AU697662B2

AU697662B2 - Polar-substituted hydrocarbons

Info

Publication number: AU697662B2
Application number: AU76484/94A
Authority: AU
Inventors: Damian Grobelny
Original assignee: Narhex Ltd
Current assignee: Narhex Ltd
Priority date: 1993-09-10
Filing date: 1994-09-12
Publication date: 1998-10-15
Anticipated expiration: 2014-09-12
Also published as: AU7648494A

Description

WO 95/07269 PCT/AU94/00538 1 POLAR-SUBSTITUTED HYDROCARBONS TECHNICAL FIELD The invention relates to certain hydrocarbon derivatives bearing polar substituents and their use in the ibition of retroviral proteases, for example in the treatment of HIV viral infections such as acquired immunodeficiency syndrome (AIDS).

The invention also relates to processes for preparing such hydrocarbon derivatives bearing polar substituents, to pharmaceutical compositions comprising them and to methods for the treatmnent or prophylaxis of retroviral infections. The invention also relates to a process for enhancing the water-solubility of a pharmaceutical or veterinary substance.

BACKGROUND ART Human immunodeficiency virus (HIV) is a pathogenic retrovirus causing AIDS and its related disorders. The development of antiviral chemothetapy against AIDS has been the subject of an intense research effort since the discovery of HIV. (For a recent review on molecular targets for AIDS therapy see Mitsua et al, Science, 1990, pp 1533is 1544). The HIV Proteases (HIV PR), and aspartyl proteases, were first suggested as a potential target for AIDS therapy by Kramer et al. (Science 231, 1580 (1986)). Since that time the potential usefulness of HIV PR inhibitors as effective agents in treatment of AIDS has been widely recognized (for a review of the HIV PR as a therapeutic target see Tomaselli et al. Chimica Oggi, May 1991, pp 6-27 and Huff J. Med. Chem. 34, 2314-2327 (1991)). Of the classical transition state mimics for aspartyl proteases, the hydroxyethylene, dihydroxyethylene, hydroxyethylamine and phosphinic acid isosteres appear to provide the greatest affinity for HIV PR. Many inhibitors of HIV PR have been shown to have an antiviral activity at concentrations in the nanomolar range in the different celt systems and are described as such in the patent literature.

OBJECTS OF THE INVENTION It is an object of the present invention to provide compounds useful as retroviral protease inhibitors. It is another object of the present invention to provide pharmaceutical compositions comprising compounds useful for the treatment or prophylaxis of retroviral infections. It is a further object of the present invention to provide methods for the treatment or prophylaxis of retroviral infections, in particular AIDS. Other objects of the present invention are to provide processes for preparing compounds useful as retroviral protease inhibitors, and processes for enhancing the water-solubility of pharmaceutical or veterinary substances, in particular retroviral protease inhibitors.

SUMMARY OF THE INVENTION as The invention provides compounds which are useful as inhibitors of retroviral proteases, particularly aspartyl proteases and more particularly HIV proteases, and which are effective in treating conditions characterized by unwanted activity of these enzymes, in particular acquired immune deficiency syndrome.

SUBSTITUTE SHEET (Rule 26) JRN: 25059AUInstructor Code: 010854 [N:\LIBF]11166:SAK WO 95/07269 PCT/A1394/00538 2 In the following description of the invention, the teaching of eaich of the publications mentioned is incorporated herein by reference.

A first embodiment of the invention is directed to compounds of the general formula or pharmaceutically acceptable salts or prodrugs thereof: wherein w 1 20 1 25 W-(A)nW-B(A*)m-V is selected from the group consisting of Rl-X-, (N, -N =CR 5

R

5

-C(R

5

=NR

3

-C(R

5

=NOR

3

-C(NR

3

R

4 -C(D)0R 3

-C(D)SR

3 and -C(D)NR 3

R

4 wherein Y* is as defined below,

R

1

R

3 and R 4 are independently selected from the group cons isting of R 6 and a solubilising group Px which is labile in vivo, wherein R 6 is selected from the group consisting of hydrogen,

R

20 wherein R 20 is selected from the group consisting of optionally substituted (C 1 -C 18 )alkyl, optionally substituted (C 2 -C 1 8 alkenyl, optionally substituted (C 2 -C 1 )alkynyl, optionally substituted (C 3 -C 1 8 )cycloalkyl, optionally substituted. (C 3

-C

1 8 )cycloalkyl(C 1 -C 18 )alkyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl, optionally substituted (C 3

-C

1 8 )cycloalkyl(C 2 -Cl 8 )alkynyl, optionally substituted (C 6

-C

24 )aryl, optionally substituted (C 6

-C

24 )aryl(C i-c 18 )alkyl, optionally substituted (C 6

-C

24 )aryl(C 2 -C 18 )alkenyl, optionally substituted (C 6

-C

24 )aryl(C 2

-C

1 8 )alkynyl, optionally substituted (C 1

-C

1 8 )acyl, optionally substituted heterocyclic, optionally substituted heterocyclic(Cl-C 1 8 )alkyl, optionally substituted heterocyclic(C 2 -C 13 )alkeny1, and optionally substituted heterocYclic(C 2 -Cl 8 )alkynyl C(D)0R 21

C(D)SR

2 1,

C(D)NR

2 1

R

22

C(NR

21

)R

22 ,an

C(NR

2

,)NR

22

R

23 wherein R 2 1

R

22 and R 23 independently are selected from hydrogen and R 20 as previously defined, or I, A 0 i. it WO 95/07269 PCT/AU94/00538 3

R

21 and R 22 together, or R 22 and R 23 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, or R 3 and R 4 when present, together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, D is selected from O and S, X is selected from the group consisting of Y, S(O) and S(0) 2 wherein Y is as defined below, X* is selected from the group consisting of NR 1 0 O and S, wherein R 1 o has the meaning of R 6 as previously defined,

R

1 is selected from the group consisting of R 1 as previously defined,

P(O)(OR

7

)R

8 S(O)zOR 7 and S(O)zNR 7

R

8 wherein z is 1 or 2 and R 7 and R 8 independently have the meaning of R 20 as previously defined, or

R

7 and R s together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,

R

5 and R5* are independently selected from the group consisting of H, CF 3

C(D)OR

103

C(D)SR

103

C(D)NR

1 0 3

R

10 4 and R 20 as previously defined, wherein D is as previously defined, and wherein R 103 and R 104 have the meaning of R 6 as previously defined, or R 103 and R 104 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and

R

5 is selected from hydrogen and R 20 as previously defined; n is 0-6; m is 0-6 and n+m 1; A at each occurrence is independently selected from the group consisting of R,2 R12* I I I I

R

1 3 R*R R 9 R" -C C- R, R2 R,2 R, R2' R 1 2

*R

I I I I I C- -C-C- I I I I I I I i

R

1 3 R Rn R 1 3

R

13

R

1 3 R 1 3 and a residue of a naturally occurring or synthetic amino acid; A* at each occurrence is independently selected from the group consisting of I* i A l i i 1

NNW*

optionally substituted (C 6

-C

24 )aryl(C 2 -Cl)alkyflyl, optionally substituted:,(Cj-C 1 8 )acyl, WO 95/07269 PCT/AU94/00538 4 R,2 9 R,.

Rv R R12 R2 R,2 Re R,- I I I I I I I I -c-c- I I I I I I I I R13 R 1 3 R, Rn R,3* Re' R 1 3 and a residue of a naturally occurring or synthetic amino acid; wherein

R

12

R

13

R

9 and R 9 are independently selected f.-om the group consisting of F, Cl, Br, I and R 5 as previously defined, RI I has the meaning of R, as previously defined,

R

12 has the meaning of R, 6 as previously defined,

R

13 is selected from the group consisting of F, Cl, Br, 1, R 6 as previously defined, and R 200 wherein R 200 is selected from the group consisting of

CN,

NCO,

NCS,

OCN,

SCN,

N

3

OR

60

NR

6 oR61,

DIC(D

2

D

1

C(D

2

)D

3

R

60 D IC(D 2 )NR6oR6, NR6oC(DI)R6, NR6oC(DI)D 2 R6 1 RC(IN lR2 NR6oOR6 1 amidino, guanidino, 02 P6, S(O)NR6oR6i, S(0) 2 NR0R, 61 Ij L~ :'13 i It-~dlsP-P~3PI.. WO 95107269 PCT/AU94/00538

D

1

S(O)

2 0R 60 D 1

S(O)NR

60

R

61 DlS(0) 2

NR

60

R

61 P(D,)(2R60)R1,

P(D

1

)(D

2 R60)D 3

R

61

P(D

1

)(D

2

R

6 0

)NR

6 1

R

62 P(Dj)R 60

R

6 1

D

1

PD

2 3

R

60 61

D

1

P(D

2

)(D

3

R

60

)D

4

R

6 1

D

1

P(D

2

)(D

3 R60)NR 6

R

62

D

1

P(D

2

)R

6 0

R

6 1

NR

60

NR

6 1

R

62 and

ONR

60

R

6 1 wherein D 1

D

2

D

3 and D 4 independently have the meaning of D as previously defined, and R6), R6 and R 62 independently have the meaning of R 6 as previously defined or any two or more of R60, R6 and R 62 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, or R 12 and R 13 together are selected from the group consisting of =S, C =N0R 6 0

=NR

60 -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (C 1

-C

12 )alkylidene as defined below and R6 is as previously defined, and L is selected from the group consisting of a bond, D D II II

-N-C-

-S()zN -NS(0)z NS()zN I I D D D II II II -S(O)z-N-C-N- I II I I

R

11 Ri 1 R 1 1

R

11 Rll* 4

I

LI

D

II

R

11

D

II

R

1 1 R13**

N

NR

1

I

II

-Ce-N-- 111 I i -ll I- IY I I

-C-C-

I I R, R3 I I

-C-C-

R

1 3 3 1(12 K12

-C-C-

I I

R

1 3 Re 3 F\12- IX12 1 1 Reg Re 3 ItV ,12.

r PCT/AU94/0 0 5 3 8 WO 95/07269 NRii

R

1 1

D

11

-C-N-N-

O 11 1 1

D

D1 1 D D II

II

-O-P-

DI

II

-Gil 2 and -CH 2

-CH

2 wherein

R

11 and D are as previously defined,

R

11 and D* have the meaning of R, I and D respectively, and z is 1 or 2;

R

13 is F, Cl, Br, OR 60 or NR 60

R

60 wherein

R

60 and R 61 are as previously defined, B is selected from the group: consisting of

ZM

-N-

M

-C-

-N-

ZM

-C-

R

14

-N-

M 2

-C-

N

2 I I

-C-

M

1

DI

ZM

II

D*

0 11

-S

0 11

-S

11

C

-C-

N 1 N 17

R

203 C "z

S

-C-C-

R

1 4

R

14

R

14 -R14**

C"

I >iZM

N-ZM

-C-C-

R

14

ZM

C,

MI R 203

R

203

C"

C-

R

14

"'R

1

C

I-SI

-N-

-S-

11 0

-C-C-

I I

R

1 4

*R

14

R

14

IR

14 I-sI

R

14

.Z*M*

C"

II>ZM

OR

18 and

SR

19 R14*

I

P-

C-

OR

19 -C-s

OR

1 NRja*Rig* V_ i) 6 I

S(O)

2

DIR

60 S(Q)NR6R 6 1 '47/ WO 95/07269 PCT/AU94/00538 wherein R 203 and R 20 3* independently have the meaning of R 6 as previously defined,

R

14 and R 1 are independently selected from the group consisting of hydrogen,

R

20 as previously defined,

CF

3

C(D*)OR

40

C(D*)SR

40 and

C(D*)NR

40

R

4 1 wherein R 40 and R41 independently have the meaning of

R

2 1 and R 22 as previously defined or R40 and R41 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,

R

1 4 is selected from the group consisting of F, Cl, Br, I, R 1 4 as previously defined and R 200 as previously defined,

R

17 and R 1 7* independently have the meaning of R 6 as previously defined, D* has the meaning of D as previously defined, Z is a saturated or unsaturated (C 2

-C

4 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 14 as previously defined, Z* is a saturated or unsaturated (Ci-C 3 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 14 as previously defined,

M

1 is selected from the group consisting of OR 15

SR

15 and NR 15

R

1 7, wherein R 1 5 is selected from the group consisting of: Px as previously defined, and R6 as previously defined, and a glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and

R

17 is as previously defined, or

R

15 and R 1 7 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, M and M* are independently selected from the group consisting of M 1 as previously defined, OCN, SCN, YR 2 Y* and N=CR 30

R

3 1 wherein Y, Y* and R 2 are as defined below, and R 30 and R 31 independently have the meaning of R 20 as previously defined,

M

2 is selected from the group consisting of R 1 4 as previously defined,

-CR

3 and -CR 30

,=NR

17 where is as defined below, R 3 0* I I Kin R11* R11

R

11 R1I* "j7 WO 95 107269 PCT/AU94100538 8 has the meaning of R 20 as previously defined, and R 17 is as previously.

defined,

R

18 and R 19 independently have the meaning of R 20 as previously defined or

R

18 and R 19 together form part of ai saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and

R

18 and R 19 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below; V is selected from the group consisting of YR 2 Y* and C(R 30 wherein Y is absent or is selected from the group consisting of: 0-

I

0 11 -S-N ii I

OR

50 0 0 I I K0U1 0 11 P I I

R

51 0 R 50 0 11 -N-S

K

50 0 11 0

R

5 o0R 51 0 I I

R

50

OR

51 0-

II

0 0 0S0 I I

R

51 0 R 50 0

OR

51 0.

I I -Si-N-

II

K0 0 I I 0 0 11 -0-P-N-

R

51 0 R 5 o 0

I

OR

51 o 0

D**R

52 D*-*R 52 0

II

wherein is selected from the group consisting of a bond, 0, S and

NR

50

R

50 has the meaning of R 6 as previously defined, R 51 has the meaning of R 15 as previously defined and R 52 has the meaning O w of R20 as previously defined, or R50 and R51, when present, together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and I R33 2 SR2 -N=C -N-O-R2* N-R2* O O 1I II D**RI15 of R 2 as previously defined, or R 5 and R 1 when present, together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and I I I I -N=O R14* 114* R114* R1 14* 0 0 S= -S=0 -S=NR117* D** 1 I I I -aP=D* R114"

P=D*

I wherein D* and independently have the meaning of D as R114** previously defined; R 1 14

R

1 14

R

115 and R 1 17 have the meaning of

R

1 4

R

14

R

15 and R 17 respectively, as previously defined; R 50 and R 5 1 are as previously defined or R 50 and R 5 1 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below; R 2 is selected from the group consisting of R 2 as previously defined, Px as previously defined, S(O)zOR120 and S(O)zNR120R1 2 1, wherein z is 1 or 2;

R

33 and R 34 are independently selected from the group consisting of hydrogen and R 20 as previously defined, or R 33 and R 34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and R 120 and R 121 independently have the meaning of R 20 as previously defined, or R 1 20 and R 121 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,

R

30 is as previously defined, and is selected from =N-NR 115

R

1 7 and =N-OR 1 1 5 wherein R 1 15 and R 117 have the mea'.ag of R 1 5 and R 6 respectively, as previously defined, or

R

115 and R 11 7 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and wherein any group selected from R 1

R

1 R2, R2*, R 9

R

11

R

1 2

R

13

R

14

R

14

R

17 R5O and R 5 1 may, together with any other group selected from R 1

R

1

R

2

.R

2

R

9

R

10

R

11

R

12

R

1 3

R

14

R

14

R

17

R

50 and R5 1 form one or more saturated or unsaturated cyclic, bicyclic or fused ring system(s) as defined below, preiosl deindOCN, SCN, YR 2 Y~ and N=CR 30

R

31 wherein Y I

I

I K 4 WO 95107269 PCT/AU94100538 and wherein any tertiary amino nitrogen atom may be replaced by the group and, wherein any hydroxyl, mercapto or amino group may be protected by a protecting group which is labile in vivo.

Compounds of the general formula are usefu as inhibitors of retroviral proteases, in narticular IVY proteases.

One form of the first embodiment of the invention is directed to compounds of the general formula or pharmaceutically acceptable salts or prodrugs thereof: W t-v'(11) wherein W1 is selected from the group consisting of R 1

-CN,

-N=CR

5

R

5

-C(R

5

)=NR

3

-C(R

5 )=N0R 3 -C(D)0R 3

-C(D)SR

3 and

-C(D)NR

3

R

4 wherein Y* is as defined below, RI, R 3 and R 4 are independently selected from the group consisting of R 6 and a solubilising group Px which is labile in vivo, wherein R 6 is selected from the group consisting of hydrogen,

R

20 wherein R 20 is selected froma the group consisting of optionally substituted (C 1

-C

1 8 )alkyl, optionally substituted (C 2

-C

1 8 )alkenyl, optionally substituted (C 2

-C

18 )alkynyl, optionally substituted (C 3

-C

1 8 )cycloalkyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 1

-C

1 8 )alkyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2

-C

1 8 )alkenyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2

-C

1 8 )alkynyl, optionally substituted (C 6

-C

24 )aryl, optionally substituted (C 6

-C

24 )aryl(C 1 -C 18 )al~kyl, optionally substituted (C 6

-C

2 4)aryl(C 2

-C

1 5 )alkenyl, optionally subst-isted (C 6

-C

24 )aryl(C 2 -C 15 )alkynyl, optionally sut' aited (C 1

-C

18 )acyl, optionally '-,tituted heterocyclic, optiona] y substituted heterocyclic(C 1 ,)alkyl, optiqn?,lly substituted heterocyclic(C 2

-C

1 8 )alkenyl, and opI' iaily substituted heeocci(C-I)alkynyl C (D j$R 21 and

I

11 ic~

A

L I m 4 WO 95/07269 PCTIAU94/00538

C(D)NR

21

R

22 wherein R 2 1 and R2 2 independently are selected.

from hydrogen and R 20 as previously defined, or R 2 1 and

R

22 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, or R 3 and R 4 when present, together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, D is selected from 0 and S, X is selected from the group consisting of S(O) and S(0) 2 wherein Y' is as defined below, X* is selected from the group consisting of NR 10 0 and S, wherein R 10 has the meaning of R 6 as previously defined, RI* is selected from the group consisting of R 1 as previously defined, S(O)zOR 7 and S(O)zNR 7

R

8 wherein z is 1 or 2 and R 7 and R 8 independently have the meaning of R 20 as previously defined, or R 7 and

R

8 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,

R

5 and R 5 are independently selected from the group consisting of H, CF 3

C(D)OR

10 3

C(D)SR

10 3 C(D)NRl 03

R

1 04 and. R2 0 as previously defined, wherein D is as previously defined, and wherein R 1 03 and R 104 have the meaning of R 6 as previously defined, or R 10 3 and R 104 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below; n' is 0-8; m' is 0-8 and 1; A' and are independently at each occurrence selected from the group consisting of 0, S, S(0) 2

NR

11

CR

12

R

13 and CR 12

.R

13 or two consecutive

-C=C-

groups or are a structural unit selected from R I wherein and

R

12

R

13

R

9 and Rg, are independently selected from the group consisting of F, Cl, Br, I and R 5 as previously defined,

R

11 has the meaning of R as previosly defined,

R

12 has the meaning of R 6 as previously defined,

R

13 is selected from the group consisting of F, Cl, Br, I, R 6 as previously defined, and R 200 wherein R 2 0 is selected from the group consisting of

A

a PCT/AU94/00538 WO 95/07269 12

CN,

NCO,

NCS,

OCN,

SCN,

N

3

OR

60

SR

60

NR

60

R

61 D (D 2

)R

6 o, D 1

C(D

2

)D

3 R6o, DlC(D 2 )NR6oR61, NR6oC(D 1

)R

61 NR6oC(D 1

)D

2 R6 1

NR

60

C(D

1

)NR

6 lR 62 NR6oOR6i, amidino, guanidlino, 4 S(O)R 60 20 S(OADR6o,

S(O)NR

60

R

6

S(O)

2

NR

6 oR6, DS(O)R6o, DlS(0) 2 0R60, DjS(O)NR60R61,

D

1

S(O)

2 NR0R 6 j, P(D 1

)(D

2

R

6 o)R61, P(Di)(D 2

R

6 o)D 3 R6 1

P(D

1

)(D

2

R

60

)NR

6 1

R

62 430 P(Di)R 6 oR 6 1,

DP(D

2

)(D

3 R6 0 )R61, DlP(D 2

)(D

3

R

6 o)D 4 R6, II D 1

P(D

2

)(D

3

R

6 o)NR6IR6 2

DP(D

2 )R6oR 6 1, NR6oNR61R62 and 61 wherein D 1

D

2

D

3 and D 4 independently have the meaning of D as previously defined, and R60, R61 and R62 oraytoo oeo 6 ,RiadR2fr atoindependently have the meaning of R6 as previously defined Wo 95107269 PCTIAU94/00 3 8 saturated or unsaturated cyclic, bicyclic or fused ring system* as defined below, si g o =S or R 12 and

R

13 together are selected from the group consitnof=0 =NOR 6 o,

NR

60 -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (Cl-C,2 )alkylidene as defined below and

R

60 is as previously defined; B'is selected from the group consisting Of j

ZM

M

-C-

MI

-N-

ZM

R1-

-N-

-C-

I

-C-

1

DI

ZM

II

0

-S-

0

NR

17 11 0

~R

7

R

2 03-,C .'Z*M R203-NC "R 20 3*

S

R

14 *Ri4-~ R 1 4 A 1 C

W

1.1ZM

-C-C-

I I

R

1 4 *Ri 4 C14* Z*M

IC"~

Rj4*N-,. 'Ri 4 7

C

R14 Z* I i

R

14

R

1 4**

R

14 ,Z1*

C

1."NZM

C--

/R17

F-

-N-

-R1-

OR

19 -C-8

-S-

ORI

8

OR

1 and

SR

1 9 NR1 8 -R19* wherein

R

203 and R 203 independently have the meang fr 6 sprvoul defined,

R

14 and

R

14 are independently selected from the group consisting of hydrogen,

R

20 as previously defined,

CF

3 WO 95/07269 PCT/AU94/00538 14

C(D*)OR

40

C(D*)SR

4 o and

C(D*)NR

4 0

R

4 1 wherein R40 and R41 independently have the meaning of

R

2 1 and R 22 as previously defined or R 40 and R 4 1 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,

R

14 is selected from the group consisting of F, Cl, Br, I, R 14 as previously defined and R200 as previously defined,

R

1 7 and R 17 independently have the meaning of R 6 as previously defined, D* has the meaning of D as previously defined, Z is a saturated or unsaturated (C 2

-C

4 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 1 4 as previously defined, Z* is a saturated or unsaturated (C 1

-C

3 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 14 as previously defined,

M

1 is selected from the group consisting of OR 15

SR

15 and NR 1 5

R

1 7 wherein R 15 is selected from the group consisting of: Px as previously defined,

R

6 as previously defined, and a glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and

R

17 is as previously defined, or

R

15 and R 17 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, M and M* are independentfr selected from the group consisting of M 1 as previously defined, OLN, SCN, Y'R 2 Y* and N=CR 3 0

R

3 1 wherein Y* and R 2 are as defined below, and R 30 and R 31 independently have the meaning of R 20 as previously defined,

M

2 is selected from the group consisting of R 14 as previously defined,

-CR

3 and -CR 30

*=NR

1 7 where is as defined below, R 30 has the meaning of R 20 as previously defined, and R 1 7* is as previously defined,

R

18 and R 19 independently have the meaning of R 20 as previously defined or

R

18 .and R 19 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and

R

18 and R 19 togther form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below; J proteases, particularly aspartyl proteases and more particularly HIV proteases, and which ?i are effective in treating conditions characterized by unwanted activity of these enzymes, in particular acquired immune deficiency syndrome; SUBSTITUTE SHEET (Rule 26) -i m l iiiiiii i ii iiY"! i WO 95/07269 PCT/AU94/00538 V is selected from the group consisting of Y'R 2 Y' is selected from the group consisting of Y* and C(R 30 wherein

O

II

-S-N II I O R 5 0

O

II

0

O

II

S-S-

II

O

I I

R

50

OR

51

O

I I

R

51 0 R 50

O

II

-O-P-O-

OR

51 0-

II

-N-S Ro 5 0

O

0

II

-S-O-

0-

O

II

-N-S-

O

II

-S-O-

O

I I 0 0

-P-N-

R

51 0 R 50

O

II

-S-N-

R

50

O

0

II

-O-S

II

O

0

II

-S-S-

O

II

-0-P-N- I I

R

51 0 R 5 o

O

0P-

I

ORa 5 1

O

II

-N-P-O-

II

-N -P I I

R

so

OR

5 1

O

II

OR51 ii 0

II

O-

R

5 2

O

II

-O-P-

wherein R 50 has the meaning of R 6 as previously defined, R 51 has the meaning of R 15 as previously defined and R 52 has the meaning of R2 0 as previously defined, or R 50 and R 5 1 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and

R

2 has the meaning of R 6 as previously defined, Y* is selected from the group consisting of L p IL~ll i4 WO 95/07269

C(UN

21

)OR

22 and C( 1

)NR)NR

22

R

23 wherein

R

21

R

22 and R 23 independently are selected from hydrogen and R 20 as previously defined, or

-J

PCT/AU94/0053 8 16 ,/R33

-N-N-R

2

N-N=C

IR I I "R34 Rso R51 R50

-N-

0 -R2 0 -N-R2' I I K50 0

II

-S=O S=O Rl14* R114*

O

II

-S=NR117* Rl114* I- PD

-F=U-

R114*

-P=D*

I wherein D* and independently have the meaning of D as R114** previously defined; R 11

R

1 14

R

115 and R 117 have the meaning of

RI

4

R

1 4

R

15 and R 17 respectively, as previously defined; R 50 and R 51 are as previously defined or R 50 and R 5 1 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below; R2* is selected from the group consisting of R 2 as previously defined, S(O)zOR120 and S(O)zNR12OR1 2 1, wherein z is 1 or 2; R 33 and R 34 are independently selected from the group consisting of hydrogen and R 20 as previously defined, or R 33 and R 34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and R 1 20 and R 12 1 independently have the meaning of R 20 as previously defined, or R 120 and

R

121 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,

R

30 is as previously defined, and is selected from =N-NRI 15

R

1 7 and =N-ORIll, wherein R 115 and R 117 have the meaning of R 15 and R 6 respectively, as previously defined, or

R

11 5 and R 117 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, and wherein any group selected from R 1 RI*, R 2

R

2

R

9

R

11

R

1 2

R

50 and R 5 1 may, together with any other group selected from R 1

R

1 I, R 2

R

2

R

9

R

10

R

11

R

1 2

R

50 and R 5 1 form one or more saturated or unsaturated cyclic, bicyclic or fused ring system(s) as defined below,

N-O

and wherein any tertiary amino nitrogen atom may be replaced by the group and, where the sequence contains a grouping of three heteroatoms together, one atom of those three heteroatoms is oxidised sulfur in the form of S(O) or S(0) 2 or oxidised phosphorus in the form of or the three heteroatoms comprise two nitrogen atoms which form part of a heterocycle, Iq WO 95107269 PCT/AU9400538 17 provided that the sequence does nit contain two oxygen.

atoms together or three sulfur atoms together; and wherein when W' is R 1 wherein X* is NR 10 and V' is Y* wherein Y* is -N-N-R2

OR

80 o R51 ,and B' is I or Ra wherein R 81 is selected from the group consisting of hydrogen, -RlooH,

-R

1 0C()ORjo 0

-R

1 00C(O)NR 0 1

R

102

-R

1 00NR 102 C(0)R 1 00* and Rj00C(0)Rj00*I wherein R 10 1 and R 102 are independently selected from the group consisting of hydrogen, optionally substituted (C 1

-C

18 )alkyl, optionally substituted (C 3

-C

18 )cycloalkyl, optionally substituted

(C

3 -C 18 )cycloalkyl-(C -C 18 )alkyl, optionally substituted (C 6

-C

24 )aryl, optionally substituted (C 7

-C

25 )aralkyl, optionally substituted

(C

2 -C 18 )alkenyl, optionally substituted (C 8

-C

26 )-aralkenyl, optionally substituted (C 2

-C

1 8 )-alkynyl, optionally substituted (Cg-C 2 6 aralkynyl and optionally substituted heterocyclic, and wherein R100 and R 103 o are independently divalent radicals derived from a member selected from the group consisting of (C 1

-C

18 )alkyl,

(C

3

-C

18 )cycloalkyl, (C 3

-C

18 )cycloalkyl(C 1

-C

1 8 )alkyl, (C 6

-C

24 )aryl,

(C

7

-C

2 5 )aralkyl, (C 2 -C18)alkenyl, (C 8

-C

26 )aralkenyl, (C 2

-C

1 8)alkynyl, (C 8

-C

26 )aralkynyl and heterocyclic, any of which may be optionally substituted as defined below, and R 80 is selected from the group consisting of R81 as previously defined and a solubilising and/or protecting group Px which is labile in vivo, then at least one of the following applies:

R

50 is a group R 53 wherein R5 3 is selected from the group consisting of

C(D*)OR

2 1

C(D*)NR

21

*R

22 C(D*)SR21*, C(D*)R 5 5

CF

3

R

55 and a solubilising group Px which is labile in vivo, wherein D* has the meaning of D as previously defined, Rz 21 and R 22 have the meaning of R 2 1 and R 22 respectively, as previously defined, and wherein R 55 is selected from the group consisting of optionally substituted (C 1

-C

18 )alkyl(C 6

-C

24 )aryl, optionally substituted

(C

2

-C

18 )alkenyl(C 6

C

2 4 ryl, optionally substituted (C 2

-C

1 8)alkynyl(C 6

-C

24 )aryl, optionally substituted (C 3

-C

18 )cycloalkyl- (C2-C 1 8 )alkenyl, optionally substituted (C 3

-C

1 g)cycloalkyl(C 2

-C

18 )alkynyl, optionially substitutod (C 3

-C

18 )cycloalkyl- 1.

