds.; Lea and Febiger: Philadelphia, 1993; 12th Edition'Vol. 2, pp. 1723; Dean, D.D. Sem.

Arthritis Rheum. 1991, 20, 2; Crawford, H.C; Matrisian, L.M. Invasion Metast. 1994- 14, 234; Ray, Stetler-Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 323].

It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which may lead to tumor metastasis [Powell, Matrisian, L.M. Cur. Top. Microbiol. and Immunol. 1996, 213, 1; Crawford, H.C; Matrisian, L.M. Invasion Metast. 1994-95, 14, 234; Ray, Stetler- Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323; Himelstein, Canete- Soler, Bernhard, Dilks, Muschel, R.J. Invasion Metast. 1994-95, 14, 246; Nuovo, MacConnell, Simsir, Valea, French, D.L. Cancer Res.

1 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 1995, 55, 267-275; Walther, Levy, Hurley, Venzon, Linehen, W.M.; Stetler-Stevenson, W. J. Urol. 1995, 153 (Suppl. 403A; Tokuraku, M; Sato, H.; Murakami, Okada, Watanabe, Seiki, M. Int. J. Cancer, 1995, 64, 355; Himelstein, Hua, Bernhard, Muschel, R.J. Proc. Am. Assoc. Cancer Res. Ann.

Meet. 1996, 37, 632; Ueda, Imai, Tsuchiya, Fujimoto, Nakanishi, I.; Katsuda, Seiki, Okada, Y. Am. J. Pathol. 1996, 148, 611; Gress, Mueller- Pillasch, Lerch, Friess, Buechler, Adler, G. Int. J. Cancer, 1995, 62, 407; Kawashima, Nakanishi, Tsuchiya, Roessner, Obata, Okada, Y.

Virchows Arch., 1994, 424, 547-552.]. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology [Crawford, H.C; Matrisian, L.M. Invasion Metast. 1994-95, 14, 234; Ray, Stetler- Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323.]. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis [Dollery, McEwan, Henney, A.M. Circ. Res. 1995, 77, 863; Zempo, Koyama, Kenagy, Lea, Clowes, A.W. Arterioscler. Thromb.

Vasc. Biol. 1996, 16, 28; Lee, Schoen, Loree, Lark, Libby, P.

Arterioscler. Thromb. Vasc. Biol. 1996,16, 1070.]. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection.

The hypothesis that MMPs are important mediators of the tissue destruction that occurs in arthritis has long been considered, since it was first recognized that these enzymes are capable of degrading collagens and proteoglycans which are the major structural components of cartilage [Sapolsky, Keiser, Howell, Woessner, Jr.; J.

Clin. Invest. 1976, 58, 1030; Pelletier, Martel-Pelletier, Howell, Ghandur- Mnaymneh, Enis, Woessner, Jr., Arthritis Rheum. 1983, 26, and continues to develop as new MMPs are identified. For example, collagenase-3 (MMP-13) was cloned from breast cancer cells in 1994, and the first report that it could be involved in arthritis appeared in 1995 [Freiji, Diez-Itza, Balbin, Sanchez, Blasco, Tolivia, Lopez-Otin, C. J. Biol. Chem. 1994,269, 16766; Flannery, Sandy, J.D. 102-17, 41st Ann. Meet. Orth. Res. Soc. Orlando, FL. February 13-16, 1995.].

2 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Evidence is accumulating that implicates MMP-13 in the pathogenesis of arthritis. A major structural component of articular cartilage, type II collagen, is the preferred substrate for MMP-13 and this enzyme is significantly more efficient at cleaving type II collagen than the other collagenases [Knauper, Lopez-Otin, Smith, Knight, Murphy, G. J.

Biol. Chem., 1996, 271, 1544-1550; Mitchell, Magna, Reeves, L.M.; Lopresti-Morrow, Yocum, Rosner, Geoghegan, Hambor, J.E. J.

Clin. Invest. 1996, 97, 761.]. MMP-13 is produced by chondrocytes, and elevated levels of MMP-13 has been found in human osteoarthritic tissues [Reboul, Pelletier, J-P.; Hambor, Magna, Tardif, Cloutier, Martel-Pelletier, J. Arthritis Rheum.

1995, 38 (Suppl. S268;Shlopov, Mainardi, Hasty, K.A. Arthritis Rheum.

1995, 38 (Suppl. S313; Reboul, Pelletier, Tardif, Cloutier, Martel- Pelletier, J. J. Clin. Invest. 1996, 97, 2011]. Potent inhibitors of MMPs were described over 10 years ago, but the poor bioavailability of these early peptidic, substrate mimetic MMP inhibitors precluded their evaluation in animal models of arthritis. More bioavailable, non-peptidic MMP inhibitors may be preferred for the treatment of diseases mediated by MMPs.

TNF-a converting enzyme catalyzes the formation of TNF-a from membrane bound TNF-a precursor protein. TNF-a is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, insulin resistance and HIV infection in addition to its well documented antitumor properties. For example, research with anti-TNF-a antibodies and transgenic animals has demonstrated that blocking the formation of TNF-a inhibits the progression of arthritis [Rankin, E.C.; Choy, Kassimos, Kingsley, Sopwith, Isenberg, Panayi, G.S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 au197-M2Z.]. This observation has recently been extended to humans as well.

Other conditions mediated by TNF-a are congestive heart failure, cachexia, anorexia, inflammation, fever, inflammatory disease of the central nervous system, and inflammatory bowel disease.

It is expected that small molecule inhibitors of gelatinase and TACE therefore have the potential for treating a variety of disease states. While a variety of MMP and TACE inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic or peptide-like compounds that may have bioavailability and pharmacokinetic problems that would limit their clinical effectiveness. Low molecular weight, potent, long-acting, orally bioavailable inhibitors of gelatinases, collagenases and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states. Several non-peptidc, sulfur-containing hydroxamic acids have recently been disclosed and are listed below.

3 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 U. S. patents 5,455,258, 5,506,242 and 5,552,419, as well as European patent application EP606,046A1 and WIPO international publications W096/00214 and W097/22587 disclose non-peptide matrix metalloproteinase inhibitors of which the compound CGS27023A is representative. The discovery of this type of MMP inhibitor is further detailed by MacPherson, et. al. in J. Med. Chem., (1997),4Q, 2525. Additional publications disclosing sulfonamide based MMP inhibitors which are variants of the sulfonamide-hydroxamate shown below, or the analogous sulfonamide-carboxylates, are European patent application EP-757984-A1 and WIPO international publications W095/35275, W095/35276, W096/27583, W097/19068 and W097/27174.

/N

SHO Me CGS 27023A Publications disclosing P-sulfonamide-hydroxamate MMP inhibitor analogs of CGS 27023A in which the carbon alpha to the hydroxamic acid has been joined in a ring to the sulfonamide nitrogen, as shown below, include WIPO international publications W096/33172 and W097/20824.

Ar 02S o HO.

N

Hm )n m n The German patent application DE19,542,189-A1 discloses additional examples of cylic sulfonamides as MMP inhibitors. In this case the sulfonamide-containing ring is fused to a phenyl ring to form an isoquinoline.

4 SUBSTITUTE SHEET (RULE 26) L WO 98/16514 PCT/US97/18281 Ar O2S/

O

HO.

N

N H n M R Analogs of the sulfonamide-hydroxamate MMP inhibitors in which the sulfonamide nitrogen has been replaced by a carbon atom, as shown in the general structure below, are European patent application EP-780386-A1 and WIPO international publication W097/24117.

O R 3

R

4 HOHN S

R

1

R

2 02 Summary of the Invention The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by the formula

R

7

-NHOH

N-A

Z-S

where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons of group A where: A is a 5-6 membered heteroaryl having from 1 to 2 heteroatoms independently selected from N, 0, and S, and substituted by R 1 and R 2 on adjacent carbons wherein R' and R 2 together with the carbons to which they are attached form a fused phenyl ring or a 5-6 membered heteroaryl ring having from 1 to 3 heteroatoms selected independently from N, O and S, wherein either ring can be substituted by one or more substituents selected from R 4 Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTIUS97/18281 where aryl is phenyl or naphthyl optionally substituted by R 1

R

2

R

3 and heteroaryl is a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, 0, and S, and optionally substituted by R 1

R

2

R

3 and R 4 and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R 1

R

2

R

3 and R 4 R I, R 2

R

3 and R 4 are independently

-COR

5 -Cl, -L,

-C(O)NR

5

OR

6 -0R 5

,-C

1 -C4-perfluoroalkyl, S(O)xR 5 where x is 0-2, -OPO(0R 5 )0R 6

-PO(OR

6

)R

5

-OC(O)NR

5

R

6

-COOR

5

-CONR

5

R

6

-SO

3 H, -NR 5

R

6

-NR

5

COR

6

-NR

5

COOR

6 -S02NR 5

R

6

-NO

2

-N(R

5 )S0, -NR 5

CONR

5

R

6 6

)NR

5 R6, 3-6 membered cycloheteroalkyl having one to three heteroatoms independently selected from N, 0, and S and optionally having 1 or 2 double bonds and optionally substituted by one to three groups each selected independently from R -aryl or heteroaryl as defined above,

-SO

2 NHCOR 5 or -CONHSO 2 R 5 weeR 5 isnot H; -SO2NHCN, -SO2NHCONR 5

R

6 or straight chain or branched -C 1

-C

6 alkyl, -C2-C6-alkenyl, or -C2-C6-alkynyl, or C-6 cycloalkyl optionally having I or 2 double bonds each optionally substituted with -COR 5 -CN, -C2-C 6 alkenyl, -C2-C 6 alkynyl,-0R 5 -Cl-C 4 perfluoroalcyl, -S(O)xR 5 where x is 0-2, -OC(O)NRSR 6

-COQR

5

-CONR

5

R

6

-SO

3 H, -NR 5

R

6

,-NR

5

COR

6

-NR

5

COOR

6

SO

2

NR

5

R

6

-NO

2

-N(R

5 )S0 6

-NR

5

CONR

5

R

6

-C

3

-C

6 cycloalkyl as defined above, 3-6 membered cycloheteroalkyl as defined above, aryl or heteroaryl as defined above, -SO2NHCOR or-CONHSO 2

R

5 where R 5 is not hydrogen, -PO(0R 5 )0R 6 PO(0R 6

)R

5 -tetrazol-5-yl, -C(0)NR 5

OR

6

NR

5

C(=NR

6

)NR

5

R

6

,-S

2 NHCONR5R6 or -SO 2

NHCN;

R

5 and R 6 are independently defined as aryl and heteroaryl as defined above, -C3-C6-cycloalkyl as defined above, -C3-C6-cycloheteroalkyl as defined above, -Ci-C4-perfluoroalkyl, or straight chain or branched -Cj-C 6 alkyl, -C2-C6-alkenyl, or -C2-C6-alkynyl each optionally substituted with -OH,

-COR

8 -CN, -C(O)NR 8

OR

9 -C2-C6-alkenyl, -C2-C6-alkynyl, 6 SUBSTITUTE SHEET (RULE 26) II. UPBU. UI 11:30 riuuri DMOrVA n III 1.

M

-OR

8 -Cl-C4-pcrfluoroalkyl, -S(O)xR 8 where x is 0-2.

