AU708620B2 - Inhibitors of farnesyl-protein transferase - Google Patents

Description

Inhibitors of Farnesyl-Protein Transferase Background of the Invention The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive states, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form Lowy and D.M. Willumsen, Ann. Rev.

Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in S: their GTPase activity and constitutively transmit a growth stimulatory signal.

000 Ras must be localised to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localisation, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa 1 -Aaa 2 -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature :1 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which 0 [R:\L1BAA07294.doc:TAB _1 WO 96/34010 PCT/US96/03975 -2catalyze the alkylation of the cysteine residue of the CAAX motif with a or C20 isoprenoid, respectively. Clarke., Ann. Rev. Biochem.

61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209- 237 (1992)). The Ras protein is one of several proteins that are known to undergo post-translational farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of faresyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of rasdependent tumors in nude mice Kohl et al., Proc. Natl. Acad. Sci 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al.. Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis i ~1 WO 96/34010 PCT/US96/03975 -3by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the faresyl-protein transferase enzyme, or may be purely competitive inhibitors Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.

It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).

It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).

Imidazole-containing inhibitors of famesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).

It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit farnesyl-protein transferase and thus, the post-translational WO 96/34010 PCT/US9603975 -4farnesylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.

SUMMARY OF THE INVENTION The present invention comprises analogs of the CA 1

A

2

X

motif of the protein Ras that is modified by farnesylation in vivo. These

CA

1

A

2 X analogs inhibit the farnesylprotein transferase. Furthermore, these CA 1

A

2 X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thioldependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A 2 position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

r WO 96/34010 WO 96/40 10PCTIUS96/03975 The compounds of this invention are illustrated by the formulae:

(R

8 )r (R9 z R~aFI -A(CRa ),A 2 (CRa On (CRb 2 )p V~iN

N

(R

8 )r

R

II Re A'l(CR a 2

A

2 (CRia 2 On WI (CRlb 2

N

x

R

2 3 II R4a/

(R

8 )r

R

R

V Al(CRla 2 )nA 2 (CRla 2 WxC~ 2p xR2R III R4a/ V Al(CRla 2 )nA 2 (CRlaOn (CRlb 2 )p

YR

2

R

3 IV Ra DETAILED DESCRIPTION OF THE INVENTION R 4 b 0 R 4 b The compounds of this invention inhibit the farnesyl-protein transferase. In a first embodiment of this invention, the farnesyl-protein transferase inhibitors are illustrated by the formula I: WO 96/34010 WO 9634010PCTIUS96/03975 -6- V Al(CRla 2

),A

2 (CRla On)U R 6 Y11

OH

R 4 b wherein: R Ia and Ri1b are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R 10 0-, RI IS(O)m-, Rl 0 C(O)NRIO-, CN, N02, (Rl 0 )2N- C(NRIO)-, RlOC(O)-, RIOOC(O)-, N3, -N(RIO)2, or

R

1 lOC(O)NR 10 C) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloallcyl, alkenyl, alkynyl, RIO0-,

R

1 R' 0

C(O)NR

10 CN, (R 10 )2N-C(NR' RlOC(O)-, RIOOC(O)-, N3, -N(Rl 0 or RI IOC(O)-

R

2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted ClI-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 1 0 R1 1 R I C(O)NR 1 0 CN, (RlO)2N-C(NRIO)-, RlOC(O)-, RIOOC(O)-, N3, -N(R 10)2, R1 1 OC(O)NR 10 and C1I-C20 alkyl, and WO 96/34010 WO 96(40 10PCTfUS96/03975 -7d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Clo cycloalkyl; or

R

2 and R 3 are combined to form (CH2)s or R2or R3are combined with R 6 to form a ring such that

R

6 is (HA) R2R 3 R~a R 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) C 1-C6 alkyl unsubstituted or substituted by alkenyl, R 100-, Rl Rl 0

C(O)NR

10 CN, N3, (Rl 0 )2N-C(NRIO)-, RlOC(O)-, RIOOC(O)-, -N(R 1 0 or RI c) aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 0-, Rl 1 Rl 0

C(O)NR

10 CN, N02, (Rlo)2N- C(NR1 0 RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 )2, or R I IOC(O)NR 10 and d) C1I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-ClO cycloalkyl; and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-C 10 cycloalkyl, aryl or heterocycle group, WO 96/34010 WO 96/40 10PCT/US96/03975 -8wherein the substituent is selected from F, Cl, Br,