S(O)

2

NR

60

R

61

DIS(O)R

60 WO 95/07269 pcT/AU94/00538 18

(C

6

-C

24 )aryl, optionally substituted acyl(C 6

-C

24 )aryl, optionally substituted heterocyclic(Cl-C, 8 )alkyl, optionally substituted heterocycliC(C 2

-C

18 )alkenyl, optionally substituted heterocyclic-

(C

2 -Cl 8 )alkynyl and optionally substituted heteroCYCliC(C 2

-C

1 8

(C

6

-C

24 )aryl, and in', Rl*, RIO, R 51 and R 2 are as previously defined, (ii) one of R 2 and R 51 is a group R 54 wherein R 54 is selected from the group consisting of R 55

C(D*)NR

2 1*R 22 C(D*)0R 55

C(D*)R

55

C(D*)SR

2 1

CF

3 S(O)zOR1 2 0, S(O)zNR1 2 OR1 2 1, and a solubilising group Px which is labile in vivo, wherein z is 1 or 2 and R 120 and R 121 are as previously defined or R 120 and R 121 together form a saturated or unsaturated cyclic, bicyclic, or fused ring system as defined bekfw, and wherein R 21 and R 22 have the meaning of R 21 and R 22 respectively, as previously defined, and R 5 5* has the meaning of R 55 as previously defined, and in', Rl*, RIO, R 50 and the other of R 2 and R 51 are as previously defined, (iii) at least one A' or is selected from the group consisting of CR 112

R

13

CR

12

R,

13

CR

112

R

13 and -CR 12

*R,

13 wherein R 112 and R 113 are independently selected from the group con.sting of R 55 as previously defined, C(D)0R 2

C(D)SR

2

C(D)NR

2

,*R

22 F, Cl, Br and I, wherein R 21 and R 22 have the meaning of R 21 and R 22 respectively, as previously defined, and D, in', Ri*, R 2 RIO, R 11

R

12

R

12

R

13

R

13 RSj and R 51 are as previously defined, (iv) is selected from the group consisting of optionally substituted

(C

2 -C 18 )alkenyl, optionally substituted (C 2

-C

1 8 )alkynyl, optionally substituted (C 3 -C 18 )cycloalkyl(C 2 -C 18 )alkenyl, optionally substituted

(C

3 -C 18 )cycloalkyl(C 2

-C

1 8 )alkynyl, optionally substituted (C 6

-C

24 )aryl-

(C

2 -C 18 )alkenyl, optionally substituted (C 6

-C

24 )aryl(C 2 -C 18 )alkynyl, optionally substituted (C 2 -Clg)acyl, wherein the optional substituent is other than amino, opiiornally substituted (C 6

-C

24 )aryl(C 2

-C

1 8 )acyl, optionally substituted heter'ocyclic(ClC 1 8 )alkyl, optionally substituted heterocyclic(C 2

-C

1 8 )alkeiiyl, optionally substituted heterocyclic(C 2

-C

18 S)alkynyl, _C(O)OR90, C(O)NRqjR 92

CF

3

S(O)ZOR

12 0, S(O)ZNRt1 2

OR

12 1 and a solubilising group Px which is labile in vivo, wherein z is 1 or 2 and R 120 and R 121 are as previously defined,

-C-N-

WO 95/07269 PCT/AU94/00538 19 wherein R90 is selected from the group consisting Of (C 3

-C

18 )cycloalkyl,

(C

3 -C 8 )cycloalkyl(C i-c 8 )alky1, heterocyclic, (C0 1 -C 1 8 )alkylheterocyclic, (C 6

-C

24 )aryl, (C 6

-C

24 )aryl(C 1 -Cj 8 )alkyl and

(C

6

-C

24 )aryl(C 1 -C 18 )allylheterocyclic, and wherein R 91 and R 92 are independently selected from the group consisting of option'"lly substituted (C 2

-C

18 )alkenyl, optionally substituted (C 2

-C

1 8 )alkynyl, optionally substituted

(C

3 -C 18 )cycloalkyl, optionally substituted (C 3 -C 18 )cycloalkyl-

(C

1

-C,

8 )alkyl, optionally substituted (C 3

-C,

8 )cycloalkyl-

(C

2 -C 8 )alkenyl, optionally substituted (C 3 -C 18 )cycloallcyl-

(C

2

-C,

8 )alkynyl, optionally substituted (C 6

-C

24 )arYl-

(C

2

-C

18 )alkenyl, optionally substituted (C 6

-C

24 )aryl-

(C

2

-C

1 8 )alkynyl, optionally substituted (C 2

-C

1 8 )acyl, optionally substituted (C 6

-C

24 )aryl(C 2

-C

1 8 )acyl, optionally substituted heierocyclic, optionally substituted heterocyclic(C 1

-C

1 8 )alkyl, optionally substituted heteroCYClic(C 2

-C

1 8 )alkenyl, and optionally substituted heterocyclic(C 2

-C

18 )alkynyl, or R 91 and R 92 together form a saturated or unsaturated cyclic, bicyclic or fuised ring system as defined below, and in', R 2

R

50

R

51 and RIO are as previously defined, a group selected from R 1 Rl*, R 2

R

2

R

9

R

11

R

12

R

50 and R 51 taken together with another group selected from RI, Rl*, R 2

R

2

R

9 RIO, R 11

R

12

R

50 and R 5 1 is selected from the group consisting of and optionally substituted methylene;

R

2 1 1 when W' is R 1 wherein is NRI 0 and V' is Y* wherein Y* is R 50

R

51 and B' is selected from -CH(OH)- and then at least one of the following also appits when one of the conditions to (iv) defined above in applies: (vi) n' 1, (vii) n' 0, (viii) m' 1, (ix) m' 0,

R

50 and R 51 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, (xi) R 50 is a group R 56 wherein R 56 is selected from the group consisting of C(D*)0R 2

C(D*)NR

21 *rt' 22

C(D*)SR

2

C(D*)R

55 and a solubilising and/or protecting group Px which is labile in vivo, wherein R 21 and R 22 are as previously defined, and i i:.

i:: i ii i rS Orig1q1\J--\9 I I -i- WO 95107269 PCT/AU94/00538 (xii) n' m' 1 and is other than -CH 2

R

14

I

and when B' is selected from -p-

-S-

R

17

R

14 I I

-N-

I'

1~

-C-

R14* and 1, wherein R 1 4

R

14 and R 17 are as previously defined, then at least one group selected from R 2 or R2*, R 11

R

12

R

50 and R 51 together with another group selected from R 1 or R1*, R 10

R

11 and R 1 2 forms a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, said ring being substituted with at least one polar group selected from =O, OH, SH, NHRo* and C(O)OH, wherein R 10 has the meaning of Rio as previously defined, said polar group being sterically capable of being located within the compound of formula not more than 5 Angstrom units from the P, O, S, N or C atom of group B, provided that when W' is R 1 and X* is NH and V' is Y* wherein Y* is -N-N-R2.

R

71

R

72 wherein R 1 is other than H and R 71 and R 72 are independently selected from the group consisting of H, (C 1

-C

6 )alkyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted phenyl(C 1

-C

2 )alkyl and optionally substituted naphthyl-

(C

1

-C

2 )alkyl, and when B' is -CH(OH)- and is -CH(R 73 wherein R 73 is selected from the group consisting of (C 1

-C

6 )alkyl optionally substituted with 1-5 fluorine atoms,

(C

3

-C

6 )alkenyl, (C 1

-C

6 )alkoxy-CHz-, (CH 2 )pphenyl, (CH2)pnaphthyl, (CH 2 )p-

(C

5

-C

6 )cycloalkyl and (CH 2 )pindolyl, wherein said (CH 2 )nphenyl,

(CH

2 )nnaphthyl, (CH 2 )n(C 5

-C

6 )cycloalkyl and (CH2)nindolyl are optionally substituted with nitro, halogen, (C 1

-C

4 )alkyl, (C 1

-C

4 )alkoxy or

(C

1

-C

4 )alkylthio and wherein p is 0, 1 or 2, then is other than

OHO

I II

-CH

2 wherein R 74 has the meaning of R 73 as previously defined, and R74 when i i.

i 1 is~ s WO 95107269 PCT/AU94/00538 21

OH

B' is wherein R 74 has the meaning of R 73 as previously defined and

R

74

HHH

is wherein R 73 is as previously defined, then is

R

73

OHH

other than and when

HHHH

B' is and is c-c-c- wherein R 73 is as previously

R

73 OHH OH defined, then m' is other than 0.

As used herein, the term 8 )alkyl" includes within its meaning straight and branched chain alkyl groups having from 1 to 18 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1, 1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3 4Methylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 6- or 7-methyl-octyl, 4- or 5-ethyheptyl, 2- or 3-propylhexyl, decyl, 2-, 7- or 8-methylnonyl, 5- or 6-ethyloctyl, 3- or 4-propylheptyl, undecyl, 8- or 9-methyldecyl, 6- or 7-ethylnonyl, 4- or 5-propyloctyl, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 9- or 10-methylundecyl, 7- or 8-ethyldecyl, 5- or 6-propylnonyl, 3- or 4-butyloctyl, 1- or 2-pentylheptyl, tridecyl, tetradecyl, hexadecyl, octadecyl and the like.

Typically an alkyl group is (Ca-Cb)alkyl, in which a is selected from a value presented in the column headed in Table A below at one of entries 1-17, and b has one of the values presented in the column headed at that entry.

Table A Entry a b 1 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. 15, 16, 17, 18 2 2 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 3 3 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 4 4 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 5 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 6 6 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 mu the meaning of R 1 5 as previously defined and R 5 2 has the meaning hi 3i I -J Ii,-I El -IVllliV L IIIUI 'llU \I WO 95/07269 PCT/AU94/00538 22 7 7 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 8 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 9 9 10, 11, 12, 13, 14, 15, 16, 17, 18 10 11, 12, 13, 14, 15, 16, 17, 18 11 11 12, 13, 14, 15, 16, 17, 18 12 12 13, 14, 15, 16, 17, 18 13 13 14, 15, 16, 17, 18 14 14 15, 16, 17, 18 15 16, 17, 18 16 16 17, 18 17 17 18 As used herein, the term "(C 2

-C

18 )alkenyl" includes within its meaning ethylenically mono-, di- or poly-unsaturated alkyl groups having from 2 to 18 carbon atoms, and may be straight-chain or branched. Examples of such alkenyl groups are vinyl, allyl, 1-methylvinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 2-methylpentenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1,3-octadienyl, 1-nonenyi, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1-undecenyl, oleyl, linoleyl and linolenyl.

Typically an alkenyl group is (Ca-Cb)alkenyl, in which a is selected from a value presented in the column headed in Table A above at one of entries 2-17, and b has one of the values presented in the column headed at that entry.

As used herein, the term "(C 2

-C

18 )alkynyl" includes within its meaning mono-, di- and poly-acetylenically unsaturated alkyl groups having from 2 to 18 carbon atoms, and may be straight-chain or branched. Examples of such alkynyl groups are ethynyl, propynyl, n-b uty yl, .,-pentynyl, 3-methyl-1-butynyl, n-hexynyl, methyl-pentynyl and

(C

7 -C 1 2 )alkynyl.

Typically an alkynyl group is (Ca-Cb)alkynyl, in which a is selected from a value presented in the column headed in Table A above at one of entries 2-17, and b has one of the values presented in the column headed at that entry.

As used herein, the term "(C 3

-C

18 )cycloalkyl" refers to otionally unsaturated mono-, di- or polycyclic alkyl groups having from 3 to 18 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononyl, cyclodecyl, cyclounderyl, cyclododecyl, _i I m WO 95107269 PCT/AU94/00538 23

(C

9 12 )cycloalkynyl, bicyclo[2.2. 1]heptanyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]heptadienyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[3.3.1]nonyl, bicyclo- [3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.0]octyl, bicyclo- [3.3.0]octenyl, bicyclo[3.3. 1]nonyl, bicyclo[4.4.0]decyl, adamantyl, tricyclo[5.2.1.0 2 6 ]decyl and the like.

Typically a cycloalkyl group is (C-Cb)cycloalkyl, in which a is selected from a value presented in the column headed in Table A above at one of entries 3-17, and b has one of the values presented in the column headed at that entry.

As used herein, the term "(C 3

-C

18 )cycloalkyl(Cl-C 18 )alkyl" refers to a

(C

1

-C

1 8 )alkyl group as defined above, substituted with a (C 3

-C

18 )cycloalkyl group as defined above. Examples of cycloalkylalkyl groups include cycloalkyl-loweralkyl groups, such as cycloalkylmethyl, cycloalkylethyl, cycloalkylpropyl, cycloalkylbutyl, cycloalkylisopropyl, cycloalkylisobutyl, cycloalkylpentyl and cycloalkylhexyl, wherein the cycloalkyl is as exemplified in the preceding paragraph.

As used herein, the term "(C 3

-C

18 )cycloalkyl(C 2

-C

18 )alkenyl" refers to a

(C

2

-C

18 )alkenyl group as defined above, substituted with a (C 3

-C

1 8 )cycloalkyl group as defined above. Examples of cycloalkylalkenyl groups include cycloalkyl-loweralkenyl groups, such as cycloalkylethenyl, cycloalkylpropenyl, cycloalkylbutenyl, cycloalkylisobutenyl, cycloalkylpentenyl and cycloalkylhexenyl, wherein the cycloalkyl is as exemplified above under "(C 3

-C

18 )cycloalkyl".

As used herein, the term "(C 3

-C

18 )cycloalkyl(C 2

-C

18 )alkynyl" refers to a

(C

2

-C

18 )alkynyl group as defined above, substituted with a (C 3

-C

18 )cycloalkyl group as defined above. Exainples of cycloalkylalkynyl groups include cycloalkyl-loweralkynyl groups, such as cycloalkylethynyl, cycloalkylpropynyl, cycloalkylbutynyl, cycloalkylpentynyl and cycloalkylhexynyl, wherein the cycloalkyl is as exemplified above under "(C 3

-C

18 )cycloalkyl".

As used herein, the term "(C 6

-C

24 )aryl" refers to single, polynuclear, conjugated and fused residues of alomatic hydrocarbons having from 6 to 24 carbon atoms.

Examples of such groups are phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, acenaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, indanyl, azulenyl, chrysenyl and the like. In all cases, any available position of the fused or conjugated bicyclic system can be used for attachment to the remainder of the molecule of formula Typically an aryl group is (Ca-Cb)aryl, in which a is selected from a value presented in the column headed in Table B below at one of entries 1-18, and b has one of the values presented in the column headed at that entry.

Table B Entry a b ~L -rr" -I -1 ~~1111 WO 95/07269 PCTIAU94100538 24 1 6 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 2/ 2 10 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 3 12 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 8 13 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 9 14 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 15 16, 17, 18, 19, 20, 21, 22, 23, 24 11 16 17, 18, 19, 20, 21, 22, 23, 24 12 17 18, 19, 20, 21, 22, 23, 24 13 18 19, 20, 21, 22, 23, 24 14 19 20, 21, 22, 23, 24 20 21, 22, 23, 24 16 21 22,23,24 17 22 23,24 18 23 24 As used herein, the term "(C 6

-C

24 )ary(C 1

-C

18 )alkyl" refers to a (C 1 -Cl 8 )alkyl group substituted with one or more (C 6

-C

24 )aryl groups as previously defined. Examples of such groups are aryl-loweralkyl groups such as arylmethyl, arylethyl, arylisopropyl, arylpropyl, arylbutyl, arylisobutyl, arylpentyl and arylhexyl, w!erein the aryl is as exemplified in the preceding paragraph, such as benzyl, diphenylmethyl, 2-phenylethyl, 1-phenylethyl, naphthylmethyl, 3-phenylpropyl, triphenylmethyl, 1,3-diphenylpropyl, 2or 3--naphthylpropyl, 2-benzyl-propyl and the like.

As used herein, the term "(C 7

-C

25 )aralkyl" refers to an alkyl group substituted with an aryl group, wherein the total number of carbon atoms in the aryl-substituted alkyl group is from 7 to 25. Optional substituents for (C 7

-C

25 )aralkyl are as defined below with respect to (C 6

-C

24 )aryl(C 1

-C

18 )alkyl.

As used herein, the term "(C 6

C

24 )aryl(C 1

-C

18 )alkenyl" refers to a

(C

1

-C

1 8 )alkenyl group substituted with one or more (C 6

-C

24 )aryl groups as previously defined. Examples of such groups are aryl-loweralkenyl groups such as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl, arylpentenyl and arylhexenyl, wherein the aryl is as exemplified above under "(C 6

-C

24 )aryl" such as styryl, cinnamyl, 2-naphtbhlethenyl, 1-phenyl-2-methyl-1-propenyl, 2-phenyl-2-butenyl and the like.

As used herein, the term "(Cg-C 26 )aralkenyl" refers to an alkenyl group substituted with an aryl group, wherein the total number of carbon atoms in the arylsubstituted alkenyl group is from 8 to 26. Optional substituents for (C 8

-C

26 )aralkenyl are as defined below with respect to (C 6

-C

24 )aryl(C 2

-C

18 )alkenyl.

As used herein, the term "(C 6

-C

24 )aryl(C 1

-C

18 )alkynyl" refers to a

(C

1

-C

18 )alkynyl group substituted with one or more (C 6

-C

24 )aryl groups as previously ii -A 10LUIr:, VL

MIL

WO 95/07269 PCTIAU94100538 defined. Examples of such groups are aryl-loweralkenyl groups such as arylethenyl, aryipropenyl, arylbutenyl, arylisobutenyl, arylpentenyl and aryihexenyl, wherein the aryl is as exemplified above under "(C 6

-C

24 )aryl" such as phenylethynyl and the like.

As used herein, the term "(C 8

-C

26 )aralkynyl" refers to an alkynyl group substituted with an aryl group, wherein the total number of carbon atoms in the arylsubstituted alkynyl group is from 8 to 26. Optional substituents for (C 8

-C

26 )aralkynyl are as defined below with respect to (C 6

-C

24 )aryl(C 2

-C,

8 )alkynyl.

As used herein, the term "(C 1 -Cj 8 )acyl" refers to a group R 3 (yOC(O)- or

R

3 wherein R3) is selected from the group consisting of hydrogen, (C 1

-C

1 g)alkyl, (C 2

-C

18 )alkenyl, (C 2

-C

18 )alkynyl, (C 3 -C 18 )cycloalkyl (C 3 -C 18 )cycloalkyl- (C -C1 8 )alkyl, (C 3 -C 18 )cycloalkyl(C 2

-C

18 )alkenyl, (C 3

-C

1 8 )cycloalkyl(C 2

-C

1 8 )alkynyl,

(C

6

-C

24 )aryl, (C 6

-C

24 )arYl(C i-c 8 )alkyl, (C 6

-C

24 )aryI(C 2

-C

1 8 )alkenyi, (C 6

-C

24 )aryl-

(C

2 -C 18 )alkynyl, heterocyclic, heterocyclic.(C 1

-C

18 )alkyl, heterocyclic(C 2 -C 18 )alkenyl, and heterocycliC(C 2 -C 18 )alkynyl.

Typically an acyl group is (Ca-Cb)acyl, in which a is selected from a value presented in the column headed in Table A above at one of entries 1-17, and b has one of the values presented in the column headed at that entry.

Examples of acyl groups include loweralkylcarbonyl such as formyl, acetyl, propionyl, butyryl; loweralkeriylcarbonyl such as pivaloyl, acryloyl, vinylacetyl, crotonoyl, 3-pentenoyl, 4-pentenoyl; and loweralkynylcarbonyl such as propioloyl, 2butynoyl and 3-butynoyl, any of which may be substituted with cycloalkyl, aryl or heterocyclic as exemplified herein, as, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, 1 -cyclopentenylcarbonyl, cyclopentylacetyl, cyclohexylcarbonyl, 1-cyclohexenylcarbonyl, 1 ,4-cyclohexadienylcarbonyl, cyclohexylacetyl, cyclohexenylacetyl, 1 ,4cyclohexadienylacetyl, bicyclo[2 1]hept-2-ylcarbonyl, bicyclollheptylacetyl, bicyclo[2 1]hepten-2-ylcarbonyl, bicyclo[2 2]oct-2-ylcarbonyl, bicyclo2 .2.2]octylacetyl, bicyclo[2.2 .2]octyl-3-propionyl, bicyclo[2 octen-2-ylcarbonyl, bicyclo[3 1]non-9-ylcarbonyl, bicyclo[3 .3.1 ]non-9-ylacetyl, bicyclononyl-3propionyl, bicyclo[4.4.Oldee-2-ylcarbonyl, bicyclo[4. 4.O]dec-2-ylacetyl, 1-adamantylcarbonyl, 2-adamantylcarbonyl, 1 -adamantylacetyl, 2-adamantylacetyl, .2.1 .0 2 6 ]dec-8-ylacetyl, benzoyl, phenylacetyl, diphenylacetyl, triphenylacetyl, 3-phenyipropionyl, dibenzylacetyl, a-naphthoyl, P-naphthoy1, cx-naphthylacety1, f3naplithylacetyl, indenylcarbonyl, indanylcarbonyl, phenanthrenylcarbonyl, 9-fluorenylcarbonyl, pyrrolylcarbonyl, pyrrolylacetyl, furylcarbonyl, furylacetyl, thienylcarbonyl, 3thienylacetyl, pyrazinylcarbonyl, pyrazinylacetyl, pyrrolidinylcar'bonyl, pyrrolidinylacetyl, pyridylcarbonyl, pyridylacetyl, pyrimidinylcarbonyl, pyrimidinylacetyl, piperidylcarbonyl, piperidylacetyl, piperazinylcarbonyl, piperazinylacetyl, morpholinylcarbonyl, morpholinylacetyl, thiomorpholinylcarbonyl, thiomorpholinylacetyl, indolylcarbonyl, indolylacetyl, quinolylcarbonyl, quinolylacetyl, isoquinolylcarbonyl, isoquinolylacetyl, WO 95/07269 PCT/A1J94100538 quinoxalinylcarbonyl, benzofuranylcarbonyl, benzofuranylacetyl, indolinylcarbonyl, indolinylacetyl, 1,2,3 ,4-tetralydroquinolylcarbonyl, 1,2,3 ,4-tetrahydroquinolylacetyl, 1,2,3 ,4-tetrahydroisoquinolylcarbonyl, 1,2,3 ,4-tetrahydroisoquinolylacetyl, cyclohexylacryloyl, cinnamoyl, styrylacetyl and phenyipropioloyl.

As used herein, the term "heterocyclic" refers to any saturated or unsaturated 3to 16-membered monocyclic, bicyclic or polycyclic ring containing one or more heteroatom independently selected from oxygen, nitrogen and sulphur. The term "heterocyclic" includes any group in which a heterocyclic ring is fused to one or more benzene, naphthalene or cycloalkane rings. Sulfur-containing heterocyclics may be lo substituted at sulfur with one or two oxygen atoms. Examples of heterocyclics are pyridyl, thienyl, furyl, pyrrolyl, indolyl, pyridazinyl, perhydropyridazinyl, pyrazolyl, pyrazoldinyl, 2,3,5, 6-tetrahydropyrazinyl, phthalazinyl, 1,2,3 ,4-tetrahydrophthalazinyl, perhydrophthalazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl, piperidyl, tetrahydrofuryl, imidazolyl, oxazolyl, thiazolidino, oxazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolinyl, benzothienyl, berizisoxazolyl, benzoisothiazolyl, benzothiadiazolyl, tetrazolyl, triazolyl, thiadiazolyl, benzimidazolyl, pyrrolinyl, quinuclidinyl, 1 ,4-thioxanyl, 1 ,3-thioxanyl, azanorbornyl, isoquinuclidinyl, pyranyl, furazanyl, azepinyl, 1H-indazolyl, 2 ,3-dihydro-1Hindazolyl, quinoxalinyl, cinnolyl, 1,2,3 ,4-tetrahydrocinnolinyl, pteridinyl, naphthyridinyl, 411-quinolizinyl, benz[e]indolyl, benzoxazinyl, benzoxadiazolyl, benzothiazinyl, benzotriazolyl, carbazolyl, f-carbolinyl, 1,2,3,4, 5,6-hexahydro-fp-carbolinyl, phenanthridyl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthenyl, thiatriazolyl, oxadiazolyl, thiadiazolyl, chromanyl. thiachromanyl, isochromanyl, chromenyl, cyclohexa[b]pyrrolyl, cyclohepta[b]pyrrolyl, cyclohexa[dlpyrazolyl, cyclohexa[b)pyridyl, cyclohexa[b]pyrazinyl, cyclohexa[blpyrimidinyl, cyclohexa[b]- 1,4-oxazinyl, cyclohexa[b]- 1 ,4-thiazinyl, 2-imidazolinyl, 2, 3-dihydropyridyl, piperazinyl, thiomorpholinyl, S dioxo-thiomorpholinyl, indolinyl, S ,S-dioxo-1 3-beazothiadiazolylI, S ,S-dioxo-1 ,2thioxanyl, S ,S-dioxo-1 ,4-thioxanyl, isoindolinyl, 4,5,6 ,7-tetrahydroindolyl, 1,2,3 ,4-tetrahydroquinolyl, 1,2,3 ,4-tetrahydroisoquinolyl, hexahydroquinolyl. hexahydroisoquinolyl, 1,2,3 ,4-tetrahydro-3, 1-benzodiazinyl, 3 ,4-dihydro-3H-4, 1-berizoxazinyl, 3 ,4-dihydro-3H- 4, 1-benzothiazinyl, 2,3,4, 5-tetrahydro-l11-5, 1-benzazepinyl and 5, 6-dihydrophenanthridinyl and the like.

Configurations which result in unstable heterocyclics are not included within the scope of the definition of "heterocyclic" or "saturated or unsaturated cyclic, bicyclic or J fused ring system".

As used herein, the term "heterocyclic(Cl-C, 8 )alkyl" refers to a (Cl-C 1 8 )alkyl group as previously defined, which is substituted with a heterocyclic group as previously defined. Examples of sudh groups are heterocyclic-loweralkyl groups such as heteroill~L~IIC-II-- IC~-Y I~CW-- I- L~l i r: l l l r:"r***l*llllM- ^a -j ^sll~a i«^ail'l^*' l l.* WO 95/07269 PCT/AU94/00538 27 cyclicmethyl, heterocyclicethyl, heterocyclicisopropyl, heterocyclicpropyl, heterocyclicbutyl, heterocyclicisobutyl, heterocyclicpentyl and heterocyclichexyl, wherein the heterocyclic is as exemplified in the preceding paragraph.

As used herein, the term "heterocyclic(Ci-C18)alkenyl" refers to a

(C

1

-C

18 )alkenyl group as previously defined, which is substituted with a heterocyclic group as previously defined. Examples of such groups are heterocyclic-loweralkenyl groups such as heterocyclicethenyl, heterocyclicpropenyl, heterocyclicbutenyl, heterocyclicisobutenyl, heterocyclicpentenyl and heterocyclichexenyl, wherein the heterocyclic is as exemplified above under "heterocyclic".

As used herein, the term "heterocyclic(C 1

-C

18 )alkynyl" refers to a

(C

1 -Cg 1 )alkynyl group as previously defined, which is substituted with a heterocyclic group as previously defined.

As used herein, the term "alkylidene" refers to divalent radicals derived from alkyl groups. Examples of such radicals are -CH2-, -CH 2

CH

2

-CH=CH-,

-CH

2

CH

2

CH

2

-C(=CH

2

)CH

2

-CH

2 CH=CH-, -(CH 2 4

-CH

2

CH

2

CH=CH-,

-CH

2

CH=CHCH

2 and -(CH2)r- where r is 5-12. The term also refers to such radicals in which one or more of the bonds of the radical from part of a cyclic system, and to such radicals wherein one or more carbon atoms is replaced by O, S or NH. Examples of such radicals are groups of the structure N N

NN

N N N 'N I I N N N) N S S S (i WO 95/07269 PCT/AU94/00538

I

-N

0? N

NY

II I 0 N N 9T 0oC 0 C 0 i 6- c N N Co Cs 0 O) .N 0 -0

N

N-

7

N

-_N

N

SN

and 7,C \7 N 7~)

N"

and similar groups, including those shown above wherein any N or 0 atom laced by As used herein the term "saturated or unsaturated cyclic, bicyclic or fused ring system" refers to a stable cyclic system of up to 16 carbon atoms, wherein said ring system may contain: for 3- and 4-membered rings, one heteroatom; for rings, one or two heteroatoms; for 6- and 7-membered rings, one to three heteroatoms; for 8- and 9-membered rings, from one to four heteroatoms; for 10- and 11-membered rings, from one to five heteroatoms; for 12- and 13-membered rings, from one to six heteroatoms; for 14- and 15-membered rings, from one to seven heteroatoms; and for 16-membered rings, from one to eight heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur; which ring system may be substituted with one or more substituents independently selected from: R 1 50 and a group T, where R 150 has the meaning of R 20 as previously defined, and where T is selected from the group

I

ir-- WO 959 PPCT/AU944lo538 -S(0) 2

-S(O)

2 0R', -S(Q) 2

=N

2

=NOH,

=NOR', -NR"OR', -CHO, -OC(O)OR', -OC(O)NR'R", -OC(S)OR', -OC(S)INR'R", -C(S)OR', -SC(O)OR', -SC(0)NR'R", -SC(S)OR', -SC(S)NR'R", NR' NR')NR"R', -OS(0)R',

-OS(O)

2 -OS(G)OR', -OS(0) 2 0R', -OS(0)NR'R", -OS(0) 2

NR'R",

NR' S(O) 2 NR' -NR' S(0) 2 -NHC(=NH)NR', =NH)NR', -OP(0)(OR')NR" and wherein and are independently selected from the group consisting of hydrogen, (C- 1 )lytpcly(Cl-C 12 )alkyl; (C 3

-C

18 )cycloalky1, typically (C 3

-C

12 )cylakl (C- 1 )yloly( C 18 )alkyl, typically (C 3

-C

12 )CYCloalkyl(Cl-C 6 )alkyl; (C 6

-C

24 )aryl, typically ((2 6 -C 16 )aryl; (C 6

-C

24 )aryl(Cj C 8 )alkyl, typically (C 6 -Cl 0 )aryl(Cl-C 6 )allcyl; (C 2

-C

18 )alkenyl, typically (C 2 -C 12 )alkenyl; (C 6

-C

24 aryl(C 2

-C

18 )allcenyl, typically (C 6

-CI

0 )aryl(C 2

-C

6 )alkenyl; (C 2

-C

1 8 )alkynyl, typically

(C

2 -C 12 )alkYnYl; (C 6

-C

24 )aryl(C 2 -C 1 8 )aralkynyl, typically (C 6 -C 10 )aryl(C 1

-C

6 )alkynyl, heterocyclic, heterocyclic(Cl-C 18 )alkyl, typically heterocyclic(C 1 -C 12 )alkyl, heterocyclic-

(C

2

-C

1 g)alkenyl, typically heterocyclic(C 2 -C 12 )alkenyl and heterocyclic(C 2

-C

1 g)alkynyl, typically heterocyclic(C 2 -Cj 2 )alkynyl, and wherein R" and may be optionally substituted with up to six groups independently selected from hydroxy, (Cl-C 6 )alkoxy, (Cl-C 6 )aryloxy, (Cl-C 6 )thioalkoxy, (Cl-C 6 )thioaryloxy, (Cl-C 6 )alkoxy(Cl-C 6 )alkoxy, amino, (Cl-C 6 )alkylamino, di(C 1

-C

6 )alkylamino, fluoro, chioro, bromo, iodo, carboxy, (C 1

-C

6 )alkoxycarbonyl, (Cl-C 6 )alkylaminocarbonyl and di(C 1

-C

6 )alkylaminocarbonyl.

Examples of saturated or unsaturated cyclic, bicyclic or fused ring systems are the heterocyclic and cyclic aikylidene groups exemplified above.

As used herein, the term "optionally substituted (Cl-C, 8 )alkyl" refers to a

(C

1

-C

18 )alkyl group as defined above wherein one or more hydrogen atoms are replaced by one or more substitutents T as previously defined.

Examples of sabstituted (C 1

-C,

8 )alkyl groups include hydroxy-loweralkyl such as hydroxymethyl, hydroxyethyl and 3-hydroxypropyl; loweralkoxy-loweralkyl such as methioxymethyl, 2-methoxyethyl, 2,2-dimethoxyethyl and 3-methoxypropyl; aryloxyloweralkyl such as phenoxymethyl, phenoxyethyl, C-naphthyloxymethyl and (-naphthyloxyethyl; arylloweralkoxy-loweralkyl such as benzyloxymethyl, benzyloxyethyl and 3-benzyloxypropyl; halo-loweralkyl such as chloromethyl, trifluoromethyl, 2-fluoro-, 2-chioro-, 2-bromo- or 2-iodo-ethyl, 2, 2,2-trifluoro-ethyl, 2,2,2-trichioro-ethyl, 3-chioropropyl and 3-bromopropyl; amino-loweralkyl such as aminomethyl, 2-aminoethyl, 3aminopropyl, 5-aminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl and 3-phenylform of S(O) or S(0) 2 or oxidised phosphorus in the form ot 1ikU), UL heteroatoms comprise two nitrogen atoms which form part of a heterocycle, WO 95/07269 PCT/A1394/0053 8 aminopropyl; carboxy-loweralkyl such as carboxymethyl, carboxyethyl and 3-carboxypropyl; acyllowerailkyl such as acyhnethyl, acylethyl, acyipropyl, acylisopropyl, acylbutyl, acylisobutyl, acylpentyl and acyihexyl wherein the acyl is as exemplified above under 1

-C

18 )acyl"; acyloxy-loweralcyl such as acetoxymethyl, acetoxyethyl, 2-acetoxypropyl, 3-acetoxypropyl, propionyloxyethyl and 3-propionyloxypropyl; loweralkylcarbonylamino-loweralkyl such as acetylaminomethyl, acetylaminoethyl, 2-acetylaminopropyl, propionylaminomethyl and propionylaminoi.kyl; loweralkylaminocarbonylamino. .loweralkyl, such as dimnethylaminocarbonylam inn. WlyI; sulfonyl-loweralkyl such as methylsulfonyl-methyl, ethylsulfontyl-methyl, tert-butylsulfonyl-methyl, phenylsulfonylmethyl, phenylsulfonylethyl, 4-to hienesulfonylethyl and 4-toluenesulfonylmethyl; cyano-loweralkyl such as cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 2-cyanobutyl, 3-cyanobutyl and 4-cyanobutyl; oxo-lowerakl such as 2-oxopropyl, 2-oxo-butyl, 3-oxo-butyl, 3- or 4-oxo-pentyl and 2,4-dioxo-pentyl; and loweralkyl groups substituted with two or more than different substitutents as exemplified above.