-OPO(ORB)OR

9

-PO(OR

8

)R

9

-OC(O)NR

8

R

9

-COOR

8

-CONR

8

R

9 -S03H, -NR 8

R

9

,-NCOR

8

R

9

-NR

8

COOR

9 -SO2NR 8

R

9 -N02, -N(RB)S0 2

R

9

-NR

8

CONR

8

R

9 -C3-C 6 cycloalkyl as defined above -Cj-C 6 cyclobeteroalkyl as defined above, -aryl or boreroaryl as defined above. -SO2NCOR 8 or -CONHSQRB where R' is nor hydrogen, -rczrazol-5-yl,

-NR

8 C(4qR 9 )NRSR9 -SO2NHCONR 9

R

9 or -SOaNHCN;

R

7 is hydrogen, stuighr chain or branched -C 1 -C6-alkyl, -C2-C-akcknyl, or -C2- C6-allynyl each optionally substituted with -OH, -COt 5 -CN, -C2-C 6 alienyl. -C2-C6-alkyny, -OR 5 -CI-C4-prfluoraalkyl, where x is 0-2. -OPO(OR 5 )0R 6

-POCORS)R

6

-OC(O)NR

5

R

6

COOR

5

-CONR

5

R

6

-SO

3 H, -NRSR6,-NRSCOR 6

-NR

5

COOR

6 1 S02NR 5

R

6

-NO

2 -N(RS)50 2

R

6

-NR

5

CONR

5

R

6 -C3-C6 cycloalkyl as defined above, -C3-C6-cycloheteroallyl as defined above, -aryl or hereroaryl as defined above. -S02NIiCOR 5 or

CONHSO

2

R

5 where R 5 is not hydrogen, -tetrazol-5-yl, NR'C(=NR6)NR'R, -C(O)N R 5 0R 6

-SO

2 NHCONR'R'or 2o SO2NCN; or R 7 is phenyl or naphthyl, optionally substituted by R 2

R

3 and R 4 or a 5 to 6 rembcred heteraryl group having I to 3 heteroatoms selected independently fwm N, 0, and S and optionally substituted by R 2

R

3 and R 4 or R 7 is Cr-C6 cycloalkyl or 3-6 membered cycloheteroalkyl as defined above; or R 7 CH2-N-A-, where A is as defined above, can form a non-aromatic, A-fused, 7-12 membcred beterocyclic ring, optionally containing an additional heteroatoi 3o selected from 0, S and N wherrin said-hecerocyclic ring may be optionally fused to a benzene ring;

R

8 and R 9 arc independently H aryl or heeroaryl as defined above, -C3-C7cycloalyl or cycloheceroalkyl as defined above, -Cj-C4-pcrfluoroalkyl, straighr chain or branched -C:-C6-alkyl, -C2-C-alkenyl, or -C2-C6- 36 allynyl, each optionally substituted with hydrxy, alkoxy, aryloxy, -CI- CA-pefluoroalkyl, amino, mono- and di-C1C6-alkylamino, carboxylic WO 98/16514 PCT/US97/18281 acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono- and di-CI-C6-alkylcarbamoyl; and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.

Preferred compounds are those wherein both of the carbons of A adjacent to the carbon bearing the sulfonamido group have a substituent other than hydrogen. Also preferred are compounds where Z is 4-alkoxyphenyl, 4-aryloxyphenyl or 4heteroaryloxyphenyl.

The term "heteroaryl" as defined hereinabove includes, but is not limited to, pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine,triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole and oxazole. The term "heteroaryl fused to a phenyl" includes, but is not limited to, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole.

The following compounds (I-XXI) which may be used in preparing compounds of the invention are known and references are given hereinbelow.

8 SUBSTITUTE SHEET (RULE 26) -17_.t WO 98/16514 WO 9816514PCT/US97/18281 cI R0 2

CN

1

R

EtO2C~r%

N

N s ,u

OHNC>

EtO 2 C

N

IM/

N

Ph 0

LYI

CI

R

2C*

KNAS

YM

VI

\N

N S ix C02

XYNI

R0 2

C.

CI

RO 2C' Cl 0

N

N EtON N xX cI 0 Q~0^\

C"N)

my1 OH 0 Cl 0 RN

N

R

xxi Cl 0 N 0-

RNN

xx 9 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTIUS97/18281 Compound 1: a) Springer, RH; Scholten, MB; O'Brien, DE, Novinson, T; Miller, JP; Robins, RK J.

Med. Chem. (1982), 25(3), 235-42.

b) Elworthy, Ford, et.al. J. Med. Chem. (1997), 40(17), 2674-2687.

Compound II: Masui, T; TAkura, T; JP 46043792; JP 690307; CAN 76:59604 Compound III: Camparini, A; Ponticelli, F; Tedeschi, P J. Chem. Soc., Perkin Trans.1 (1982), 239 1-4.

Compound IV: Abdalla, GM; Sowell. JW J. Heterocyci. Chem. (1990), 27 1201-7.

Compound V: a) Denzel, T; Hoehn, H J. Heterocyclic Chem. (1977), 14, 813-817.

b) AI-Shaar, AHM; Chambers, RK; Gilmour, DW; Lythgoe, DJ; McClenaghan, 1; Ramsden, CA J. Chem. Soc.; Perkin Trans. I (1992) 21, 2789-2812.

c) Elworthy, Ford, et.a1. J. Med. Chem. (1997), 40(17), 2674-2687.

Compound VI: a) Forbes, IT; Johnson, CN; Jones, GE; Loudon, J; Nicholass, JM J. Med. Chem (1990) 2640- 2645.

b) Kan, MA; Guarconi, AE J. Heterocyclic Chem (1977) 14, 807-812.

Compound VII: a) Forbes, IT; Johnson, CN; Jones, GE; Loudon, J; Nicholass, JM J. Med. Chem (1990) 2640- 2645.

b) Kan, MA; Guarconi, AE I. Heterocyclic Chemn (1977) 14, 807-812.

Compound yIII: Richardson, TO; Neale, N; Carwell, N J. Heterocyclic. Chem. (1995), 32, 359-361.

Baker, JM; Huddleston, PR; Keenan, GJ J. Chem Research Miniprint, (1982) 6, 1726-1746.

Compound IX: a) Forbes, IT; Johnson, CN; Jones, GE; Loudon, J; Nicholass, JM JI Med. Chem (1990) 2640- 2645.

b) Kan, MA; Guarconi, AE 3. Heterocyclic Chem (1977) 14, 807-812.

Compounds X, XI and XII: Elworthy, Ford, et.al. J. Med. Chem. (1997), 40(17), 2674-2687.

Compound XIII: Heterocycles, (1997), 45, 980.

Compound XIV: SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Yokoyama, Naokata. Eur. Pat. Appl., 61 pp. CODEN: EPXXDW. EP 115469 Al 840808.

Compound XV: Mendes, Etienne; Vernieres, Jean Claude; Simiand, Jacques Edouard; Keane, Peter Eugene. Eur. Pat. Appl., 12 pp. CODEN: EPXXDW. EP 346207 Al 891213.

Compound XVI: Mendes, Etienne; Vernieres, Jean Claude; Simiand, Jacques Edouard; Keane, Peter Eugene. Eur. Pat. Appl., 12 pp. CODEN: EPXXDW. EP 346207 Al 891213.

Compound XVII: Morita, Yoshiharu; Wagatsuma, Kazuo. Japan. Kokai, 4 pp. CODEN: JKXXAF. JP 50058094 750520 Showa.

Compounds XVIII and XIX: Armitage, Bernard John; Leslie, Bruce William; Miller, Thomas Kerr; Morley, Christopher. PCT Int. Appl., 110 pp. CODEN: PIXXD2. WO 9500511 Al 950105.

Compound XX: Minami, Matsumoto, Kawaguchi, Mishio, Shimizu, Takase, Y.; Nakamura, S. (Dainippon Pharmaceutical Co., Ltd., Japan) Japan. Kokai, 3pp. CODEN: JKXXAF. JP 50014697 750215 Showa.

Compound XXI: Kihara, Tan, Takei, Ishihara, T. (Mitsui Pechochemical Industries, Ltd., Japan; Suntory, Ltd.) Jpn. Kokai Tokyo Koho,, 11pp. CODEN: JKXXAF. JP 62221686 A2 870929 Showa.

The compounds of this invention are shown to inhibit the enzymes MMP-1, MMP- 9, MMP-13 and TNF-a converting enzyme (TACE) and are therefore useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HIV infection.

Detailed Description of the Invention The invention compounds are prepared using conventional techniques known to those skilled in the art of organic synthesis. The following scheme (Scheme I) illustrates the reaction sequence employed. For purposes of illustration only, wherein the bicyclic heteroaryl group A shown is a quinoline, 4 -chloro-7-trifluoromethylquinoline-3-carboxylic acid ethyl ester, prepared from the corresponding aniline, is reacted with N-benzyl-pmethoxybenzenesulfonamide, wherein Z is p-methoxybenzene, to provide the requisite N,N-disubstituted sulfonamido-ester which is then convened into the corresponding hydroxamic acid in two steps.

11 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Alternatively, the 4-chloroquinoline carboxylic acid ester could be first reacted with R'-NH2 and the resulting 4-(R 7 -amino)quinoline carboxylic acid ester then reacted with the appropriate Z-SO 2 -CI. Hydrolysis of the ester and reaction with hydroxylamine hydrochloride would then give the invention compound.

Scheme I.

o o EtO OEt

R

OH 0 R- OEt C1 o R 2l~Et -0 Bn-NH N 'Et

F

3 C SO O Me Bn-N 0 F3C F-3C N Functionalization of the quinoline ring via a palladium catalyzed Heck coupling between the iodoquinoline and tributylvinyltin is shown in Scheme II. a,P-Unsaturated esters and amides can be coupled to the haloquinoline via Heck reactions. A variety of other trialkyltin reagents are readily available and may be similarly used. Boronic acids, commercially available or readily prepared, may also be coupled to the iodoquinoline using the Suzuki reaction.

12 SUBSTITUTE SHEET (RULE 26) 4 WO 98/16514 WO 9816514PCT/US97/18281 Scheme 11.

El-NH N N OEt Et-N P0 El-N 0 OH

IB

N

N-

ElN a EtN N N-

H

N-

Functionalization of haloquinolines may also be accomplished via palladium catalyzed couplings of alkynes, as illustrated in Scheme III. Hydrogenation of the alkynes accesses the olefins and alkanes as well.

13 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Scheme III.

SO- OMe Me-NH CI N. I OEt )CeN Nu SO -OMe Me-N 0 N. N. OEt Me-d 0

"H

S02-- OMe \A Me-N

O

r OEt

I^

Schemes IV and V illustrate two methods for incorporating amino groups into the substituent attached to the sulfonamide nitrogen of the compounds of the invention. Thus, in Scheme IV the NH-sulfonamide is alkylated with propargyl bromide to provide the propargyl sulfonamide. This alkyne is reacted with paraformaldehyde in the presence of a primary or secondary amine and cuprous chloride to give the propargyl amine which is converted, as before, to the desired hydroxamic acid.

14 SUBSTITUTE SHEET (RULE 26) :n Ill 1 ~vi- WO 98/16514 WO 9816514PCTIUS97/18281 Scheme IV.

MeO R0 2

C

HCCCH

2 Br NaH

DMEF

C0 2

R

$(CH

2

O),

CuOi

HNR

5

R

6

NRR

6 MeO CONHOH

~ONI

NR

5

,R

6 2O 2 In Scheme V, selective hydrolysis of the ester of the p-.carboethoxybenzyl sulfonamride group provides a mono-carboxylic acid. This acid may be converted into an mide (not shown), followed by conversion of the second ester, A-CO 2 R, into the corresponding hydroxamate, or reduced to the corresponding alcohol with diborane. The alcohol may be converted into the analogous amine via the benzylic bromide, followed by conversion of the the ester, A-CO 2 R, into the corresponding hydroxaniate.

Scheme V.

CO

2 Et MeO%~ C0 2

R

1) NaO- 2) BH 3 -THiF C0 2

R

1) PPh 3 CBr 4 2) HNR 5

R

6

K

2 C0 3

NR

5

R

6

CONHOH

NR

5

R

6 MeO -C0 2

R

SUBSTITUTE SHEET (R .ULE 26) WO 98/16514 PCT/US97/18281 Methods for synthesizing variations of substituents on the sulfonyl aryl group are shown in Schemes VI through VIII. As shown in Scheme VI, biaryl sulfonyl groups are synthesized by Suzuki couplings on a bromo-substituted benzene sulfonamide. The starting bromo-substituted benzene sulfonamide is synthesized from the commercially available bromobenzenesulfonyl chloride and the amino-acid or amino-ester, H 2

N-A-CO

2

R,

followed by alkylation of the resulting NH-sulfonamide. Altematively, the bromo aryl sulfonamide is converted into the corresponding boronic acid by the method of Ishiyama, et.al. Org. Chem. (1995), E6, 7508] followed by coupling with an appropriate aryl halide.

Scheme VI.

ArB(OH) 2 Pd(PPh 3 4 Na 2

CO

3 (aq)

DME

R7

I

COOR

1. Bis(Pinacolato)diboron (dppf)PdCl 2 KOAc;

DMSO

2. aq. HCI Ishiyama, T; Murata, Miyaura, N.

J. Org. Chem. 1995, 60, 7508.

ArX Pd(PPh 3 4 Na 2

CO

3 (aq)

DME

Methods for synthesizing sulfonyl aryl ethers are shown in Schemes VII through IX. In Scheme VII biaryl ethers, or aryl heteroaryl ethers, are synthesized starting from the known sulfonyl chlorides (see for example: Zook SE; Dagnino, R; Deason, ME, Bender, SL; Melnick, MJ WO 97/20824).