(R

1 0 N02, RIO0-, Rl IS(O)m7-,

R

1 OC(O)NRIO0., CN, (Ri 0 )2N-C(NR 1 R 1

OC(O)-,

R 1OOC(O)-, N3, -N(R 10 R I IOC(O)NR 1 0- and C1I-C20 alkyl, d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Clo cycloalkyl; or R5a and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and -N(COR 10)-

R

6 is independently selected from hydrogen or C I -C6 alkyl;

R

8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalcyl, F, Cl, Br, R 100-, R1 1 S RIOC(0)NRIO-, CN, N02, R102N-C(NR 1 0 RlOC(0)-, R 1OOC(0)-, N3, -N(R 10 or R1 1 OC(O)NR 1 0 and c) Cl1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, peffluoroalicyl, F, Cl, Br, R 1 0 R I IS(0)m-, R I C(0)NH-, CN, H2N- RlOC(0)-, RlOOC(0)-, N3, -N(RIO)2, or

R

1 OOC(0)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIOO-, RI RIOC(O)NRIO-, CN, N02, (RIO)2N-C

(NR

1 RIOC(O)-, RIOOC(0)-, N3, -N(R 1 0 or R1 1 0C(O)NR 1 0 and WO 96/34010 PCT/US96/03975 -9c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R100-, R 1 1 R10C(O)NR10-, CN, (R10)2N-C(NR10)-, R10C(O)-, R10OC(O)-, N3, -N(R10)2, or R11OC(O)NR10-;

R

10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;

R

1 1 is independently selected from C1-C6 alkyl and aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, O, -S(0)2N(R10)-, -N(R 1 0 or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; 1, WO 96/34010 WO 9634010PCTfUS96/03975 p is 0,1, 2, 3or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or t is 3, 4or u is 0Oorl1; or the pharmaceutically acceptable salts thereof.

In a second embodiment of this invention the prodrugs of compounds of formula I are illustrated by the formula H:

(R

8 )r (R9 y) R 6Y 7 Z N OR 12 V-Al(CRla 2 )nA (CRla 2 )n H CI2 II

R

4 a R 4 b wherein: Ri1a and Ri1b are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R 1 0 0-, RIIS(O)m-, RIOC(O)NRIO-, CN, N02,

(R

1 0 )2N-C(NRIO)-, R10C(O)-, R10OC(O)-, N3, -N(R 10)2, or Ri 11OC(O)NR c) Ci1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 1 00-., R 11 S R 1 C(O)NR 1 0 CN, (R 1 02N-C(NR 10 RlOC(O)-, R 10 N3, -N(R 1 0 or R 1 1OC(O)-

R

2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and WO 96/34010 WO 9634010PCTIUS96/03975 11 c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-ClO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R'0%2, N02, RIO0-, R 1 IS(O)m-, RIOC(O)NRIO-, CN, (R 1 0 )2N-C(NRIO)-, RIOC(O)-, RlOOC(O)-, N3,

-N(R

1 0 RI I0C(O)NRIO- and Cl-C20 alkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO0 cycloalkyl; or

R

2 and R3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that R 6 is (HA) R2RR7aR 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) Cl1-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, RIIS(O)m-, RIOC(O)NRIO-, CN, N3, (Rlo)2N-C(NR 10 RIOC(O)-, RIO0C(O)-, -N(RIO)2, or RI lOC(O)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, R100-, RIIS(O)m-, RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, RlOOC(O)-, N3, -N(R 1 0 )2, or R1 1 0C(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, WO 96/34010 WO 9634010PCT1US96/03975 -12b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1I-C20 alkyl, C2-C20 alkenyl, C3-C1O cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,

(R

1 0 N02, R 10 RI 1 S(O)m-, Rl OC(O)NRl CN, (RI 0 )2N-C(NRl0)-, Rl 0 R IOOC(O)-, N3, -N(R 10 R I IOC(O)NR 10- and C1I-C20 alkyl, d) C I -C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Ci 10 cycloallcyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and

R

6 is independently selected from hydrogen or C1I-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroatkyl, F, Cl, Br, R 1 0 R I IS(0)m-,

R

1 OC(O)NR' CN, N02, Rl 0 2N-C(NR 1

R

1 OC(0)-, RIOOC(O)-, N3, -N(R 1 0 or RI IOC(0)NRIO-, and c) Cl -C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R I IS(0)m-, R I C(O)NH-, CN, H2N- RIOC(0)-, R 1 0 N3, -N(RIO)2, or RIOOC(0)NH-;