As used herein, the term "optionally substituted (Cl-C 1 8 )alkenyl" refers to a (Cl-Cls)alkenyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents T as previously defined.

As used herein, the term "optionally substituted (Cj-Cj 8 )alkynyl" refers to a (Cl-C 18 )alkcynyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents T as previously defined.

As used herein, the term "optionally substituted (C 3

-C

24 )cycloalkyl" refers to a

(C

3

-C

24 )cycloalkyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents independently selected from RIV and T as previously defined, wherein RIV is selected from (Cl-C 1 8 )alkyl, (C 2 -Clg)alkenyl,

(C

2 -C 18 )alkynyl, (C 3

-C,

8 )cycloalkyl, (C 3

-C

1 8 )cycloalkyl(C 1 -C 18 )alkyl, (C 3

-C

1 8 )CYClOalky(C 2 1 8 alkeyl,(C 3

-C

1 8 )cycloalkyl(C 2

-C

1 8 )alkynyl, (C 2

-C

1 )cl

(C

6

-C

24 )aryl(C 2

-C

1 8 )acyl, heterocyclic, heterocyclic(CI-C 8 )alkyl, heterocyclic (C 2

C

18 )alkenyl, and heteroCYClic(C 2

-C

18 )alkynyl, and wherein RIV may be substituted with Up to six groups independently selected from hydroxy, amino, (C 1

-C

6 )alkoxy, (C 1

-C

6 )alkoxy(Cl-C 6 )alkoxy, amino, (C 1

-C

6 )alkylamino, di(C 1

-C

6 )alkylamino, fluoro, chioro, bromo, iodo, carboxy, (C 1

-C

6 )alkoxycarbonyl, (Cl-C 6 )alkylaminocarbonyl and di(C 1

-C

6 )alkylaininocarbonyl.

As used herein, the term "optionally substituted (C 3

-C

24 )CYCloalkyl(C 1 -C 18 alkenyl" refers to a (C 3

-C

24 )cycloalkyl(C 1

-C,

8 )alkenyI group as defined above which are substituted in the cycloaikl Igroup by a substituent or substitutents independently selected from the substituents defined above for (C 3

-C

24 )CYcloalkyl, and/or substituted in the alk,-nyl group by one or more substituents T as previously defined.

-~(U2.ClS)alkenyl, optionally substituted (C 3

-C

1 8 )CYCloalkl(C-C 1 )alyny, Otionally substitutFd (C 3

-C

1 g)cycloalkyl- WO 95107269 PTA9/0 3 31 As used herein, the term "optionally substituted (C 3

-C

24 )cyCloalkyl(C 1

-C

18 )alkynyl" refers to a (C 3

-C

24 )cycloalkvl(C 1

I-C

1 8 )iallcnyl group as defined above which are substituted in the cycloalkyl group by a substituent or substitutents independently selected from the substituents defined above for (C 3

-C

24 )cycloalkyl, and/or substituted in the alkynyl group by one or more substituents T as previously defined.

As used herein, the term "optionally substituted (C 6

-C

24 )aryl" refers to a

(C

6

-C

24 )aryl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents independently selected from RV and wherein T* is selected from the group consisting of -Cl, -Br, -CF 3 -CN, -NCO, -NCS, -OCN, i-SCN, -N 3 -NR'C(O)OR", -NO 2

-S(O)

2

-S(O)

2 0R', -S(O) 2 NR', -NR"OR', -CHO, -OC(O)OR', -OC(O)NR'R", -C(O)NR'R", -OC(S)OR', -OC(S)NR'R", -SC(O)R', -SC(O)OR', -SC(O)NR'R", -SC(S)OR', -C(S)SR', =NR' -OS(O) 2

-OS(O)OR',

-OS(O)

2 0R', -OS(O)NR'R", -OS(O) 2 NR'R", NR'S(O) 2 NR" NR'S02" -NHC(=NH)NR', -CQ=NH)NR', OP(O)(SR')OR", -OP(O)(OR')NR' and wherein R', R" and are as defined above with respect to the substituent T; and wherein RV is selected from (C 1

-C

1 8 )alkyl, (C 2 -C 18 )alkenyl, (C 2

-C

1 g)alkynyl, (C 3 -C 18 )cycloalkyl,

(C

3

-C

1 8 )cycloalkyl(C i-C 18 )alkyl, (C 3

-C

18 )cycloalkyl(C 2

-C,

8 )alkenyl, (C 3 -C 18 )cycloalkyl-

(C

2 -C.'8)alkynyl, (C 2 -17 18 )acyl, (C 6

-C

24 )aryl(C 2 -C 18 )acyl, heterocyclic, heterocyclic-

(C

1

-C

1 )alkyl, heterocyclic(C 2 -Cj 8 )alkenyl, and heterocycliC(C 2

-C

1 8 )alkynyl, and wherein RV may be substituted with up to six groups independently selected from hydroxy, amino, (C 1

-C

6 )alkoxy, (Cl-C 6 )aryloxy, (Cl-C 6 )thioalkoxy, (Cl-C 6 )thioaryloxy, (C 1

-C

6 )alkoxy(C 1

-C

6 )alkoxy, amino, (C 1

-C

6 )alkylainino, di(CI-C 6 )alkylainino, fluoro, chloro, bromo, iodo, carboxy, (C 1

-C

6 )alkoxycarbonyl, (Cl-C 6 )alkylaminocarbonyl and di(C 1

-C

6 )alkylaminocarbonyl. The term "optionally substituted (C 6

-C

24 )aryl" includes mono-, di- and polysubstituted (C 6

-C

24 )aryl groups.

4030 Examples of substituted aryl groups are loweralkyl-aryl, loweralkenyl-aryl, arylloweralkyl-arylloweralkylcarbonyl-aryl, heterocyclic-aryl and heterocyclicloweralkyl-aryl wherein the aryl group is as exemplified above; halo-aryl such as 4-chlorophenyl, 2,4-dichiorophenyl, 1-chloro-2-naphthyl and 4-chloro-1-naphthyl; hydroxy-aryl such as 2-hydroxyphenyl, 1-hydroxy-2-naphthyl, 2-hydroxy-1 -naphthyl, 2-hydroxy-8-naphthyl, 3 ,4,5-trihydroxyphenyl and 2,4,5-trihydroxyphenyl; loweralkoxyaryl such as 4-methoxyphenyl, 3,4-diinethoxyphenyl, 2,4-diniethoxyphenyl and 1-inethoxy-2-naphthyl; carboxyaryl such as 2-carboxy-phenyl, 2-carboxy-1-naphthyl, 1-carboxy-2-naphthyl and 9carboxy-2-anthracyl; acylaryl, whereinp the acyl group is as exemplifed above under

(C-

1 acyl", such as 4-formiylphenyl, 4-acetylphenyl, 2-benzoylphenyl, II(C1_C18 wherein z is 1 or 2 and R 120 and R 1 2 1 are as previously defined, WO 95/07269 PCT/AU94/00538 32 2-methoxycarbonyl-phenyl, 2-ethoxycarbonyl- 1-naphthyl, 1-methoxycarbonyl-2-naphthyl, 9-methoxycarbonyl-2-anthracyl, 2-carbamoyl-phenyl, 2-carbamoyl-1-naphthyl, 1-carbamoyl-2-naphthyl, 4-dimethylaminocarbonyl-phenyl, 4-morpholinocarbonylphenyl, 4-(2-pyridylmethoxy)carbonyl-phenyl and 4-benzyloxycarbonyl-phenyl; nitro-aryl such as 4-nitrophenyl and 2,4-dinitrophenyl; amino- or (substituted amino)-aryl such as 4-aminophenyl, 2,4-diaminophenyl, 4-dimethylaminophenyl, 4-anilinophenyl, 2-(2,6dichloroanilino)-phenyl, 2,4-di-(benzyloxycarbonylamino)-phenyl and 4-(2-quinolinecarbonylamino)-phenyl; and cyano-aryl such as 4-cyanophenyl, as well as aryl groups substituted with two or more of the substituents exemplified above.

As used herein, the term "optionally substituted (C 6

-C

24 )aryl(C 1

-C

18 )alkyl" refers to a (C 6

-C

24 )aryl(C 1

-C

1 8 )alkyl group as previously defined substituted in the aryl group with one or more substitutents defined above for (C 6

-C

24 )aryl and/or substituted in the alkyl group with one or more substitutents defined above for (C 1

-C

18 )alkyl.

Examples of such groups are (substituted aryl)-lower-alkyl such as (substituted aryl)methyl, (substituted aryl)ethyl, (substituted aryl)propyl, (substituted aryl)iso-propyl, (substituted aryl)butyl, (substituted aryl)pentyl and (substituted aryl)hexyl, aryl(substituted loweralkyl) such as phenyl(substituted loweralkyl), naphthyl(substituted loweralkyl), biphenyl(substituted loweralkyl), tetrahydronaphthyl(substituted loweralkyl), indenyl- (substituted loweralkyl) and indanyl(substituted loweralkyl), and (substituted aryl)- (substituted loweralkyl), wherein in each case substituted aryl is as exemplified above with respect to "optionally substituted (C 6

-C

24 )aryl" and (substituted loweralkyl) is as exemplified above with respect to "optionally substituted (C 1

-C

18 )alkyl".

As used herein, the term "optionally substituted (C 6

-C

24 )aryl(C 1

-C

18 )alkenyl" refers to a (C 6

-C

24 )aryl(C 1

-C

18 )alkenyl group as previously defined substituted in the aryl group with one or more substitutents defined above for (C 6

-C

24 )aryl and/or substituted in the alkenyl group with one or more substitutents defined above for (C 1

-C

18 )alkyl.

As used herein, the term "optionally substituted (C 6

-C

24 )aryl(C 1

-C

18 )alkynyl" refers to a (C 6

-C

24 )aryl(C 1

-C

18 )alkynyl group as previously defined substituted in the aryl group with one or more substitutents defined above for (C 6

-C

24 )aryl and/or substituted in the alkynyl group with one or more substitutents defined above for (C 1

-C

1 8 )alkyl.

As used herein, the term "optionally substituted (C 1

-C

18 )acyl" refers to a

(C

1

-C

18 )acyl group as previously defined which may be substituted with one or more groups selected from the substituents defined for (C 1

-C

18 )alkyl, and includes within its meaning an acyl residue of a naturally occurring or synthetic amino acid or azaamino acid, or an acyl residue of a peptide chain containing 2-4 na;drally occurring or synthetic amino acids and/or azaamino acids.

Examples of substituted acy) groups include acyl residues of any of the naturally occurring or synthetic amino acids exemplified herein, hydroxyloweralkanoyl, loweralkoxyloweralkanoyl, acetylloweralkanoyl, cyanolowetalkanoyl, carboxyloweralkanoyl,

I

a- s 5-FI.x JLLy A WIIIWJ15 sb14L1LL IM VIVU, W1C111I 121* apue df22* nred n as previously defined, and WO 95/07269 PCTAU94/00538 hydroxycarboxyloweralkanoyl, fluoroloweralkanoyl, chloroloweralkanoyl, bromolower-.

alkanoyl, thioloweralkanoyl, loweralkanethioloweralkanoyl, aminoloweralkanoyl, loweralkylaminoloweralkanoyl, di-(loweralkylamino)loweralkanoyl, carbamoylloweralkanoyl, loweralkoxycarbonyl, carbamoyl, loweralkylaminocarbonyl and di-(lowerallr mino)carbonyl, where loweralkanoyl is an alkanoyl group of from 1 to 6 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl, and where loweralkyl signifies a (C 1

-C

6 )alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl and hexyl.

As used herein, the term "optionally substituted heterocyclic" refers v. a heterocyclic group as previosly defined wherein one or more hydrogen atoms Iny be replaced with a group selected from the substitutents defined above with regard to optionally substituted (C 6

-C

24 )aryl. Examples of substited heterocyclic groups include loweralkylheterocyclic, arylheterocyclic, aryloxyheterocyclic, loweralkoxyheterocyclic, oxo-heterocyclic, hydroxyheterocyclic, loweralkoxycarbonylheterocyclic and loweralkanoylheterocyclic.

As used herein, the term "optionally substituted heterocyclic(C 1 -Cl 8 )alkyl" refers to a heterocyclic(C 1

-C

18 )alkyl group as previously defined substituted in the heterocyclic group with one or more substitutents defined above for heterocyclic and/or substituted in the alkyl group with one or more substitutents defined above for (C 1

-C

18 )alkyl.

Examples of such groups are (substituted heterocyclic)-lower-alkyl such as (substituted heterocyclic)methyl, (substituted heterocyclic)ethyl, (substituted heterocyclic)propyl, (substituted heterocyclic)iso-propyl, (substituted heterocyclic)butyl, (substituted heterocyclic)pentyl and (substituted heterocyclic)hexyl, heterocyclic(substituted loweralkyl) such as pyrrolyl(substituted loweralkyl), indolyl(substituted loweralkyl), quinolyl(substituted loweralkyl), tetrahydroquinolyl(substituted loweralkyl), pyridyl- (substituted loweralkyl), morpholinyl(substituted loweralkyl), piperidinyl(substituted loweralkyl), thiomorpholinyl(substituted loweralkyl), thienyl(substituted loweralkyl), furanyl(substituted loweralkyl), benzfuranyl(substituted loweralkyl), pyrrolidinyl- (Substituted loweralkyl) and iso-quinolyl(substituted loweralkyl), and (substituted heterocyclic)(substituted loweralkyl), wherein in each case substituted heterocyclic is as exemplified above with respect to "optionally substituted heterocyclic" and (substituted loweralkyl) is as exemplified above with respect to "optionally substituted (C 1

-C

8 )alkyl".

As used herein, the term "optionally substituted heterocyclic(C 1

-C

18 )alkenyl" 3' refers to a heterocyclic(C 1

-C

1 8 )alkenyl group as previously defined substituted in the heterocyclic group with one or more substitutents defined above for heterocyclic and/or substituted in the alkenyl group with one or more substitutents defined above for

(C

1

-C

18 )alkenyl.

L

i.

i i i' I WO 95/07269 PCT/AIJ94/00538 34 As used herein, the term "optionally substituted heterocyclic(Ci-C 18 )alkynyl" refers to a heterocyclic(C 1

-C

18 )alkynyl group as previously defined substituted in the heterocyclic group with one or more substitutents defined above for heterocyclic and/or substituted in the alkynyl group with one or more substitutents defined above for

(C

1

-C

18 )alkynyl.

As used herein, the term "optionally substituted alkylidene" refers to an alkylidene radical as previously defined, in which one or more hydrogen atoms is replaced by substituent(s) independently beiected from the substituents defined above in connection with "optionally substituted (C1-C 1 8 )alkyl".

As used herein, the term "naturally occurring or synthetic amino acid" refers to a compound of the formula HN(R 4 01)(CH(R 4 00))pCOOH, wherein R400 and R 40 1 independently have the meaning of R 20 as previously defined, and p is 1, 2 or 3, and wherein R 4 00 and R401, together with the carbon and nitrogen to which they are bound may together form a saturated or unsaturated cyclic, bicyclic or fused ring system.

Examples of naturally -,curring or synthetic amino acids include alanine, cyclohexylalanine, anthranilic acid, arginine, asparagine, aspartic acid, cysteine, 3phenylcysteine, cystine, glutamic acid, glutamine, glycine, cyclohexylglycine, tetrahydrofuranylglycine, histidine, homoserine, hydroxyproline, isoleucine, leucine, lysine, 4-azalysine, 8-hydroxylysine, methionine, norleucine, norvaline, ornithine, phenylalanine, 4-aminophenylalanine, 4-carboxyphenylalanine, 4-chlorophenylalanine, phenylglycine, 8-phenylserine, proline, serine, threonine, trans-3-hydroxyproline, trans-4hydroxvtroline, tryptophan, tyrosine, valine, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, a-aminobutyric acid, a,y-diaminobutyric acid and a,p-diaminopropinic acid. Other amino acids, and peptides derived therefrom, are disclosed in J. S. Davies, ed., Amino Acids and Peptides, Chapman and Hall, London, 1985, the disclosure of which is incorporated herein by reference.

As used herein, the term "residue of a naturally occurring or synthetic amino acid" refers to a group of the formula -N(R 4 01)(CH(R400))pC()-, wherein R400, R401 and p are as defined above with regard to "naturally occurring or synthetic amino acid".

As used herein, the term "azaamino acid" refers to an amino acid in which a -CH(R400)- group has been replaced by a group -N(R 401 wherein R401 has the meaning of R 20 as previously defined.

Suitable pharmaceutically acceptable salts of the compound of formula are, where the compound of formula contains a basic nitrogen atom, acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, hydrobromic or hydriodic, or with pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, methylmaleic, fumaric, malic, citric, lactic, mucic, gluconic, i

LI

Oi 6 "6 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 WO 95/07269 PCT/AU94/00538 glucoheptonic, glucaric, glucuronic, lactobionic, benzoic, naphthoic, succinic, oxalic, phenylacetic, methanesulphonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethane-1,2disulfonic, laurylsulfonic, toluenesulphonic, benzenesulphonic, naphthalene-2-sulfonic, salicylic, 4-aminosalicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric, glycolic, cinnamic, mandelic, 2phenoxybenzoic, 2-acetoxybenzoic, embonic, nicotinic, isonicotinic, Ncyclohexylsulfamic or other acidic organic compounds, such as 2- or 3-phosphoglycerate and glucose-6-phosphate. Where the compound of formula contains an acid group, suitable pharmaceutically acceptable salts of the compound of formula are addition salts of pharmaceutically acceptable bases such as lithium, sodium, potassium, ammonium, magnesium, calcium and zinc salts, or salts formed with organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, N-methyl-N-ethylamine, mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, tris(hydroxymethyl)methylamine, N,N-dimethyl-N-(2-hydroxyethyl)-amine, tri-(2hydroxyethyl)-amine, N-methyl-D-glucamine, or tributylamine. Compounds of formula I having acid and basic groups can also form internal salts. Other suitable salts are described, for example, in S. M. Berge, et al., "Pharmaceutical Salts" J. Pharm. Sci., 66 1-19 (1977) which is incorporated herein by reference.

The expression "prodrug" as used herein refers to a pharmaceutically acceptable derivative of a compound of formula which is transformed into a compound of formula after administration of the prodrug to a living animal or human, and which has enhanced stability, delivery characteristics and/or therapeutic value compared to the compound of formula from which it derives.

The expression "protecting group" as used herein refers to a group which may be used temporarily to modify a functional group, for example to prevent that functional group from being affected by, or from undesirably affecting the outcome of, a desired reaction involving another functional group in the molecule and/or to prevent prem" metabolism of the compound of formula after administration to a patient bet..

compound can reach the desired site of action. Suitable protecting groups are de for example in Greene, T. Protective Groups in Organic Synthesis (John Wile, Sons, New York, 1981) and McOmie, J. F. Protective Groups in Organic Chemistry (Plenum Press, London, 1973).

Examples of suitable protecting groups for hydroxyl or mercapto substituents include substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, t-butyloxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl, benzyl, allyl, triphenylmethyl and the like, other etherifying groups such as 2tetrahydrofuryl, 2-tetrahydropyranyl and vinyl, or by acyl and carbonate groups such as formyl, 2,2-dichloroacetyl, 2,2,2-trichloroacetyl, t-butyloxycarbonyl, benzyloxycarbonyl, cyclooctatrieflyl, cyclooctatetraelyl, cyclononyl, cycloclecyl, cyciounciecyi, C;YLCUUUU-;Y I, WO 95107269 PCTAU94OOS38 36 4-nitrobenzyloxy, arbonyl, and 4-methoxybenzyloxycarbonyl, or by silyl groups such as trimethylsilyl, t-butyldimnethylsilyl, tribenzylsilyl, triphenylsilyl and the like.

Suitable protecting groups for amino substituents include acyl groups such as formyl, acetyl, 3-phenyipropionyl, chioroacetyl, trifluoroacetyl, trichioroacetyl, benzoyl, 4-nitrobenzoyl, 4-methoxybenzoyl, t-butyloxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 9fluorenylmethoxycarbonyl, (2-pyridyl)methoxycarbonyl, quinoline-2-carbonyl, 2trimnethylsilylethoxycarbonyl, or trimethylsilyl, or an aminoacyl residue.

Suitable protecting groups for carboxyl substituents include esters, for example methyl, ethyl, tert-butyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, 2 ,2,2-trichloroethyl, 2bromoethyl, 2-iodoethyl, 2-trimethylsilylethyl, 2-triphenylsilylethyl, t-butyldimethylsilyl or trimethylsilyl esters.

Suitable protecting groups for carbonyl substituents include acetals such as dimethyl, diethyl, dibutyl and dibenzyl, thioacetals such as S,S-dimethyl and S,S-diethyl, cyclic acetals and thioacetlas such as 1,3-dioxanes, 1,3-dioxolanes, 1,3-oxathiolanes, 1 ,3-dithianes and 1 ,3-dithiolanes, and oximes and hydrazones such as O-benzyl oximes, O-phenylthiomethyl oximes and N,N-dimethyl hydrazones.

The expression "solubilising group Px" as used herein refers to a group which may be used to derivatise a functional group so as to enhance the solubility of the compound of formula in water or aqueous media. Examples of solubilising groups for inclusion in the compound of formula are groups of the formula Px* or salts thereof, where Px* is selected from: 0 s0 0 0 ~P-OH OH IPKOH "O O H p1-OH OH OH H OH OH0 0 0 00 BKOH

-NO

2 "I x'

OH

S, S(O) 2, 0 i.ii i WO 95/07269 PCT/AU94/00538 O 0 I "OH

O

O R

NR'

O H

(CH

2 4

NH

2 O H

NH

wherein R and R' are independently hydrogen or C 1

-C

4 alkyl. Also included within the meaning of Px are groups of the following formulae, wherein Px* and D are as previously defined, and R is H or C 1

-C

4 alkyl: 0 0 P* TD Px* -Dp Px* D

R

and Where the compound of formula includes two functional groups capable of being derivatised by a solubilising group, the two funtional groups being in sufficiently close proximity to one another, it will be appreciated that certain of the solubilising groups exemplified above are capable of forming cyclic structures, for example including the following structural units: O OH 0 H O\ X2- -X X -XI X IV', X2- -X1 X2- -I Xor 0 OH -Xi O OH or wherein X, aid X 2 are independently selected from 0, S and NR 6 wherein R 6 is as previously defined. Solubilising groups in a cyclic structure, such as those exemplifed is above, also fall within the meaning of "solubilising group" as used herein.

Where the solubilising group is acidic, a salt thereof is typically a salt of an alkali metal or ammonia, such as Na+, K+ or NF ''re the solubilising group is basic, a salt thereof is typically a salt of a strong in -h as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid. Typ, group is a sodium or potassium salt of a phosphate or phosphite reside Solubilising or protecting groups which are inci,. ,pound of formula must be amenable to hydrolytic or metabolic cleavage in vivo.

(c 1 -Cj 8 )alkynyl group substituted with one or more (C 6

-U~

24 )arY1 groups as previuusiy a

AT

WO 95/07269 PCTIAU94100538 In one form of the present invention, in the compound B is typically selected from the group consisting of of the general formula

ZM

-N- -N- N- 0*

M

ZM M2

I

-C-

I

K14 0 -c-C- R14*.N R 1 4 I1"0 R14 ,'Z*M

OR

18

-C-

OR

19

SR

18 -C-9

OR

18 Iand

S

1

OR

1 -C-*lg 4

I

where Z, M, M 1

M

2

R

14

R

14

R

14

R

15

R

18

R

18

R

19 and R 19 are as previously defined, and V is YR 2 Y* or C(R 30 wherein R 2

R

30 and Y* are as previously defined, and wherein Y is selected from the group consisting of NN- 0- 0- I I cossig -N-N-R 2 and Y* is selected from the group cossigof I I I +K5 1

,NN="R

33 N0R NR2 0 R34 KSnd K wherein R 33 R50 34

R

50

R

51 and R 2 are as previously defined.

More typically, the compound of the general formula in this form of the invention has the structure represented by formula (IA):

R

1

R

12

R

12

P

13

R

13 15 where Rl*, R 10

R

12

R

12

R

13 and R 13 are as previously defined, B* the group consisting of

ZM

-N- -N-

M

0*4

ZM

R

14 is selected from

-M-

0 -c-c-

R

14 ,Rl 4

IO

C 11

R

14 C Z* I".0

C-

OR

18

OR

19 and

SR

18

SR

19

A

indolylacetyl, quinolylcarbonyl, quinolylacetyl, isoquinlyOcarooupy jA WO 95/07269 PCT/AU94/00538 39 where Z, M, M 1

M

2

R

14

R

14

R

14

R

18 and R 19 are as previously defined, and Y 1 is selected from the group consisting of

-N-N-R

2 -N-O-R2* -O-N-R 2 I III

R

50

R

51

R

50 and R 50 wherein R 50

R

51 and R 2 are as previously defined.

Even more typically, the compound of the general formula in this form of the invention has the structure represented by formula (IB):

R

5 12

R

542

R

1 C CC

N

N C C N R 5 M (IB)

R

5 R550 x y wherein x and y are independently 0 or 1, B is selected from the group consisting of

OR

1 i OR R 14

OR

14

R

1 (R560)2 0O R14*\ ,R4I I C O -C C- C I0 II I and I

R

14

*R

14

R

14

OR

1 9 4 wherein R 14

R

14

R

15

R

18 and R 19 are as previously defined and each

R

560 is independently hydrogen or (C 1

-C

4 )alkyl,

R

502 and R 506 are independently a group R60 0 wherein R600 is selected from the group consisting of hydrogen, C(0)OR 6 2 1 C(0)SR 6 2 1 C(0)NR 62 1

R

622

(C

1

-C

6 )alkyl, (C 2

-C

6 )alkenyl, (C 5

-C

10 )cycloalkyl, (C 5

C

10 )cycloalkyl(C 1

-C

6 )alkyl, (C 5 -Co 10 )cycloalkyl(C 2

-C

6 )alkenyl, (C 6

C

1 o)aryl, (C 6

-C

10 )aryl(C 1

-C

6 )alkyl, (C 6 -C 10 )ary(C 2

-C

6 )alkenyl, (Cl-

C

6 )acyl, heterocyclic, heterocyclic(C 1

-C

6 )alkyl and heterocyclic(C 2

C

6 )alkenyl, each of which may be substituted by up to three substituents selected from the substituents defined above for "optionally substituted

(C

1

-C

18 )alkyl" and R 62 1 and R 622 have the meaning of R 21 and R 22 respectively, as previously defined, or R 621 and R 622 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,

R

501 is selected from the group consisting of R6o as previously defined, S(0)OR 632 S(0) 2

R

632

S(O)NR

6 32

R

63 3 S(0) 2

R

632

R

633

NH

2

NHR

6 3 1 and NR 631

R

632 wherein R 631 has the meaning of R 6 as previously defined and R 632 and R 633 independently have the meaning of R 20 as i I~ C1 P -~TrpL ~LC91 s~er- I- -~I defined. Examples of sudh groups are heterocyclic-loweralkyl groups such as netero- WO 95/07269 PCT/AU94/0053 8 previously defined, or R 50 1 and R 506 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system, or R 631 and R 632 or

R

632 and R 633 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below,

R

5 1 2 and R 542 independently have the meaning of R600 as previously defined,

R

522 and R 532 are independently selected from the group consisting of R600 as previously defined, F, Cl, Br and I,

R

513 and R 543 are independently selected from the group consisting of Ro00 as previously defined and R200 as previously defined,

R

523 and R 533 are independently selected from the group consisting of R 6 00 as previously defined, F, Cl, Br, I, and R200 as previously defined,

R

550 has the meaning of R 6 as previously defined and R 55 1 is selected from the group consisting of R650, hydrogen, S(0)OR 32 S(0) 2

R

632

S(O)NR

632

R

6 33 and S(0) 2

R

632

R

633 wherein R 6 50 has the meaning of

R

6 as previously defined and R 632 and R 6 33 are as previously defined, or

R

632 and R 6 33 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, or R 550 and one of R 551 and R 502 together form a diazaheterocycle wherein R 550

R

55 1 or R 502 and the two nitrogen atoms to which they are bonded are part of a stable 5 to membered ring which may comprise up to two further heteroatoms selected from O, S and N and to which may be fused one or more cycloalkyl, cycloalkenyl, aryl or heterocyclic residues, which diazaheterocycle may be substituted by one or more of the substituents defined above for "optionally substituted (C 1

-C

18 )alkyl", and wherein two substituents may together form part of a ring, or one pair selected from R 512 and R 513

R

522 and R 523 (when present), R 532 and R 533 (when present), and R 542 and R 543 together are =0; 0 OR 1 wherein, when B is other than or then at least one of C- I R14* conditions to (xi) below applies: at least one of R 512 and R 542 is a group R 655 wherein R 655 is selected from the group consisting of (C 1

-C

6 )alkyl(C 6

-C

0 o)aryl, (C 2

-C

6 )alkenyl-

(C

6 -CIo)aryl, (C 5 -Clo)cycloalkyl(C 2

-C

6 )alkenyl, (C 5

-C

1 o)cycloalkyl-

(C

6

-C

1 o)aryl, acyl(C 6

-C

1 o)aryl, heterocyclic(C -C 6 )alkyl, heterocyclic(C 2

-C

6 )alkenyl, heterocyclic(C 6

-C

1 0 )aryl, C(D*)OR 2 1

C(D*)SR

21 and C(D*)NR 2

R

2 wherein R 2 1* and R 22 are as previously defined, WO 9507269PCT/AU94/0 0 53 8 41 (ii) at least one of R 522 and R 532 when present, is selected from the group consisting of R 6 55 as previously defined, F, Cl, Br and 1, (iii) at least one of R 513 and R 543 when present, is selected from the group consisting of R 655 as previously defined, and R 2 0yj as previously defined, (iv) at least one of R 523 and R 533 when present, is selected from the group consisting of R 655 as previously defined, F,Cl Br, I and R 200 as previously defined,

R

550 is a group R 656 wherein R 0 ,j 6 is selected from the group consisting of (Cl-C 6 )alkyl(C 6 -C 10 )aryl, (C 2

-C

6 )alkenyl(C 6 -Cl 0 )aryl, (C 5 C 1 )cycloalkyl(C 2

-C

6 )lenyl, (C 5 -Cj 0 )cycloalkcyl(C 6 -C 10 )aryl, acyl(C 6 C 10 )aryl, heterocyclic(Cl-C 6 )alkyl, heterocyclic(C 2

-C

6 )alkenyl, heterocyclic(C 6

-C,

0 )aryl, (vi) R 55 1 is selected from the group consisting of R 656 as previously defined, S(O)0R 632

S(O)

2

R-

632

S(O)NR

632

R

633 and S(O) 2

R

632

R

633 wherein

R

632 and R 633 are as previously defined, (vii) R 502 is selected from the group consisting of R 656 as previously defined,

C(D*)SR

21 and C(D*)NR 2 1

*R

22 wherein R 21 and R 22 are as previously defined, (viii) R 502 and R 551 are both hydrogen or are both (Cl-C 6 )acyl, (ix) R 14 is selected from the group consisting of C(D*)0R 40

C(D*)SR

4 o and C(D*)NR 4 oR 4 i, wherein R 40 and R41 are as previously defined,

R

50 1 is selected from the group consisting of R 656 as previously defined, S(O)0R 632

S(O)

2

R

632

S(O)NR

632

R

633

S(O)

2

R-

632

R-

633

NH

2

NHP-

631 and NR 631

R

632 wherein R 632 and R 633 are as previously defined, (xi) R 501 and R 506 are both (Cl-C 6 )acyl,

OH

-C 0 and herin henB i or then at least one of the

H

following conditions also applies: (xii) x y 0, (xiii) x y 0 and at least one of R 532 and R 533 is other than hydrogen, (xiv) R 50 and R 51 together form a diazaheterocycle as previously defined, (xv) at least one of R 501

R

502

R

506 and R 551 is optionally substituted heterocyclic(C 1

-C,

8 )alkyl, and (xvi) at least one of R 512

R

542

R

522

R

532

R

5 13

R

543

R

523 and R 533 is selected from the group co12s!iting of C(O)0R 62 1

C(O)SR

62 1 i:I .1 WO 95/07269 PCTIAU94/00538 and C(O)NR 62 1

R

6 22, wherein R 621 and defined.