16 SUBSTITUTE SHEET (RULE 26) i- i ~1 _i WO 98/16514 WO 9816514PCTIUS97/18281 Scheme VII.

R

4

-R

1

A

~COOR

2 S

A

Pyridine H 0,fAr

R

4

-R

1

A

8 2

NCOOR

Nail

R

7

CH

2

X

~CONHOH

13 4 1 82 1%.COOR Alternatively, the biaryl ethers may be prepared from the corresponding bowonic acids or via the sulfonyl phenols as shown in Scheme VIII.

Scheme VIII.

R4R- A 02

NCOOR

Cu(QAch2 Pyridine or Et 3 N R7

CH

2 Ch X

RX[K

X=QOH, NHR N

R

4

R

1 -A 02

~COOR

(R7

OH

R

4 -R-A 02

~COOR

ArB(OH) 2 Cu(OAc) 2 Pyridine or Et 3

N

CH

2

CI

2

R

7 OAr R4-RI -A 82

~COOR

K

2 C0 3

R

4 -R -A 02 ~C0OR 17 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Aryl ethers may also be prepared via displacement of the fluorine from a parafluorobenzene sulfonamide, as shown in Scheme IX. Aryl or alkyl ethers may be prepared in this manner.

Scheme IX.

SO

2

CI

NH

2

I

A -COR

P

R,-R

4 2

CO

2

R

I

R

7

CH

2

X

K

2 C 0 3 or NaH C0 2

R

8§N-A--R1-R4 R7 RsOH NaH

DMF

FR, C 2R s-N-A-R-R 4 R7 RsO

CONHOH

N- A- RR 4 R7 Scheme X illusstrates the synthesis of pyrazolopyridines of the invention. Thus, a substituted amino-pyrazole is condensed with ethoxymethylene malonate to provide the pyrazolylamino methylene malonate, B. This compound is converted into the pyrazolopyridine, C, by heating at 240 0 C. Compound C is then converted into the chloroester, D, via reaction with phosphorus oxychloride. Displacement of the chloro substituent with a sulfonamide then gives compound E. Hydrolysis of the ester and conversion of the carboxylate into the hydroxamate then gives compound G.

18 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Scheme X.

S C 2

H

5 0CH=(COOEt)

NH

Y

A

N \'COOEt

NHCH.C(COOEOQ

2

'O

B

Y

MeO-- S02

POC

3 X COOEt

D

INNaOH N F (COCI)jNH 2

OH

The following specific examples are provided to illustrate the preparation of compounds of this invention and are not to be construed as limiting this invention in any way. Other procedures for preparing the compounds of this invention will be apparent to those skilled in the art of organic synthesis. All starting materials, intermediates, and reagents are either commercially available or can be readily prepared following standard literature procedures by one skilled in the art of organic synthesis.

Example 1 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-trifluoromethylquinoline-3-carboxylic acid ethyl ester To a solution of 1.85g (6.67 mmol) of N-benzyl 4-methoxyphenylsulphonamide in of DMF was added, in one portion, 0.267g (6.67 mmol) of 60% sodium hydride and the resulting mixture was stirred at room temperature under nitrogen for 15 min. Ethyl 4 -chloro- 7 -trifluoromethyl-3-quinolinecarboxylate (2.02g, 6.67 mmol) was then added to the solution in one portion and the resulting mixture was heated at 85 'C for 24h. The reaction mixture was then cooled to room temperature, poured into a mixture of water (300 mL) and HCI (IN, aqueous, 100 mL) and extracted with ethyl acetate (2x100 mL). The 19 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCT[US97/18281 combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then chromatographed on silica gel eluting with 15%-50% ethyl acetate/ hexane to give 3 .11lg of the desired product. Electrospray Mass Spec 545.1 Example 2 4- [Benzyi-( 4 -methoxy-benzenesulfonyl)..amino]-8-.tri luoromethy'l quinoline-3-carboxylic acid ethyl ester In the same manner as described in Example 1, 1.012g (3.34 mmol) of ethyl 4chloro-8-trifluoromethyl-3-quinolinecartboxylate provided 1.509g of the desired quinoline ester as a white solid. Electrospray Mass Spec 545.1 Example 3 4 (Benzyl- 4 -methoxy- ben zenesu lfonyl)..amino] 6-bromo-quinoline-3carboxylic acid ethyl ester In the same manner as described in Example 1, 0.848g (2.70 mmol) of ethyl 6bromo-4-chloro-3-quinolinecarboxylate provided 1.4 18g of the desired quinoline ester as a white solid. Electrospray Mass Spec 557.1 Example 4 4 -[Benzyl-(4-methoxy-benzenesulfonyl)-amino]- 7-bromo-quinoline-3carboxylic acid ethyl ester In the same manner as described in Example 1, 0.777g (2.47 mmol) of ethyl 7bromo-4-chloro-3-quinolinecarboxylate provided 1.1 69g of the desired quinoline ester as a white solid. Electrospray Mass Spec 557.1 Example 4 [Benzyl 4 -methoxy- benzenesulfonyl)..amino] -6-t tri nuoromethyl.

quinoline-3-carboxylic acid ethyl ester In the same manner as described in Example 1, 1.216g (4.02 mmol) of ethyl 4chloro- 6 trifluoromethyl-3-quinolinecarboxylate provided 2.171g of the desired quinoline ester as a white solid. Electrospray Mass Spec 545.0 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTIUS97/18281 Example 6 4 -[Benzyl-( 4 -methoxy-benzenesulfonyl)-amino]-7..trinluoromethyquinoline-3-carboxyljc acid To a solution of 1 .065g (2.00 mmol) of the product from Example 1 in 4mL of methanol/THF was added 2mL of 1IN sodium hydroxide solution and the resulting mixture was stirred at 25 *C for 1 8h. The reaction was then acidified with 1 N HCl and extracted with ethyl acetate (200 mL). The organic layer was washed with water and brine, dried over MgSO 4 filtered and concentrated in vacuo. The resulting residue was triturated with ethyl acetate/hexane and filtered to provide 828 mg of the desired carboxylic acid as a white solid. Electrospray Mass Spec 517.1 (M+H) Example 7 4- (B en zyl met hoxy- ben zen es u fon y )-amino] trinfu orom ethyl quinoline-3-carboxyljc acid In the same manner as described in Example 6, 1.255g (2.64 numol) of the product from Example 2 provided 0.988g of the desired quinoline acid as a white solid.

Electrospray Mass Spec 517.1 Example 8 4 -[Benzyl- 4 -methoxy. ben zenesulfonyl)..amino] bromo-quinoline.3 carboxylic acid In the same manner as described in Example 6, 1.1 98g (2.16 mmnol) of the product from Example 3 provided 0.921g of the desired quinoline acid as a white solid.

Electrospray Mass Spec 529.0 Example 9 4 [B enzyl. methoxy- ben zenesul fon yl)-ami 7-bromo-quinoline-3carboxylic acid In the same manner as described in Example 6, 0.969g (1.74 numol) of the product from Example 4 provided 0.804g of the desired quinoline acid as a white solid.

Electrospray Mass Spec 529.0 Example 4- [BenzyI-( 4 -methoxy-benzenesulfonyl).amino1.6..trifluoromethy..

quinoline-3-carboxylic acid In the same manner as described in Example 6, 2 .0 4 3g (3.75 numol) of the product from Example 5 provided 1.82g of the desired quinoline acid as a white solid.

21 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTIUS97/18281 Electrospray Mass Spec 515.0 Example 11 4 [Ben zyl met hoxy- benzenesul fon yI)am ino] -7-.tri fl uoromethyl quinoline-3-carboxyljc acid hydroxyamide To a solution of 0.636g (1.26 mmol) of the product from Example 6 in 12.5 mL of dichioromethane was added 0.05 roL of DMF followed by 1.26 mL (2.52 mmol) of 2 M oxalyl chloride and the resulting reaction mixture was stirred at room temperature for 1h.

In a separate flask, 2.6 mL (19 mmol) of triethylamine was added to a 0 0 C mixture of 350 mg (13 mmol) of hydroxylanine hydrochloride in 14 niL of THF and 3.5 mL of water. After this mixture had been stirred for 15min at 0 the acid chloride solution was added to it in one portion and the resulting solution was allowed to warm to room temperature and stirred for another 4h. Water was then added to the reaction flask and 0.488g product was collected via filtration. Electrospray Mass Spec 532.1 (M+H) Example 12 4- [Benzyl 4 -met hoxy- ben zenesul fon y I)-am ino] -8t ri n uorometh ylquinoiine-3-carboxyiic acid hydroxyamide In the same manner as described in Example 11, 0.

4 44g (3.75 mmol) of the product from Example 7 provided 0.143g (3 of the desired quinoline hydroxamic acid as a cream colored solid. Electrospray Mass Spec 532.1 Example 13 4 -[Benzyl.(4-methoxy-benzenesulfonyl)..amino]. 6-bromo-quinoline-3carboxylic acid hydroxyamide In the same manner as described in Example 11, 0.527g (1.00 mmol) of the product from Example 8 provided 0.367g of the desired quinoline hydroxamic acid as a offwhite solid. Electrospray Mass Spec 541.9 Example 14 4 -IIBenzyI-(4-methoxy-benzenesulfonyl)..aminol. 7-bromo-quinoline-3carboxylic acid hydroxyamide In the same manner as described in Example 11, 0.527g (1.00 mmol) of the product from Example 9 provided 0.

2 80g of the desired quinoline hydroxamic acid as a white solid. Electrospray Mass Spec 541.9 22 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTIUS97/18281 Example 4 -[Benzyl-( 4 -methoxy-benzenesulfonyl)-aminol..6.trifluoromethyl.

quinoline-3-carboxylic acid hydroxyamide In the same manner as described in Example 11, 0.527 g (1.06 mmol) of the product from Example 10 provided 0.

4 35g of the desired quinoline hydroxarnic acid as a cream colored solid. Electrospray Mass Spec 532.1 Example 16 Methoxybenzenesulfonyi )-pyridin-3-ylmethylamino]-7trilluoromethyl-quinoline-3-carboxylic acid hydroxyamide Following the procedure of example 1 and substituting N-(3-pyridinylmethyl)-4methoxybenzenesulfonamide for N-benzyl-4-methoxybenzenesulfonarride, the intermediate 4 4 -methoxybenzenesulfonyl)-pyridin-3-ylmethylamino].7-trifluoromethyl-quinoine3 carboxylic acid ethyl ester is obtained. Following the procedures of example 6 and 11, the title product is obtained. Electrospray Mass Spec 533.0 Example 17 4 -[BenzyI-( 4 -methoxybenzenesulfonyl)..amino]-8-t-butyl.quinoline.3carboxylic acid hydroxyamide In the same manner as described in Example 1, 1.1 67g (4.00 mmol) of ethyl 4chloro-8-butyl-3-quinolinecarboxylate provided 1.413g of the desired quinoline ester as a white solid. Electrospray Mass Spec 533.3 In the same manner as described in Example 6, 1 .065g (2.00 mnmol) of the ester provided 0.478g of the desired quinoline acid as a white solid. Electrospray Mass Spec 503.3 Following the procedures of example, the tide compound is obtained from the carboxylic acid. Electrospray Mass Spec. 520.3 Example 18 4 -[Benzyl.( 4 -methoxybenzenesulfonyl)-amino]-8..methyl..quinoline-3carboxylic acid hydroxyamide In the same manner as described in Example 1, 1.00g (4.00 mmol) of ethyl 4 -chloro-8-methyl-3-quinolinecarboxylate provided 0.53 Ig of the desired quinoline ester as a white solid. Electrospray Mass Spec 491.3 In the same manner as described in Example 6, 0.470g (0.85 1 mmol) of the ester provided 0. 160g (41 of the desired quinoline acid as a white solid. Electrospray Mass Spec 461.3 23 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTfUS97/18281 Following the procedure of example 11, the title compound is obtained from the carboxylic acid. Electrospray Mass Spec. 478.3 Example 19 4 [Ben zy (4-methoxy benzenesul fonyi) -ami no]- 8-ethyl-quinoline-3carboxylic acid hydroxyaxuide In the same manner as described in Example 1, 1.055g (4.00 mmol) of ethyl 4chloro-8-ethyl-3-quinolinecarboxylate provided 0.

6 70g of the desired quinoline ester as a white solid. Electrospray Mass Spec 505.3 In the same manner as described in Example 6, 0.615g (1.22 mmol) of the product from Example 7 provided 0-353g of the desired quinoline acid as a white solid.