R

9 is selected from: WO 96/34010 WO 9634010PCTIUS96/03975 13 a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI 1 Rl 0 C(O)NRIO-, CN, N02, (Rl 0 )2N-C- (NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(Rl 0 or R I I0C(O)NR 10-, and c) C1I-C6 alkyl unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, R100-, RI IS(O)m-, RIOC(O)NR10-, CN, (Ri 0 )2N-C(NR 1 R' R 1 OOC(O)-, N3, -N(RL 0)2, or R 1 R 1 0 is independently selected from hydrogen, C1I-C6 alkyl, benzyl and aryl; R I is independently selected from C1I-C6 alkyl and aryl;

R

12 is a) substituted or unsubstituted ClI-C8 ailkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1I-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R 1 1 )2,

-OR'

0 or b) R 1 3 0o

R

13 is independently selected from hydrogen and ClI-C6 alkyl;

R

14 is independently selected from ClI -C6 alkyl; i WO 96/34010 PCT/US96/03975 -14- Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NRO1C(O)-, O, -S(0)2N(R 10 -N(R1 0 or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; mis 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or t is 3, 4 or 5; and u is 0 or 1; or the pharmaceutically acceptable salts thereof.

In a third embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula III: I- WO 96/340 10 PCTIUS96/03975

HOCH

2

(CH

2 )q

(R

8 )r

R

I(aRI lb R6Z

OH

-Al(CRla 2 )nA 2 (CRla) O W- C 2p N N U 0 wherein: IIx R Ia and Ri1b are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R1 0 0-, Rl 1 RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NRIO)-, Rl 0 RlOOC(O)-, N3, -N(RIO)2, or Ri 11OC(O)NR C) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R 10 0-,

R

1 1 RIOC(O)NRIO-, CN, (RIO)2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(R 1 0 or R 1 1OC(O)- R2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RlO0-, RI IS(O)m-, RIOC(O)NRIO-, CN, (RI 0 )2N-C(NRl RI R 1 OOC(O)-, N3, -N(RIO)2, RI I0C(O)NRIO- and Cl-C20 alkyl, and WO 96/34010 PTU9/37 PCTIUS96/03975 -16d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or

R

2 and R3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that Nis

(HA)

R2RR 7 a R 7 b R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) C 1-C6 alkyl unsubstituted or substituted by alkenyl, R 100-, RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (RIO)2N-C(NRIO)-, RlOC(O)-, RIO0C(O)-, -N(RlO)2, or R 1 lOC(O)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, R 100-, R1 1 RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NR R 1 R' OOC(O)-, N3, -N(Rl 0)2, or R1 1 'OC(O)NR 1 and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloalkyl; R6 is independently selected from hydrogen or C I -C6 alkyl;

R

8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 100-, R I 1 S(O)m-, RIOC(O)NRIO-, CN, N02, R 1 0 2N-C(NRIO)-, RIOC(O>-, RIO0C(O)-, N3, or RI 1 0C(O)NRIO-, and

I

WO 96/34010 WO 96/40 10PCTfUS96/03975 17 c) C I -C6 ailkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, ailcenyl, alkynyl, peffluoroalkyl, F, Cl, Br, R 10 0- R 1 1S(O)m-, R IOC(O)NH-, CN, H2N- RIOC(O)-, RIO0C(O)-, N3, -N(R 1 0 or RIO0C(O)NH-;

R

9 is selected from: a) hydrogen, b) alcenyl, alkynyl, perfluoroalcyl, F, Cl, Br, R 1 00.., RIIS(0)m-, RIOC(0)NRIO-, CN, N02, (RIO)2N-C- RIOC(O)-, RIO0C(0)-, N3, or

R'

1 0OC(O)NRIO-, and c) C1I-C6 alkyl. unsubstituted or substituted by peffluoroalkyl, F, Cl, Br, R 10 RI IS RIOC(0)NRIO-, CN, RIOC(O)-, R 1 0 N3, -N(R 1 0 )2, or R1 1 0C(0)NR10-; R 10 is independently selected from hydrogen, ClI-C6 alkyl, benzyl and aryl;

R

1 is independently selected from ClI-C6 alkyl and aryl;

A

1 I and A 2 are independently selected from: a bond, -CH=CH-, -C=EC-, -C(0)NRIO-, -NRlOC(0)-, 0, -N(RIO)-, -S(0)2N(RlO)-, -N(RlO)S(0)2-, or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring; V is selected from: a) hydrogen, b) heterocycle, c) aryl, WO 96/34010 PCT/US96/03975 -18d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if

A

1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; m is n is p is q is ris s is t is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 4 or 3, 4 or 5; and 0or 1; or the pharmaceutically acceptable salts thereof.