Examples of typical unsubstituted diazaheterocycles are: "N0 0 R6 22 are as previously

'N

c,-

N/

N Nk

-N

Nt

"N

N

"N

N

'IN

"N

s No

N

"N/

"N

"'N

N

"N "N"

N

"N N "Na IN 0

"N

D

N "N/

I

N and Other forms of the first embodiment of the invention have the structures represented by formulae (IC) to (IAW) below, in which each AA is independently a residue of a naturally occurring or synthetic amino acid as herein defined; R 1

R

1 X and X* are as previously defined; Ra to Rj independently are -(CH 2 )a-60Py, wherein a can be 0, 1, 2, 3, 4 or 5, halogen or R 6 more typically -(CH 2 0 30Py, fluoro, chloro or R 6 wherein Py is a solubilising group Px as defined herein, R6 is as previously defined and R 6 is is selected from the group consisting of hydrogen,

R

20 wherein R 20 is selected from the group consisting of optionally substituted (Cl-C 6 )alkyl, optionally substituted (C 2

-C

6 )alkenyl, optionally substituted (C 2

-C

6 )alkynyl, optionally substituted (C 3

-C

8 )cycloalkyl, optionally substituted (C 3

-C

8 )cycloalkyl(C 1 -Cs)alkyl, optionally substituted (C 3

-C

8 )cycloalkyl(C 2

-C

6 )alkenyl optionally substituted (C 3

-C

8 )cycloalkyl(C 2

-C

6 )alkynyl, optionally substituted (C 6

-C

10 )aryl, optionally substituted (C 6

-C

10 )aryl(C 1

-C

6 )alkyl, L-

L:

WO 95/07269 PCT/AU94/00538 43 optionally substituted (C 6 -Cj 0 )aryl(C 2

-C

6 )alkenyl, optionally substituted (C 1 -C%-'acyl, optionally substituted heterwc.y' 'ic, and optionally substituted heterocyclic(C 1

-C

6 allcyl, C(O)0R 2 1

C(O)SR

2 1 and

C(O)NR

21

R

22 wherein R 21 and R 22 independently are selected from hydrogen and R 20 as previously defined, or R 21 and R 22 together form a sajurated or unsaturated cyclic, bicyclic or fused ring system as previously defined: Ra G R'f I c I R'd I R A CI ILI- I'CR

(IC)

11 Rb G I Rh L) 0-3Re OPy wherein D' is 0 or S, and each G is independently hydrogen or R 200 as previously defined and wherein R' d and R' f are Rd arJ Rf or, taken together, may be trimethylene or tetram ethylene optimally substituted with -C(O)OR; or -C(C)/NRiRj; OPy Ra 11 RC IRf h

(D

RiX, C NH, CI C "C f I IRe I Ri 11k /0-4i Rd Rg 1-2 wherein G is selected from RI* and X*R 1 Ra Ra' 0 I Rc I Rd 11 )NH, 1,NA)IC

G

03 M, Re 0-

(IE)

wherein Ra' is OPy or R6 as previously defined, Mlis P.6 as previously defined, (CH 2 1 '1 2 OPY or (CH 2 1 2 NHPy, and G* is OR 2 or NRjR 2 incdepencdently selectedt trom tie sutttuents cletineci an~ove ior kk3k2XLiuMI luu substituted in the alkenyl group by one or more substituents T as previously defined.

WO 95107269 PCT/A1394/00538

OPY

(C-IM

2 0-2 Ra Rh I Rc Rf I CA IC. C A RI Re I R C11 R K d Rg 0-i 0 0-3 0-3 C 0I

(IF);

OPY

(C;H

2 0 2 GN R IN Rf 11 I RelC Ii Rd Rg 0'(IG) wherein G is hydrogen, Ra, R 1 or Rl*X*C(Ra)(Rb)C(O), and wherein Ra, Rl*, and the atoms to which they are bound may optionaEy form a saturated or unsaturated cyclic, bicyclic or fused ring system; I I Re! Rg I I I RX II" HeI C ,NC fAAJRj I) Rb H -3 Rd I Rh \0-3 wherein Rai Rl*, and the atoms to which they are bound may optionally form a saturated or unsaturated cyclic, bicyclic or fused ring system; Ra Rd IRc I Rf W2 C I I ,Rg N H I C I C R b!I Re OR'

(CH

2 0-2 Ip

I

wherein W2 is RjX or R 6 as previously or R' and Py, taken together with the group selected fro 0- O,0 (11) defined, and R' is Py or R 6 as previously defined, oxygen atoms to which they are attachedi form a 0 0 and k aryl such as 2-carbOXY-Phenyl, ~abX~~l~~l -auly' carb~y~an~c~l aclayl, wherein the acyl group is as exemplifed above under

"(C

1

C

18 acyl", such as 4-for(1ylphell 4-acety1PhelYl7 eZY1hnl WO 95/07269 PCT/AU94/00538 oPz Rb

(CH

2 0 2 I Rd IIRf) Rc RI1 3 \Rg

(CH

2 )0- 2

IIJ

wherein each L is independently as previously defined and each Pz is independently hydrogen or Py, provided that at least one Pz is Py or, when each Pz is Py, the groups Py, together with the oxygen atoms to which the are bound define a cyclic group selected HOO HO0 0 0 from >1PI Pl. and /S11

QPY

R'I

R

1 NH yC'

I

AA'C'IH iAA

G

I R 0

I

R

2 Rd 0-3

(IK)

wherein Q is 0 or NRf and G is Rj* or XR* opy Rb? YH 2 0 2 \NH I I C RatAAt NHet AA) 2 -C I Het -A R Rb' R wherein each N3e is independently a 5- or 6- membered saturated or unsaturated heterocycle containing a nitrogen atom and optionally additionally one or two lieteroatoms selected from nitrogen, oxygen and sulfur, and wherein Ra' and Rb' independently have the meaning of -(CH 2 0 6 OPy or R 6 or taken together are 0; QPy

(CH

2 0 2 o 0 H Ra IRdI I Ri.NH%,. C_ NH ICN'IIIC 'Rf AA 1 2 IC N

W

1 Rb Re-, Rg

(IM)

occurring or synthetic amino acids exemplified herein, hydroxyloweralkanoyl, loweralkoxyloweralkanoyl, acetylloweralkanoyl, cyanoloweralkanoyl, carboxyloweralkanoyl, PC121AU94100 3 8 .pCT/AU94/00538 WO 95107269 4 7I ic selected from

FR

1 X and R 1 and Q is selected from 0 and NRh; wrierew. 1

(H

2 0 -2 (CH-2)ol2 0 Ra R

H

1 NH'~ L; 1 u Rg RIN I -2 RC l C I-

R

R(IN wheein~~ s elected from RX and

R

1 each Pz isidPendently hydrogen or Py, prvie tha at est on is Py, and Q is selected from 0 and NRh; 6pz wherein each Pz is independently hydrogen or Py, provided that at least one Pz is Py; H9-2)0-2 Ra Ib C NIHet -C AtO-R2

R

1 "CI 0 IRd I0 Rc Rf

(IP)

whereint is a 5- or 6- membered saturated or unsaturated heterocycle ontainingI a weren atoadptoal additionally one or two h-eteroatoms ,selected from nitrogen, 1o oxygen and sulfur;

P

(CH2)O -2 b C R f R h R 1 Rd eRg

,(Q

whriPa n are independently selected from and

R

1 as previously defined; (Cj-Cj 8 )alkenyl.

WO 95/07269 PCT1A1J94100538 47 QPy Ra 0 1Rb 1 1 0-1 Rd

(IR)

Re Re Rg wherein G3 is selected from -C and a saturated or unsaturated Rf Rf Kh cyclic, bicyclic or fused ring system, Q is 0 or NH, and G* is X or X* as previously defined;

P

(H

2 02 RRa Rd I,-Rf I Rd ON _2 Rb Re

(IS)

wherein NS~et is a 5-12 membered saturated or unsaturated cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur; Q*Py Ra I Rg'I 0-I b Re lo wherein G3 is selected from hydrogen and R 1 Q is 0, S or NH, Q* is 0 or NH, and G, is selected from R, and R 1 Rt (Cj~ 2 -i Rd R 200

(IU)

A

acceptable organic acids such as acetic, propionic, butyric, tartaric, maltec, hydroxymaleic, methylmaleic, fumaric, malic, citric, lactic, mucic, gluconic, WO 95107269 PCT/AU94/00538 48 wherein R200 is as previously defined; OPy

(CH

2 0-2 Ra Rd R, NH, I /N INHet AA R AA C I C 0-1 I Rc 1 1-3 Rb Re

(IV)

wherein NH is an optionally substituted 5-12 membered saturated or unsaturated cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur; OPz

(C

H2 b Rf R Ra RdI N H I C -N

R'

0-4 Rb Re 1-3

(IW)

wherein b is 0, 1 or 2, provided that at least one b is greater than 0, and each Pz is independently hydrogen or Py, provided that at least one Pz is Py; G* Rb Re G* Rd N(IX) G N N Ri I Rc Rf I 0-2 Ra Rg Rh

(CH

2 )o-2 OPy Rb Rd SnG*R and C R2l S\ 0.1 QPz wherein G is or -CH 2 G* is R 1 or R 1 is or -NRh-, Q is or -NR i and Pz is selected from the group consisting of OH OH

OH

G* Rb Re G l i- k A\(x formyl, 2,2-dichioroacetyl, 2,2,2-trichioroacetyl, t-butyloxyCarL)onyI, UDZywxyL~d.I I WO 95107269 PCT/AU94100538 0 0 ,A~xJ--OH

-NO

2 X 0, S, S(0) 2 O H (0H 2 4

NH

2

H

0 0 0 OH I A IF'OH 0 0 0 H KR 0 O R

D

0 0

R

,and wherein R and R' are independently hydrogen or Cl-C 4 alkyl, D is 0 or S and Px* is as previously defined; wherein G is R, (CH2)0-2 0 OPz or Rl*, G* is or -NRv- and Pz is selected from the group consisting 0 00 0 11 11 0x P~ P,11OH ~B:-OH 'J X JOH OH 0 1 OH -NO 2 X S, S(0) 2

S

IIIP-OH

"OH

0

OH

0 0 0

S

IIN11OH 0 0O 0 0 H

(CH

2 4 NH2 O H

I)

0 0 -1 Pk*

R

"'D'X

wherein R and R' are independently hydrogen or Cj-C 4 alkyl, D is 0 or S and Px* is as previously defined;

(IAA)

wherein G is R, or Rl*, and each Q is independently H, -OPz or -NRdjPz, wherein each Pz is independently hydrogen or Py, provided that at least one Pz is Py; PCT/AU94/00538 p WO 95/07269AU9I 3 8 0 OPy 0 1 Rd II R (CH 2 )o.2 I I CH 2 Ilet RIX* I Re Rb Rc wherein N et is a saturated or unsaturated cyclic, bicyclic or fused nitrogen containing ring system and G is a bond or is or -NRf; OPy Rd( 2)O-2 ,NH H G (IAC) IRc II Rb 0O wherein G is absent or X*R and H is a 3 to 10-membered saturated or unsaturated heterocycle containing a nitrogen atom and optionally additionally one to three heteroatoms selected from nitrogen, oxygen and sulfur; Ra RcQRd AA I I AA~ RI* 'NH C I

R

2 (lAD) Rb Re O

(CH

2 0 -2 y wherein Qis selected from and -NRf-; OPy wherein Q is selected from and -NRf- Rb'

(CH

2 )0-2 Rd R

(IAE)

Ca~ NH 9 G2 EY I Rf I 0 Re Rh

RI

wherein G is O, S, S(0) or S(0) 2 and Ra' and Rb' have the meaning of Ra and Rb or Raand Rb' together are trimethylene or tetramethylene; P P'z Rd (iCH 2 )0- 2 (C1 2 )0- 2 Re R C CH CH C ,R 1

(IAF)

I A Ar NH NH RbI I Rf Rc' Rd' L, It;, c 2_ li~ll(~ie~L~(I~BI~ WO 95/07269 PCT/AU94/00538 51 wherein each Ar is independently (C 6

-C

1 4 )aryl, R'c and R'd are R c and Rd or, taken together, are or and wherein Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the HO O H 0 oxygen atoms to which they are attached form a group selected from and OPz' Ra (CH 2 )0-2 Rg R"C .Re h' R IC1, N CH 2 GAG) G G NH P C C 0 Rb I IRd (CH 2Rf Ri OPz wherein G is a bond or X as previously defined, Rg' and Rh' are Rg and Rh or together form a saturated or unsaturated cylic, bicylic or fused ring system, and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz l 1 and Pz' together with the oxygen atoms to which they are attached form a group selected HO, .pO H, O O .SO from -o -o and -o 0o- OP'z OPz (CH )o

P

H2 0 -2 RI,. NH I C AA Ri (IAH) C AAC C G I Rc I f I 0-2 /0-3 Rb Re 0 'h 0-2 wherein G is a bond, 0, S or NRj, Rg' and Rh' are Rg and Rh, or taken together may be and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are HO, O H,PO O s0 attached form a group selected from and -o UrPy

(CH

2 )0-2 S* N \II

G

SRI*I AA N\ R2 (IAI) Rb Rd wherein G is OPy, NHRe, NPyR e or Re; ~ILI 1 I I r s It~ _lil WO 95/07269 PCT/AU94/00538 52 OPy

I

Ra (CH2)0-2 R Ra R R-T -AG o-1 C 'Q'C'C IQ 'NH( 1 Rb I Rd I Rg I Rj 0-3 O R'c Re R'h 0-11 0-1 wherein G and G* are independently a bond, 0, S or NH, and R'd and Rh' are Rd and Rh or taken together are -CR' 2 or -CR 2 wherein each R' independently has the meaning of R 6 as previously defined, Q and Q* are independently N or CR 6 or when Q* is CR 6 then Rg and R6 together may be a double bond;

OPY

I

a (CH2C0-2

R*

Ri NHNCs GA 0- RR* (IA AAii CiRd CH 'CH/G C AA' CIM Rg R 0-4 Ra

R

14 3 Rb! Re 0-4 wherein G is or 2)0-40G* wherein G* is R6 or Py; OPy (CH2)0-2 R RH 0-3 -2

I

R R eI a d RA I G (IA) Rj- H I CI O -C -A Rb I Re 0-2 (CH2)0-2 Id e)Py lo wherein G is seelecd from hydrogen and X*RRI* and wherin rprsents a 4t-10 membered saturated or unsaturated cyclic, bicylic or fused ring system as defined herein; GGPz a

P,

G A -1 G*-y (IAN) WO 95/07269 PCT/AU94/00538 53 wherein Q is selected from O, S and NRg, G and G* are independently selected from R 1

R

1

-C(R

5

)=NR

3 and -C(R 5

)=NOR

3 wherein R 3 and R 5 are as previously defined, R'e and R'f are Re and Rf, and is R 20 as previously defined; 0 Ra II R/ CI C AA H CH (IAO) Rz -2 Rb wherein each R z is independently selected from R 1 and PyOG* wherein G* is optionally substituted alkylelne, provided that at least one R z is PyOG*, and G is -NR d or CRdRe-; OPy (C H 2 0 -2 i RNX* AA Ra Rd 0-1 1 a C C I C-NH AA G

(IAP)

O I R 0-2 SRb Re 0-1 wherein represents an optionally substituted saturated or unsaturated ring system optionally containing up to three heteroatoms selected from N, O and S, G is selected from R 1

XR

1 or X*R 1 and R a and Rb taken together may optionally be Ra R c o I I Re 11 AA C .C CI CNHR2 A) RI NH I B* IC C NAA

(IAQ)

iRb Rd I Rf wherein B* is a group B, as previously defeined, derivatised with a solubilising group Py; OPy

(CH

2 )-2 RR. NH CI 2 (IAR) RI AANHc I He R 2 2 Rb Het wherein represents an optionally substituted cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 3 heteroatoms selected from N, 0 and S; WO 95/07269 PCT/AU94/00538 54 OPy (L R2 0 2 Re (lAS)

I/NI

11 R' Rb IR'g11 0-2 Rd Rd wherein Q 1 and Q2 are independently selected from 0 and S, and R' f and R' g are respectively Rf and Rg or are selected from OR', SR' and NRhR' wherein R' is H, Ri or Py;

OPY

(CH-

2 0 2 F~ (j REd [RF~ "C,,II C C. N c

(IAT)

R I G~ CH 2

ICH

2 CH' G I R Rb 1\ 0- R1 0Il Rh Rc Rf wherein each G is independently selected from 0 and NR*, and R'is(H 1-0YoR6 Ra Rc Kj, 1I ;GI

IU

G IG I R 2 Rb Rd OQ OQOQ wherein G and G* are independently selected from Re Re~ Rf and L, wherein L is as previously defined and Q is H or Py, provided that at least one of G and G* is other than L and provided that at least one Q is Py, or wherein two groups OQ taken together HO, 0O HO 0 Q* are a cyclic group slected from -0 0-and OPy

(CH

2 0 2 Ra\, /Rb

R

6 Rc C 0 R 6 wherein Rx and Ryare independently R 6 or (CH 2 1 2

OPY;

Jr& WO 95/07269 PCT/AU94/00538 Ra R 0

R(AW

ICH, CH2. INH(AM) (IG* Rb I R OPy wherein G and G* are independently selected from R 1

R

1

-C(R

5

=NR

3 and -C(RS)N=0R 3 wherein R 3 and R 5 are as previously defined.

Still other compounds of the first embodiment are those compounds exemplified in International Patent Application no. WO 93/18006, namely: t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (ii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-valyl)amiino-4-phenylbutyllcarbazate, (iii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-.4-phenylbutyl]carbazate, (iv) t-butyl 3-(l -methyl-3-phenylpropen-3-yl)-3-[(2R or S, 3S)-2-hydroxy-3- (phenylmethoxycarbonyl)amino-4-phenylbutyllcarbazate, t-butyl 3-(1-methyl-3-phenylpropyl)-3-[(2R or S, 3S)-2-hydroxy-3-(Nquinaldoyl-L-asparaginyl)aniino-4-phenylbutyl]carbazate, (vi) cis-1, ,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-amino-4-phenylbutylj-3 ,4-diazabicyclo[4 .4 .0]decane, (vii) cis- 1 ,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl] -diazabicyclo[4.4.0]decane, (viii) cis- 1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lvalyl)amino-4-phenylbutyl]-3 ,4-diazabicyclo [4.4 .0]decane, (ix) cis-1, ,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3..[N-(2-pyridyl)methoxycarbonyl)-L-valyl)amino-4-phenylbutyl]-3 ,4-diaza-bicyclo decane, cis-1 ,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)anmino-4-phenylbutyl]-3 ,4-diazabicyclo[4. 4. Oldecane, (xi) cis-1, ,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lglutaminyi)amino-4-phenylbutyl]-3 ,4-diazabicyclo[4 .4 .Q]decane, (xii) cis- 1, 6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hiydroxy-3-(N-quinaldoyl-Lthreonyl)amino-4-phenylbutyl] -3 ,4-diazabicyclo[4.4.0]decane, (xiii) 2-t-butoxycarbonyl-3-[R2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2 ,3-diazabicyclo[2 (xiv) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]-2 ,3-diaza-bicyclo[2.2. 1]heptane, WO 95/07269 PCTIAU94/00538 56 (xv) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2-pyridyl)methoxy-L-.

valyl)amino-4-phenylbntyll-2,3-diaza-bicyclo[2 1]heptane, (xvi) 2-[N-(1S)(2-methy1-l-methoxycarboflpropy1)carbamoy1I-3-[(2R or S, 3S)-2hydroxy-3-[N-(2-pyridyl)methoxy-L-valyl]amino-4-phenylbutyl]-2,3-diazabicyclo[12.2. 1]heptane, (xvii) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl]- 2 -diazabicyclo[2 llheptane, (xviii) 1-[2-(2-pyridyl)methoxycarbonylamino-Ibenzoyl-2-[(2R or S, 3S)-2-hydroxy- 3-(N-quinaldoyl-L-asparaginyl)amino-4-phelylbutyl-2-isopropyl-hydrazile, (xix) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)aniino-4-phenylbutyll-1 ,2,3 ,4-tetrahydrophthalazine, (xx) 1-trimnethylacetyl-2-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)arnino-4-phyenylbutyl]-2-isopropylhydrazine, (xxi) 1 -trimnethylacetyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl) amino-4-phenylbutyll-2-isopropylhydrazine, (xxii) 1-(t-butylaniino)carbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-LasparaginyI)amiino-phenylbutyl]-2-isopropylhydrazine, (xxiii) t-butyl 3-isopropyl-3-[2R or S, 3S)-2-hydroxy-3-(N-picolinoyl-Lasparaginyl)amino-4-phenylbutyllcarbazate, (xxiv) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2-pyridyl)-methoxycarbonylanthraniloyl)amino-4-phenylbutyl]carbazate.

(xxv) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyllcarbazate, (xxvi) t-butyl 3-benzyl-3--[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyllcarbazate, (xxvii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenyl-methoxycarbonyl)amino-4-phenylbutyl]carbazate, L(xxviii) t-butyl 3-cyc-iOhexyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyljcarbazate, (xxix) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(1-carbamoyl-rnethyl)acryloyl)amnino-4-phenylbutyllcarbazate, (xxx) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio- (xx)2-carbamoyl-methylpropionyl)amino-4-phenylbutyl]carbazate, (xx)t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(1 -benzoyl-Lasparaginyl)amnino-4-phenylbutyljcarbazate, (xxxii) 1-t-butyloxycarbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]hexahyciropyridazine, (xxxiii) 1-t-butyloxycarbonyl-2-[X2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lasparagrniyl)amino-4-phenylbutyllhexahydropyridazine, and WO 95/07269 PCT/AU94/00538 57 (xxxiv) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl- 3-cyano-L-alanyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4,4,0]decane, wherein the 2-hydroxy group has been derivatised with a solubilising group Px as herein defined. Typically, in this form of the first embodiment, compounds to (xxxiv) o referred to above are derivatised with a solubilising group selected from /POH and

OH

0

II

IP-OH*

H

The compounds of formulae to (IAW) can exist in optically isomeric forms and the present invention includes within its scope all these forms in all proportions including all diastereoisomers and mixtures thereof and all enantiomers, mixtures of enantiomers and racemic mixtures. Where a double bond occurs in the compound of the invention, the double bond may be present in the cis- or trans- configuration. It will be understood that only compounds of formula with combinations of substituents or functional groups which give rise to stable compounds, are within the scope of the present invention.

The compounds of general formula may be prepared by methods known generally in the art. Suitable methods for the synthesis of compounds of formula and intermediates thereof are described, for example, in Houben-Weyl, Methoden der Organischen Chemie; J. March, Advanced Organic Chemistry, 3rd Edition (John Wiley Sonn, New York, 1985); D. C. Liotta and M. Volmer, eds, Organic Syntheses Reaction Guide (John Wiley Sons, Inc., New York, 1991); R. C. Larock, Comprehensive Organic Transformations (VCH, New York, 1989), H. O. House, Modern Synthetic Reactions 2nd Edition A. Benjamin, Inc., Menlo Park, 1972); N. S. Simpkins, ed.

100 Modern Reagents (The Royal Society of Chemistry, London, 1989); A. H. Haines Methods for the Oxidation of Organic Compounds (Academic Press, London, 1988) and B. J. Wakefield Organolithium Methods (Academic Press, London, 1988).

For example, a compound of formula may be prepared from synthons W*, and wherein each synthon identified thus is a synthetic precursor of the corresponding portion of the molecule Thus, a compound of formula may be prepared, for example, in any of the following ways: by reaction of with H-V; by reaction of with G-V; by reaction of W-H with and by reaction of W-G with wherein G is a-leaving group such as halogen, typically chlorine, bromine or iodine; a 3,a sulfonate such as methanesulfonate, trifluoromethanesulfonate, benzenesulfonate or toluenesulfonate; an alkoxy, thioalkoxy, aryloxy or thioaryloxy group such as ethoxy, .0 WO 95/07269 WO 9507269PCT/AU94100538 methoxy, thiomethoxy or phenoxy; acyloxy such as acetyl, trifluoroacetyl or benzoyl; hydl ixy; amino or protonated amino; nitrate; phosphate; borate and the lie. If appropriate these reactions may be carried out in the presence of a base such as triethylamine, pyridine or other tertiary amine, butyllithium, sodium tert-butoxide or similar, and/or a coupling reagent such as a carbodiimide, When V is YR 2 where Y is or when V is Y* where Y* is a member of the group

-N-N--R

2

-N-O-R

2 I II

R

5 o R 51

R

5 o -0-N-R2*

I

the compound of formula may be prepared as shown in Scheme 1 or Scheme Ia. In lo the Schemes and in the Examples herein, the terms Me, Et, Pr, Ph and Bz signify methyl, ethyl, propyl, phenyl and benzyl respectively and the following additional abbreviations are used: flip t-Bu or But n-Bu iPr or Pr' Hal Ts

DMF

CDI

BOP

HBT

AcCN

DMSO

PY-XS0 3

QC

PC

MC

TMC

Val Asn Dle Gly Glu Thr Ala tetralhydropyranyl, tertiary butyl n-butyl isopropyl halogen; fluorine, chlorine, bromine or iodine para-toluenesulfonyl dimethyl formamide N ,N -carbonyldiimidazole benzotriazol-1-yloxytris(dimnetliylamaino)-phosphoniuin hexafluorophosphate I-hydroxybenzotriazole acetonitrile dimethyl sulfoxide pyridine/sulfur trioxide complex quinoline-2-carbonyl 2-pyridinemethoxycarbonyl N-morpholinocarbonyl N-thiomorpholinocarbonyl valinyl asparaginyl isoleucyl glycinyl glutaminyl threonyl alanyl WO 95/07269 PCTIAU94100538 59 (CN)Ala cyanoalanyl (p-F)Bz 4-fluorobenzyl (p-CN)Bz 4-cyanobenzyl Z benzyloxycarbonyl Boc t-butyloxycarbonyl Ac acetyl TFA trifluoroacetyl

CA,

1 cyclohexyl.

Scheme 1 HN 5 R (~BA)O~R H NROOR 2 W (A)nB(A*)-mON

R

2

R

5 0 W-(A)n-B(A*)m.Hal W(A)nB(A*)riiNNR 2 synton W(A~nB~(A)m~al wth H~if pprpriae inthe renceo*f a stron2 ae

IH

Kd ^g r v wherein Ra and Rj are independently selected from

R

1 and R 1 as previously defined; i

I

1 112 i ii

I

i WO 95/07269 Scheme 1a PCT/AU94/00538 RaNHNH 2 Ra-N-NH2 Rb

(RO)

2

C(O)

base H30 ,11 RaNHNHC(O)OR RbHal base Ra-N-NHC(O)OR

R

Rb RcHal base Ra-N-NHRc

I

Rb In Scheme la, R represents an alkyl, aryl or aralkyl group, such as t-butyl, phenyl or benzyl. Suitable bases include pyridine, triethylamine and other tertiary amines, alkali metal carbonates and alkali metal hydroxides. The moiety may be represented by R a in which case Rb represents R 50 as previously defined, and Rc represents R 2 as previously defined, or may be represented by Rc, in which case Rb represents R 51 and Ra represents R 2 1R33 When V is Y* where Y* is -N-N=C the compound of formula may be RsO R34 prepared from by reacting a hydrazine wherein R 51 and R 2 are both hydrogen, which may be prepared as shown in Scheme 1 or Scheme la, with an aldehyde or ketone.

O- When V is YR 2 where Y is or =N the compound of formula may be prepared as shown in Scheme lb Scheme lb W-(A)n-B-(A*)m-Hal R 2

-N=N-O-

R

2 -Hal N=N-R2

N=N-R

2 6 When V is YR 2 where Y is a member of the group R 0,J<O Rd R0

(IU)

WO 95/07269 0

II

R

50 0 11 -0-6- 0 11 -Sj-N- I I I O R 50 0 11 0 0 11 11

-N-S-

I 1 11 K50 R 50 0 O 0 11 11 -s-aO- 11 11 0 0 PCTIAU94/00538 0 11 -0-S- 0 0 I1 0 0 -s-S--PN

R

51 O0 R 5 o 0 11

K

51 0 R 5 o 11 -N-P I I

R

50

OR

51 0

R

50

OR

51 O 0 0

OR

51

OR

51

R

51 0 R 50 0 0

P-O-

R

52

OR

51

I

UR

51 the compound of formula may be synthesised by coupling a synthon Za with a synthon Zb, where Za includes one of the heteroatoms of Y, and Zb includes the other heteroatom or atoms, as shown in schemes 2a and 2b: L I I

~OH

"OH

P P, OH 01- -OH B;-OH

OH

and Pz is selected from the group consisting of ,Ji.

WO 95107269 Scheme 2a PCT/AU94/00538 -H CIS(O)Rq 0

CIS(O)

2

R

2 R5- 0 R0 CiP(O)(0R 5

)R

2 W(A),rB(A*)h

R

2

R

0 -P-0R 2 R~o0R 51 CIS(O)Rq b 0 W-(A)7B-(A*)rT0 4

S-R

2 CIS(0) 2

R

2 0 W-(A)mrB-(A*)rff0-H CI()R 9 ~W -(A)ITB-(A)MC 4

-R

2 CIP(O)(0R 5

,)R

2 W(~BA)0

OR

5 1 CIP(O)(0R 5 1 )0R 2 0 W-(A)rrB-(A*)rmf 4 -0R 2

OR

5 1 W~v'(A)trB-(A*)mO0- H rB-(A*)f mS-H

CIS(O)R

2 0.

0 W-(A)rFB-(A*)rff 0-9R 2

HSR

2 b W (rB-A)fS

-R

WO 95/07269 FTA9/03 PCT/AU94100538 Scheme 2b 0 W-(A4nB(A)mrCI 0

CI

0 0 W-(A)jrB(A*)mwI-CI 0 11 W-(A)-B-(A*hryrIP CI

OR

51 0 11

OR

5 1 0 11 W- fjB-(A 1 jS-CI 0 W- (A)ff-B-(A*)ffS CI 0 0 W-(A)ff-B-A*)rwPCI k 52 0 W-(A)f-B-(A*),w-i9CI 0

OR

51 0 W-(A)n-b-(A*)ff-O 4 0CI

OR

51 Analogous methods may and thionophosphonates.

HNR

5 oR,

HNR

5 0

R

2

HNR

50

R

2

HNR

5 0

R

2

HNR

5 0

R

2 HOR9

HOR

2

HOR

2 HSRq

HOR

2

HOR

2 0 W-(A)rB-(A*)ygN-R 2 0 W-(A~rrB-(A*)rrF-M-R 2 0OR 50 W-(A)rB-(A*)vP N-R 2

R

5 2 0OR 50 W-(A)rB-(A*)TiP-NR 2 6R 51 W-(A)rB(AI')ff-O-PNR 2

OR

51 0 W-(A)ffB-(A*)rW -0R2 0 W-(A)ffB-(A*)ffi+0R 2 0 0 0 0 W-Af--A*fi 0R

OR

51 be used to obtain the corresponding thionophosphates When V is C(R 30 the compound of formula may be prepared from a synthon having a ketone or aldehyde function, by condensation with a substituted hydrazine or substituted hydroxylamine corresponding to When V is where Y* is the compound of formula may be prepared by oxidising the corresponding primary amine, for example with Caro's acid, or l v r WO 95/07269 PCT/AU94/00538 64

H

2 0 2 in acetic acid, or H 2 0 2 with sodium tungstate. It will be appreciated that a compound of formula wherein Y* is -N=O will only be isolable as a nitroso compound when the carbon atom bearing Y* has no a-hydrogens.