Electrospray Mass Spec 475.3 Following the procedure of example 11, the title compound is obtained from the carboxylic acid. Electrospray Mass Spec. 492.3 Example 4 .[BenzyI.(4..methoxybenzenesul fonyl) amino] 8 (1 -mthyI thyI)quinoline-3.carboxylic acid hydroxyamide In the same manner as described in Example 1, 1. 111 g (4.00 mmol) of ethyl 4chloro- 8 -isopropyl-3-quinolinecarboxylate provided 0.754g of the desired quinoline ester as a white solid. Electrospray Mass Spec 519.3 In the same manner as described in Example 6, 0.686g 127 mmol) of the ester provided 0.532g of the desired quinoline acid as a white solid. Electrospray Mass Spec 489.2 In the same manner as described in Example 11, 0.440g (0.897 mmol) of the hydroxamic acid provided 0.270 g of the desired quinoline hydroxamic acid.

Electrospray Mass Spec. 506.3 Example 21 4 -[Ethyl-( 4 -methoxy-benzenesul fonyl).a min ol 8-iodo-quinoline-3carboxylic acid ethyl ester In the same manner as described in Example 1 and substituting N-ethyl-4methoxybenzenesulfonamide for N-ezl4mtoyeznsloaie 1 .076g (5.00 mmol) of ethyl 8 -iodo- 4 -chloro-3-quinolinecarboxylate provided 2.438g (4.51 mmol, of the desired quinoline ester as a white solid. Electrospray Mass Spec 541.0 24 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTIUS97/18281 Example 22 4- [Ethyl -(4-met hoxy- ben zen esu I fony I) am in 0-8-vi nyl -qu inoli ine-3.

carboxylic acid ethyl ester The product from example 21 (2.438g, 4.5lmrnol) in 150 mL DMF was added tributylvinyltin (1.43g, 4.51 mxnol), tetrakis~triphenylphosphine)palladium(o) (520mg, cuprious iodide (171mg, and 5 mL triethylamine. The mixture was stirred under N2 and heated at 85*C for 18 hours. The it was poured into a mixture 1) of 400 mL saturated sodium bicarbonate and saturated amoniumn chloride and extracted with ethyl acetate (2x200 m1L). The combined organic layers were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was column chromatographed using 300 mL silica gel and gradient elution with hexane/ethyl acetate This provided 1.706g (3.88 mmol, 86%) of the desired quinoline ester. Electrospray Mass Spec 441.1 Example 23 4 -[Methyl-( 4 -methoxy-benzenesulfonyl).aminol..6.phenylethynyl..quinoline- 3-carboxylic acid ethyl ester Combining the procedures of examples 1 and 22, and substituting phenylacetylene for vinyltin, N-ethyl- 4 -methoxybenzenesulfonamide for N-benzyl-4methoxybenzenesulfonamide, the intermediate 4 -Ilethyl-(4-methoxy-benzenesulfonyl)amino] -6-phenylethynyl-quinoline-3-carboxylic acid ethyl ester is obtained from ethyl -4chloro-3-quinolinecarboxylate. Electrospray Mass Spec 515.3 Example 24 4 [EthylI-( 4 -methoxy- benzenesul fonyl).amino].8vinyl..quinoline.3carboxylic acid In the same manner as described in Example 6, 1 .593g (3.62 mmol) of the product from Example 22 provided 1 .333g of the desired quinoline acid as a white solid.

Electrospray Mass Spec 411.1 Example 4 -[Methyl.( 4 -methoxy-benzenesulfonyl).aminoI..6-phenylethynyl.quinoline.

3-carboxylic acid In the same manner as described in Example 6, the title compound was synthesized from the product of example 23. Electrospray Mass Spec 485.3 SUBSTITUTE SHEET (RULE 26) WO 98/16514 W098/6514PCTIUS97/18281 Example 26 4-[Benzyl-(4-methoxy- benzenesulfonyl)..aminol..6.nitro..quinoline-3 carboxylic acid In the same manner as described in Example 1 and 6, 5.613g (20.0 mmol) ethyl 4chloro-6-nitro-3-quinolinecarboxylate provided 2 6 76g (27% for two steps) of the title compound as a white solid. Electrospray Mass Spec 492.3 Example 27 4 [Met hyl -(4-methoxy- benzenesul fonyl)-a mno]- 8-brono-quinoline-3carboxylic acid Combining the procedures of example 1 and 6, and substituting N-rnethyl-4methoxybenzenesulfonarnide for N-benzyl-4-methoxybenzenesulfonanmide, the intermediate 8 -bromo- 4 -tmethyl-(4-methoxy-benzenesulfonyl).amjno] -quinoline-3-carboxylic acid is obtained. Electrospray Mass Spec 449.2 Example 28 4 -{MethyI-( 4 (pyridin .4-yloxy)- benzenesul fonyI -aminol -6..iodo.quinoine.

3-carboxylic acid Combining the procedures of example 1 and 6, and substituting N-methyl-4- (pyridin-4-yloxy)-benzenesulfonamide the intermediate 6-iodo-4- (methyl-(4--(pyridin-4yloxy)-benzenesulfonyl] -amidno) -quinoline-3-carboxylic acid is obtained from ethyl 6-iodo- 4-chloro-3-quinolinecarboxylate. Electrospray Mass Spec 559.9 Example 29 4- [Ethyl -(4-rnet h ox y- ben zen esu I fon y 1) -arni n oJ- 8-vi nylI q u i nol in e- 3carboxylic acid hydroxyarnide In the same manner as described in Example 11, 0.484g 17 mmol) of the product from Example 24 provided 0.360g of the desired quinoline hydr-oxamric acid.

Electrospray Mass Spec. 428.0 Example 4 [Benzyl-( 4 -rnethoxy- benzenesul fonyl)..amino]..6-nitro.quinoline.3 carboxylic acid hydroxyarnide In the same manner as described in Example 11, 0.

8 2 5g (1.67 mmol) of the product from Example 26 provided 0.227g (0.446 mmol, 26%) of the desired quinoline hydroxamic acid. Electrospray Mass Spec. 509.0 26 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCTIUS97/18281 Example 31 4-[Methyl-(4-methoxy-benzenesulfonyl)-amino]- 8-bromo-quinoline-3carboxylic acid hydroxyamide In the same manner as described in Example 11, 0.664g (1.47 mmol) of the product from Example 27 provided 0.145g (0.311 mmol, 21%) of the desired quinoline hydroxamic acid. Electrospray Mass Spec. 468.0 Example 32 4-{Methyl-[ 4 -(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quinoline- 3-carboxylic acid hydroxyamide To a 0 *C solution of of 4.5 mL oxalyl chloride (0.90 mmol, 2M in dichloromethane) was added dropwise 0.69 mL of DMF. The resulting solid was kept at 0 *C for another 15 minutes and followed by addition of 2.50g (4.46 mmol) of the product from Example 28 in 50 mL DMF. The mixture was stirred for 1 hour at room temperature and then kept at 0 "C for an additional 15 minutes. An aqueous solution of hydroxylamine 50%) was then added all at once to the above solution and the mixture was stirred at room temperature for 3 hours. The mixture was next poured into 300mL water and extracted with dichloromethane (4xl00mL). The combined organic layers were washed with brine (300mL) and dried over magnesium sulfate. After filtration and concentration on a rotary evaporator the residue was column chromatographed using gradient methanol in ethyl acetate (20-100%) and it provided 1.36g (2.36mmol, 53%) of the desired quinoline hydroxamic acid. Electrospray Mass Spec. 576.9 Example 33 4 -{Methyl-( 4 -(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quinoline- 3-carboxylic acid hydroxyamide hydrochloride The product from example 32 (0.952 g, 1.65 mmol) was dissolved in 100 mL methanol in a Parr reactor. Degussa catalyst (10% Pd-C, 200mg) was next added under N2. The mixture was then hydrogenated (35 psi) for one hour at room temperature. The mixture was then filtered through a pad of celite and concentrated on a rotary evaporator.

The residue was chromatographed with methanol and ethyl acetate The product obtained was next dissolved in methanol and anhydrous hydrochloride was bubbled into the solution for 5 minutes. Removal of the solvent through rotary evaporation and vacuum pump gave 0.707g (1.45 mmol, 88%) product. Electrospray Mass Spec. 450.9 27 SUBSTITUTE SHEET (RULE 26) WO 98/16514 W098/6514PCTfUS97/18281 Example 34 4 -[EthyI.( 4 -methoxy-benzenesulfonyI).amino..6phenylethynyi..quinoline.

3-carboxylic acid hydroxyamide In the same manner as described in Example 11, 2.432g (5.00 mmol) of the product from Example 25 provided 2.1 59g of the desired quinoline hydroxamic acid.

Electrospray Mass Spec. 502.1 (M+fl).

Example 4 -[MethyI-( 4 -methoxy-benzenesulfony).amino..6phenylethy..quinoine.3 carboxylic acid hydroxyamide The product from example 34 (0.82g, 1.64 mmol) was dissolved in 50 ml, methanol in a Parr reactor. Degussa Catalyst (10% Pd-C, 200mg) was next added under N2. The mixture was hydrogenated (45 psi) for one hour at room temperature. The.mixture was then filtered through a pad of celite and concentrated on a rotary evaporator. This gave 0.76g (1.50 mmol, 92%) product. Electrospray Mass Spec. 506.0 Example 36 4 4 -Methoxy-benzenesulfonyl)-pyridin3ylmethyl.amino]. 8-methoxyquinoline-3-carboxylic acid hydroxyamide Following the procedure of Example 16 and starting with ethyl 4-chloro-8methoxy-3-quinolinecarboxylate the tidle compound was obtained as a yellow powder.

Electrospray Mass Spec. 495.3 Example 37 A- 4 -Methoxy-benzenesul fonyl)- pyridin3.yl met hyl -amino]-. 8-bromoquinoline-3-carboxylic acid hydroxyamide Following the procedure of Example 16 and starting with ethyl 4-chloro-8-bromo- 3-quinolinecarboxylate the title compound was obtained as a white powder. Electrospray Mass Spec. 543.2 Example 38 4 4 -methoxy-benzenesulfonyl).pyridin-3.yImethyI amino]-.8-Benzylquinoline-3-carboxylic acid hydroxyamide Following the procedure of Example 16 and starting with ethyl 4-chloro-8-benzyl- 3-quinolinecarboxylate the title compound was obtained as a beige powder. Electrospray Mass Spec. 555.4 -28 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTIUS97/18281 Example 39 4 4 -Methoxy- benzenesul fonyl)- pyrid in.3.ylmethyl -amino] 8-iodoquinoline-3-carboxylic acid hydroxyamide Following the procedure of Example 16 and starting with ethyl 4-chloro-8-iodo-3quinolinecarboxylate the title compound was obtained as a yellow powder. Electrospray Mass Spec. 590.8 Example 4 4 -Met hoxy- ben zen esu Ifon yl) -py rid in 3.yl meth yI-a mino] -8-phen y I quinoline-3-carboxyijc acid hydroxyamide Following the procedure of Example 16 and starting with ethyl 4-chloro-8-phenyl- 3-quinolinecarboxylate the title compound was obtained as a beige powder. Electrospray Mass Spec. 541.4 Example 41 4- (4-Met hoxy- benzenes ul tony!) p yrid in -3 -y I met hyl -amino] t hi oph en -2yi-quinoline-3-carboxylic acid hydroxyamide Combining the procedures of Examples 22, 6 and 11 and starting with4-[(4mehx-eznsloy)prdn3ymty-mnl 8-bromo-quinoline-3-carboxylic acid ethyl ester and 2 -tributylstannylthiophene the title compound was obtained as a yellow powder. Electrospray Mass Spec. 545.0 Example 42 4 i phenyl- 4 -su IfonyI)- pyri din -3..ylmet hyl -a minoI.-7-trifluoromethylquinoline-3-ca rboxylic acid hydroxyamide Following the procedure of Example 1 and substituting N-(3-pyridinylmethyl)-4bromobenzenesulfonamide for N-benzyl- 4 -methoxybenzenesulfonamide, the intermediate 4-(-rmbneeufnl-yii--letyann]7tilooehlqioie3 carboxylic acid ethyl ester is obtained.

To 8.5 mL of degassed ethylene glycol dimnethyl ether, was added 500 mg (0.85 mmol) of the ester, 110 mg (0.93 mmol) of phenylboronic acid, 80 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium and 1. 1 ml (2.2 mmol) of 2M aqueous Na 2

CO

3 and the mixture ws heated to reflux under nitrogen for 36 hr. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO 4 filtered and concentrated in vacuo to give 4 -[(bipheny1-4-sulfonyl)..pyidin.3ylmethylaminoI- 7 -trifluoromethyl-quinoline3.carboxylic acid ethyl ester.