In a fourth embodiment of this invention the prodrugs of compounds of formula III are illustrated by the formula IV:

(R

8 r 9 Z q

S

R 6 OCRb V- A'(CR'a 2 )nA 2

(CR

1 a 2 n

(CR

1 2

H

IV R4a/ R 4 b wherein: R a and Rlb are independently selected from: a) hydrogen, Il I r I II I I I WO 96/34010 WO 96(40 10PCT1US96/03975 -19b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R 100-, RI 1 RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NR1O)-, RlOC(O)-, RIOOC(O)-, N3, -N(RIO)2, or R I IOC(O)NR C) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloallcyl, alkenyl, alkynyl, R 1 0 0-,

R

1 RIOC(O)NRIO-, CN, (RIO)2N-C(NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or RI IOC(O)-

NRIO-;

R

2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1I-C20 alkyl, C2-C20 alkenyl, C3-C1O cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,

N(R

1 0 N02, RIO0-, RI 1 RIOC(O)NRlO-, CN, (R 1 0 )2N-C(NRIO)-, RIOC(O)-, RlOOC(O)-, N3,

-N(R

1 0 RI IOC(O)NRlO- and C1-C20 alkyl, and d) Ci1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R2 and R 3 are combined to form (CH2)s or R2or R3 are combined with R 6 to form a ring such that R 6

(H

2 )t R7a R 7 b WO 96/34010 WO 9634010PCT/US96/03975 20 R4a, ROb, R' 7 a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, RIIS(O)m-, RIOC(O)NRIO-, CN, N3, (Rl 1 %2N-C(NRIO)-, RIOC(O)-, R10OC(O)-, -N(R 1 0 or RI IOC(O)NRIO-, c) aryl, heterocycle, cycloalkyl, ailkenyl, R 10 0-,

R

1 1 RIOC(O)NRIO-, CN, N02, (RIO)2N- RIOC(O)-, R10OC(O)-, N3, -N(R 1 0 )2, or R1 1 OC(O)NR 10-, and d) C1I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C1O cycloalkyl;

R

6 is independently selected from hydrogen or C 1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, ailkynyl, peffluoroalkyl, F, Cl, Br, R 1 0 R I R 1 0 C(O)NRIO0, CN, N02, Ri 0 2N-C(NR 1

R

1

OC(O)-,

R IOOC(O)-, N3, -N(Rl10)2, or R I I0C(O)NR 10-, and c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RllS(O)m-, Rl 0 C(O)NH-, CN, H2N- RIOC(O)-, RIOOC(O)-, N3, -N(Rl 0 or

R

10 0C(O)NH-;

R

9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RIOO-, R I IS(O)m-, R 1 C(O)NR 10 CN, N02, (RI 0 )2N-C RIOC(O)-, RIO0C(O)-. N3, -N(R 1 O)2, or R I

I

OC(O)NR 10 and

I

WO 96/34010 PCT/US96/03975 -21c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10

R

1 1 R10C(O)NR 10

CN,

(R

10 )2N-C(NR10)-, R 10 R10C(O)-, N3, -N(R10)2, or R11OC(O)NR 10

R

10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl; Rl 1 is independently selected from C1-C6 alkyl and aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, O, -S(0)2N(R 10 -N(R10)S(0)2-, or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; WO 96/34010 PCT/US96/03975 -22pis q is r is s is tis u is 0,1, 2, 3 or4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 4 or 3, 4 or 5; and Oor 1; or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the Ras farnesyl transferase inhibitors are illustrated by the Formula I:

R

5a

R

5 b (R )r R9 V A'(CRa 2 )nA 2 (CR1a 2 W u

O

R

4 b wherein: Ra is independently selected from: hydrogen or Cl-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10

-N(R

1 0 )2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2;

R

2 and R3 a) b) are independently selected from: a side chain of a naturally occurring amino acid, an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, WO 96/34010 WO 9634010PCTIUS96/03975 c) substituted or unsubstituted C I-Ci10 alkyl, C2-C 10 alkenyl, C3-C 10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 RI IS(O)m-, RIOC(O)NR 10