0 -S=O II When V is where Y* is I or S=O, the compound of formula R4114* R114* may be prepared by oxidation of the corresponding thioether W-(A)n-B-(A*)m-S-R11 4

(IV)

with hydrogen peroxide and acetic acid. The thioether (IV) may be synthesised by coupling a halide W-(A)n-B-(A*)m-Hal with a thiol R 114 under basic conditions, or by reacting a disulfide R 11 4*SSR 11 4* with an organolithium reagent W-(A)n-B-(A*)m-Li derived from the corresponding halide.

OR

1 1 5 R114* -P=O -P=O When V is where Y* is I or I the compound of formula Rl14** R114** may be prepared by the Arbuzov reaction as shown in scheme 3: Scheme 3 SR14* MeO-P R14** R114* W-(A)n-B-(A*)f-Hal W1-(A)-B

OR

1 1 MeO-P

R

1 14

R

1 1 W-(A)n-B-(A*)rmHal W-(A)rB -(A*)rmP=O R114** The synthon where Z is any of the functional groups bound to which are represented in schemes 1 to 3, may be prepared by coupling a suitably functionalised fragment W* with a correspondingly functionalised fragment Alternatively, the compound of formula may be synthesised by first coupling V to m as described above with reference to schemes 1 to 3, and then coupling the resulting molecule to a functionalised fragment Methods for coupling a precursor of group W with a functionalised fragment are well known in the art, and include methods analogous to those represented in schemes 1 to 3. For example, when W is RIX and X is Y, the coupling may be achieved as described in schemes 1 to 3 above. When W is R 1 X and X is NRio, O or S, the coupling may be achieved by any of the known methods for the alkylation of amines, and the hLr-, L -C l'~'q wherein G is OPy, NHRe, NPyRe or Re;

F

WO 95107269 PCT/AU94/00538 synthesis of ethers and thioethers, respectively. That is, the coupling may be achieved by reacting a fragment wherein Z* is a leaving group such as halogen, sulfonate ester, acetate or trialkylammonium salt, with RIR 1 iNH, R 1 OH or R 1 SH, if Snecessary in the presence of strong non-nucleophilic base such as butyllithium, sodamide or potassium tert-butoxide. Compounds in which X is S(O) or S(O) 2 may be prepared by the oxidation of the corresponding compound in which X is S. Compounds in which W is -CN, -C(R 5

)=NR

3

-C(R

5

)=NOR

3

-C(D)OR

3

-C(D)SR

3 or -C(D)NR 3

R

4 may be prepared from the fragment wherein Z* is an aldehyde, ketone or carboxyl group as shown in Scheme 3a.

Scheme 3a O 0

S

SR

3 SH Lawesson's 11

C=NOR

3 -C-CI -C-SR 3 Reagen -C-SR 3 S(0)CI 2

R

3

ONH

2 O R 3 OH

S

O I Lawesson's 1 C=O

NH

3

NH

0 o s SLawesson's 11 S--NH2

-C-NR

3

R

4 n -C-NR 3

R

4

R

3

NH

2 Reagent P205 C=NR3 CN Compounds in which W is -N=CR 5

R

5 may be prepared by reacting the fragment where Z* is NH2, with an aldehyde or ketone having group(s) R 5 and R 5 bound to the carbonyl.

The fragment may be prepared by methods which depend on the nature of B. Where B is a substituted carbon atom, the fragment may be conveniently prepared from a fragment in which E is a fragment and E* is a fragment as shown in scheme 4: 6Mi WO 95/07269 pCTIAU94/0053 8 66 Scheme 4

R

203

*R

203 KSCN IR 5 1 9- 7 0H tTyE ECSE*E SE*HNR 1 5

R

1 7

,H

Peradd

H

2 IPt

BNR

203

*R

203

DR

18

'-E

ISH SR 1 EC'E DR 1 9

ECE

Reductic i 2 R 1 5 Br H ,~DH,sH

R

1 9

DH

H+ C, P1h 3 E' E* OH LaCwessons .R 1 Mgr SH

ISR

1 OH~~ I base

R

4 L or R 1 4 MgHal Reagent E-C- E* 2. RI 5 Br E-Y9-E* k4 IE'C'E*

R

14 R4 O9H 1. PhIo Pi, 3 c C1 H 2 0H COOH EI-E RirN 2. H+ E-C-E* ED "fta L0--6-E*

H

H *R 1 7 PhCO 3 H N1 CHO NaBH 4

N

1 IA*EC~* 1 Morpholine CHO COOH R~IiiE--6-E* RuO 4 /a-1O 4 E.-6-VE 114R 14

R

14 ?R14* CrO 3 -Pyridine HOCHR 11 E C- E* E-C-E* 1 2. Huang-Minlon I IBH

CH

2 0H E E* 0 Fragments 11 which are starting materials for compounds of formula are known compounds or analogs of known compounds which can be prepared by methods analogous to methods used for preparation of the known compounds. The 0 synthesis of known fragments 11 may be found with reference, for example, to Beisteins Handbuch der Organischen Chemie or to J. Buckingham, ed., Dictionary of Organic Compounds 5th Edition (Chapman Hall, New York, 1982). Alternatively, a functionalised group E may be coupled to a group E*C(O)H, or a functionalised group E* may be coupled to a group EC(O)H, followed by oxidation. For example, a halide EBr may be coupled to E*C(O)H with an organolithium. or organomagnesium reagent derived i~ I i N n-~II~YL~-lii~YY-__ WO 95/07269 PCT/AU94/00538 67 from EBr, followed by oxidation of the resulting secondary alcohol to the corresponding ketone, if desired. Alternatively a carboxylic acid EC(O)OH may be converted to an activated derivative, such as an ester or amide: for example an amide obtained by reaction of the carboxylic acid with N,0-dimethyl hydroxylamine hydrochloride in the presence of a carbodiimide and tertiary base, followed by addition of an organolithium or organomagnesium reagent derived from E*Br, E*Cl or E*I.

O

When B is an epoxide of the type G- the fragment E-B-E* may be R14*R14* prepared from the corresponding olefin by reaction with a per-acid such as trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid. Suitable olefins for conversion to the fragment E-B-E* are commercially available or may be synthesised by known methods, for example by means of the Wittig reaction or by an elimination reaction of an alcohol, alcohol sulfonate, ester, halide or the like.

OH OH I I When B is a diol of the type the compound of formula may R14*R14** conveniently be prepared by reductive coupling of aldehydes EC(O)H and E*C(O)H as described in J. Org. Chem 55, 4506 (1990) and U.S. Patent No. 5,294,720.

When B is a heteroatom or substituted heteroatom, the fragment is a substituted amine, phosphine or phosphine oxide, or is an ether, thioether, sulfoxide or sulfone. Substituted amines, ethers, thioethers, sulfoxides and sulfones may be prepared as described above. Secondary or tertiary phosphines may be prepared by alkylation of the corresponding primary or secondary phosphine as described, for example, in J. D. Roberts and M. C. Caserio, Basic Principles of Organic Chemistry Igenjamin, Inc., New York, 1965).

In any of the reactions described above, it may be necessary to protect reactive group(s) in the compound of formula other than those participating in a desired coupling or oxidation reaction using suitable protecting group(s) in order to carry out the desired coupling or oxidation reaction without chemically affecting those reactive groups.

Suitable protecting groups for this purpose are described in the works of Greene and McOmie referenced above.

The compounds of formula (IB) wherein x and y are both 1 may be prepared as o3 generally described above. A compound of formula (IB) which is OH Re RaRbN N NRd

H

PCTAU94I00 38 Wo 95/07269 68 where Ra and Rb have the meaning of R 501 and R 506 as previously defined and Rc and Rd have the meaning Of R 551 and R 502 as previously defined, may be prepared from ethylene cyanohydrin by the method shown in Scheme Scem 51. BZCI, Ag 2 O/DMF OH CN",-,OBZ

B

HOBr 2. H 3

O,

Mg, PhNIEt 2

O

TsOH (Va) Br,~CN Br 0g Z 01.

LIAIH

4

OCH

2 0(CH 2 2 0CH3 (V)-'OBZ 2. MeO(CH 2 2 00H2 0 0 OBz 0b) EtN(i-Pr)2 STsOi-VMeOH (CV- 20CH32. NH 4

CIO

4 VVc (V)RaRbWNB Ra-3abNJD bNO"

B

2N d

OCH

2 0(CH 2 2 0CH3 RaRbN

R

H 0 R N.N Rd

IIIH

A substituted compound of formula (IB) may be prepared by the general method of Scheme 5, with the substituelits

R

5 12

R

513

R.

522

R.

523

R

532

R

533

B

542

R.

543 and

R

550 being introduced, as desired, into the compoudoforlaVaVb,(can (Vd) shown in Scheme 5 by the methods illustrated in Scheme (Xiv) 2-t-bUt0XYCaTDUlYI-O-Lkz" -9i' amno4-phelylbutyl]2,3-diaza-bicyclo[ 2 2 11heptane,

"A

PCTIAU94100538 WO 95107269 Scheme ,(Va00,

C

1. NaNH 2 2. RHaI 1. NaNH 2

C

R R R' 5a-1 (Vb)a QL 0 OBz R R' (Vb)a QL 0 OBz R R'

OCH

2

O(CH

2 2

OCH

3 (Vc) HO OBz 1. NaNH 2 2. R'Hal 0 0 -k--OBz R R' R" 5a-2 LIR', CO0 0 0 OBZ R R 0 5a-3 TsCI, Me 2

SO

H OCH 2 O(0H 2 2 0CH 3 0 OBz I RMgHaI 5a-4 R R' OCH 2

O(CH

2 2 0CH 3 R OCH 2

O(CH

2 2 0CH 3 Oz 1. Me 2 CO, AI(OBut) O 2. RMgHaI

OCH

2

O(CH

2 2 0CH 3

OCH

2

O(CH

2 2 00H 3 (Vd) RaRbN RNH 2 RaRbN 4 RMgHaI

OCH

2 O(0H 2 2 0CH 3

OCH

2 O(0H 2 2 0CH 3 RaRbN .91. HN0 2 RaRbN H R' tJNH2 2, LIAIH 4

HN

I

V

,m reaction 5a-1 shown above, it will be appreciated that the step of introducing the j h. ubstituent R' will only be carried out if it is desired that both R 522 and R~ 523 be other than hydrogen, The reactions shown in 5a-2 and 5a-3 may be repeated, if desired, so as to introduce a second sub stituent on the carbon atom bearing R" or R" The second substituent can be the same as or different from the first. Where one or both of R 522 and R 523 is acyl, this group may be introduced as shown in reaction 5a-3 with respect to compound Where R 522 and R 523 are both hydrogen, the lo reactions shown in 5a-2 and 5a-3 may give mixtures of products and in that case it may be preferable to introduce the desired groups R 532

R

543

R

542 and R 543 by replacing the (xxxiii) 1-t-butyloxycarouunyix-i asparaginyl)amino-4-phenylbutyl]hexahydropyridazine, and PCT/AU94!0 0 538 WO 95/07269 ethylene bromohydrin shown in Scheme 5 with a suitably substituted bromohydrinobtained from the coresponding olefm as shown in Scheme 5b. It will be appreciated that the nature of the groups

R

532

R

543

R

542 and

R

543 will determine the stereochemistry of the addition of HOBr to the olefin and of the opening of the epoxide.

Scheme

R

5 3 2 0 R542

R

53 3 R543

CF

3

C(O)OOH

OH R542

R

53 2 R54 2 Br2/H 2 O

R

5 32 R543 R533 Br

R

53 R54333

B

Compounds of formula (IB) wherein B is other than -CH(OH)- may be prepared by the methods shown in Scheme 4 after oxidation of the secondary alcohol to the corresponding ketone.

o0 The compounds of formula (IB) wherein B is a substituted carbon atom and y is 0 Scan be prepared by reacting a compound of formula (IIA) or (IIB) R50S R522 Rc4n

R

5 06

R

5 22

R

50 6

R

2 2 42 I R 51 2 542

R

5 12 O R R 52 3 R513 R4"

R

5 13 H R 51 3

R

1 4* (ll)

(IA)

Re0

R

522 R542 I 512 R51 IiR 2 3

R

54 3

R

513 0 (11B) wherein R 14

R

5 0 1

R

5 02

R

5 6

R

5 1 2

R

51 3

R

522

R

52 3

R

54 2 and R 5 4 3 have the significance given earlier and Hal is a group selected from -Cl, -Br or with a compound of formula

(III)

|/R 551 H-N-N R 5 5 0 wherein

R

502

R

550 and R 5 1 have the significance given earlier. Where a compound of Sformula I) is used, the reaction may be followed by oxidation of the resultant secondary Si _I r ii_ Ic c -e4 WO 9/0729 .PCT/AU9400 5 3 8 71 alcohol to the corresponding ketone. This ketone may be used for elaboration of the substituents on B as shown in Scheme 4.

A compound of formula (HIA) or (HB) may be prepared from a P-amino acid or a P-axnido acid as shown in Scheme 6. A compound of formula III may be prepared as shown in Scheme la.

Scheme 6 o R2 S1. LU, MeNH 2 2. H 3 0'

R

5 0 R 5 22 1 i 5 3 R, WH MgX 522

R

50

R

522 ,--"it"COH

NI~K

Ph-S-CPR"I Ph-S R IHR4 k 52 HrO 3 /P"1 II

C

513 2 (II, R5A R52 k1 H orR543 e 1 51~ R02

R

5 0

R

1 1" R543 s<~~NR4 Ph-S-C-R13 H53 N~~~~2Hl 2 H1.11,R 3 0r 1.

R522 1 51 R5o< R52 R51Hal 1"1/ A5111n' ternaiv rot ote0aioleyesow nShm sb euto of2 I'h mehy ese f h orepndn."Rm cisuin isouyalmnu 103 hydride.23H'-54 p-ainoacdsor~3-i o cids may covnenl 3e0rprd yte arc or Ane altraieruetth -mnldehydesoni cee6 sb euto A compound of formula (IB) wherein x and y are both 0 may be prepared by reacting a compound of formula (11C) or (LID) j,.

WO 95/07269 PCT/AU94/00538 72 Rso 0 H Rso 6 0 RI I 12 Rs 42 IN- I.C- I R4.N2 1| C, I .,.Hal I I I I Rso N C C-R2 Rso1 C C Rsz R 54 3

R

5 1 3

RS

43 (IIC) (lID) with a compound of formula (III) as shown above. An analogous procedure, utilising a primary or secondary amine rather than a hydrazine as shown in formula (III) yields a hydroxy diamine. A compound of formula (IIC) may be prepared from an a-amino acid by a method analogous to that shown in Scheme 6, such as described in the following: Evans, et al., J. Org. Chem., 50, 4615-4625 (1985); Luly, et al., J. Org. Chem., 52, 1487-1492 (1987); Handa, et al., European Patent Application No. 346,847-A2 (1989) and Marshall, et al, International Patent Application No W091/08221.

Suitable a-amino acids may be prepared, for example, by the Strecker synthesis, starting from an appropriate ketone. The overall route to the compound of formula (IIC) is shown in Scheme 7. Other suitable methods are described in Coppola, et al.

Asymmetric Synthesis. Construction of Chiral Molecules using Amino Acids (Wiley Interscience, New York, 1987).

Scheme 7 NaCN,

R

512 O NH4C R 512 NH2 H 3

R

512

NH

2 R513 R513 CN R 513

C(O)OH

SRC(0)CI

NHC(O)R

NH512 C)R Ph4SCR4232 R 512 NHC(0)R 1. Li, MeNH 2

R

5 12

NHC(O)R

RE

13 0

R

543

R

51 3 CHO 2. H30 R 513

C(O)OH

Where W is a nitrogen-containing group, and one of R 1 and R 10 is a protected amino acid residue, the coupling of the protected amino acid residue may be accomplished as shown in Scheme 8, in which the amino acid (designated AA) protecting group is benzyloxycarbonyl, designated Z. Methods for the formation of peptide bonds and for the protection of peptide residues are described, for example, in Gross and Meienhofer, eds., The Peptides, (Academic Press, New York, 1983). Suitable other coupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and diphenylphosphoryl azide (DPPA).

ii *\h 1 Scheme 8 1. CD1, dimane 0 LiOH, AAlwater0 Z~~KOH 3. Acid, pH =2 ZLA O BOP, HBT, EtN(i-.Pr) 2

IDMF,

0 Numerous synthetic routes exist to substituted hydrazines, including the hydrazines of formula useful in the synthesis of compounds of formula The hydrazine intermediates (III) can be obtained using k methods such as those described in the following: Dutta, etal., J. C'hem. Soc. Perkin Trans. 1, (1975) 1712-1720, Ghali, et al., J. Org. Chem., 46, 5413-5414 (1981), Gante, Synthesis (1989) 405-413 and Houben-Weyl's Methoden der Organische Chemie, vol. 16a, Part 1, pp 421-855; Georg Thieme Verlag, Stuttgart (1990) Other methods for preparing substituted hydrazines are illustrated in Scheme 9.

Scheme 9 >4NJ-NH, N-aoBr '-NNH, R LiAIH 4 or ZnHCI R R/or H 2 Pt R l-NH 1or2)

H

2 /catalyst R-N=N-R oriime R-NH-NH-R l~iA IH 4 ZNaOH 03 Oor CF 3

C(Q)OQH

R- NH 2 Per-acid 0"R-N0 2 -d R=N-OH Compounds of formula wherein a group selected from RI, Rl*, R 2

R

2

R

9 RII, R 12

R

50 and R 51 together with another group selected from RI, Rl*, R 2

R

2

R

9 'It RIO, R 11

R

12

R

50 and R 51 forms a cyclic, bicyclic or fused ring system may be prepared by variants on the above methods which will be readily apparent to persons skilled in the art in the light of 'the foregoing.

PCT/AU94/00538 WO 95/07269 74 An example of a method of preparing one class of cyclic compounds of formula is presented in Scheme Scheme OH Rso

H

2 N N .H HN'(A)n

,N

R51 Me 2 ButSi 0 Rso Imidazole,

I

H2N (A)n ,H (Me) 2 ButSiCI, (A)n N DMF

R

5 1

CDI,

Dioxane O 0 R J RS I H Rsi N N Alkylation, etc (optional) N N R50 HO O Me 2 ButSi Compounds in accordance with the present invention which do not include a solubilising group Px typically exhibit low to very low water solubility. Inhibitors of HIV proteases which have hitherto been described, and many other pharmaceutically or veterinarily active substances also typically exhibit low to very low water solubility. This property tends to cause the bioavailability of such substances to be relatively low. There is thus a need for a HIV protease inhibitor having enhanced water solubility.

Surprisingly, it has been found that the inclusion of a solubilising group Px as defined herein in a substance having low to very low water solubility results in enhancement of the water solubility of the substance. Thus, substances in accordance with the invention which include a solubilising group Px exhibit superior bioavailability, including superior oral bioavailability, compared to compounds in accordance with the invention which do not include a solubilising group Px.

Thus, according to a second embodiment of the present invention, there is provided process for enhancing the water-solubility of a pharmaceutical or veterinary substance, comprising derivatising a ftinctional group of said substance with a solubilising group Px, wherein Px is selected from the group consisting of Px*, 0 WO 95/07269 PCT/AU94/00538 o DPx D PX* R and wherein D is O or S, R is H or C 1

-C

4 alkyl, and wherein Px* is selected from: 0 0 O S O II II O II II II PN OH'- 11-OH /PTOH /POH /POH OH OH OH H OH OH /V"0 0 0 0 /B--OHH -NO 2 X OH

OHOH

X=0O,S,S(O),S(O) 2 0 0 O

H

O 01 II 0 R N 0 OR' N

(CH

2 4

NH

2 O H H NH HN "N NH2 I H and said functional group being capable of being derivatised with said solubilising group Px.

Generally, a compound according to the first embodiment includes at least one solubilising group Px as defined above. More generally, a solubilising group in a compound of the first embodiment or in the method of the second embodiment is selected o o from /P-OH and /P\OH OH H Typically, a solubilising group is introduced into the molecule as the last stage of its synthesis. For example, a solubilising group P(O)(OH) 2 may be introduced to a free amino, hydroxy or mercapto group by reaction of the amino, hydroxy or mercapto group with dimethyl chlorophosphate, followed by mild hydrolysis to remove the methyl ester groups. Other solubilising groups referred to above may be introduced by analogous methods: that is, by reaction of an amino, hydroxy, mercapto or other group capable of being derivatised with a solubilising group, with a reagent PxX', suitably protected if necessary (for example as methyl or benzyl esters), wherein Px is as defined above and X' is a leaving group such as Cl, Br, OH, OS(0) 2 R and the like, where R is C 1

-C

6 alkyl, for example methyl, C 6 -C10 aryl, for example phenyl or 4-methylphenyl, or C7-Cll W8 5)510; i 7269 PCT/AU94/00538 arylalkyl, for example benzyl. Alternatively, a solubilising group P(O)(OH) 2 may be introduced to a free hydroxy group by reaction with phosphorous acid and mercuric salts in the presence of a tertiary amine, as described by Obata and Mukaiyama in J. Org.

Chem., 32, 1063 (1967). As a further alternative, an amino, hydroxyl or mercapto group may be reacted with phosphorous acid preferably in the presence of a coupling agent such as dicyclohexylcarbodiimide and pyridine to yield a molecule possessing the solubilising group -OP(O)(OH)H. Optionally, this group may be oxidised to the corresponding phosphate derivative, for example using bis(trimethylsilyl) peroxide (see Scheme 14 below for an illustration of this method). A further process for the introduction of a group -P(O)(OH) 2 is described in Australian patent application no. 54311/86, and involves the reaction of an amino, hydroxy or mercapto group with certain diesters of amides of phosphorus acid, followed by oxidation and hydrolysis of the resulting intermediate compounds.

Suitable reagents for the introduction of a solubilising group -NO 2 are lower alkyl nitrates such as methyl nitrate or ethyl nitrate, and acyl nitrates such as acetyl nitrate or benzoyl nitrate.

Other methods for the preparation of compounds of formulae to (IAW) referred to herein are disclosed in US Patent Nos. 5,116,835, 5,126,326; 5,132,400; 5,145,957; 5,198,426; 5,212,157; 5,215,968; 5,212,667; 5,294,720; and 5,296,604; Internatiornal Patent Application Nos. 91/08221; 91/10442; 92/151319 and 92/21696; European Patent Application Nos. 0528242; 0519433 and 0432595 and Australian Patent Application Nos. 35700/89; 53716/90; 63221/90; 71319/91; 71320/91; 71323/91; 82313/91; 83206/91; 87594/91; 90531/91; 90851/94; 90925/91; 91251/91; 91332/91; 18355/92; 26424/92; 37160/93; 38808/93 and 44930/93, the disclosures of each of which are incorporated herein by reference.

A third embodiment of the invention is directed to pharmaceutical compositions comprising a compound of formula together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients.

In a fourth embodiment of the invention there is provided a method for inhibiting retroviral proteases in a mammal in need of such inhibitic n, comprising administering to the mat imal an effective amount of a compound of the first embodiment or of a composition of the second embodiment. In one form of the third embodiment, there is provided a method for the treatment or prophylaxis of HIV viral infections such as AIDS.

For inhibiting retroviral proteases or the treatment of HIV viral infections, a composition of the second embodiment may be administered orally, topically, parenterally, e.g. by injection and by intra-arterial infusion, rectally or by inhalation spray.

:_i For oral administration, the pharmaceutical composition tablets, lozenges, pills, troches, capsules, elixirs, powders, includin may be in the form of [g lyophilised powders, 11 A- WO 95/07269 PCT/AU94/00538 77 solutions, granules, suspensions, emulsions, syrups and tinctures. Slow-release, o.

delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules.

Solid forms for oral administration may contain pharmaceutically acceptable binders, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methyicellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copo.ymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.

Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or cetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol monoor di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.

The emulsions for oral administration may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth.

For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, gel, jelly, tincture, suspension or emulsion. The pharmaceutical composition may contain pharmaceutically acceptable binders, diluents, disintegrating agents, preservatives, lubricants, dispersing agents, suspending agents and/or emulsifying agents as exemplified above.

L. i a a- WO 95107269 PCT/AU94/00538 For parenteral administration, the compound of formula I or its salt may be prepared in sterile aqueous or oleaginous solution or suspension. Suitable non-toxic parenterally acceptable diluents or solvents include water, Ringer's solution, isotonic salt solution, 5% dextrose in water, buffered sodium or ammonium acetate solution, 1,3butanediol, ethanol, propylene glycol or polyethylene glycols in mixtures with water.

Aqueous solutions or suspensions may further comprise one or more buffering agents.

Suitable buffering agents include sodium acetate, sodium citrate, sodium borate or sodium tartrate, for example. Aqueous solution r for parenteral administration are also suitable for administration orally or by inhalation.

For rectal administration, the compound of formula I is suitably administered in the form of an enema or suppository. A suitable suppository may be prepared by mixing the active substance with a non-irritating excipient which is solid at ordinary temperatures but which will melt in the rectum. Suitable such materials are cocoa butter, waxes, fats, glycerol, gelatin and polyethylene glycols. Suitable enemas may comprise agents as exemplified above with reference to forms for topical administration.

Suitably, an inhalation spray comprising a compound of formula I will be in the form of a solution, suspension or emulsion as exemplified above. The inhalation spray composition may further comprise an inhalable propellant of low toxicity. Suitable propellants include carbon dioxide or nitrous oxide.

The dosage form of the compound of formula I will comprise from 0.01% to 99% by weight of the active substance. Usually, dosage forms according to the invention will comprise from 0.1% to about 10% by weight of the active substance.

The compound of formula I may be administered together or sequentially with one or more other active substances known or believed to have anti-viral activity.

Examples of such other active substances include AZT, acyclovir, ddC, ddA, trisodium phosphonoformate, castanospermine, rifabutin, ribaviran, bropirimine, phosphonothioate oligodeoxynucleotides, dextran sulfate, o-interferon and ampligen.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the transformation of the compound of Example ("Prodrug") into the compound of Example 20 of International Patent Application No.

PCT/AU93/00103 ("Drug") in rabbit's blood in vitro.

Figures 2 and 3 are graphs showing the transformation of Prodrug into Drug in vivo following intravenous and intramuscular (respectively) administration to a rabbit.

1.

1 BEST MODE OF CARRYING OUT THE INVENTION Methods for the preparation of compounds of formula (IB) wherein x and y are both 0, B is -CH(OH)- and R 506

R

5 1 3

R

542 and R 543 are hydrogen are described in the following Schemes 11 and 12: i I~l~e~L~L1IC^~t-lllp) lpC~L-II--YC- I _I_ _A Wfl Qf'7)'t PCTAU94OOS38 Scheme 11

A

R

512 0 I I I I H HH H

R

55 o H-N-N -R 502

R

55 iPrOH; 60-90OC;12 hr Yield 70-90%, or (il) A1 2 0 3 ether, RT.

12-24hr, Yield 30-45%

R

512

R

55 R5o1,-,N N 'N NR0 H O H R 55 o Scheme 12

R

512

R

55

R

5 1-N-C-CCH2-HaI H-N-N-R 502 I 1 1 H H 0R 550 NaVDMF orAcCN; 1 hr, RT; (ii) NaHCO 3 or tertiary amine; 2-12 hr, RT (iii) NaBH- 4 30 min; RT

R

512

R

551 R5o,1,N

NN

H OH. R 55 o Scheme 13 presents an example of a method of preparation of Examples 11 and 12, commencing with the product of Scheme 12 in which R 50 is benzyloxycarbonyl,

R

5 12 is methoxycarbonyl, R 550 and R 551 together form a 3,4-diazabicyclo[4.4.0]decane system and R 502 is tert-butoxycarbonyl: WO 95/07269 Scheme 13 PCT1AU94100538 0

-I-OH

1. CDI, dioxane, RT, 2. LiOH, L-valineIH 2

O

3. H 3 pH 2

H

2 10%Pd/C, MeOH, RT H OH C0 2 Me 1 BOP, HBT, EtN(I-Pr) 2 /DMF, RT, 12 hrs DMSO, Py~xSO 3 Et 3 N, RT, K>l' Scheme 14 presents an example of a method of preparation of compounds of formula shown in Table 4 below, in which the solubilising group Px is P(O)(OH)H or i5PO(H2 i :r WO 95/07269 PCT/AU94/00538 Scheme 14 R12 Rss P-olN N, R502 RI I Rsso

R

5 o OH Rs 5 o

H

3 PO3; DCC; Pyridine 60°C R2 R 5 5 1 R5 N NN

R

5 02 Rso O\ R 5 so P=0

H/\

OH

(Me 3 SiO) 2

NH

2. (Me 3 SiO) 2 3. MeOH 4. 1R55 N T^ N R 50 2 Rsoe O Rsso H P=0 HO

OH

2R 55 1 Ro, N N AR50 2 I I R506 O R 5 50 NaO' ONa S2 eq NaHCO 3 Compositions of the third embodiment may be prepared by means known in the art for the preparation of pharmaceutical compositions including blending, grinding, homogenising, suspending, dissolving, emulsifying, dispersing and mixing of the compound of formul' together with the selected excipient(s), carrier(s), adjuvant(s) and/or diluent(s).

In the method for the treatment of HIV viral infections in accordance with the fourth embodiment of the invention, a compound of the first embodiment will usually be administered orally or by injection. A suitable treatment may consist of the administration of a single dose or multiple doses of the compound of formula or of a composition of the third embodiment. Usually, the treatment will consist of administering from one to five doses daily of the compound of formula for a period of from one day to several years, up to the lifetime of the patient. Most usually, the treatment will consist of the administration of the compound of formula for a period of from one day to one year.

The administered dosage of the compound of formula I can vary and depends on several factors, such as the condition of the patient. Dosages will range from 0.Olmg to 200 mg per kg. Usually, the dose of the active substance will be from 0.01mg to 25 mg per kg of body weight.

Examples of dosage forms in accordance with the invention are as follows: 1. Tablet Compound of formula I 0.01 to 20 mg, generally 0.1 to

Y

Dc~ _~z WO 95/07269 PCT/AU94/00538 Starch Lactose Gelatin Magnesium stearate 10 to 20 mg 100 to 250 mg 0 to 5 mg 0 to 5 mg 2. Capsule Compound of formula I Glycerol Distilled water Saccharin Methyl Paraben Polyvinylpyrrolidone 3. Injectable solution Compound of formula I Sodium chloride Potassium chloride Calcium chloride Water for injection, q.s. to 4. Elixi Compound of formula I Sucrose Glycerol Carboxymethylcellulose Cherry flavour Water 0.01 to 20 mg, 100 to 200 mg 100 to 200 mg 0 to 2 mg 1 to 2 mg 0 to 2 mg 0.01 to 20 mg, 8.,5 mg 3 mg 4.8 mg 10 ml generally 0.1 to generally 0.1 to 0.01 to 20 mg, generally 0.1 to 100 mg 2ml 2 mg q.s. to 10 ml 1

I

Si

EXAMPLES

The following Examples describe the preparation of compounds according to the inventionand are intended to illustrate the invention. The Examples are not be construed as limiting in any way the scope of the present invention. Starting materials for the syntheses described in the following Examples are described in International Patent Application No. PCT/AU93/00103. In these Examples, melting points were taken on a hot stage apparatus and are uncorrected. Proton and phosphorus NMR spectra were recorded at 100 MHz or 300MHz on Perkin Elmer R32 or Bruker EM 300 spectrometers, respectively, in CDC1 3 unless otherwise stated. Chemical shifts for proton NMR are ppm downfield from tetramethylsilane; chemical shifts for P 31 NMR are ppm downfield from 1,2-bis(diphenylphosphino)ethane external standard. Thin layer chromotography (TLC) i WO 95/07269 PCT/AU94/00538 83 was performed on silica gel 60-F254 plates (Merck). Compounds were visualized by ultraviolet light and/or 2% aqueous potassium permanganate solution. The composition (by volume) of the TLC solvent systems were hexane/ethyl acetate 3:2, and (B) concentrated NH 4 0H/isopropanol 1:3.