29 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PTU9/88 PCTIUS97/18281 This ester was converted to the title compound (off-white powder) as described in Examples 6 and 11. Electrospray Mass Spec. 579.1 Example 43 4-[(Octane- lI5uII'onyl) pyridin-3-ymethyI.aminoi..7.trifluoromethylquinoline-3-carboxylic acid hydroxyamide Combining the procedures of Examples 1, 6 and I11 and substituting N-(3pyridinylmethyl)-octanesulfonamide for N-benzyl-4-methoxybenzenesulfonamide the title compound was obtained as a yellow solid. Electrospray Mass Spec. 539.5 Example 44 4 -[Pyridin- 3 -ylmethyl-(toluene..4.sulfonyl)..aminoI..7.trifluoromethyl quinoline-3-carboxylic acid hydroxyamide Combining the procedures of Examples 1, 6 and 11 and substituting N-(3pyridinylmethyl)-toluenesulfonainide for N-benzyl-4-methoxybenzenesulfonaxpjde the title compound was obtained as a white powder. Electrospray Mass Spec. 517.1 Example Diethyl{[ (l-phenyl-5-pyrazolyl) amino methylene) malonate A mixture of 15.9 g. 10 mole) of Il-phenyl-5-aminopyrazole and 21.6 g. mole) of diethyl ethoxymethylenemnalonate was heated at 1 15-120(' in an oil bath for 2 hours. After cooling, the crystalline mass was recrystallized from hot hexane containing 1 of ethanol. Cooling to room temperature and filtering gave 24.8 g. (75 of off-white cry stals, m.p. 96-97'C.

Example 46 Ethyl 4 -hydroxy-l-phenyl-lH-pyrazolo A mixture of 18.1 g. (0.055 mole) of diethyl pyrazolyl)amino]methylene) malonate and 150 mld of diethyl phthalate was heated at 240- 2500 for 1 hour. The mixture was chilled and diluted with hexane. Chilling and filtering gave crystals which were washed with hexane and with hexane-ethanol 1) to give 11I g.

of off white crystals m.p. 149-1 50-C. From a similar small scale run 1.75 g. was recrystallized from 110 ml. of ethanol to give 1.58 g. of off white crystals, m-p. 149-150'

C.

SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTfUS97/18281 Example 47 Ethyl 4 -chloro-l-phenyl.1H..pyrazolo [3,4-blpyridine-S-carboxylate A mixture of 5.76 g (20.33 mmol) of ethyl 4 -hydroxy-l-phenyl-1H-pyrazolo[3,4.

b] pyridine-5- carboxylate and 15.58 g of phosphorus oxychioride was refluxed 1.5 hr, chilled and poured slowly onto crushed ice. The mixture was filtered and the solid washed with ice-water and dried to give 6.0 g of solid, m.p. 89-91' C.

Example 48 Ethyl 4 -chloro-l,3-dimethyl-1H..pyrazolo [3,4-blpyridine-5-carboxylate Following the procedures of Examples 45, 46 and 47, starting from 1,3-dimethylthe chloro-ester is prepared. m.p. 89-W0 C.

Example 49 Ethyl 4 [ben zyl 4 -methoxy benzenesul fonyl)a min 1,3-dimethyl-1Hpyrazolo[3,4- b] To a solution of 1. 16 g (4.2 mmol) of benzyl-(4-methoxybenzenesulfonyl)amine in 6 ml of anhydrous l-methyl-2-pyrrolidinone was added 0.168 g (4.2 mrmol) of sodium hydride (60% in oil) and the mixture stirred at room temperature until gas evolution ceased.

The preceding mixture was added to mixture of 1.01 g (4 mmnol) of ethyl 4-chloro-1,3dimethylpyrazolo(3,4-bjpyridine -5-carboxylate in 2 mrl of 1 -methyl -2-pyrrolidinone.

The mixture was heated in an oil bath at 50'C overnight and then was heated in an oil bath at 1000 C for 1.5 days. The mixture was poured into 800 ml of water and extracted with ethyl acetate. The extract was washed with water, 2N citric acid, water, brine and dried (Na 2

SO

4 The solvent was removed and the residue chromnatographed on silica gel with hexane-ethyl acetate 1) as eluent to give 0.64 g of product as a solid, mp 170-1720.

From a larger scale run of 5.07 g (0.02 mmol) of ethyl 4-chloro-1,3-dimethylpyrazolo [3,4-blpyridine-5-carboxylate and 8.0 g (0.0289 mmnol) of benzyl methoxybenzenesulfonyl) amnine (as sodium anion) in 30 ml of 1 -methyl-2-pyrrolidinone heated at 900 C for 3 days there was obtained 3.65 g of product.

Example 4 [Benzy] 4 -methoxy ben zenesul fonyl)amin o] -1,3.dimethyl- IH..pyrazolo 3,4-b] pyridine-5-carboxylic acid.

A mixture of 0.48 g (0.97 mmol) of ethyl 4 -[benzyl-(4-methoxybenzenesulfonyl) amino] -l, 3 -dimethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate and 0.29 ml of iON NaQH in 4 mld of tetrahydrofuran-methanol was heated in an oil bath at 700 C for 2 hours and the solvent removed under vacuum. The residue was dissolved in 20 ml of 1120 31 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 and the solution extracted with 10 ml of diethyl ether. To the aqucous layer was added 2N citric acid (pH 4-5) and the precipitated solid filtered and washed with H 2 0 to give a white solid which was dried under vacuum overnight to give crystals, mp 165-167 0

C.

Example 51 4 -[Benzyl-( 4 -methoxybenzenesulfonyl)amino]-1,3-dimethyl-lHpyrazolo[3,4-b] pyridine-5-carboxylic acid, potassium salt.

A mixture of 3.60 g (7.28 mmol) of ethyl 4-[benzyl-(4methoxybenzenesulfonyl)amino]- 1,3-dimethyl- H-pyrazolo[3,4-b]pyridine-5-carboxylate and 0.44 g (7.84 mmol) of potassium hydroxide (pellet) in 15 ml of methanol- water (1:1) was refluxed overnight. An additional 40 mg of potassium hydroxide was added and the mixture refluxed for 4 hours (all the solid dissolved). The solvent was removed under vacuum and toluene added and removed under vacuum. The residue was triturated with ethyl acetate, filtered and the solid washed with ethyl acetate to give 3.8 g of product as a white solid.

Example 52 4 -[Benzyl-( 4 -methoxybenzenesulfonyl)amino]-1,3-dimethyl-1Hpyrazolo[3,4-b] pyridine-5-carboxylic acid, hydroxyamide To a chilled solution of 1 ml (2 mmol) of oxalyl chloride in 8 ml of CH 2 C12 was added dropwise 0.154 ml (2 mmol) of N, N-dimethylformamide and the solution stirred min. To the preceding chilled solution was added 0.504 g (1 mmol) of 4-[benzyl-(4methoxybenzenesulfonyl) amino]-1,3-dimethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, potassium salt and the mixture stirred under nitrogen for 2 hrs at room temperature (solution A solution of 0.278 g (4 mmol) of hydroxylamine hydrochloride and 0.834 ml (6 mmol) of triethylamine in 5 ml of H20-tetrahydrofuran was chilled at in an ice bath for 20 min. and to this solution was added dropwise the chilled solution of A. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed and the residue extracted with CH 2 Cl 2 The CH 2

C

2 extract was washed with 2N citric acid, H 2 0, IN NaHCO 3

H

2 0, brine and dried (Na 2

SO

4 The solvent was removed to give 0.53g of solid. Trituration with ethyl acetate gave 0.278 g of white solid, mp 184-186°C.

32 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Example 53 Ethyl 4-[(4-methoxybenzenesulfonyl)pyridin -3-ylmethylamino] -1,3dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate To a solution of 1.39 g (5 mmol) of 4 -methoxybenzenesulfonyl)(3pyridinylmethyl) amine in 4 ml of anhydrous l-methyl-2-pyrrolidinone was added 0.2 g mmol) of sodium hydride (60% in oil) and the mixture stirred at room temperature until gas evolution ceased. To this mixture was added 1.15 g (4.54 mmol) of ethyl 4-chloro-1,3dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 2 ml of anhydrous 1-methyl-2pyrrolidinone. The mixture was stirred in a sealed tube under nitrogen in an oil bath at for 3 days. The mixture was cooled, poured into water and extracted with ethyl acetate. The extract was washed with H 2 0, brine and dried (Na 2 S0 4 The solution was filtered through a thin pad of hydrous magnesuim silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness under vacuum to give 1.3 g of solid.

Chromatography on silica gel with ethyl acetate as solvent gave 0.35 g of product as a solid, mp 152-154°C.

Example 54 4-[(4-Methoxybenzenesulfonyl) pyridin -3-ylmethylamino] dimethyl 1H-pyrazolo[3,4-b]pyridine -5-carboxylic acid A mixture of 1.34 g (2.7 mmol) of ethyl 4 4 -methoxybenzenesulfonyl)pyridin-3ylmethylamino]-l,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-carboxylate, 2.97 ml of IN potassium hydroxide in 7.8 ml of ethanol and 4.83 ml of water was refluxed for 20 hr.

Another 0.54 ml of 1N potassium hydroxide was added and the mixture refluxed 4 hrs.

The solvent was removed under vacuum and toluene added and removed under vacuum.

The residue was dissolved in water (20ml) and extracted with ethyl acetate. The aqueous layer was acidified with 2 N citric acid and the precipitated solid filtered off and washed with water. The solid was dried under vacuum to give 0.98 g of solid, mp 256-258 0

C.

Example 4-[(4-Methoxybenzenesulfonyl) pyridin -3-ylmethylamino] dimethyl 1H-pyrazolo[3,4-b]pyridine -5-carboxylic acid, potassium salt A mixture of 0.34 g (0.68 mmol) of ethyl 4 4 -methoxybenzenesulfonyl) pyridin- 3-ylmethylamino]-l,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 0.748 ml of 1 N potassium hydroxide in 4 ml of ethanol- water was refluxed for 24 hr. The solvent was removed under vacuum and to the residue was added toluene. The solvent was 33 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 removed under vacuum to remove the water and the residue triturated with ethyl acetate to give the product as a solid, mp 160-167° C.

Example 4-[(4-Methoxybenzenesulfonyl)pyridin -3-ylmethylamino] dimethyl 1H-pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide A 1.5 g (2.459 mmol) sample of 4 4 -methoxybenzenesulfonyl)pyridin-3ylmethylamino]- 1,3-dimethyl- H-pyrazolo[3,4-b]pyridine-5-carboxylic acid was dissolved in 2.70 ml of 1N KOH. The water was removed by repeated additions and removal of toluene under vacuum to give 1.34 g of solid (potassium salt of the acid). A solution of 2.65 ml (5.3 mmol) of oxalyl chloride was cooled in an ice bath and 0.389 ml of N,Ndimethylformamide added dropwise. After 5 min. the 1.34 g of the previously prepared potassium salt was added and the mixture stirred for 10 min. in an ice bath and then allowed to warm to room temperature (mixture A mixture of 0.737 g (10.6 mmol) of hydroxylamine hydrochloride and 2.21 ml (15.9 mmol) of triethyamine in 9.39 ml of tetrahydrofuran and 2.45 ml of water was chilled in an ice bath (mixture The mixture A was chilled in an ice bath and added to the chilled and stirred mixture B. The mixture of A and B was stirred at 0°C for 10 min and allowed to warm to room temperature and stir overnight. The solvent was removed under vacuum and the residue diluted with H 2 0, acidified with 2 N citric acid and extracted with two 30-ml portions of CH 2 C1 2 The aqueous layer was neutrallized with solid NaHCO 3 to bring the pH to 7. The solid which precipitated was filtered and washed with H 2 0 to give 0.610 g of product as a solid, mp.

202-204 0 C. The CH 2 C1 2 ett extract was exted with 2 N citric acid and the aqueous layer neutrallized with solid NaHCO 3 The precipitated solid was filtered off and washed with water to give 0.226 g of product, mp 196-198C. (mass spectrum (ES) 483.5 Example 61 4 4 -Methoxybenzenesulfonyl)pyridin-3-ylmethylamino] dimethyl lH-pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide hydrochloride To a solution of 0.610g (1.265 mmol) of 4 4 -methoxybenenzenesulfonyl)pyridin -3-ylmethylamino]-l,3-dimethyl-5-carboxylic acid, hydroxyamide in 40 ml of CH 2 Cl 2 methanol cooled to 10 0 C was added dropwise 1.51 ml of 1M hydrogen chloride in diethyl ether. The mixture was stirred at 10 0 C for 10 min. and allowed to warm to room temperature for 1 hr. The solvent was removed under vacuum and toluene (2ml) added 34 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCT/US97/18281 twice and removed under vacuum after each addition. The residual solid was dried under vacuum to give 0.641 g of product as a solid, m.p. 170 0 -174"C.