CN,

(R

1 0 )2N-C(NRIO)-, RIOC(O)-, RIOOC(O)-, N3,

-N(R

1 0 RI lOC(O)NRIO- and Cl-C20 ailkyl, and d) C1I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or

R

2 and R3 are combined to form (CH2)s or R2 or R3are combined with R 6 to form a ring such that R6 Nis

(H

2 )t R 2R30"R 7 b R4a and R 7 a are independently selected from: a) hydrogen, b) C1I-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, RI IS(O)m-, R 10 C(O)NRIO-, CN, N3, (Rl 0 )2N-C(NR 10 RIOC(O)-, RIOOC(O)-, -N(RIO)2, or R1 IOC(O)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, R1 1 RIOC(O)NRIO-, CN, N02, (Rl 0 )2N- C(NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(Rl 0 )2, or R IIOC(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- Ci 10 cycloalkyl; R4b and R7b are hydrogen; WO 96/34010 WO 96/40 10PCTfUS96/03975 -24is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I-Ci1Q alkyl, C2-C 10 alkenyl, C3-C 10 cycloalkyl, aryl or heterocyclic group, wherein the sub stituent is selected from F, Cl, Br, N02, RIO0-, Rl 1

RIOC(O)NR

10 (Rl 0 CN, (Ri 0 )2N-C(NR10)-, R 1

OC(O)-,

RIO0C(O)-, N3, -N(R 1 0 RI IOC(O)NRIO- and C1I-C20 alkyl, and d) C I -C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; is selected from: a) hydrogen, and b) ClI-C3 alkcyl;

R

6 is independently selected from hydrogen or C 1-C6 alkyl; R8 is independently selected from: a) hydrogen, b) ClI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ClI-C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (RI 0 )2N-C(NR 1

R

1

R

1 OOC(O)-, -N(Rl 0)2, or R 1 1 0OC(O)NR 1 and c) ClI-C6 alkyl substituted by ClI-C6 perfluoroalkyl, Rl100-, RlOC(O)NRIO-, (R 10 )2N-C(NRI10>, RIOC(O)-, RIOOC(O)-, -N(RlO)2, or RI WO 96/34010 WO 96/40 10PCTIUS96/03975 25 R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl1-C6 perfluoroalkyl, F, Cl, R1 0 RI IS(O)m-, RIOC(O)NR 1 0 CN, N02, (RIO)2N-

C(NR

10 RlOC(O)-, RIOOC(O)-, -N(Rl 0 or Ri 1 OC(O)NR10-, and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, RIO0-, RI IS(O)mw-, Rl 0

C(O)NRIO-,

CN, (Ri O)2N-C(NR 1

R

1 R lOOC(O)-, -N(Rl 0)2, or R1 OC(O)NR 10 R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl; R 1 is independently selected from C1I-C6 ailkyl and aryl; Q is selected from: N ~and +Nb Al and A 2 are independently selected from: a bond, -CH=CH-, -C=EC-, -C(O)NR10-, 0, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from'pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, WO 96/34010 PCT/US96/03975 -26d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is n is pis r is t is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4 or 5; and 0or 1; or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention, the prodrugs of the preferred compounds of Formula I are illustrated by the Formula II:

R

5 b 1r R 9 Z ORr I |R6 Y N O': V A(CR1a 2 )nA 2 (CRla 2 )n (CR1b 2 Q H

R

4 b

II

4a wherein: Ra is independently selected from: hydrogen or C1-C6 alkyl; WO 96/34010 PCT/US96/03975 -27- Rlb is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R 10)2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2;

R

2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R1 0

R

1 1

R

10

C(O)NR

10

CN,

(R10)2N-C(NR 1 R10C(O)-, R10OC(O)-, N3,

-N(R

10 R11OC(O)NR10- and C1-C20 alkyl, and d) C 1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or

R

2 and R 3 are combined to form (CH2)s or R2 or R 3 are combined with R 6 to form a ring such that