Example 1 4S,5S-5,6-Dibenzyl-1,2-(cis-l,2-cyclohexane)dimethyl-4-hydroxy-7-oxo-perhydro- 1,2,6-triazepine H O Step A: 4S,5S-5-benzyl-1,2-(cis-1,2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy-7-oxoperhydro-1,2,6-triazepine: Hydrogen chloride gas was bubbled through the solution of 0.51 g (1.26 mmol) of cis-l,6-3-t-butoxycarbonyl-4-[(2S,3S)-2-hydroxy-3-amino-4phenylbutyl]-3,4-diazabicyclo[4,4.0]decane (isomer having Rf 0.16 when eluted with 8% methanol in dichloromethane) in 10 ml of 1% solution of methanol in methylene chloride for 30 min at room temperature. After purging the excess of hydrogen chloride with nitrogen gas the solvent was removed under reduced pressure to give 0.42 g (100% yield) of the hydrochloride salt of cis-1,6-4-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]- 3,4-diaza-bicyclo[4.4.0]decane as a hygroscopic, white solid. This was dissolved in 1 ml of dry DMF and 0.114 g (1.68 mmol) of imidazole and 0.21 g (1.38 mmol) of tbutyldimethylsilyl chloride were added under nitrogen. The resulting mixture was stirred overnight at room temperature and evaporated to dryness in vacuo. The residue was diluted to 20 ml with ethyl acetate, washed with saturated sodium bicarbonate and dried over anhydrous potassium carbonate and filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in 20 ml of dry dioxane.

To this, 0.204 g (1.26 mmol) of -carbonyldiimidazole was added and the resulting mixture was stirred for 24 hrs at room temperature. After evaporation of the solvent under reduced pressure the residue was diluted to 15 ml with ethyl acetate and washed with water (3x) and saturated aquecus sodium chloride solution, and then dried over I anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel; hexane/ethyl acetate 3:2) gave 0.095 g (17% yield) of the title compound, melting at 145 146 0 C; Rf 0.43; NMR 0.07, 0.09 (s,s 6H, CH 3 0.94 9H, t-butyl CH 3 1.2 2.0 L K WO 95/07269 PCTIAU94/00538 cyclohexane CH 2 CH); 2.5 2.8 (im, 414, C11 2 benzyl CH 2 3.2 3.7 (in, 4H, dimebyl CH 2 3.9 4.0 (in, 3H1, CH-4,5, NH); 7.1 7.32 (in, 5H1, aromatic).

Step B: 4S, SS-S, 6-dibenzyl-1, 2- (cis-1, 2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy-7oxo-perhydro-1, 2, 6-triazepiae: 4.5 mng (0.15 minol) of 80% dispersion of sodium hydride in mineral oil was added to a solution of 0.0665 g (0.15 mmol) of the product of StepA in 0.2 ml of dry DMF at room temperature. After stirring for 30 min at room temperature, 0.0179 ml (0.15 minol) of benzyl bromide was then added. The resulting mixture was stirred overnight, then diluted to 15 ml with ethyl acetate and washed with water, saturate i aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography gave 0.029 g (36% yk ,ld) of the title compound as a heavy syrup; Rf 0.77; NMR -0.35, -0.18 s, CH 3 0.8 9H-, t-butyl CH 3 1.2 2.2 (in, 1011, cyclohexane CH 2 CHI); 2.56 4.18 (in, 1211, benzyl CH 2 dimethyl CH 2

CH

2 CH-4,5); 6.8 7.4 (in, 1OH, aromatic).

Step C: 4S, SS-S, 6-Dibenzyl-1 (cis-1, 2-cyclohexane)dimethyl-4-hydroxy-7-oxo-perhydro- 1,2,6-triazepine: A mixture of 29 mng (0.0543 minol) of the product of Step B and 0.0426 g inmol) of tetrabutylammonium fluoride hydrate in 1 ml of anhydrous acetonitrile was stirred at 45±5'C for 3 hrs and evaporated to dryness. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate 3:2) to give 0.019 g (86% yield) of the title compound as a colourle!;s foam; Rf 0.26; NMR 1.2 2.1 (in, 1811, cyclohexane C11 2 CH, OH, 3.5 x 1120); 2.6 4. 0 (in, 111-1, benzyl C11 2 dimethyl '1 2

CH

2 C11-5); 4.83 (in, 111, CH-4); 7.0 7.4 (in, 10H1, aromatic).

Example 2 45,5S-1, 5,6uTribenzy1-2-isopropy1-4-hydroxy-7-oxo-perhydro-, 2, 6-triaze~pine 0

N)KN

H

Step A: 4S, SS-S-benzyl-2-isopropyl-4-t-butyldimet hylsily. oxy- 7- oxo-perhydro-1 2,6triazepine: When t-butyl 3-iiopropyl-3-[(2S,3S)-3-amino-2-hydroxy-4,.phenylbutyl]carbazate was substituted for cis- 1, 6-3 -t-butoxycarbonyl-4- ,3S)-2-hydroxy-3-amino- 4.-phenylbutyl]-3 ,4-diazabicyclo[4.4.0]decane in Step A of Example 1. the identical process afforded the title compound in 20% overall yield; melting point 131 132 0

C

(hexane); Rf 0.18; NMR 0.10, 0.11 s, 611, silyl CE 3 0.95 911, t-butyl reacting a compound of formula (TIC) or (LID) 4 WO 95/07269 PCT/AU94100538 GCl 3 1. 1 1. 35 (in, 6H, isopropyl CH 3 2.8 3.2 (mn, 511, CH 2 CH-5, benzyl GCl 2 3.45 (mn, 111, isopropyl CH); 4.18 (mn, 1H1, CH-4); 4.41 (mi, 1H1 N11-6.; 5.63 1H1, NH- 7.1 7.4 (in, 5H, aromatic).

Step B: 4S, SS-1, 5, 6-tribenzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-1, 2,6triazepine: A mixture of 0.07 g (0.185 iniol) of the product of Step A and 0.012 g (0.371 minol) of sodium hydride in 0.2 ml of dry DMF was stirred for 30 min at roomn temperature, then 0.0441 nil (0.37 1 rnmol) of benzyl bromide was added. The resulting mixture was stirred overnight and worked up as described in Step B of Example 1. The purification of the crude product by column chromatography (silica gel, hexane/ethyl acetate 3:2) gave 0.031 g (30% yield) of the title compound as a colourless syrup; Rf (A) 0.74, NMR -0.28, -0.22 611, silyl C11 3 0.8 911, t-butyl C11 3 1.0 1.35 (in, 6H, isopropyl GCl 3 2.35 3.3 (nm, 511, C.H 2 3 CH-5, 5-benzyl CM1 2 3.45 3.82 (in, 211, isopropyl CH1, CH-4); 4.0 -5.38 4H, 1,6-benzyl C11 2 6.6 7.8 (mn, Also, the fractions with Rf =0.63 were combined and evaporated to dryness under rediice d pressure to give 0.061 g (70% yield) of 4S,5S-5,6-dibenzyl-2-isopropyl-4-t-butyldiinethiylilyloxy-7-oxo-perhydro-1 ,2,6-triazepine as a colourless solid; NMR 0.11 (d, 6H, silyl C11 3 0.93 911, t-butyl GCl 3 1.24 (mn, 611, isopropyl CH 3 2.4 3.4 (in, 5H1, CH 2 CH-5, 5-benzyl C11 2 3.75 (in, 111, isopropyl CH); 4.0 4.7 (in, 311, CH-4, 6-benzyl CII 2 5.05 (in, 111, NH); 7.0 7.7 (in, 1511, aromatic).

Step 4S, 5S-1, 5, 6-Tribenzyl-2-isopropyl-4-hydroxy- 7- oxo-perhydro-] 6-triazepine: When the title compound of Step B was substituted for 4S,5S-5,6-dibenzyl-1 ,2-(cis-1 ,2cyclohexane)-dimethyl-4-t-butyldimnethylsilyloxy-7-oxo-perhydro- 1,2, 6-triazepine in Step C of Example 1, the identical process afforded the title -ompound with 98% yield as a foam; P1 =0.68; NMR (CDCl 3 1.07, 1.19 d, 611, isopropyl C11 3 1.58 111, 0OH); 2.6 3.15 (in, 511, C11 2 CH-5, 5-benzyl CH 2 3.2 5.3 (in, 611, isopropyl CH, C11-4, 1,6-benzyl C11 2 6.8 7.6 (in, 1511, aromatic).

Example 3 4S,SS-5,6-dibenzyl-2-isopropyl-4-hydroxy-7-oxo-perhydro-1,2, 6-triazepine 0 N N"

/N

WO 95/07269 PCT/A1J94/00538 86 When 4S ,5S-5 ,6-dibenzyl-2-isopropyl-4-t-butyldimnethylsilyloxy-7-oxo-perhydro-1 ,2 ,6triazepine was substituted for 4S ,5S-1 ,5 ,6-tribenzyl-2-isopropyl-4-t-butyldimnethylsilyloxy- 7-oxo-perhydro-1 ,2,6-triazepine in Step C of Example 2 the identical process afforded the title compound in 88 yield; melting point =191 193'C; Rf 0. 17; NMR (DMSO-d 6 80'Q) 2.5 3.0 (in, 411, CH 2 5-benzyl CH 2 3.28 (in, 1H1, CH-5); 3.6 (in, 1H, CH-4); 3.8 (in, 1H, isopropyl CH); 4.2 4.7 (in, 311, 6-benzyl CH 2 0OH); 5.41 (in, 111, NH); 7.0 7.4 (in, 1011, aromatic).

Example 4 t-Butyi 3-isopropyl-3-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl carbazate 0 0 ANH 2 N NH 0f OP(O)(OH)H H, NN To a mixture of 0.4 g (0.67 mmol) of t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3- (N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyI carbazate and 0.12 g (1.47 nrol) of anhydrous phosphorous acid in 1.5 nil of anhydrous pyridine was added 0.28 g (1.4 9~ minol) of dicyclohexylcarbodiimnike at room temperature under nitrogen, with stirring.

After stirring for 2 hours at 60'C, the solvent was evaporated under reduced pressure and the resi*due was treated with 28 ml of 0.1 ml aqueous sodium bicarbonate and vigorously stirred for 1 hour at room temperature. The precipitate was filtered off and washed with water and the filtrate was acidified to pH 1.5 with concentrated hydrochloric acid. Thle 'I 20 product was taken up by extraction with ethyl acetate (3 x 50 ml), and the organic phase was dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.42 g yield) of the title product as a colourless solid; Rf 0.62; H1NMR (CDC1 3 1.08 (in, 611, isopropyl CH 3 1.41 911, t-butyl Cl! 3 2.7 4.8 (in, 1411, asn CH 2 butyl CH 2 4; CH-2,3; isopropyl CH; P-OH x 21120); 5.12 (in, III, asn CH); 5.89 (s, 0.5 H, PH); 6.2 8.5 (in, 15.5 H, aromatic, amide NH, 0.5 PH); 9.02 (in, 1H1, asn NH); p 3 1 NMR (CDCl 3 14.99 (JP- 636 Hz).

A0 wIat in te lI e reauy aht of the foreoing art in the light of the foregoing.

WO 95/07269 p- PCT/AU9400538 87 Example t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl carbazate A suspension of 0.4 g (0.6 mmol) of the product of Example 4 in 2 ml of hexamethyldisilazane was stirred for 45 min at 120 5 0 C. At this point the reaction mixture became homogeneous. To this 0.3 ml of bis(trimethylsilyl)peroxide (Cookson, P.G et al., J. Organometal. Chem., 1975, 99, C31) was added and stirring was continued for 1 hour at the above temperature. The reaction mixture was coo)hd to room temperature, then evaporated to dryness in vacuo. The residue was dissolved in 20 ml of methanol, evaporated to dryness under reduced pressure and redissolved in 12 ml of 0.1 ml aqueous sodium bicarbonate. The resulting mixture was acidified to pH-1.5 with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate (3 x 50 ml). The combined organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.39 g (96% yield) of the title compound as a colourless solid; Rf(B) 0.07; H 1 NMR (CDC13): 1.2 6H, isopropyl CH3); 1.4 (s, 9H, t-butyl CH 3 2.8 4.2 8H, asn CH 2 butyl CH 2 CH-3, isopropyl CH); 4.2 6.4 5H, asn CH, butyl CH-2, NH, POH); 6.5 8.4 14H, aromatic, NH); 8.78 2H, NH); P 3 1 NMR (CDC1 3 9.6 PCT/A1194/00538 WO 95/07269 88 Example 6 cis-1,6-3-t-Butoxycarbonyl'4-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyll- 3 ,4-diaza-bicyclo[4.4.O]decane When cis-1, ,6-3-t-butoxycarbonyl-4-[(2S, 3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl]-3 ,4-diaza-bicyclo[4 0]decane is substituted for t-butyl 3-isopropyl-3-I(2S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phelylbutylcarbazate in Example 4, the identical process affords the title compound in 89% yield, as a colourless solid; Rf(B) 0.64; H 1 NMR (CDCl 3 1.1 1.8 (in, 19H, t-butyl CH 3 l0 decane CH 2 -7,8,9,10, CH-1,6); 2.12 (in, 1H, butyl CH-3); 2.6 5.1 (mn, 19H, asn CH 2 CH, butyl CH 2 CH-2, decane CH 2 POH x 2.5 H 2 6.1 8.4 (in, 15H, amide NH, PH, aromatic); 9.08 (in, 1H, asn NH); p 3 1NMR (CDCl 3 16.43 (UPH 700 Hz).

Example 7 cis-1,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl]-3 ,4-diaza-bicyclo[4.4.O]decane 0 0 NH 2 N -N NH ONH 0 0 OP(O)(OH) 2 When the product of Example 6 is substituted for t-butyl 3-isopropyl-3-I(2S, 3S)-Zphosphitooxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutylI carbazate in Example the identical process affords the title compound in 83% yield, as a colourless solid; Rf(B) 0.12; HINMR (CDCl 3 1.1 2.4 (mn, 20H1, t-butyl CH 3 decane CH 2 -7,8,9,10, CH-1,6, butyl CH-3); 2,7 3.9 (in, 9H1, asn CH 2 butyl CH 2 CH-2, decane CH 2 I a i. avuL g up sucr as ui, Br, OH, OS(O) 2 R and the like, where R is C 1

-C

6 alkyl, for example methyl, C 6

-C

1 o azyl, for example phenyl or 4 -methylphenyl, or C7-Ci o Dsrsllrr-r3lrs I~v-~r r Isa WO 95/07269 PCTIAU94/00538 5.1 1H, asn CH); 6.1 8.3 21H, amide NH, aromatic, POH x 2.5 H20); 9.05.

1H, asn NH); P 3 1 NMR (CDC1 3 10.5 Other representative compounds in accordance with the invention are described in Tables 1 to 5. Other compounds in accordance with the invention are substances in which a hydroxyl, amino or mercapto group is any of the compounds described in the Examples and disclosures of the following, has been derivatised with a solubilising group Px as defined herein: US Patent Nos. 5,116,835, 5,126,326; 5,132,400; 5,145,951; 5,198,426; 5,212,157; 5,215,968; 5,221,667; 5,250563; 5,268,361; 5,294,720; and 5,296,604; International Patent Application Nos. 90/09191; 91/08221; 91/10442; 92/15319 and 92/21696; European Patent Application Nos. 0574135; 0528242; 0519433 and 0432595 and Australian Patent Application Nos. 35700/89; 42308/89; 45665/89; 46115/89; 53716/90; 63221/90; 66334/90; 71319/91; 71320/91; 71323/91; 77326/91; 81910/91; 82054/91; 88900/91; 82313/91; 83234/91; 83206/91; 85877/91; 87309/91; 87409/91; 87594/91; 88900/91; 89941/91; 90531/91; 90851/91; 90925/91; 91223/91; 91251/91; 91332/91; 91790/92; 10812/92; 18355/92; 19373/92; 21944/92; 22889/92; 24129/92; 24690/92; 26424/92; 31628/93; 35165/93; 35621/93; 37160/93; 38808/93; 41230/93; 41659/93; 44930/93 and 49072/93, the disclosures of each of which are incorporated herein by reference.

Example 8 In Vivo Removal of Phosphono Group Solutions: The product of Example 5 was converted quantitatively into the corresponding disodium salt by treatment of the free acid with 2 equiv. of 0.2 M sodium bicarbonate and lyophilization of the resulting solution. The stock solutions of the disodium salt of the product of Example 5, for blood and animal experiments, were prepared in sterile water.

Analyses: Reverse phase analyses (HPLC) were performed on Waters ternary gradient liquid chromatograph equipped with 996 diode array detector set at 238 nm. Separations were achieved on Alltima RP-18 (250 x 4.6 mm, 5 I particles), with the flow rate of 1 ml/min. The isocratic mobile phase composition used for analyses consisted of 40% of 0.1% aqueous trifluoroacetic acid (TFA) and 60% of acetonitrile containing 0.1% TFA and 10% water. The retention time of the product of Example 5 (referred to below as "Prodrug") was in the range of 3.6 3.9 minutes and the retention time of t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutyl -carbazate (referred to below as "Drug) was about 6.2 minutes. Detector response was linear from 0.5 to 120 ltM for Prodrug and 0.05 to 50 .M for Drug.

1 For oral administration, the pharmaceutical composition may be in the form ot tablets, lozenges, pills, troches, capsules, elixirs, powders, including lyophilised powders, WO 95/07269 PCT/AU94/00538 Standards and Sample Processing: The standards were prepared by serial dilution of.

Prodrug or Drug in rabbit blood collected into heparinised tubes. Blood samples were transferred into vials containing 150 units of heparin. and stored on ice until processed.

The blood samples were then separated by centrifuging at 6000 rpm for 10 min. The plasma samples were frozen and stored at -20 0 C until they were analysed.

Plasma preparation for HPLC analysis: An equal volume (100 pL) of thawed plasma and acetonitrile was stirred with a vortex mixer and allowed to stand at room temperature for 5 minutes, then centrifuged at 14000 rpm for 10 minutes. Samples of the supernantant RL) were injected into the chromatograph.

to Transformation of Prodrug into Drug by Blood was established by measurement of prodrug and drug concentrations in plasma following the prodrug incubation in whole rabbit's blood (100 tM) at 36 0 C for 19 hours. Fig. 1 shows the concentrations of prodrug and drug under these conditions over 19 hours.

Transformation of Prodrug into Drug after intravenous (IV) administration of prodrug (9.2 mg/kg) to rabbit was established by measurement of prodrug/drug concentrations in plasma over 120 min. The formulated product, containing 30 mg/ml of prodrug, was well tolerated by the rabbit. The plasma profiles of prodrug and drug disappearance are shown in Fig. 2.

Transformation of Prodrug into Drug after Intramuscular (IM) administration of prodrug (7.9 mg/kg) to rabbit was established by measurement of drug concentrations in plasma over 330 min. The formulated product, containing 30 mg/ml of prodrug was well tolerated by the rabbit. The time dependence of the plasma concentration of the drug are shown in Fig. 3.

When prodrug was administered to a dog orally at a dose of 20mg/kg, the blood plasma concentration of drug was found to be 0.044, 0.141, 0.189, 0.172, 0.164, 0.132, 0.089 and 0.060 respectively, after 5, 15, 30, 47, 63, 93, 124 and 155 minutes. When prodrug was administered to a second dog orally at a dose of 10mg/kg, the blood plasma concentration of drug was found to be 0.137, 0.371, 0.297, 0.242, 0.176, 0.11, 0,071, and 0.050 IM, respectively, after 5, 15, 30, 45, 60, 94, 123 and 154 minutes.

V i.1 i TABLE 1 Compounds of formula

I

0 Compound No.

9.

11.

BzOC(O)- 0C~ O(>H0

R

506 Et me

H

EtO(CH 2 2

A

-Gil 2 COOMe COOMe

-CH

2

CF

2

R

5 01 A At "N BW -R 502 I I F-506R 5 5 0 B A

CH

2 0H I

-CH

2

-CH-

CH-,OH

I -Gil 2 CH(OH)- -Gil 2

R

550 R1551 -(Gil 2 4

R

502 t-BuOC(O)-

-SO

2 Me t-BuOC(O)- 0 t-BuOC(O)- -Gil(OAc)- -CF 2

CH

2 TABLEI1(CONT.) Compound: No.

14.

16.

R

501 Ac MeS(O) MeS(O) 2

R

506 A 1R550 R 551 R15020 OH OH Ph -CH 2

CH

2 II CO 2 Me Pr H -UC-Gi 2 Iz

GO

2 Me 0 I I

-GH

2

CHF-

H

-GHFCH

2 COOMe

H-

-S(O)

2 Ph BzG(O)- 00 aQ 0 cn

C,

0c -CH(Me)- -GH(OTHP)-

OH

-C(e)-C G(O)NMe 2 BzOC(O)- Bz Bz

OS(O)

2 Me

OS(O)

2 Me

-GH-

-GH(OH)-

0 -Gil- 0 0 -S(O)Me -S(O)Me 01

C

00r.~jUtC IF TABLE 1 (CONT.)

R

550

R

551

R

502 Compound No.

R

501 BZOC(O)NH -r 0

R

506

N

-CH-

NHC(0)OBut 21.

0

OR

-CH-

-CH(OH)-

-CH(Me)i-Pr S(0) 2

\CH

3 i-Pr

-CH

2

)CCI

2 -CC1 2

CH

2

NH

2 HOJf 0

H

2

NCH

2

CH

2

-CH

2

CHCI-

C(O)N11 2

C(O)NH

2

-(CH

2 3

C(O)-

H

2

NCH

2

CH

2

-CH

2 CHC1- 0 Me 2

N

-CII

2

CF

2

CH

2 OAc

-CI

0

-CF

2

CI

2 11 -CF2H2-CH 2

CNH

2 0 n-Bu N(Me)Ph

-CH

2

-CH-

OR

CF'

3 0 F v TABLE 1 (CONT.) Compound No.

26.

27.

28.

29.

31.

R

501 Me H0 0

-NH

[CH

2

H

BzC(O)

A

0

OP(O)(O)CH

3 )2

-CH

Et

-CH-

C(O)NJI

2 Ph

-CH-

-CHI-

B

H H0

OCH

3

CI-

OCH

3

OH

-C-

IOE

CH

2

OH

R1550 R 551

NH

-CH

2

CH

2

C(O)-

-CH-

s Et Ph C(0)NH 2

-CHI-

-S(

R

502 0 Me 0) 2 NMe 2 3(O) 2 Ph Et

HO

0

A-L

0 00 aCH 2 1nt CH 2 Ac MeOCH 2

CH

2 Ph N t-BuOC(O) 4 TABLE 1 (CONT.) Compound No.

32.

R

501 PhOC(O) R1506

R

550

R

551

R

502

IIOCH

2

CH

2 0 N o0

NCCH

2

CH

2

II

2

NC(O)

H

2

NC(Q)

IIOC(O)C11 2 -CH- GF 2 -CL-CHF

CL'

3

CH-

Bz IC

CH

2 0H'

-C-

CH

2 0H'

CO

2 Me

-CH(OH)-

-CF

2

-CLI-

CH

3

-CF-CL'-

CL'

3

-CL'-

-CH'-

COOH

0 0 -a n-Pr n-Bu 0 C 0 .N-f

IIOC(O)CH

2 0 n-Pr MeOC(O) MeOC(O) MeOC(0)CH 2 MeOC(O)CH 2 0 NMe 2 -CH(0H)- MeOC(O)- MeOC(O)- Bz

-CI

0 0 yNMC 2 -(Cl! 2 3 TABLEI1(CONT.) Compound No.

R

506 U2 *1 Me 2

NS(O)

2 Me 2

NS(O.)

N

t-BuOC(O)- Ph OMe Ac

H

A

-CH-

N)

-CH-

Bz

-CH-

Bz

-CHI-

OH

CO

2 NMe 2

OH

C(O)SCH

3

-CH-

VN

-CC1 2

.CH-

lI 3

R

550

R

551 H S(O)NMe 2 S(O)NMe 2

R

502

NH

2

-S(O)

2 0C11 3 0 N0 2 -CH2 H t-BuOC(O)- 0 BzOC(O)NH-

CONH,

C(O)NH

2

-CH(OH)-

Me -CH(Et)- /M NHl-C(O)OBz 0 0 -S-N 0 0

-CH

2

CD

0 0

S

0)

L

TABLE 1(CONT.)

B

Compound No.

R

501 CON1H6 CONIIa

CONH

0 CONIa

R

5 06

H

Hl

R

550

R

551 Bz

CI-

Bz

-CH-

Bz

CI-

Bz

CI-

Bz

-CHI-

-CH(OH)-

R

502

-CH

2

-CH

2 0 6- 0 11 -S-CH2 -0 0

-CH(OH)-

-CLI(OH)-

-CH

2 -S(0) 2 OBz

-CH

2 -S(O)OBut

CONH,

48. 0Y~f fc 3

I~YNH

-CII(OH)- -CH 2

-S(O)

2

NH

2 N< NHC(O)O~z 0 0 BzOC(0)NH) 0 Me -CLI(Et)- O

-O/

.1 1 TABLE 1(CONT.) Compound No.

R1501 0 t-BuOC(O)N

R

506 N- CHr

R

550 t-BuOC(Q)t-BuOC(O)- Bz Bz

CONH

2 Bz Bz

-GH-

-Cl-I -Cli-

-CH(OH)-

-Cil(OH)- -Gil 2 O cf -Gil 2 n-Pr

NH

0 rN

H

n-Pr

H

L551 R0 H t-BuOC(O)- H t-BuOC(O)-

-CH(OH)-

-CR

2 2S 0 0 -CH2- C>-CH 01-CHTt-BuOC(O)- NHC(O)O~z 0 0 -NH N~ Compound No.

R

501 0 orXN

NH

0

NN

t-BuOC(O)t-BuOC(O)- TABLE1I(CONT.) R1506 A B A Bz Bz H I-CH(QH)-

I

Bz Bz H I -CII(OiH)- I -CII- -CHi-Bu -C Cl 2 C(O) NC)

OH

I -CH(i-Pr)- C(Si)Nme 2 Bz H I -CII(Oll)- -Cl! 2

-CII-

Bz H1 I -CH(OH)- -Cl! 2

-CII-

K

R

550 R1551 R 502 0 00 0' H P H 1 H H NH fifQ 0 H 0 11 N C~f 00 Ci it TABLE 1 (CONT.) Compund No.

62.

R

506

R

550

R

551

R

502 Bz

-CH-

63. 1 0 Ph Ph

OH

C(O)OEt

OH

-CH2- -Gil 2 BzOC(O)- H 0\ 0 0 0 Bz

CI-

H N 0 Bz

-I-

-CH

2 TABLEI1(CONT.)

B

Compound No,.

68.

IF

K

0 0'~

R

501 0 0 Q~CH~C~0 0 Nr 0I NH 0 0 0 rBuO0C(O)N

"ICOOH

R

506

R

550 R 551 Bz

CI-

Bz

-II

Bz Bz

-I-

Bz

CI-

OH

-C-

OH

-C-Uh -Gil 2 0 H y 0 H GJ.CH,-NH 0- 0 0 0 0 H NH NNHNH 0 H 0"Q' NH' 0 H rM~C(0)NI

A

cCOOfl

R

502 -Gil 2 ~1

I

-Gil 2 -Gil 2 TABLEI1(CONT.) B) Compound No.

73.

74.

R

501 0

R

5 06 R5 50

R

502

HA

(I

Bz Bz Bz Il-- <7N 0 0 0 76. BZOC(O)N14)

OH

C(O)ORt

OH

C(O)OEt

OH

C(O)OEt

OH

C(O)OEt -Ct' 2 H'J NH N H N' 0 0 0 HI

BZOC(O)NH)

H 0 -OC(0)NHI) -Cl! 2 0

OC(O)NH

z Bz

-CH'-

-Ct' 2 IICompound No.

78.

TABLE I(CONT.) B R 501

R

5 06 R 550

R

551

R

502 0 0& 0

N

SN

Bz

CI-

-U-

Bz

-CI-

-CH(OH)- -Gil 2 0 -Gil 2

N

0

IINH

0 0 0K2 l 0 0 11 MeOCNH_ 0

M

2 NS(0) 2

NH-

OH

C

OH

C(0)OEt

-H-

-CH

2 0 0 H 11 M eOCNH l Bz

CII-

-CH

2 0 Me 2 NS(0) 2 NH

I

Compound No.

83.

84.

86.

87.

TABLEI1(CONT.)

B

R

501 0 O\}4S( Nfl 0

CNH

CONII,

0

R

5 06

HI

H

R

550 Bz

-I-

-CH-

Bz

-CH-

Bz Bz

-I-

-CHI-

U(O)NH

2 C(O)ORt

OH

C(O)ORt

CH

2 0H

-I-

CH

2 0H

-I-

-CH(OH)-

-CH

2

-CU

2 Bz i-Pr i-Pr i-Pr Bz

R

551

R

502 0 0 ONS() 2

NH

H t-BuOC(O)- II t-BuOC(O)-

-CH

2 -Cl! 2

-CH

2 H t-BuOC(O)- 0~1 H t-BuOC(O)- 88. ONk TABLE 1 (CONT.)

B

Compound No.

R

501

R

5 06

R

550

R

551

R

502

CONH

a Nlmy 0

CONII,

0 0 (ro )0

-CH-

C(O)NI1 2 0 -Gil 2 H t-BuOC(O)- Bz CH 2 0H

-I-

-Gil 2 H t-BuOC(0)- Bz -i-

CH

2 0H

-CH(OH)-

-Cl! 2

O

H t-BuOC(0)-

CA

COnE

-CH-

-CH

2

CF

3 H t-BuOC(O)-

-CHI-

(0)OBz 0

-CH

2

CF

3 H t-BuOC(O)- TABLE 1 (CONT.) Compound No.

94.

96.

97.

C1 '-o

R

501 0 0 0

CONIL

0 a yfj f)LN 0 0r)N I

R

506 A B Bz-C H I I -CH-

C(OL

Bz H I -CH(G

R

550

R

551

R

502 0 0 -4 0\ \0 )OHl

H)-

t-BuOC(O)-

-CL'

2 Corn

P

Bz I-CII(OH)- -CL' 2 -CH-

N"

C,,

U

02

H

0 0~ Bz Bz

ICH

-CH(OH)-

-CL'

2

-CH

2 0R0

N

H

0 t-BuOC(O)t-BuOC(O)- 11

I

TABLE 1 (CONT.) Compound No.

99.

100.

101.

102.

*1

I

0

R

501 0

CONH,

0

CON

0 0 0

R

506

H

A

Bz Bz Bz Bz ICu

B

-CH-

-CH--

-CH-

C(o)O'Pt

R

550

R

551 Comp

N(

-Gil 2

-C!

2 H t-BuOC(Q)- H t-BuOC(O)- H t-.BuOC(O)- H t-BuOC(O)-

R

502 -CH2- H-NO-CH2 -CH2- H-NO-04,

CA

103.

Bz

-CI

-CH(OH)- -Cl! 2 0 11 'i~e 2 F, C~4 TABLEI1(CONT.) Compound No.

104.

105.

106.

107.

R

501 CON116 0

NN

0

H

2

N

0 0 Bz Bz

-CH-

CH

2

-CH-

OS(0) 2 Me Bz

CI-

B

1I10

R

550

R

551

R

502 HI t-BuOC(O)- Compol No.

26.

-Gil 2 H t-BuOC(Q)-

-CH-CHI-

O)S(0))Me 0 BzOC(0)-

N

H

,w 108.

PhCO -CH(OH)- -CH(OH)- -CH(OH)me N{i -C(0)SMe

IL

TABLEI1(CONT.) Compound

R

501 No.

MeO 109.-

S

R

5 06 11

A

OH

B

-CH(OH)-

R

550

R

551

R

502

OH

-C-CH27 0

CA

t3 ji

C

t

C

COM

3

CA

Compi TAB.LE 2 Compounds of formula W(AhrB(A*)IlV (Az (A*)m -Cu 2 Compound No 110.

112.

113.

-CII-

-N-

0 "N-N I OBut 0 it c" -Cl' 2 0 tJ

BZC(O)

0 'h iPr Bz

-CI

2 7-CL

-CH(OII)-

Bz -H CH2- -N-OC(O)Bz iPr -N=N-Ph 0 11

-S-

Ph -cH 2 -CHrCH2- TABLE 2 (CONT.) Compound

W

No (A)n 1 Comf Ni 114.