Example 62 4-[Benzyl-(4-methoxybenzenesulfonyl)amino] 1.phenyl-1IH-pyrazolo[3,4b] pyridine -5-carboxylic acid, hydroxyamnide Following the procedure of Example 49, the product of Example 47 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl- (4-methoxybenzenesulfonyl)amrino] I-phenyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylate.

m.p. 124'- 126 0

C.

Following the procedure of Example 50, the above ester is hydrolyzed to provide 4- [benzyl-(4-methoxybenzenesulfonyl)amino]- 1 -phenyl- I H-pyrazolo[3,4-blpyridine-5carboxylic acid. m.p. 108'- 1 10 0

C.

Following the procedure of Example 52, the carboxylic acid is converted into the corresponding hydroxamic acid, 4 -[benzyl-(4-methoxybenzenesulfonyl)aminoy I -phenyl- 1H-pyrazolo[3,4-b] pyridine -5-carboxylic acid, hydroxyamide. m.p. 152 0 -154 0

C.

Example 63 4-[(4-Methoxybenzenesulfonyl)pyridin -3-ylmethylamino] -1-phenyl- 1Hpyrazolo[3,4-b] pyri dine -5-carboxylic acid, hyd roxyamnide Following the procedure of Example 53, the product of Example 47 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl 4 4 -methoxybenzenesulfonyl)pyridin-3-ylmethylaminoy 1 -phenyl-l1H-pyrazolo[3,4m.p. 890-9 1T.

Following the procedure of Example 54, the above ester is hydrolyzed to provide 4- 4 methoxybenzenesulfonyl)pyridin-3-ylmethylarrino] I -phenyl- 1 H-pyrazolo[3,4b1 acid. m.p. 136*- 138 0

C.

Following the procedure of Example 60, the carboxylic acid is converted into the corresponding hydroxamic acid, 4 4 -methoxybenzenesulfonyl)pyridin.3-ylmethylamino]- 1 -phenyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamnide. m.p. 11 4 0 C(dec).

Example 64 4 4 -Methoxybenzenesulfony) py ri din ylmethylaminol 1 -p henyI..1H.

pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide, hydrochloride Following the procedure of Example 61, the product of Example 63 is converted into the corresponding hydrochloride salt. m.p. 161'C(dec).

SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTfUS97/18281 Example Ethyl 4 -chloro-l-phenyl-3..methy-lHpyrazolo [3,4-b]pyridine-5carboxylate Following the procedure of Example 45, starting with 1-phenyl-3-methyl-5aminopyrazole, diethyl -phenyl- 3 -methyl-5-pyrazolyl)amino]methylene )malonate is obtained. m.p. 70 0 -72 0

C.

Following the procedure of Example 46, the methylene malonate is convented into ethyl 4-hydroxy-l1-phenyl-3-methyl- 1H-pyrazolo[3,4..b~pyridine..s-carboxylate. m.p. 1 32*'- 134 0

C.

Following the procedure of Example 47, the hydroxy-ester is converted into the chioro-ester, ethyl-4-chloro-l1-phenyl-3-methyl- lH-pyrazolojl3,4-blpyridine-5-carboxylate.

in.p. 108 0 -1 10 0

C.

Example 66 4 -[Benzyl-(4-mIethoxybenzenesul fonyj)aminoI. I--phenyl-3-methyl-11pyrazololl3,4b] pyridine-5-carboxylic acid, hydroxyamide Following the procedure of Example 49, the product of Example 65 is reacted with benzyl-(4-methoxybenzenesulfonyl)amnine and sodium hydride to provide ethyl 4-Ijbenzyl- (4-methoxybenzenesulfonyl)amino]- 1 -phenyl-3-methyl- 1H-pyrazolo[3,4-blpyricline-5carboxylate. m.p. 1640.1 66*C.

Following the procedure of Example 50, the above ester is hydrolyzed to provide 4- [benzyl-(4-methoxybenzenesulfonyl)anino.. 1-phenyl-3-methyl- 1H-pyrazolo[3,4-bI acid. m.p. 246 0 -248 0

C.

Following the procedure of Example 52, the carboxylic acid is converted into the corresponding hydroxamic acid, 4 -[benzyl-(4-methoxybenzenesulfonyl)aino]. I-phenyl- 3-methyl- lH-pyrazolo[3,4-blpyridine-5-carboxylic acid, hydroxyamide. m.p. 207'-210 0

C.

Example 67 4 4 Methoxybenzenesu Ifon yl) py ridin.3.yl met hylami no] Ipheny..3methyl -1H-pyrazolo[3,4- bl]pyrid ine-5ca rboxy] ic acid, hydroxyamide Following the procedure of Example 53, the product of Example 65 is reacted with 4 -methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl- 4 4 -methoxybenzenesulfonyl)pyridin-3.ylmethylaminoy- 1 -phenyl-3methyl- lH-pyrazolo[3, 4 -b~pyridine-5-carboxylate. m.p. 1480.1 50 0

C.

Following the procedure of Example 54, the above ester is hydrolyzed to provide 4- 4 -methoxybenzenesulfonyl)pyridin-3-ylmethylamino]- 1 -phenyl-3-methyl- 1pyrazolo[3,4-blpyridine.5-carboxylic acid. m.p. 235'-236 0

C.

36 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCT[US97/18281 Following the procedure of Example 60, the carboxylic acid is converted into the corresponding hydroxamic acid, 4 4 -methoxybenzenesulfonyl)pyridin-.3..ylmethylarjno..

1 -phenyl-3-methyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide. mn.p.

1 92oc I 940(2.

Example 68 4-[(4-Methoxybenzenesulfonyl) pyridin-3-ylmethylamino-1pheny..3methyl-1H-pyrazolo[3,4.blpyridine-5-carboxylic acid, hydroxyamide, hydrochloride Following the procedure of Example 61, the product of Example 67 is converted into the corresponding hydrochloride salt. m.p. 2250-2260C.

Example 69 4 -Methoxy benzenesul on yl) pyri di n.2.y Imet hyl amino] dilnethyl lH-pyrazolo[3,4-b]pyridine -5-carboxylic ac 'id, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-ainino) 1,3-dimethyl- IH-pyrazolo[3,4-bjpyridine-5-carboxylic acid, hydroxyaiides, the title compound may be prepared.

Example 4- 4 -Methoxy benzenesul fonyl) py ri di n-4-ylimet hylamino] dimethyl 1H-pyrazolo[3,4-blpyridine -5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-diinethyl- 1H-pyrazolo[3,4-bjpyridine-5-carboxylic acid, hydroxyamides, the title compound may be prepared.

Example 71 4 4 -Methoxybenzenesulfonyl)pyridin.3-ylmethylamino] -1-isopropyi lH-pyrazolo[3,4-blpyridin -5-carboxylic acid, hydroxyamide.

Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-dimethyl- lH-pyrazolo[I3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the tidle compound may be prepared.

37 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCT/US97/18281 Example 72 4 4 -Methoxy benzenesulIfonyl) py ridin 3-yl rneth ylamino] -1-benzyl-1Hpyrazolo[3,4-b] pyridin -5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the title compound may be prepared.

Example 73 (4-Methoxybenzenesujfonyl)aminoI -1-benzyl -3-methyl -111pyrazolo[3,4-b] pyridine -5-carboxyli c acid, hyd roxyamnide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- 1H-pyrazolo[3,4-b] pyridine-5-carboxylic acid, hydroxyamides, the title compound may be prepared.

Example 74 4-I(4-Methoxybenzenesulfonyl) 2 -thienylmethylamino] 3- dimethyl lH-pyrazolo[3,4-blpyridine -5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amnino) 1,3-dimethyl- 1H-pyrazolo[3,4-b] pyridine-5-carboxylic acid, hydroxyaxnides, the title compound may be prepared.

Example 4-[(4-Methoxybenzenesulfonyl) 3 -thienylrnethylamino] 3- dimethyl lH-pyrazoto[3,4 -b]lpy ridine -5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- IH-pyrazolo[3,4-b] pyridine-5-carboxylic acid, hydroxyamnides, the title compound may be prepared.

Example 76 4-[(4-Methoxybenzenesulfonyl) pyridin-3-ylmethylamino] (2,4.

dimethoxyphenyl) 3-methyl- lH-pyrazolo[3,4-b]pyridine acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (s ubstituted-4-amino) 1,3-dimethyl- IH-pyrazolo[3,4-b]pyridine-5-.carlyjxylic acid, hydroxyainides, the tidle compound may be prepared.

38 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCT/US97/18281 Example 77 4 4 .Methoxybenzenesulfonyl)pyridin-3-ylmethylaminoI methoxyphenyl)-3-meth yi-1 H-pyrazo o pyri dine -5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-dimethyl- lH-pyrazolo[3,4-b~pyridine-5-carboxylic acid, hydroxyamides, the title compound may be prepared.

Example 78 4- (Methyl py rid in yloxy )ben zen esulIfon y I ani n o} di methyl-iH pyrazolo[ 3,4-b] pyridine-S-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazoloI3,4-b~pyridine-5-carboxylic acid, hydroxyamides, the title compound may be prepared.

Example 79 4 -{(Met hyl 4 henoxy benzen es ul onyl)ami no .1,3 di met hyl 1 H -py razolo[ 3,4-b] pyridine-5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-axnino) 1,3-dimethyl- 1H-pyrazolo[3,4- bipyridine-5-carboxylic acid, hydroxyaxnides, the title compound may be prepared.

Example 4 [Methyl -(4-methoxy ben zenesu Ifonyl)ami 1,3-dimethyl- 1H-pyrazolo[ 3,4-b] pyridine-5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-dimethyl- lH-pyrazolo[3,4-b]pyridine.5.carlboxylic acid, hydroxyaxnides, the tidle compound may be prepared.

Example 81 4 -[Methyl- propyloxybenzenesulfonyl)amino]- 1,3.dimethyl.1H..pyrazolo[ 3,4-b] pyridine-5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-dimethyl- IH-pyrazolo[3,4-b]pyridine.scarboxylic acid, hydroxyamides, the title compound may be prepared.

39 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCTIUS97/18281 Example 82 4- [(4-Methoxybenzenesulfonyl)pyridin..3-y1methylamino]- 1-methyl-3.

phenyl-lH-pyrazolo[3,4-b]pyridine.S-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-dimethyl- lH-pyrazolo[3,4-bjpyridine-5.carboxylic acid, hydroxyam-ides, the title compound may be prepared.

Example 83 4

-I(

4 -Methoxybenzenesulfonyl)pyridin..3.ylmethylamino]. 1-ethyl-3-phenyllH-pyrazolo[3,4-blpyridine-5.carboxylic acid, hydroxyamnide Following procedures described in Examples 45-68 for the preparation of the (substituted-4- amino) 1 ,3-dimethyl- IH-pyrazolo[3,4-b] pyridine-5-carboxylic acid, hydroxyamides, the title compound may be prepared.

Example 84 4 4 -Methoxybenzenesulfonyl)pyridin.3-ylmethylamino]. 1.tert- butyl-3methy]I1H-pyrazoloII3,4-bjpyridine-5-carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substituted-4-axnino) 1 ,3-dimethyl- lH-pyrazolo[3,4-blpyridine-5-carboxylic acid, hydroxyamides, the title compound may be prepared.

Example 4 4 -Metoxybenzenesulfonyl)pyridin3ymethylaminollmethyl3tert.

butyi-lH-pyrazolo[3,4-b]pyridine.5.carboxylic acid, hydroxyamide Following procedures described in Examples 45-68 for the preparation of the (substtuted-4-amino) 1 ,3-dimethyl- lH-pyrazolo[3,4-blpyridine-5-.carlboxylic acid, hydroxyaxnides, the title compound may be prepared.

SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Pharmacology Procedures for Measuring MMP-1, MMP-9, and MMP-13 Inhibition These assays are based on the cleavage of a thiopeptide substrates such as Ac-Pro- Leu-Gly( 2 -mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt by the matrix metalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9 (gelatinase), which results in the release of a substrate product that reacts colorimetrically with DTNB (5,5'-dithiobis(2-nitro-benzoic acid)). The enzyme activity is measured by the rate of the color increase. The thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 5 mM CaCl 2 before use. The stock of enzyme is diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCI 2 0.02% Brij) to the desired final concentration. The assay buffer, enzyme, vehicle or inhibitor, and DTNB/substrate are added in this order to a 96 well plate (total reaction volume of 200 tl) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader and the increase in color over time is plotted as a linear line.

Alternatively, a fluorescent peptide substrate is used. In this assay, the peptide substrate contains a fluorescent group and a quenching group. Upon cleavage of the substrate by an MMP, the fluorescence that is generated is quantitated on the fluorescence plate reader. The assay is run in HCBC assay buffer (50mM HEPES, pH 7.0, 5 mM Ca 2 0.02% Brij, 0.5% Cysteine), with human recombinant MMP-1, MMP-9, or MMP- 13. The substrate is dissolved in methanol and stored frozen in 1 mM aliquots. For the assay, substrate and enzymes are diluted in HCBC buffer to the desired concentrations.

Compounds are added to the 96 well plate containing enzyme and the reaction is started by the addition of substrate. The reaction is read (excitation 340 nm, emission 444 nm) for min. and the increase in fluorescence over time is plotted as a linear line.

For either the thiopeptide or fluorescent peptide assays, the slope of the line is calculated and represents the reaction rate. The linearity of the reaction rate is confirmed (r 2 The mean (x±sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's multiple comparison test.

Dose-response relationships can be generated using multiple doses of drug and IC50 values with 95% CI are estimated using linear regression.

In vivo MMP Inhibition A 2 cm piece of dialysis tubing (molecular weight cut-off 12-14,000, 10 mm flat width) containing matrix metalloproteinase enzyme (stromelysin, collagenase or gelatinase 41 SUBSTITUTE SHEET (RULE 26) I r lr: L~ i- i WO 98/16514 PCT/US97/18281 in 0.5 mL of buffer) is implanted either ip or sc (in the back) of a rat (Sprague-Dawley, 150-200g) or mouse (CD-1, 2 5-50g) under anesthesia. Drugs are administered PO, IP, SC or IV through a canula in the jugular vein. Drugs are administered in a dose volume of 0.1 to 0.25 mL/animal. Contents of the dialysis tubing is collected and enzyme activity assayed.

Enzyme reaction rates for each dialysis tube are calculated. Tubes from at least 3 different animals are used to calculate the mean± sem. Statistical significance (p<0.05) of vehicle-treated animals versus drug-treated animals is determined by analysis of variance.

(Agents and Actions 21: 331, 1987).

Procedure for Measuring TACE Inhibition Using 96-well black microtiter plates, each well receives a solution composed of ;iL TACE (Immunex, final concentration 14g/mL), 70L Tris buffer, pH 7.4 containing glycerol (final concentration 10 mM), and 10 pL of test compound solution in DMSO (final concentration 1pM, DMSO concentration and incubated for 10 minutes at room temperature. The reaction is initiated by addition of a fluorescent peptidyl substrate (final concentration 100 to each well and then shaking on a shaker for 5 sec.

The reaction is read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate.

The linearity of the reaction rate is confirmed (r 2 The mean (x±sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drugtreated rates using Dunnett's multiple comparison test. Dose-response relationships can be generate using multiple doses of drug and IC 50 values with 95% CI are estimated using linear regression.

Results of the above in-vitro and in-vivo matrix metalloproteinase inhibition and TACE inhibition pharmacological assays are given in Table I below.

42 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCT/US97/18281 Table I. Inhibition of MMP and TACE in-vivo Example -MMP-1 1 MMP-9 1 MMP-13 1 TACEI MMp 2 11 172 11 7 >1000 12 933 2 1 190 13 82 15 9 3% 14 108 8 6 24% 139 25 12 7% 16 99 6 3 36% 64%(100) 17 3100 8 16 401 18 152 26 627 19 194 2 4 314 344 6 9 589 29 200 5 4 22 11 467 47 31 225 2 2 32 456 1 1 24 33 1012 1 1 34 301 9 12 234 4 5 49 36 46 2 1 226 81%(50) 37 65 2 1 124 38 100 4 3 336 39 75 2 2 53 151 3 4 120 41 136 2 2 161 65%(50) 42 5200 874 37 16% 43 43% 71% 63% 44 65% 59% 73% 52 45 2.4 1.4 236 39 2.9 2.5 160 61 36 2.3 2.3 214 62 1236 5.7 23 46% 63 721 6.8 23 64 913 5.5 19

IC

50 nM or inhibition at 1 jiM concentration 2. inhibition (dose, mg/kg), p.o. vs MMP-13 43 SUBSTITUTE SHEET (RULE 26) WO 98/16514 PCT/US97/18281 Pharmaceutical Composition Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.

Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, glycols) and their derivatives, and oils fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.

Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.

The compounds of this invention may be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a 44 SUBSTITUTE SHEET (RULE 26) I 1:1: L. WO 98/16514 PCT/US97/18281 transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.

The dosage to be used in the treatment of a specific patient suffering a MMP or TACE dependent condition must be subjectively determined by the attending physician.

The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles.

Preferably the pharmaceutical composition is in unit dosage form, as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.

The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

SUBSTITUTE SHEET (RULE 26)

Claims (14)

1. A compound having the formula: R 7 NHOH Z-" O where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons of the heteroaryl ring of group A where: A is a 5-6 membered heteroaryl having from 1 to 2 heteroatoms independently selected from N, 0, and S, and substituted by R 1 and R 2 on adjacent atoms wherein R 1 and R 2 together with the carbons to which they are attached form a fused phenyl ring or a 5-6 membered heteroaryl ring having from 1 to 3 heteroatoms selected independently from N, O and S, wherein either ring can be substituted by one or more substituents selected from R 4 Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, where aryl is phenyl or naphthyl optionally substituted by R 1 R 2 R 3 and R4; heteroaryl is a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, 0, and S, and optionally substituted by R 1 R 2 R 3 and R 4 and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R 1 R 2 R 3 and R 4 R 1 R 2 R 3 and R 4 are independently -COR 5 -Cl, -I, -C(O)NR 5 OR 6 -OR 5 ,-Cl-C4-perfluoroalkyl, -S(O)xR 5 where x is 0-2, -OPO(OR 5 )OR 6 -PO(OR 6 )R 5 -OC(O)NR 5 R 6 -COOR 5 -CONR 5 R 6 -SO 3 H, -NR 5 R 6 -NR 5 COR6, -NR 5 COOR 6 -SO2NR 5 R 6 -NO 2 -N(R 5 )S0 2 R 6 -NR 5 CONR 5 R 6 -NR 5 C(=NR 6 )NRSR6, 3-6 membered cycloheteroalkyl having one to three heteroatoms independently selected from N, 0, and S and optionally having 1 or 2 double bonds and optionally substituted by one to three groups each selected independently from R -aryl or heteroaryl as defined above, -SO 2 NHCOR 5 or -CONHSO 2 R 5 where R 5 is not H; 46 SUBSTITUTE SHEET (RULE 26) -7 WO 98/16514 WO 9816514PCT/US97/18281 -SO2NHCN, -SO2NHCONR 5 R 6 or straight chain or branched -C 1 I-C 6 alkyl,. -C2-C6-alkenyl, or -C2-C6-alkynyl, or -C 3 -C 6 cycloalkyl optionally having 1 or 2 double bonds each optionally substituted with -CORS, -CN, -C 2 -C 6 alkenyl, -C2-C 6 alkynyl,-0R 5 -Cl-Ct- perfiuoroalkyl, -S(O)xR 5 where x is 0-2, -OC(O)NR 5 R 6 -COOR 5 -CONR 5 R 6 -SO 3 H, -NR 5 R 6 ,-NR 5 COR 6 -NR 5 COOR 6 SO2NR 5 R 6 -NO 2 -N(R 5 )S0 2 R 6 -NR 5 CONR 5 R 6 -C 3 -C 6 cycloalkyl as defined above, 3-6 membered cycloheteroalkyl as defined above, aryl or heteroaryl as defined above, -SO 2 NHCOR or-CONHSO 2 R 5 where R 5 is not hydrogen, -PO(0R 5 )0RO, PO(0R 6 )R 5 -tetrazol-5-yl, -C(O)NR 5 OR 6 6 )NRSR6,SO 2 NHCONR5R6 or -SO2NHCN; R 5 and R 6 are independently defined as H, aryl and heteroaryl as defined above, -C3-C6-cycloalkyl as defined above, -C3-C6-cycloheteroalkyl as defined above, -CI-C4-perfluoroalkyl, or straight chain or branched -C 1 -C 6 alkyl, -C2-Q-alkenyl, or -C2-C6-alkynyl each optionally substituted with -OH, -COR 8 -CN, -C(O)NR 8 OR 9 -C2-C6-alkenyl, -C2-C6-alkynyl, -OR 8 -Cl-C4-perfluoroalkyl, -S(O)xR 8 where x is 0-2, -OPO(0R 8 )0R 9 -PO(0R 8 )R 9 -OC(O)NR 8 R 9 -COOR 8 -CONR 8 R 9 -SO 3 H, -NR 8 R 9 ,-NCOR 8 R 9 -NR 8 COOR 9 -S02NR 8 R 9 -NO 2 -N(R 8 )S0, -NR 8 CONR 8 R 9 -C3-C 6 cycloalkyl as defined above, -C 3 -C 6 cycloheteroalcyl as defined above, -aryl or heteroaryl as defined above, -SO2NHCOR 8 or -CONHSO 2 R 8 where R' is not hydrogen, -tetrazol-5-yl, -NR8C(=NR 9 )NR8R9, -SO2NHCONR 8 R 9 or -SO 2 NHCN; R 7 is hydrogen, straight chain or branched -Cl-C6-alkyl, -C2-Q-alkenyl, or -C2- C6-allcynyl each optionally substituted with -OH, -COR 5 -CN, -C2-C 6 alkenyl, -C2-C6-alkynyl, -OR 5 -C 1 -C4-perfiuoroalkyl, -S (O)xR where x is 0-2, -OPO(0R 5 )0R 6 -PO(0R 5 )R 6 -OC(O)NR 5 R 6 COOR 5 -CONR 5 R 6 -SO 3 H, -NR 5 R 6 ,-NR 5 COR 6 -NR 5 COOR 6 SO2NR 5 R 6 -NO 2 -N(R 5 )S0 2 R 6 -NR 5 CONR 5 R 6 -C 3 -C6 cycloalkyl as defined above, -C3-C6-cycloheteroalkyl as defined above, -aryl or heteroaryl as defined above, -SO 2 NHCOR 5 or CONHSO 2 R5 where R 5 is not hydrogen, -tetrazol-5-yl, 47 SUBSTITUTE SHEET (RULE 26) 11 DEC. UU001 11:56 SPRUSON FERGUSON NO. 2291 P. 6 NR'C(=NR6)NR'R, -C(O)N R 5 0R 6 -SONHCONR'R' or SO 2 NHCN; or R' is phenyl or naphrhyl, optionally substituted by R 1 R 2 R 3 and R 4 or a 5 to 6 membered heteroaryl group having 1 to 3 heceroatoms selected independently from N, 0, and S and optionally substituted by R2, R 3 and R 4 or R7 is C 3 -C 6 cycloalkyl or 3-6 membered cyclohereroalkyl as defined. above; or R 7 CH2-N-A- where A is as defined above, can form a non-aromatic, A-fused, 7-12 membered heterocyclic ring, optionally containing an additional heteroatomrn selected from O, S and N wherein said heterocyclic ring may be optionally fused to a benzene ring; R 8 and R 9 are independently H, aryl or heceroaryl as defined above, -C 3 -C7- a; cycloalkyl or cyclohereroalkyl as defined above, -Ci-C4-perfluoroalkyl, straight chain or branched -CI-C6-alkyl, -C2-C6-alkenyl, or -C2-C 6 alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy, -C 1 Ci-perfluroalkyl, amino, mono- and di-Cj-C6-alkylamino, carboxylic acid, carboalkoxy and carboaryloxy, nitron, cyano, carboxamido primary, Ic mono- and di-Cl-C6-alkylcarbamoyl; a pharnaceutically acceptable salt thereof when one can be formed; an optical isomer or diastereornmer thereof.

2. A compound according to claim I wherein both of the carbons of A adjacent to the carbon bearing the sulfonamido group have a substituent other than hydrogen.

3. A compound according to claim 2 wherein the Z group is para-alkoxyphenyl, para- aryloxyphenyl or para-heteroaryloxyphonyl.