115.

116.

HO-N=C-

6U 3 0 N

NHA

PhC(O)NH-

-CH-

6112

OCH-

3 Bz

-C-

6H3

-CH(NH

2

-CH-

Cl

-NH-S(O)

2

\CIT

3

(CH

2 2 0H -N4- Me-N Me -CT-Gi 2 6(0)NH 2

-CH-CH

2 6H 2 C(O)OMe 117.

118.

0 N H 0, 0 MeO II IP-0 me, -CH9-CH 2 -C(0)-CH 2

-CH

2

-CH

2

-CH-CH

2 C(O)OBz 0 Et OMe me

N-N

Ph Ph -C1H 2

-CH-

6(0)OBz

-NH-

(P

TABLE 2 (CONT.) Compound (A)n 1 (A*)m Comy

N,

H

3 C \S(O)X-NHC(O)NH- Bz

I'

-CH-

(YHOH)

CH

2 0H Et

N

A

120.

COOMe

CH-

N'OH

121.

()Ny NH

NHN,

0 COOMe

-CH-

NNH2

A.

-Cl' 2 122.

-CN -(CH 2 2 0(CH 2 2 0- 0 0

-CH

2

CH

2

C=N

Me' bOH -N=N-Bu 0 123.

MeOC(O)- -CH 2 CH2- -O(CH 2 2 0(CH 2 2 p.- Compound No 124.

w

-CN

TABLE 2 (CONT.) (A)n 1

B

Me 0 (A*)m

-CH

2

CH

2

V

~C=N

Me' OHl 125.

CA

126.

127.

me Mew. A..

Me N N NHY

NHN'

0 EtN'~ Bz -0- COOMe OS(0) 2 Me OS(0) 2 Me

CI-

-(CH

2 '.CH(Me)- N'Ph N'

O

C1 WONl-

-CH=CH-

-OS(0) 2

CII

2 Ph 0 N-N ',OBut I ,-'S(O)Me I ,-'S(O)Me 00 Corn!

N

rJ2 EtN'.

AZ

N NH2

-CHI=CH-

o '.0 0

N

a' '.0 TABLE 2 (CONT.) Compound No 129.

(A)n Comj

N

6

-CH-

N'OC(O)Ph If

'-CN

-CHI-

COOH

'I

~=gw '-3 0 130-.

131.

0

H

2 N) N' lyOH 0 0 MeoJ N' yOMe 0 0 C(O)NH 2 YN NH

NH-.

NHPh

-CHI-

COOH

Bz

ICH

N'OC(O)CH3 o NMe 2

-CH-

0 >-OMe

H

N' NC(O)OBut

ND

132.

-CH-

C()NH-

2 N'OBz 11 I-Cl SUBSTITUTE SHEET (Rule 26) WO 95/07269 PCTIAU94/00538 u 0

I

z

I

u

Z

0

N

wL Io

N

Z=Q

0/ 0=U e

Z

0 1 U-u

I

0

Q-Q

0 z

C)

o0 SUBSTITUTE SHEET (RULE 26)

A

TABLE 2 (CONT.) Compound No 137.

138.

139.

140.

w 0

C()H

N. NH NW2

CO

2 Me Bz

-CII-

Bz

-CHI-

-CII

2

CII

2

B

-CII(OI)-

-CH(OH)-

0

HI

(A*)m

-CH

2 Cl C=c-CI4 2 Cl

-C"

2

-CII

2

CH

2

V

0 N-N jOBut 0 N-N R OBut Pri/ Me Ph\~ me/

V

SUBSTIUTE SHEET (Rule 26) WO 95/07269 PCTAU~94I0S38 Table 3 Examples of Other Compounds of Formula (I) 141.

142.

O H )N N~yOBut 'N 0 143.

OMe

S(O)

2 NMe 2 145.

BzOC(O: SUBSTITUTE SHEET (RULE 26) 0 SUBSTUTE SHEET (Rule 26) WO 95/07269 PCT/AU94/00538 Table 3 (cont.) 146.

147.

IyOBut 148.

0 N~"Me 149.

150.

SUBSTUTE SHEET (Rule 26) 4 WO 95/07269 PCT/AU94100538 Table 3 (cont.) 151.

0 0 O-KBz 152.

BzO 153.

154.

ButO N 0 155.

BzO

NH

0 7

A

PCT/A1194100538 WO 95107269 Table 3 (cont.) 156.

MeOOC 157.

159.

ci NH NH]Bz 160.

0 Bz OP(O)(OM-H BzN fNH NH

NP

0H(OH)P(O)O Bz 0 0 Bz OP(OXOI-D2 0 EtOl N NH NH)- NH HINf 0 (HO) 2 P(O)O Bz 0 0 SUBSTUTE SHEET (Rule 2b) IWO 95/07269 PCTIAU94/00538 Table 3 (cont.) 162.

163.

165.

N

0 166.

BocNH

I

p 0 SUBSfTtYM SHEET (Rule 26) PCT/A1194/00538 WO 95/07269 Table 3 (cont.) 167.

BocNH 169.

-NHBz H 0 SUBsniTUTE SHEET( Rule 26) PCT1AU94/00538 *NHBz WO 95/07269 171.

123 Table 3 (cont.) 172.

NH0 Bz 0 NH)rH0 e NHH NH N HOP(OeM 0

OPOO)

2 o 174.

0 Bz 0 ZNH-T kHB H(

OH

H(HO)P(O)O Bz 175.

SUJBSTrrUh EE (Rule 26)

-A

WO 95/07269 PCT/AU94I00538 Table 3 (cont.) 176.

Me

CH

3 0CH 2

CH

2

OCH

2

OCH

2

CH

2

-N

177.

OMe 0 HO J NH

NH

0 Bz 178.

'P(O)(OHi) 2 0 0 SUBSflUME SHEET (Rule 26) WO 95/07269 PCT/AU94/00538 Table 3 (cont.) 179.

NHk 181.

b 2> TABLE 4

R

1 2 H R551 Compounds of formula8 IHIH'I" R0 R-0 OPx R 5 Comi No ii! Compound No.

182.

183.

R

501 z z

R

506

R

550 i-Pr

R

551

H

P(O)(OH)

2

P(S)(OH)

2

P(O)(OH)

2

P(O)(OH)

2

R

502 Boc Boc Boc 8 184.

185.

186.

187.

188.

189.

Bz Bz Bz Bz Bz Bz Boc I1P(Q)(OH) Bp(o)(OH) 0 0 '1 01)--H P(O)(OH)2 i-Pr Bz

C

6 Hj 1 -C(O)But Boc

-(CH

2 4 Boc

I

Compound No.

190.

191.

192.

193.

194.

195.

Z-Val Z-Val Z-Val Z-Val Z-Val R1506

H

TABLE 4 (cont.)

R

12

PX

O 0 Bz HI 11 P P OH OH 0z H Bz O- H Bz K)

H

O 0 0 Bz OIJ1H Bz

)KIO"H

0 (p-F)Bz

OH

RS50 i-Pr Bz

CH

2

C

6

H

11 (p-F)Bz (p-F)Bz (p-F)Bz (p-F,)Bz (p-F)Bz

H

R

502 Z-Val Z-.Val Boc Boc-Val Val It 196. -Val MC-Gly-Val 197. Z-Val Boc TABLE 4 (cont.) Compound R501 R 506

R

12 Pk R 550

R

551 1R502 No. Co k'0 0 198. Z-Val H (p-F)Bz OH (p-F)Bz H H 0 199. ZVlH(p-F)Bz (Ip-F)Bz H

N

N 0 0 CONH, 200. Z-Val H (p-F)Bz N 2 (p-F)Bz H Ph 0 201. Z-Val H Bz O P(OX(OH) 2

CH

2

C

6

H

11 H TMC-Val 0 0.Z-Val H Bz NH 2 (p-F)Bz H Z-Val

FD

(CH

2 )4iNH 2 t 0 203. Z-Val H Bz NH 2 (p-CN)Bz H Z-Val

(CH

2 4

NH

2 TABLE 4 (cont.) Compound No.

R1506

R

550

R

551 R1502 Corn 13 204.

205.

206.

207.

208.

209.

Z-Val Z-Val Z-Val Z-Val Z-Val Z-Val

NH

2

H

NH

2

H

0 NH NH2 H 0 NH NHj H n-Bu n-Bu 0

H

0

N-N

0

N

O N

H

o H 0 KmO O N

N,

H

n-Bu

P(O)(OH)

2 (p-F)Bz (p-F)Bz 0 N P(0)(OH)2 (p-F)Bz Js

I.

I

TABLE 4 (cont.) I- N Compound No.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

R

501 Z-VaI Z-Val Z-Asn Z-Asn Z-Asn Z-Ile Z-Glu QC-Val QC-Val QC-Val QC-Asn

R

506 0 (p-F)Bz N. P(O)(OH)2

R

550 (p-F)Bz (p-F)B1z (p-F)Bz (p-F)Bz Bz (p-F)Bz Bz Bz Bz 13z Bz P(O)(Oll) 2

P(O)(OH)

2

P(O)(OH)

2

P(Q)(OH)

2

P(S)(OH)

2

R

551

H

R

502 0

H

MC-Gly-Val Boc Z-Val Boc Z-Ile Con

N

CA1 0 0

O"H

P(O)J(OH)

2

P(O)(OH)

2

HP(O)(OH)

(p-F)Bz i-Pr Bz i-Pr 8 Z-Glu Boc Boc QC-Val Boc

V

N

CompoundR No.

R

506 TABLE 4 (cont.) 2 NX

P(O)(OH)

2

R

550 i-Pr

R

551

HI

R

502 0 221. QC-Asn 222.

223.

224.

225.

QC-Asn QC-Asn QC-Asn QC-Asn

HP(O)(OH)

P(O)(OH)

2 P(O)(O11) 2 0 I~yH

P(O)(OH)

2 "J

OH

0 H o0, 11 Boc QC-Val Ph 226. QC-Asn QC-Asn 8 8 Boc Boc Boc 227.

TABLE 4 (cont.)

R

12

R

Compound No.

228.

R

501 R1506 R551

R

502 229.

230.

231.

232.

233.

234.

QC-Asn QC-Asn QC-Asn QC-Asn QC-Asn QC-Asn QC-Asn 0

OH

P(O)(OH)

2 P(O)(Oll) 2

P(O)(OH)

2 P(O)(Oll) 2 03 0 '3-OH i-Pr Bz

C

6 Hj 1 -C(O)But -C(O)NHBut Boc Hoc Hoc (p-F)Bz Hoc (p-F)Bz QC-Val 235.

236.

QC-Asn

P(O)(OH)

2 Hoc QC-Thr

P(O)(OH)

2 Hoc TABLE 4 (cont.) Compound No.

R

501

R

506

R

550 R1551 R502 237.

238.

239.

240.

241.

242.

243.

244.

245.

246.

QC-(CN)Ala BzC(O) BzC(O)-Val PC-Val PC-Val P(Q)(O1I) 2

P(O)(O)

P(O)(OH)

2

P(O)(OH)

2

P(O)(OH)

2

P(O)(OH)

2

P(O)(OH)

2

P(O)(OH)

2

P(O)(OH)

2

P(O)(OH)

2 8 _Ph Boc BzC(O)-Val 8 Boc Boc PC-Val PC-Val PC-Val PC-Val PC-Asn

CO

2 Me

-C(O)NH_

Bz i-Pr

CH

2

C

6

H

11 i-Pr PC-Val PC-Val PC-Val Boc -TABLE 4 W~ont-)

PR

1 2

R

5 02

P-

5 51

CD

Compound No.

'247.

'248.

249.

'250.

251.

252.

253.

254.

255.

'256.

257.

258.

259.

260.

R501 14 Vat Val Val Boc Boo Boc Boc-Vat Boci-Vat Boc-Val MG-Vat MG-Vat MG-Vat MG-Vat

R

5 o6

H

Bz Bz Bz Bz Bz Bz Bz Bz Bz Bz Bz Bz Bz Bz

(OH)

2 p(0) (OH) 2 P(O) (OH) 2

P(O)(OH)

2 P(O) (OH) 2 S(0) 2 0H1 B(010) 2 S(OhO0H P(O)(OID12 P(O) (OH) 2

P(O)(OH)

2 S(OhO0H S(0) 2 0H1

P(O)(OH)

2 Bz CH4 2 C61l i-Pr

CH

2

C

6

HI

Bz Bz (p-P)Bz (p-1F)BZ (p-tF)Bz

R

55 0 Bz CH1 2

C

6 HIA1

H

Boo Val Vat Vat Boo Boo Boo BOo-Val Boc-Vat BoO-Vat MC-Vat Boo Z-Vat Vat

L

4 4 Compound No.

R

506 TABLE 4 (cont.) [2 Px O 0 OH OH

R

550 (p-F)Bz

R

551

HI

261. MC-Val

R

502 MC-Val 262. M C-Val 263.

264.

0 265.

266.

MC-Val Bz (p-F)Bz Bz Bz Bz TMC-Val N0 2 O 0 OH OH O 0 OH OH O 0 OH oH 0 0 0 0

O"H

i-Pr (p-F)Bz Bz i-Pr (p-F)Bz (p-F)Bz TMC-Val TMC-Val TMC-Val Boc Boc Asa TPA 267.

Compound No.

R

501

R

5 06 TABLE 4 (cont.) .2 rx

R

550

R

502 Z-Val 268. TFA (p-F)Bz 269.

270.

271.

272.

273.

274.

2-75.

276.

277.

278.

TFA-Val Ac-Val Ac-Val Ac-Val Ac-Val Ac-Val Ac-Val

NH

1 4 HZ H P(0)(OH) 2 P(0)(OH) 2 P(O)(OH)2

P(O)(OH)

2

NH

2 i-Pr Bz C1-1 2

CAH

1 (p-F)Bz (p-CN)Bz i-Pr i-Pr

CH

2

C

6

H

11 i-Pr i-Pr 0 o H i4 Ac Ac-Val Ac-Val Ac-Val Ac-Val IN 0 Ph 0H

CO

2

NH

2 Ac-le PhC(0)NH-Asn 0 P(0)(O11) 2 P(0)(0ll) 2 P(0)(OH) 2 Ac-ile Boc Boc -Compound No.

R

501

R

5 06

H

TABLE 4 (cont.)

R

12

P

Bz P(O)(OH) 2

R

550 i-Pr

R

551

H

R

502 Boc LI1J. 0 2

<Y

280. PC-NH,6.

281. CII 3 OC(O)-Val 282. CH 3 OC(O)-Val 283. CH 3 OC(O)-Val 284. N S0 2 8 6 N ZIN 0 P(O) (OH) 2 P(O) (OH) 2 0 ,,NH 2 0

NH

2 0

NH

2 0

NH

2 0 i-Pr i-Pr (p-F)Bz (p-CN)Bz (p-F)Bz i-Pr Bz Boc

CH

3 OC(O)-Val

CH

3 OC(O)-Val -w

CH

3 OC(O)-VaI N-Nj H 0 0 0 l Me0 (p-F)Bz

J

TABLE 4 (cont.) R12 PX Compound No.

287.

288.

289.

290.

291.

292.

R

501 MeSO 2 o N-SQ 2 -Var z QCGlu ZAsn

R

506

CH

2

C

6

H

1 1 Bz 0

I'-

"0 H

P(O)(OH)

2 P(Q) (01)2

P(O)(OH)

2

IR

550 i-Pr i-Pr Bz n-Bu Ph

R

551 11

H

R

502 H 0 0 BzC(O)-Val 0 N-SO,-Val Boc Boc Boc 8 i-Pr 293.

I I t WO 95/07269 PTA9103 PCT/AU94/00538 139 TABLE Further examples of compounds of formula (I) 294.

,NHZ

OH

295.

CONHBUt OP(OXOH)2 NH NH N B H N 0 0 H 296.

)P(O)(OH)H

)(0)(OH)H 297.

'U

NHBut WO 95/07269PC/19053 PCT/AU94/00538 298.

299.

300.

HO 0

"P\I

0 0 BzO.

'OBz 301.

ButS( 302.

0 SUBSTIUTE SHEET (RLde 26) 1 pCT/AU94/005 38 WO 95/07269 303.

304.

7 N0 Bz 0 F

NNH

0 n305.

306.

307.

BzNHz

NH

2 BocNH 7 NHc o 0 0 Op 308.

ZNHI'

0 0 SUBSTffUTE SHEET (Rule 26) I j WO 95/07269 PCT/A1194/00538 309.

310.

311.

'P(O)(OH)

2 312.

(HO)

2 P(O)O 0 313.

0 0

NH

2 OP(OXOH)2 N NH' NH 2

N?

0Bz 0 COOBut

I

PCT/AU94/0053 8 WO 95107269 314.

0

OPOOH)

2 0

NH

2 O(XN NH NH 2

N

N -0 Bz 0 COOBut aN 'OH 315.

316.

(HO)

2 P(0)NH.

317.

06 I I-

Claims

1. o p t i o n a l l y C S a k R I optonalYubstituted (C 2 -~l~l~Y p t i o n a l l y s b s t i t t e d C 3 YC 1 c y c l o a l k y l k l optionally btt'te (C 8 cycloalkyl(C 1 C 1 ll~ 0 tionally ub~ttae C )cycloa l 18 )ak n l otionally ubstituted (C 3 YClS c cla 1( .:optiona ly ubsti uted (C 6 -C 24 )aryl ak l i 0 ~tonalY 5 U stitted c 6 24 )aryl(C1 -s opinll stituted (C 6 -C 2 4 )arylC jg~I keS 25 ~optionally ub ttte (C 24 )ayl(C2i .9 optonallY 5 bstit~td (C -C )cl *00* optionally sbstituted h t rylc2, 9 9*optionally substiuted heter~g~cYlicC optionally S~bstituted heterocyclic'C s n 30 ~~~optionally substituted heterocYclic(C2 8 alnl C(D)SR21, (D~)NP-2 1R 2 2 C(NR2)P22, C(NR 2 1)O-22 and independenl"Y are C( R IN 2 2 wherein 2 R. and R 2 3 jouslY defined, Or selected from hydrogen and 2 0 as pre P- 2 and 2 2 together Or R 2 2 a d P 2 o eh r fr Lx2O 2 0U Ii i~i I 1 SUBSTIUTE SHEET (Rule 26) saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, or R 3 and R 4 when present, together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, 0 0Px Px is selected from the group consisting of Px*, 0 RI ,and wherein D isO0 or S, R is H or C 1 -C 4 alkyl, and wherein Px* is selected from: o 9 4 9 *9 0006 If,; I, I I K, I 0 0. I, I If; 0t S S 0 5 9*

055. C, S *90* 0 9* O S 11P-OH '-P"FO ~OH 0 "B-OH OH 0 OH 0 0 0 H NP-OH 1-/i 0OH H H OH OH 0 KOH 0 0 X"-""JOH X=O0, S, S(O) 2 -NO 2 0 0 11 'OH 0 0 R O H (CH 2 4 NH 2 O H 't R NH 'N NH 2 H 0 H NH D is selected from 0 and S, X is selected from the group consisting of Y, S(O) and S(0) 2 wherein Y is as defined below, ~)VT O'~IN:\LIBZ\NARHEX]250529AU:SAK V SUBST1TUTE SHEET (Rule 26) 146 X* is selected from the group consisting of NRlo, O and S, wherein Ro has the meaning of R 6 as previously defined, R 1 is selected from the group consisting of R 1 as previously defined, P(0)(OR 7 )R 8 S(O)zOR 7 and S(O)zNRRg 8 wherein z is 1 or 2 and R 7 and R 8 independently have the meaning of R 20 as previously defined, or R 7 and R 8 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, R 5 and R5* are independently selected from the group consisting of H, CF 3 C(D)OR 103 C(D)SR 103 C(D)NR 10 3 R 1 04 and R 20 as previously defined, wherein D is as previously defined, and wherein R 103 and R 104 have the meaning of R 6 as previously defined, or R 103 and R 104 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and R 5 is selected from hydrogen and R 20 as previously defined; n is 0-6; e;m is 0-6 and n+m 2 1; A at each occurrence is independently selected from the group consisting of R 1 2 R 1 2 L-C- -C=C- I I I SR, 3 R 3 R 9 R 9 -C C- 1 Ri2 R Ri 2 R 12 R 1 2* R 1 2* R2 -C-C- R: R 1 R3 R R 1 3 R 1 3 Rl R 1 3 and a residue of a naturally occurring or synthetic amino acid; A* at each occurrence is independently selected from the group consisting of R R12* -C=C- I I I I Ri3 R3* R9 R9* R12 R12 R2* R2 R,2 R2* R12* Rl2* C-C- -C-C- I I I I I I I I R 1 3 R 1 R3- R 1 3 R 3 R3* R3* R3* and a residue of a naturally occurring or synthetic amino acid; wherein R12*, R13*, R 9 and R 9 are independently selected from the group consisting of F, Cl, Br, I and R 5 as previously defined, R 11 has the meaning of R 1 as previously defined, R 1 2 has the meaning of R 6 as previously defined, PA-; R 13 is selected from the group consisting of C iNA8LIBZ\NNARHEX1250529AU:SAK 00C SUBSniTUTE SHEET (Rule 26) Al 147 F, Cl, Br, I, R 6 as previously defined, and R. 200 wherein R 200 is selected from the group consisting of CN, NCO, NCS, OCN, SCN, N 3 OR 60 SR 60 NR 60 R 61 DIC(D 2 )R 60 D 1 C(D 2 )D 3 R 60 DIC(D 2 )NR 60 R 61 NR 60 C(D 1 )R 61 NR 60 C(D 1 )D 2 R 61 NR 60 C(D 1 )NR 6 lR 62 j NR 60 0R 61 amidino, 'O.tt guanidino, :S(O)R 60 S(O)NR 60 R 6 1 S(O) 2 NR 60 R 6 1 DjS(O)R 60 D 1 S(O) 2 0R 60 DjS(O)NR 60 R 6 1 DlS(O) 2 NR 60 R 61 P(D 1 )(D 2 R 60 )R 61 P(D 1 )(D 2 R 60 )D 3 R 61 P(D 1 )(D 2 R 60 )NR 6 lR 62 P(D 1 )R 60 R 61 D 1 P(D 2 )(D 3 R 60 )R 61 D 1 P(D 2 )(D 3 R 60 )D 4 R 6 1 D 1 p(D 2 )(D 3 R 60 )NR 6 lR 62 DP(D 2 )R 60 R 6 1 NR 60 NR 61 R 62 and 0NR 60 R 61 wherein DI, D 2 D 3 and D 4 independently have the meaning of D as previously defined, and R6c0, R 61 and R 62 4 independently have the meaning of R 6 as previously defined tN-.\LBZ\NARHEX250529AU:SAK ILI I 0z 0 z C-4~ 6, V.4 L k SUBsTnumT SHEET (RLUle 26) 148 or any two or more of R 6 0 R 61 and R 62 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, together are selected from the group consisting of 0,=S or R 12 and R 13 -/R 6 0 F-6 N0R 60 =NR 60 -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (Cl-C, 2 )alkylidene as defined herein and R 60 is as previously defined, and L is selected from the group consisting of a bond, D D 11 -S- -S(O)z- 4 0q 0 *t; 00 00. 0009 0 *0 N-S(0)z-N -N-S(O)zN D D D 11 11 11 -N-C-Nq- -S(0)z-NCU -S(0)Z-NCUN III I I Ril R11*Ki Ril RII* D Ril D II R13** N 1 1 Kll N 1 1 i i D D C-N-N- I1 1 1 0 Ril Riv' D D D 0 -P-O- II I I -GCl 2 and -CH 2 -CH 2 wherein R 11 and D are as previously defined, R 11 and D* have the meaning of R 11 and D respectively, and z is 1 or 2; R 13 is F, Cl, Br, OR 60 or NR 60 R 60 wherein R 60 and R 61 are as previously defined, INALIMZNAflHMX26029AU:S3AK 0 U 0, *:i SUBsTI1Tn SMET (Rule 26) 149 B is selected from the group consisting of ZM -N- M -C- II -C- M1 I -N- ZM -C- R 14 M2 1 N- M2 R14 N 2 -C- Mi I D" D* II ZM ID 0 II -S- 0 II -5- II 0 R14* K14 NR17 II s- II 0 01 N R17 R 2 0 3 ,Z*M II II -C- R203* II -C- 6o** 6* 6 5 5 S -C-C- I I R 1 4*R 1 4** R 14 R 14 I)NZM N-ZM -C-C- R 14 *R4** R 14 Z*M C R14*C,'R14** C R4 C, 11z*M C I> S- -N- R14*R 1 4 R14-., 14-* C R 14 /Z*M* I'NZM OR 18 N11 I10 OR 1 8 -C- SR 19 R14- I pc OR18 -C- R 19 SR18 'jK19 OR 1 -C- NVR 1 8 *R 1 9 wherein R 203 and R 2 03 independently have the meaning of R 6 as previously defined, R 14 and R 1 4 are independently selected from the group consisting of hydrogen, as previously defined, CF 3 and C(D*)NR4 OR 4 wherein R 40 and R41 independently have the meaning of R 21 and R 22 as previously defined or R40 and R41 form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, 1N\LBZ\NARHEX260529AU:SAK a. ItL :4 I)-Y C I -C I z lc- C14 C- r r- r- r- l q14 N N SUBSTITUTE SHEET (Rule 26) I I II ft It I II C I 4t1 I C. II R 14 is selected from the group consisting of F, Cl, Br, I, R 14 as previously defined and R 200 as previously defined, R 17 and R 17 independently have the meaning of R 6 as previously defined, D* has the meaning of D as previously defined, Z is a saturated or unsaturated (C 2 -C 4 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 1 4 as previously defined, Z* is a saturated or unsaturated (Ct-C 3 )alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R 1 4 as previously defined, M 1 is selected from the group consisting of OR 15 SR 15 and NR 15 R 17 wherein R 15 is selected from the group consisting of: Px as previously defined, R6 as previously defined, and a glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and R 1 7 is as previously defined, or R 15 and R 1 7 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, M and M* are independently selected from the group consisting of M 1 as previously defined, OCN, SCN, YR 2 Y* and N=CR 30 R 31 wherein Y, Y* and R 2 are as defined below, and R 30 and R 31 independently have the meaning of R 20 as previously defined, M 2 is selected from the group consisting of R 1 4 as previously defined, and -CR 30 *=NR 1 7 where is as defined below, R 30 has the meaning of R 20 as previously defined, and R 17 is as previously defined, R 18 and R 19 independently have the meaning of R 20 as previously defined or Ri 8 and R 19 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and R 18 and R 19 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein; selected from the group consisting of YR 2 Y* and C(R 30 wherein Y is absent or is selected from the group consisting of: tN\LIBZ\NARHEX250529AU:SAK V is j C C 0O SUBSTMUTE SHEET (Rule 26) 0 II -S -N II I O R 5 0 O II 0- -41=N-- O N -S Rso 5 0 II -S-O- 0- I 0 N=N-- O II I II R 50 s II O O II -S-N O S-O-S O S-- II O ii *99* *999 *0 I+ I I 9. *99. 9099 U. IIC 99 9. 9 9* 99 0 II S--S 0 0 II -N -P 5 R 50 OR 5 1 O II -P-N- R 51 0 Rso 5 0 O -N- I I R 51 0 R 50 O II -O-P- O II -N-P -0- Rso50ORs51 O II O-- OR51 0 II -P-N- R 51 0 Rso O II -N-P R 5 0 oOR 5 1 O II -P-RO- D**R52 O II 11 O II -O-P -O- D**R51 wherein is selected from the group consisting of a bond, 0, S and NR 50 R 50 has the meaning of R 6 as previously defined, R 51 has the meaning of R 15 as previously defined and R 52 has the meaning of R 20 as previously defined, or R 50 and Rs 1 when present, together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and R 2 has the meaning of R 6 as previously defined, 'L? r ~II- Ir SUBSTITUTE SHEET (Rule 26) 152 Y* is selected from the group consisting of /R33 -N-N-R 2 -N-O-R 2 -O-N-R 2 I I I R I I R 50 R 51 Rso R34 R 50 R 50 0 0 II II D**Rc -S=0 -S=O -S=NR 1 1 7 115 I I I P=D* -N=0O R114* Rl14* Rl14* I and Sa Rn14** R114* -P=D* ,I wherein D* and independently have the meaning of D as R114** previously defined; R 114 R 1 14 R 115 and R 117 have the meaning of R 14 R 1 4 R 15 and R 1 7 respectively, as previously defined; R 50 and R 51 *oo are as previously defined or R 50 and R 5 1 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein; R 2 is 0 selected from the group consisting of R 2 a previously defined, Px as 10 previously defined, S(O)zOR120 and S(O)zNRi 2 oRi 2 1, wherein z is 1 or 2; R 33 and R 34 are independently selected from the group consisting of hydrogen and R 20 as previously defined, or R 33 and R 34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and R 1 20 and R 1 2 1 independently have the meaning of R 20 as 15 previously defined, or R 1 20 and R 1 2 1 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, R 30 is as previously defined, and is selected from =N-NR 11 5 R 1 17 and =N-OR 1 1 5 wherein R 115 and R 117 have the meaning of R 15 and R 6 respectively, as previously defined, or Rll5 and R 117 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and wherein any group selected from R 1 R 1 R 2 R 2 R 9 R 11 R 12 R 1 3 R5 0 and R 51 may tooether with any other group selected from R 1 RI*, R 2 R2*, R 9 R 10 R 11 R 1 2 i 30j and R5 1 form one or more saturated or unsaturated cyclic, bicyclic or fused ring system(s) as defined herein, SN-O and wherein any tertiary amino nitrogen atom may be replaced by the group and, wherein any hydroxyl, mercapto or amino group may be protected by a protecting group which is labile in vivo; provided that said compound of formula includes at least one solubilising group Px as previously defined -V6 1N[\LIBZ\NARHEX260529AU:SAK or, wherein the compound of formula includes two functional groups capable of being derivatised by a solubilising group Px, said two functional groups being in sufficiently close proximity to one another, the compound of formula comprising a cyclic structure including a structural unit selected from: O OH -X1 X 2 O H -Xl X 2 00 S-X 1-X -X and O -XlO 0H 1-OH X 2 0 OH wherein X 1 and X 2 are independently selected from 0, S and NR 6 wherein R 6 is as previously defined. 2. A compound according to claim 1, wherein B is selected from the group consisting of M ZM ZM Mi M2 -N- D* II M -C- R14* ZM R14 o. *0 o a e *Sa* e IV12 -C- R 14 SR 1 8 -C- I SR19 O0 -C-C- I I R14*Rl4**, R 14 R 14 C R14* /Z*M C'O OR 1 8 -C- OR 1 9 OR 18 -C-a I and SRi 9 OR 1 -C- NR 1 8"R 19 where Z, M, M 1 M 2 R14, R 14 R 14 R 15 R 18 R 1 8 R9 and R 19 are as defined in claim 1, V is YR 2 Y* or C(R 30 wherein R2, R 30 and are as defined in claim 1, Y is 0- 0- and selected from the group consisting of Y* is selected from the group consisting of -O-N-R2* I R and 5 0 wherein R3 ,R33 -N-N-R 2 -N-N=C, I I I R34 R 50 R 51 R 50 3, R 34 R 50 R 51 and R 2 are as defined in claim 1. 3. A compound according to claim 1 having the structure represented by formula (IA): N:\LIBZ\NARHEX1250529AU:AK ly. Y yl- R 13 R 13 (1A) wherein Rl*, RIO, R 12 R 12 R 13 and R 13 are as defined in claim 1,1 B* is selected from the group consisting of ,AZ ZIM M 1 -N- M 2 -N- D* R 14 R 14 SR 18 SR 19 0 -C-C- R 14 *RI4** 1 0 OR 19 and *9e~ 0* a. 4 a a o a a a o a a.. a I S a a a a *0 a tCa a 0 *4S~ a. 4 a S. C where Z, M, M 1 M 2 R 14 R 14 R 14 Rjg and R 19 are as defined in claim 1, and Y, is selected from the group consisting of -N-N-R N-O-R2* )O-N-R 2 R 50 R 51 R 50 and R 5 o wherein R 5 o, R 51 and R 2 are as defined in c11Iam 1.- 4. A compound according to claim 1 of the general formula (IB)* R 512 R54 2 Rsoi- C K B I Nf CA C I N Ro R~o6 R R x Y (113) wherein x and Y are Independently 0 or 1, B is selected from the group consisting of OR 1 OR 1 C(R 56 0)2 tro wherein R 14 R 14 Rjg and R 1 9 are as defined in claim 1 and each R 560 is independently hydrogen or (CI-C4 )alkyl, and R 15 is a group Px as defined in R 5 lad 1, 0 ae independently a group R 600 wherein R 600 is selected from the 20 502angRoup cnisting of hydrogen, C(O)0R6.21, C(O)SR 62 1 C(O)NR 62 lR622, (C 1 INAL1BZ\NARHEXI250529AU:SAK 155 C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 5 -Clo)cycloalkyl, (C 5 -Clo)cycloalkyl(C 1 C 6 )alkyl, (C 5 -C 1 0 )cycloalkyl(C 2 -C 6 )alkenyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl- (C 1 -C 6 )alkyl, (C 6 -C 1 o)aryl(C 2 -C6)alkenyl, (CI-C 6 )acyl, heterocyclic, heterocyclic(C 1 -C 6 )alkyl and heterocyclic(C 2 -C 6 )alkenyl, each of which may be substituted by up to three substituents selected from the substituents defined herein for "optionally substituted (C 1 -C 18 )alkyl" and R 621 and R 622 have the meaning of R 2 1 and R 22 respectively, as defined in claim 1, or R 62 1 and R 6 22 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, R 50 1 is selected from the group consisting of R 600 as previously defined, S(0)OR 632 S(0) 2 R 632 S(O)NR 632 R 633 S(0) 2 R 632 R 633 NI- 2 NHR 63 1 and NR 631 R 632 wherein R 63 1 has the meaning of R 6 as defined in claim 1 and R 632 and R 633 independently have the meaning of R 20 as defined in claim 1, or R 501 and R 506 together form part of a saturated or unsaturated cyclic, S 15 bicyclic or fused ring system, or R 631 and R 632 or R 632 and. R 633 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, R 512 and R 542 independently have the meaning of R 600 as previously defined, R 522 and R 532 are independently selected from the group consisting of R 600 as previously defined, F, Cl, Br and I, R 513 and R 543 are independently selected from the group consisting of R 600 as previously defined and R 200 as defined in claim 1, R 523 and R 533 are independently selected from the group consisting of R 600 as S" previously defined, F, Cl, Br, I, and R 200 as defined in claim 1, R 550 has the meaning of R 6 as defined in claim 1 and R 55 1 is selected from the group consisting of R 650 hydrogen, S(O)OR 632 S(0) 2 R 632 S(0)NR 63 2R633 and S(0) 2 R 632 R 633 wherein R 650 has the meaning of R 6 as defined in claim 1 and R 632 and R 633 are as previously defined, or R 632 and R 633 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, or R 550 and one of R 551 and R 502 together form a diazaheterocycle wherein R 550 R 55 1 or R 502 and the two nitrogen atoms to which they are bonded are part of a stable 5 to 10-membered ring which may comprise up to two further heteroatoms selected from 0, S and N and to which may be fused one or more cycloalkyl, cycloalkenyl, aryl or heterocyclic residues, which diazaheterocycle may be substituted by one or more of the substituents defined herein for "optionally substituted (C 1 -C 18 )alkyl", and wherein two substituents may together form part of a ring, or one pair selected from R 512 and R 513 R 522 and R 523 (when present), R 532 and R 533 (when present), and R 542 and R 543 together are =0; [N:\LIBZ\NARHEX1250529AU:SAK 156 OR 1 wherein, when B is other than then at least one of conditions to (xi) below applies: at least one of R 512 and R 542 is a group R 655 wherein R 655 is selected from the group consisting Of (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 2 -C 6 )alkenyl(C 6 -C 10 )aryl, (C 5 -C 1 0 )cycloalkyl(C 2 -C 6 )alkenYl, (C 5 -Cj 0 )cycloalkyl(C 6 -C 10 )aryl, acyl(C 6 C 10 )aryl, heterocyclic(C 1 -C 6 )alkyl, heterocyclic(C 2 -C 6 )alkenyl, heterocyclic- (C 6 -C 10 )aryl, C(D *)0R 21 C(D*)SR 2 and C(D *)NR 21 *R 22 wherein D R 21 and R 22 are as defined in claim 1, (ii) at least one of R 522 and R 532 when present, is selected from the group consisting of R 655 as previously defined, F, Cl, Br and~ 1, (iii) at least one of R 513 and R 543 when present, is selected from the group conisin oR 655 as previously defined, and R 200 as defined in claim 1, at least one of R 523 and R 533 when present, is selected from the group consisting of R 655 as previously defined, F,Cl Br, I and R 200 as defined in claim 1, R 550 is a group R 656 wherein R 656 is selected from the group consisting of (C 1 -C 6 )alkyl(C 6 -Cj 0 )aryl, (C 2 -C 6 )alkenyl(C 6 -C 10 )aryl, (C 5 -C 1 0 )cycloalkyl- (C 2 -C 6 )alkenyl, (C 5 -C 1 0 )cycloalkyl(C 6 -C 10 )aryl,, acyl(C 6 -Cl 0 )aryl, .#toheterocyclic(C 1 -C 6 )alkyl, heterocyclic(C 2 -C 6 )alkenyl, heterocyclic- (vi)20(C 6 -Cl 0 )aryl, R 551 is selected from the group consisting ofR 6 aprvosydfn, S(O)0R 632 S(O) 2 R 632 S(O)NR 632 R 633 and S(O) 2 R 632 R 633 wherein R 632 4 and R 633 are as previously defined, (vii) R 502 is selected from the group consisting of R 656 as previously defined, C(D*)SR 21 and C(D*)NR 2 ,*R 2 wherein R 21 and R 22 are as defined in claim 1, (viii) R 502 and R 551 are both hydrogen or are both (Cl-C 6 )acyl, (ix) R 14 is selected from the group consisting of C(D*)0R 40 C(D*)SR 4 o and C(D*)NR 4 oR 4 wherein R40 and R41 are as previously defined, R 501 is selected from the group consisting of R 656 as previously defined, S(O)0R 632 S(O) 2 R 632 S(O)NR 632 R 633 S(O) 2 R 632 R 633 NH 2 NHR 631 and NR 631 R 632 wherein R 632 and R 633 are as previously defined, (xi) R 501 and R 506 are both (Cl-C 6 )acyl. A compound according to any one of claims 1-4 wherein said solubilising group Px o 0 NPOH POH 5 is selected from oH and Hi [NA\LIBZkNk&RHEXj250S29AU;SAK 157 6. A compound according to claim 1, selected from the group consisting of formula (IC) to (JAW), wherein each AA is independently a residue of a naturally occurring or synthetic amino acid as herein defined; Rl*, R 1 X and X* are as defined in claim 1; Ra to Rj independently are -(Cll 2 )a- 6 OPY or R 6 wherein a can be 0, 1, 2, 3, 4 or 5, and wherein Py is a solubilising group Px as defined in claim 1, and R 6 is as defined in claim Ra G R'f I Rd R'd I NHN cR (IC) $NHS'9G I Rh R U 0-3Re wherein D' is 0 or S, and each G is independently hydrogen or R 200 as defined in claim 1 and wherein R'd and R'f are Rd and Rf or, taken together, may be trimethylene or tetramethylene optimally substituted with -C(O)OR; or -C(O)NRiRj; OPy