4. A compound according to claim 1 which is selected from the group consisting of: 4-[Bnzyl-(4-ethoxy-benzenesulfonyl)-amino-7-trifluoromethyluinoline-3- carboxylic acid hydroxyanmide, 4-[Benyl-(4-methoxy-benzenesulfonyl)-aino]-8-ifluoromethyl-quinoline-3- carboxylic acid hydroxyanide, 4-[Benzyl-(4-methoxy-benzencsulfonyl)-am ino-6-bromo-quinoline-3-carboxylic acid.hydroxyamide, S4-[nzyl-(4-methoxy-benzenesulfonyl)-aminol -brmo-quinoline-3-crboxylic WO 98/16514 WO 9816514PCTIUS97/18281 acid hydroxyamide, 4 -[Benzyl-( 4 -methoxybenzenesufony)ano]6trifluoromeffiylquinoline- 3 carboxylic acid hydroxyamride, 4 4 -methoxybenzenesufony)pyrdin3ymethylino7ifuoromety quinoline-3-carboxylic acid hydroxyanude, 4 -[Benzyl-( 4 -methoxybenzenesulfonyl)-amno]-8-.tbut,1..quin 0 1jle-3 carboxylic acid hydroxyamidde, 4 -[Benzyl-(4-methoxybenzenesulfonyl)-aminoy

8-methyl-quirioline-3- carboxylic acid hydroxyam-ide, 8 -Ethyl- 4 -[benzyl-(4-methoxybenzenesulfonyl)-ano].quinline.3 carboxylic acid hydroxyamide, 4 -[Benzyl-(4-methoxybenzenesulfonyl).amino}.8..( -methylethyl)-quinoline-3- carboxylic acid hydroxyamide, 4 -[Ethyl-( 4 -methoxy-benzenesulfony)amino]-8-iny..quinoline.3carboxyic acid hydroxyanude, 4 -[Benzyl-( 4 methoxybenzenesulfony)ano-6-nioquinoline-3carbxyic acid hydroxyamide, 4 -[Methyl-(4-methoxy-benzenesulfonyl).amino.. 8-bromo-quinoline-3-carboxylic acid hydroxyaniide, 4- (Methyl-[4-(pyridin-4-yloxy)-benzenesufony]-aino) -6-iodo-quinoline-3- carboxylic acid hydroxyarnide, 4- (Methyl-(4-(pyridin- 4 -yloxy)-benzenesulfonyl..ainino) -6-iodo-quinoline-3- carboxylic acid hydroxyarnide hydrochloride, 4 [Ethyl..( 4 -methoxy..benzenesulfonyl).aino-6phenylethynylquinoie.3 carboxylic acid hydroxyamide, 4 -[Methyl-( 4 -methoxy-benzenesulfonyl).ariino]-6-phenylethyl..quinohne-3 carboxylic acid hydroxyamide, 4 4 -Methoxy-benzenesulfonyl).pyridin-3.ylmethiyl1amno]. 8-methoxy-quinoline- 3-carboxylic acid hydroxyanide, 4 4 -Methoxy-benzenesulfonyl)-pyridin-3-ylmethy1..arjnoy- 8-bromo-quinoline-3- carboxylic acid hydroxyamide, 4 4 -methoxy-benzenesulfonyl)-pyridin.3-ylmethyI amrino]-8-Benzyl-quinoline-3- carboxylic acid hydroxyamide, 4 4 -Methoxy-benzenesulfanyI)-pyrdin-3ylmethy..ajno.. 8-iodo-quinoline-3- carboxylic acid hydroxyamnide, 4 4 -Methoxy-benzenesulfonyl).pyridin-3-ylmetiyl-aminfo]gpenyl-quinoine.3- carboxylic acid hydroxyarnide, 49 SUBSTITUTE SHEET (RULE 26) WO 98/16514 WO 9816514PCT/US97/18281 4 4 -Methoxy-benzenesulfonyl)-pyidin3ylmethyl-aminoy 8-thiophen-2-yl- quinoline-3-carboxylic acid hydroxyamide, 4 -[(Biphenyl- 4 -sulfonyl)-pyridin-3-ylmethy1..amino]-7-trfluorometly.quinoline.3 carboxylic acid hydroxyamnide, 4-[(Octane-l-ufnl yii--lehlainl7tilooehlqioie3 carboxylic acid hydroxyamide, 4 -[Pyridin- 3 -ylmethyI-(toluene-4sufony)ano]-7-tfluoromethy..quinoline-3 carboxylic acid hydroxyamide, 4 -[Benzyl-( 4 -methoxybenzenesulfonyl)apino].1 ,3-dimethyl- 1H-pyrazolo[3,4-b] acid, hydroxyamnide, 4-[(4-Methoxybenzenesulfonyl)pyridin -3-ylmedhylamino] dimethyl IH- pyrazolo[3,4-blpyridine -5-carboxylic acid, hydroxyaniide, 4 4 -Methoxybenzenesulfonyl)pyridin3ylmethyamno] dimethyl IH- pyrazolo[13,4-blpyridine -5-carboxylic acid, hydroxyamide hydrochloride, 4 -[Benzyl-(4-methoxybenzenesulfonyl)arpino.. 1-phenyl- 1H-pyrazolo[3,4-bl pyridine -5-carboxylic acid, hydroxyaniide, 4-II(4-Methoxybenzenesulfonyl)pyridin -3-ylmethylaxniino] -1 -phenyl- IH- pyrazolo[3,4b]pyridine -5-carboxylic acid, hydroxyaxnide, 4-[(4-Methoxybenzenesulfonyl)pyridin -3-yhnethylarnino] -1 -phenyl- 1H1- pyrazololi3,4-blpyridine -5-carboxylic acid, hydroxyamide, hydrochloride, 4-[Benzyl-(4-methoxybenzenesulfonyl)amnino]. 1-phenyl-3-methyl- 1H- pyrazolo[3,4b] pyridine -5-carboxylic acid, hydroxyaxnide, 4 -[(4-Methoxybenzenesulfonyl)pyridin-3ylmethylarino]. 1phenyl-3-methyl- 1H- pyrazolo[3,4-blpyridine-5-carboxylic acid, hydroxyamide, 4 4 -Methoxybenzenesulfonyl)pyridin-3-ylmethylarfno.. 1phenyl-3-methyl- 1H- pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyaxnide, hydrochloride, 4 4 -Methoxybenzenesulfonyl)pyidin-2ylmethyI amino] dimethyl 1H- pyrazlo[3,4-blpyridine -5-carboxylic acid, hydroxyaniide, 4 -[R 4 -Methoxybenzenesulfonyl)pyiin-4-ylmethylmnoI dimethyl 1H- pyrazolo[3,4-blpyridine -5-carboxylic acid, hydroxyamide, 4 4 -Methoxybenzenesulfonyl)pyridin.3.ylmethylariino] -1 -isopropyl lii- pyrazolo[3,4blpyridin -5-carboxylic acid, hydroxyanmide, 4 4 -Methoxybenzenesulfonyl)pyridin.3-ylmethylaminoI -1 -benzyl- II- pyrazolo[3,4-b] pyridin -5-carboxylic acid, hydroxyamide, (4-Methoxybenzenesulfonyl)amino] -1 -benzyl -3-methyl -1 H-pyrazolo[3,4-b] pyridine -5-carboxylic acid, hydroxyamide, SUBSTITUTE SHEET (RULE 26) If. upL, Uj 1i:00 bfKUI PU'MMIU Nlu. MI F, 1'I 4-[(4-methoxybenzenesulfonyl)-2-thienylmethylamino-1 ,3-dimethyl-1 H-pyrazolo[3 1 carboxylic acid, hydroxyamide; 44(4-methoxybenzenesulfonyl)-3-thienylmethylamino-1 ,3-dimethyl- 1 H-pyrazolof3,4-b~pyridine-5-carboxyic acid, hydroxyamide; 4-[(4-methoxybenzenesulfonyl-pyddin- 3-yimethylamino-1 -(2,4-dimethoxyphenyl)-3-methyl-1 H-pyrazolo[3,4-bjpyridine-5.carboxylic acid, hydroxyamide; 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylaminoj- -(2-methoxyphenyl)-3- methyl-I H-pyrazolo[3,4-blpyridine.5-carboxylic acid, hydroxyamide; 4-fmethyl-[4-(4- pyridinyloxy)benzenesulfonylamino- 1,3-dimethyl-1 H-pyrazolo(3,4-b]pyddine-5-carboxylic acid, hydroxyamide; 4-{methyii[4-(phenoxy)benzenesulfonyl]amino-1 ,3-dimethyl-1 H-pyrazolo[3,4- acid, hydroxyamide; 4-[methyl-(4-methoxybenzenesulfonyl)amino]-1 ,3- dimethyl-1 H-pyrazolo[3,4-blpyridine-5-carboxylic acid, hydroxyamide; 4-[methyl-(4- propyloxybenzenesultonyl)amino]-i ,3-dimethyl-1 H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide; 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylaminop- -methyl-3-phenyl-1 H- pyrazolol3,4-bjpyridine-5-carboxylic acid, hydroxyamide; 4-ll4-methoxybenzenesulfonyl)pyridin-3- ylmethylamino-1 -ethyl-3-phenyl-1 H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide; methoxybenzenesulfony)pyidin-3-ylmethylamino-1 -tert-butyl-3-methyl-1 H-pyrazolo(3,4-bjpyridine- acid, hydroxyamide and 4 -f(4-methoxybenzenesulfonyl)pyidin-3-ylmethylamino]1 methyl-3-tert-butyl-1 H-pyrazolo[3,4-b]pyridine.5-carbaxylic acid, hydroxyamide. A matrix metalloproteinase or lACE inhibiting 1-sulfonamidohydroxamic acid derivative, substantially as hereinbefore described With reference to any one of the examples. 6. A pharmaceutical composition comprising a pharmaceuical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound according to any one of claims 1 to 7, A method of inhibiting pathological changes mediated by matrix metalloproteinases in mammals which comprises administration to a mamma! in need thereof a therapeutically effective amount of a matrix metal loproteanase inhibiting compound according to any one of claims 1 to 5 or of a composition according to claim 6, 8. A compound according to any one of claims 1 to 5 or a composition according to claim 6 when used in inhibiting pathological changes mediated by matrix metalloproteinases.

9. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for inhibiting pathological changes mediated by matrix metalloproteinases. A method according to claim 7, wherein the conditVon treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque wupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumour metastasis, tumour growth, osteoarthritis, rheumatoid (RA\LIBZ]05621.doc;Iam II. UL., UUI 11 :0 bfKUbUl i EKbUbU Ul. LZI f. 52 arthritis, septic arthritis, conical ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of foetal membranes, inflammatory bowel disease, or periodontal disease.

11. A method according to claim 7, wherein the condition treated is age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumours, ocular angiogenesis/neovascularisation and comeal graft rejection. To

12. A compound when used according to claim 8, wherein the condition treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumour metastasis, tumour growth, osteoarthritis, rheumatoid arthritis, septic arthritis, conical ulceration, abnormal wound healing, is bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of foetal membranes, inflammatory bowel disease, or periodontal disease.

13. A compound when used according to claim 8, wherein the condition treated is age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumours, ocular angiogenesis/neovascularisation and coreal graft rejection.

14. Use according to claim 9, wherein said medicament is for the treatment of atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumour metastasis, tumour growth, osteoarthritis, rheumatoid arthritis, septic arthritis, conical ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of foetal membranes, inflammatory bowel disease, or periodontal disease. Use according to claim 9, wherein (as in claim 14) age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular (R[\LIBZ]05621.doc:tni r~ I11 r,- L~ II. U LU. LUUI 11:01 bS KUbUIi ftEK UbU l i 53 inflammation, keratoconus, Siogren's syndrome, myopia, ocular tumours, ocular angiogenesis/neovascularsation and comeal graft rejection.

16. A method of inhibiting pathological changes mediated by TNF-c converting enzyme (TACE) in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a TACE inhibiting compound according to any one of claims 1 to or of a composition according to claim 6.

17. A compound according to any one of claims 1 to 5 or a composition according to claim 6 when used in inhibiting pathological changes mediated by TNF-c converting enzyme (TACE). 1o 18. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for inhibiting pathological changes mediated by TNF-a converting enzyme (TACE).

19. A method according to claim 16, wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection. A compound when used according to claim 19, wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection.

21. Use according to claim 18, wherein (as in claim 14) rheumatoid arthritis, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection. Dated 11 December, 2001 AMERICAN CYANAMID COMPANY Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON (R:\LIBZ]05621 .doc:am