444.(C0H 2 )0. 2 Ri* ai 1 I Rf h ~AI(ID) C 01 1 I0 I I Re I Ri 11 Rb 104Rd R9g wherein G is selected from Rj* and X*R 1 444Ra Ra' 0 4..I Rc -~FI Rd 1 R NH I C C Rb I I 40-3 M, Re 0-3 (JE) wherein Rai is OPy or R 6 as defined in claim 1, Mlis R 6 as defined in claim 1, (CH 2 1 2 OPY or (CI{ 2 1 2 NHPy, and G* is OR 2 or NRjR 2 OPY R 1 *X a ~4 Rh AA I 0 I10 I C AANRj Rb I RelI R1 Rd Rg 0-1O 0-3 0-3 0-1 (IF); 1N:\L1IBVtNARHEX2S529AU:SAK 158 OPy (CH 2 0-2 0 R Rf II G NHC I ICX*R 2 Rd Rg 0-4 (IG) wherein G is hydrogen, Ra, R 1 or R1*X*C(Ra)(Rb)C(O), and wherein Ra, R 1 and the atoms to which they are bound may optionally form a saturated or unsaturated cyclic, bicyclic or fused ring system; Ra Rc OPy 0 Ri S I Re I Rg 11 I C NH I C C R Rb 0-3 Rd I I Rf Rh 0-3 0-1 (IH) wherein Ra, R 1 and the atoms to which they are bound may optionally form a saturated or unsaturated cyclic, bicyclic or fused ring system; tie: R Rd 0: .t I aR cI Rf "AAl ,C I cC I ,Rg f or W2 NH 1C I C 0-2 Rb I Re (C)o R OPy ;p (II) wherein W 2 is RiX or R 6 as defined in claim 1, and R' is Py or R 6 as defined in claim 1, or R' and Py, taken together with the oxygen atoms to which they are attached form a Hox#O H 0o 0 t:04 group selected from O PO and -O a: -o o 0 o o OPz d( C H2) o-2 I Rd I(Rf RaC I C IL C I C R11 Rc R I 1-3 Rg 11-3 (CH 2 )0-2 wherein each L is independently as defined in claim 1 and each Pz is independently hydrogen or Py, provided that at least one Pz is Py or, when each Pz is Py, the groups Py, together with the oxygen atoms to which the are bound define a cyclic group selected HO/ 0 H 0 0 Q from oP P and -0 0- -0 0- -o 0- INA\LBZ\NARHEXI250529AU:SAK ~r~ QPy (CH 2 R NH 0Rb RA-L \NH. I/CH IAAG \AA I Rcl -4 Ra Rd 0-3 (IK) wherein Q is 0 or NRf and G is R 1 or X*R1*; (IL) wherein each NHet) is independently a 5- or 6- membered saturated or unsaturated a e *r a a e t* e 5 heterocycle containing a nitrogen atom and optionally additionally one or two heteroatoms selected from nitrogen, oxygen and sulfur, and wherein Ra' and R b independently have the meaning of -(CH 2 )o0 6 0Py or R 6 or taken together are 0; QPy (CH 2 )o-2 0 0 H Ra Rd II R 1 .NH I \NH IC I Rf I 1 -2 1 Rc I I W1 Rb Re Rg (IM) wherein W1 is selected from R 1 X and R 1 and Q is selected from 0 and NR; OPz QPz ?P I H2)0-2 (H 2 0 .2 (CH2) 0 2 H a Ra Rd R 1 N I N' ICAIRg I 1-2 I I Rf W, Rb \R l (IN) wherein W 1 is selected from R 1 X and R 1 each Pz is independently hydrogen or Py, provided that at least one Pz is Py, and Q is selected from 0 and NRh; I[N:\LIBZ\NARHEXI250529AU:SAK ;i SI z (IO) wherein each Pz is independently hydrogen or Py, provided that at least one Pz is Py; OPY RaI IRb Re RIN( NI C, I ,NHet c AA OR 2 R A C I C 11 0_R RdI Rc Rf (IP) wherein N is a 5- or 6- membered saturated or unsaturated heterocycle containing a nitrogen atom and optionally additionally one or two heteroatoms selected from nitrogen, oxygen and sulfur; 0 4 ft S. OP/ I (CH 2 )0 -2 Rb I Rh I Re I Ra'N~ d oI Nj Rd Rg Ri (IQ) wherein Ra' and Rj' are independently selected from RI and R 1 as defined in claim 1; QPy (CH)0-2 Ra 0 Rb(IR ~G Y 0 -2 CRd (T"P qj Re Re Rg C-C-anda satur lo wherein G is selected from -C -C-C and a saur Rf Rf Rh cyclic, bicyclic or fused ring system, Q is O or NH, and G* is X claim 1; UJ w7 '?NT ated or unsaturated or X* as defined in IN:\LIBZ\RHEX1250529AU:SAK x~ t 161 OPy (H2) 0-2 R, R Rd R NH IC. NHetf AA C I C S] I Rc I 9 0 -2 Rb Re (IS) wherein NH is a 5-12 membered saturated or unsaturated cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur; Q*Py (9H 2 0-2 G NH C R a -C ,I C A AA C I RG b Re (IT) wherein G is selected from hydrogen and R 1 Q is O, S or NH, Q* is O or NH, and G is selected from R 1 and Rl*X*; S(H 2 0 2 ra Rc R I R SNH C Rg L AA C C 0R -1 Re I S0- 1 Rd R2 00 (IU) wherein R 200 is as defined in claim 1; OPy (CH2) 0-2 Ra I Rd R1. NH I C l N*Het AA-Rj AA C I C o-1 I Rc I -3 Rb Re (IV) wherein N8 is an optionally substituted 5-12 membered saturated or unsaturated cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur; LUJ [N:\LIBZ\NARHEXI250529AU:SAK I *i ,I Y I- r i i :il 0 -4 4*p* 4 I *I I. S 1-3 (IW) wherein b is 0, 1 or 2, provided that at least one b is greater than 0, and each Pz is independently hydrogen or Py, provided that at least one Pz is Py; G* Rb Re G* Ra Rg Rh (CH 2 )0-2 OPy wherein each G* is independently selected from O, S and NR 6 and G is selected from OR 6 NHR 6 and R 20 Ra Rd H Ce GRf G /H Rb( Re )203 0-2 (CH)o-2 Rg I 0-1 QPz wherein G is or -CI 2 G* is R 1 or R 1 is or -NRh-, Q is or -NR i 0 0 S1o H 1P ,P 11 -H /B-OH 7 -OH O H H B-OHH and Pz is selected from the group consisting of 0 o 0 O 0 0 X S OH X 0, S, S(0)2 0 O OH 0 O O 0H 0 R o^ 10 -NO2 lo o H NR (CH 2 4 NH2 o H NH N JNH2 0 N NH N 0 I71-v VD 0 R and DPX wherein R and R' are independently hydrogen or C 1 -C 4 alkyl, D is O or S and Px* is as defined herein; 1N,\ \NWWkWO12$052SAU:SASK L .r -C LIII -I d~ R R G' 'ONHCI CC, NHet y "2 Rb I Re R 2 (CH 2 0 2 0 ONz wherein G is R, S 11 P-H or Rl*, G* is or -NRf- and Pz is selected from the group consisting 0 00 0 11 0 .II 0 XO kBg OHH OH OH O0 OH -NO 2 X I, (0)2 0 OH 0 0 0 SN. Ii 1 OH U 0 R NNR' O H (CH 2 4 NH 2 a a a a Ii t t at C. CC C 9 C C .9t# a 9t4 CC C C C 4 *9CC I C C a 9. 990 9*tt .9 a 0*CO a I C a. C 0 H NH 0 DP 0 R and wherein R and R' are independently hydrogen or C 1 -C 4 alkyl, D is 0 or S and Px* is as defined herein; (IAA) wherein G is R, or Rl*, and each Q is independently H, -OPz or -NRdPz, wherein each PZ is independently hydrogen or Py, provided that at least one Pz is Py; 0 OjPy IRa (CH 2 a -C 2 ,R2 Ri*X*' C IIh I Het G II Re Rb Rc GlAB) wherein N Het is a saturated or unsaturated cyclic, bicyclic or fused nitrogen containing ring system and G is a bond or is or -NRf; -A (N:\Ll8Z\NAfHEXi2S529AU:SAK 164 cjwY A-,NC11, 1-Het G (JAC) Rb 0 wherein G is absent or X*Ri* and 113D is a 3 to lO-membered saturated or unsaturated heterocycle containing a nitrogen atom and optionally additionally one to three hetero- atoms selected from nitrogen, oxygen and sulfur; J Qp~Rd Rj "NH I j j( R 2 (lAD) (GIl1 2 0 2 0 OPy wherein Q is selected from and -NRf-; ?PY Rb' (Cl- 2 )0.2 C C I C 0 e C1 RIf weenG is 0, S, S(O) or S(0) 2 and Ra' and Rb' have the meaning of Ra and Rb or Ra' and Rb. together are trimethylene or tetramethylene; P PIZ a~ (CH 2 0 2 (CR 2 2 Re Cj CH-CH C (lAF) NH Rb IZ I Rf wherein each Ar is incl'pendently (C 6 -C 14 )aryl, R'c and R'd are Rc and Rd or, taken together, are or -CLI(OH)-, and wherein Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the HO, 0. H, ,0 oxygen atoms to wvhich they are attached form a group selected from -0 0o and -0o "0 ~7VTO~ NLIBZ\NARHEX125529AU:SAK L~id 165 OPz Ra (CH2)0-2 Rg' R g Rh' Se NHN (AG) c~;l NH H2 0-3 Rb Rd (CH 2 0 2 Rf OPz wherein G is a bond or X as defined in claim 1, Rg' and Rh' are Rg and Rh or together form a saturated or unsaturated cylic, bicylic or fused ring system, and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are attached form a group selected HO, HO O SO 011\0 -01' 0 from and -o 0-; OP'z OPz (C H2)0-2 9. (CH2)0-2 R*1* NH a I C g ,R (IAH) AA C CG C e I Rf 0-2 0-3 Rb -e 0-1 03 '0 1 wherein G is a bond, 0, S or NRj, Rg' and R 1 are Rg and Rh, or taken together may be and Pz and Pz' are independently hydrogen or Py with the proviso that at least one of Pz and Pz' is Py, or Pz and Pz' together with the oxygen atoms to which they are I I: HO,,O H, O O'S 0 attached form a grouo selected from -o o- -o 0 and -o 0- OPy Ra I l(CH 2)0-2 iRi* N aC IR2 (IAI) A C I C -2 1 RC I Rb Rd wherein G is OPy, NHRe, NPyRe or Re; OPy Z R dAA U C d (IA J) R 1 .G 0-1C 1Q1C 'Q INH 0-3 G*R*. Rb I Rd I RgI Rj 0 R'c Re Rh 0 0-10-1 wherein G and G* are independently a bond, 0, S or NH, and R'd and Rh' are Rd and Rh TRAL 4or taken together are -CR' 2 or -CR 2 '-CR 2 wherein each R' independently has the 1- IN:\LIBZ\NARHEX]250529AU:SAK 166 meaning of R 6 as defined in claim 1, Q and Q* are independently N or CR 6 or when Q* is CR 6 then Rg and R 6 together may be a double bond; OOy Ra (C4(H 2 0 2 RN~(A X-GIIhR 2 4RI (IA) AA 1 CH OPy II R (Ut Q 0z\ Rj al II..II C C AA 0_ -5 R I Rb R R b tee i Ki aAL PO~weenG sotoal allele, ro Ide hta e n R is Py Gan0isNd-oCde; tN:\LIBZ\NARHEXI2G0529AU:SAK (IA): wu [N:\LIBZ\NARHEX1250529AU:SAK a t at Irv II I C C t ltC C lag (IAP) wherein I represents an optionally substituted saturated or unsaturated ring system optionally containing up to three heteroatoms selected from N, O and S, G is selected from R 1 XR 1 or X*RI* and Ra and Rb taken together may optionally be Ra Rc L AA_ C .C S NH B* R NHRb Rd (IAQ) wherein B* is a group B, as previously defeined, derivatised with a solubilising group Py; OPy (CH 2 0 -2 Ra CNHI CHetR2 0-2 1 R c 0-2 Rb (IAR) Het 4 rr I r r c r r rr r r ZJ "1 I wherein represents an optionally substituted cyclic, bicyclic or fused ring system containing a nitrogen atom and optionally additionally from 1 to 3 heteroatoms 10 selected 'rom N, O and S; OPy S (CH 2 (IAS) wherein Qi and Q2 are independently selected from O and S, and R'f and R'g are respectively Rf and Rg or are selected from OR', SR' and NRhR' wherein R' is H, R i or Py; lAN;\INM MAU;S\ .Ir group consisting of hydrogen, C(O)0R 6 21 C(O)SX 621 U)I"'62lJAZ', \-I CX INALISZkNARHEXj250529AU:SAK I I II- I a" 168 OPy (CH 2 )0-2 Ra 0 Rd Re 0 Rg C, N C, N C ICN (AT) R I G CH C H 2 IC 2 CH G I R2 Rb I c 0-1 R Re R' 0- IR wherein each G is independently selected from 0 and NRi, and R' is (CH 2 1 2 OPy or R 6 R a Rc I (IAU) G IG* I R2 Rb Rd 0OQ 0000 I I Ip -C-C- wherein G and G* are independently selected from Re ReRf and L, wherein L is as defined in claim 1 and Q is H or Py, provided that at least one of G and 0* is other than L and provided that at least one Q is Py, or wherein two groups OQ taken together HO, O H, 0 -0 0- o- are a cyclic group slected from and OPy (9H 2 )0. 2 *4*4 4 4 4 *a 4*4 4 4* 4 i: 4 4 c re R 6 SR 6 K 6 (IAV) wherein Rx and Ry are independently R 6 or (CH 2 1 2 OPY; i 1 ,i i i i i I t-h 1 i G A 4 NH, 1,CH I CH 2 1"NH\(AG* (IAW) 0-4 1 1 0-4 Rb Rf (CH 2 )o. 2 OPy wherein G and G* are independently selected from R 1 R 1 -C(R 5 )=NR 3 ond -C(R 5 )N OR 3 wherein R 3 and R 5 are as defined in claim 1. 7. A compound according to claim 1 selected from the group consisting of derivatives of 15 t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amino-4-phenylbutyl]carbazate, (ii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy.-3-(N-quinaldyl-L-valyl)- amino-4-phenylbutyl]carbazate, INAUBZNARHEXi2.O529AU:SAK RA '513, "522 au- 523 (Wilen present), R 53 2, and R~ 533 (When present), and R 542 andR 5 ,toehrae=0 NALIBZMARHEXJ250529AU:SAK 169 (iii) t-butyl 3-isopropyl-3-[2R or S, 3S)-2-hydroxy-3-(N-quinal'dyl-L- asparaginyl)amino-4-phenylbutyl]carbazate, (iv) t-butyl 3-(1-methyl-3-phenylpropen-3-yl)-3-1,(2R or S ,M3)-2-hydroxy-3- (phenylmethoxycarbonyl)amiino-4-phenylbuc yl]carbazate, t-butyl 3-(1-methyl-3-phenylpropyl)-3-[(2R or S 3)-2-hydroxy-3-(N- quinalfdyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (vi) cis- 1 ,6-3-t-butoxycarbonyl-4-[(2R or S ,3S)-2-hydroxy-3-amino-4-phenyl- butyl]-3 ,4-diazabicyclo [4.4 .O]decane, (vii) cis- 1, 6-3-t-butoxycarbonyl-4-[(2R or S ,3S)-2-hydroxy-3-(phenylmethoxy- carbonyl) amino-4-phenylbutyl]-diazabicyclo [4.4 .O]decane, (viii) cis-1, ,6-3 -t-butoxycarbonyl-4-I(2 or S ,3S)-2-hydroxy-3-(N-quinialdyl-L- v alyl)arnino-4-phenylbutyl] -3 ,4-diazabicyclo O]decane (ix) cis-1, ,6-3 -t-butoxycarbonyl-4-[(2R or S ,3S)-2-hydroxy-3-[N-(2-pyridyl)- methoxycarbonyl)-L-valyl)amino-4-phenylbutyll-3 ,4-diaza-bicyclo[4 16 decane (x cis- 1, 6-3 -t-butoxycarbonyl-4-[2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-L- asparaginyl)amino-4-phenylbutyl]-3 ,4-diazabicyclo 0]decane, (xi) cis-1, ,6-3-t-butoxycarbonyl-4- [(2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-L- Vglutaminyl)amino-4-phenylbutyl] -3 ,4-diazabicyclo[4 .4 .O]decane, (xii) cis- 1, 6-3-t-butoxycarbonyl-4- [(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-L- threonyl)amino-4-phenylbutyl]-3 ,4-diazabicyclo [4.4 .O]decane, (xiii) 2-t-butoxycarbonyl-3-[(2R or S ,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amino-4-phenylbutyl]-2,3-diazabicyclo[2 (xiv) 2-t-butoxycarbonyl-3-[(2R or S ,3S)-2-hydroxy-3-(phenylmethoxycarbony1)- amino-4-pheniylbutyl]-2, 3-diaza-bicyclo[2.2. iliheptane, (xv) 2-t-butoxycarbonyl-3-[2R or S ,3S)-2-hydroxy-3-(N-(2-pyridyl)methioxy-L- valyl)amino-4-phenylbutyl]-2,3-diaza-bicyclo[2 illheptane, (xvi) 2-[N-(1S)(2-methyl- 1-methoxycarbonylpropyl)carbamoyl]-3-[(2R or S, 3S)- 2-hydroxy-3-[N-,(2-pyridyl)methoxy-L-valyl]amino-4-plenylbutyl]-2, 3- diazabicyclo[2.2. I ]heptane, (xvii) 2-t-butoxycarbonyl-3-[(2R or 5, 3S)-2-hydroxy-3-(N-quinaldyl-L- asparaginyl)amino-4-phenylbutyl] 3-diazabicyclo 1]heptane, (xviii) 1 -12-(2-pyridyl)methoxycarbonylamino-]benzoyl-2-[(2-R or S ,3S)-2- hydrc-xy-3-(N-quinaldyl-L-aparaginyl)amino-4-phenylbutyl-2-isopropyl- hydrazine, (xix) 2-t-butoxycarbonyl-3.-[(2R or 5, 3S)-2-hydroxy-3-(N-quinaldyl-L- asparaginyl)amino-4-phenylbutyl]-1 ,2,3 ,4-tetrahydrophthalazine, (xx) 1-trimnethylacetyl-2-[(2R or S ,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- 9LM amino-4-phyenylbutyljI-2-isopropylhydrazifle, (N:kLIBZNARH-EX)25O529AU:SAK 6L I-IP-OH ~P-OH 5-9A/ is selected from OH and H [N:XLIBZ\NA.9HEX250529AU:SAK 170 (xxi) 1-trimethylacetyl-2-[(2R or S ,3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl) aimino-4-phenylbutyl]-2-isopropylhydrazine, (xxii) 1-(t-butylamino)carbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-L- asparaginyl)amino-4-phenylbutyl]-2-isopropylhydrazine, (xxiii) t-butyl 3-isopropyl-3-[(2R or S ,3S)-2-hydroxy-3-(N-picolinyl-L- asparaginyl)amino-4-phenylbutyllcarbazate, (xxiv) t-butyl 3-isopropyl-3-[(2R or S ,3S)-2-hydroxy-3-(N-(2-pyridyl)-methoxy- carbonylanthranilyl)amino-4-phenylbutyl]carbazate. (xxv) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)- amnino-4-phenylbutyllcarbazate, (xxvi) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(Nq-quinaldyl-L-asparaginyl)- amino-4-phenylbutyllcarbazate, (xxvii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(Phenyl-methoxy- carbonyl)amino-4-phenylbutyllcarbazate, 16 (xxviii) t-butyl 3-cyclohexyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldyl-L- (xix)asparaginyl)aminio-4-phenylbutyllcarbazate, (xi)t-butyl 3-isopropyl-3-[(2R or S ,3S)-2-hydroxy-3-(N-(1-carbamoyl-methyl)- acrylyl)amio-4-phenylbutyllcarbazate, (xxx) t-butyl 3-isopropyl-3-[(2R or S ,3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio- 2-c arbamoyl-methylpropionyl)amino-4-phenylbutyllcarbazate, (xxxi) t-uy -spoy--(Ror S ,3 S)-2-hydroxy-3-(N-(1-benzoyl-L- asaaiylaio4phnluy..raae (xxxii) 1-t-butyloxycarbonyl-2-[(2R or S ,3S)-2-hydroxyV-3-(phenylmethoxy- *.,carbonyl)aniiino-4-phenylbutyrllhexahydropyridazilie, (xxxiii) 1-t-bvtyloxycarbonyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldyl-L- C asparaginyl)amino-4-phenylbutyl]hexahydropyridazine, and good too (xxxiv) cis- 1, 6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hiydroxy-3-(N-quinaldyl-3- t cyano-L-alanyl)amino-4-phenylbutyl]-3 ,4-diaza-bicyclo[4,4,O]decane, wherein the 2-hydroxy group is derivatised with a solubilising group Px as defined in claim 1. 8. A compound acording to claim 7, wherein said solubilising group is selected from 0 0 ~POH H O and 9. A compound according to claim 8, which compound is selected from the group consisting of: cis-1 ,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2- Phosphonooxy-3-(N-quinaldyl-L- asparaginyl)amino.-phenylbutyfl-3 ,4-diaza-bicyclo[4.4. O]decane; OI N:\LIBZ\NARHEX1250529AU:SAK (N:AL(8kNARHEXJ 2 6C2 5 O :A 171 cis-1, ,6-3 -t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldyl-L- asparaginyl)amino-4-phenylbutyl]-3 ,4-diaza-bicyclo[4 .4 .O]decane; t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphonooxy-3-(N-quiinaldyl-L-asparaginyl)- amino-4-phenylbutylcarbazate and t.KButyl 3-isopropyl-3II2S, 3S)-2-phosphitooxy-3-(N-quinaldyl-L-asparaginyl)amino- 4-phenylbutylcarbazate; or a pharmaceutically acceptable salt thereof. Cis- 1,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldyl-L- asparaginyl)aniino-4-pheniylbutyl]-3 ,4-diaza-bicycloli4.4.0]decane or a pharmaceutically acceptable salt thereof. It. t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-L-asparaginyl)- amnino-4-phenylbutylcarbazate or a pharmaceutically acceptable salt thereof. 12. A compound of formula as defined in claim 1, substantially as hereinbefore described with reference to any one of the Examples. 15 13. A process for enhancing the water-solubility of an HIV protease inhibitor, comprising derivatising a functional group of said HIV protease inhibitor with a solubilising group Px, wherein Px is selected from the group consisting of Px*, CC.. CC a e *0 0 CC., no. o~. V C Cq o *OCC C. 0 oft. C. Eq 0 0 C. eq o C *0* Can C 0 C, 0 CC 0 0 R ,and D ,wherein D is 0 or S, R is H or CI-C 4 alkyl, and wherein Px* is selected from: 0 11 0 H S 11 OH 0OH 0 P-H O 0 O H O H 0 ~OH 0 0 1'1 OH -NO 2 X S, S(O) 2 0 OH 0 BKOH OH (NAUS8?.NARI-EX1250529AU:SAK Ho H 0 from o o pP and s -0 N:\LIZ\NARHEX]250 5 2 9AU:SAK low- M"7 0 0 .A II 11 OH 0 0 R N%. 0 H (CH 2 4 NH 2 NH -N NH 2 I-! 0 H SNH f, fit flit ft e t r Ie i tt tit lit t~ i* f t t it. ii I I I I ii it it I t t «it t 4< II and "i said functional group being capable of being derivatised with said solubilising group Px. 14. A process according to claim 13 wherein said solubilising group Px is selected from 0 0 II I I JPOH and -P-OH OH H 15. A process according to claim 14 comprising reacting a hydroxyl group of said HIV protease inhibitor with phosphorous acid and optionally oxidising the product so obtained. 16. The product of the process of any one of claims 13-15. 17. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 12 or 16 together with at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. 18. A process for preparing a pharmaceutical composition according to claim 17, comprising mixing a compound according to any one of claims 1 to 12 or 16 with at least one pharmaceucically acceptable carrier, diluent, excipient and/or adjuvant. 15 19. A method for the treatment or prophylaxis of a retroviral infection, comprising administering to a patient in need of such treatment or prophylaxis a therapeutically effective amount of a compound according to any one of claims 1 to 12 or 16, or of a composition according to claim 17. A method according to claim 19 wherein said retroviral infection is AIDS. Dated 17 July, 1998 Narhex Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON lN:\LIBZNARHEXI250C29AU:SAK