R

6 R2R 7a 2 R 7 b R4a and R 7 a are independently selected from: a) hydrogen,

MENNEN

WO 96/34010 PCT/US96/03975 28 b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 100-, RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (RlO)2N-C(NR10)-, RIOC(O)-, RIOOC(O)-, or Rl IOC(O)NRlO-, c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, RIIS(O)m7, RIOC(O)NRi0-, CN, N02, (R 1 0 )2N- C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(R'O)2, or R 11OC(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- Gb1 cycloalkyl; ROb and R7b are hydrogen; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted ClI-C 10 alkyl, C2-C 10 alkenyl, cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 R II R 10 C(O)NR (Ri 0 CN, (Ri 0 )2N-C(NR Ri OC(O)-, R I 0 N3, -N(Ri1 0 Ri 11OC(O)NR 1 0- and C I -C2o ailkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 1 cycloalkyl; is selected from: a) hydrogen, and b) C I-C3 alkyl; WO 96/340 10 PCTIUS96/03975 29 R6 is independently selected from hydrogen or C I-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C1I-C6 alkyl, C2-C6 ailkenyl, C2-C6 ailkynyl, ClI-C6 perfluoroalkyl, F, Cl, R 10 RIOC(O)NRIO-, CN, N02, (Rl 0 )2N-C(NRI R 10 Rl 0 -N(Rl 0)2, or Rl 1

OC(O)NR

1 and c) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 100-, Rl OC(O)NRl (Rl 0 )2N-C(NRI

R

1

OC(O)-,

RIO0C(O)-, -N(RlO)2, or RI I0C(O)NRIO-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 aikynyl, ClI-C6 perfluoroalcyl, F, Cl,

RI

0 RI IS(O)m-, RI 0 C(O)NRIO-, CN, N02, (RI 0 )2N- C(NRIO)-, RI 0 RIO0C(O)-, -N(RlO)2, or R I I0C(O)NR 10-, and C) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 1 0 R I 1 R I C(O)NR CN, (Rl 0 )2N-C(NRl Rl Rl 0 -N(Rl 0)2, or R 1

OC(O)NRIO-;

R 10 is independently selected from hydrogen, ClI -C6 alkyl, benzyl and aryl; R I is independently selected from C I-C6 alkyl and aryl;

R

1 2 is a) sub stituted or unsubstituted C I -C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from: 1) aryl, WO 96/34010 PCTfUS96/03975 2) heterocycle, 3) -N(R11)2, 4) -OR 10 or

R

1 3 0 \^OK R 1 4

R

13 is independently selected from hydrogen and C1-C6 alkyl;

R

14 is independently selected from C1-C6 alkyl; Q is selected from:

I

N

and Al and A 2 are independently selected from: a bond, -CH=CH-,

-C(O)NR

10 O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if

A

1 is a bond, n is 0 and A 2 is S(O)m; Ir i II rl I II WO 96/34010 PCT/US96/03975 -31- W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is n is pis r is t is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4 or 5; and Oor 1; or the pharmaceutically acceptable salts thereof.

In a third more preferred embodiment of this invention, the inhibitors of farnesyl transferase are illustrated by the formula III: (R )r R9 V A'(CRla 2 nA2 (CR la 2 )n

III

.OH

R

4 b wherein: Ra is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10

-N(R

10 )2 or alkenyl, WO 96/34010 PCTIUS9603975 -32c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 or -N(R10)2; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted CI-C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0

R

1 lS(O)m-, R 10 C(O)NR1 0

CN,

(Rl0)2N-C(NR10)-, R 1

R

1 00C(O)-, N3,

-N(R

1 0 R110 C(O)NR10- and C1-C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3cycloalkyl; or

R

2 and R3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that R6 N is

H

2 R 2 R3 R7a R7b R4a and R 7 a are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R100-,

R

1 1 R1 0

C(O)NR

10 CN, N3, (R 10 )2N-C(NR 10 RIOC(O)-, R100C(O)-, -N(R 10 or R 1 1 0C(O)NR 1 0 WO 96134010 PTU9/37 PCTfUS96/03975 33 c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 0-,

R

1 IS(O)m-, Rl 0 C(O)NRiO-, CN, N02, (R'%2N- C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(Rlo)2, or R' 1 OC(O)NR 10-, and d) C I -C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 10 cycloalkyl; R4b and R7b are hydrogen; R6 is independently selected from hydrogen or C1I-C6 alkyl; R8 is independently selected from: a) hydrogen, b) C1I-C6 alkyl, C2-C6 alkenyl, C2-C6 ailcynyl, Cl1-C6 perfluoroalkyl, F, Cl, R 10 R IOC(O)NR 10-, CN, N02,

(R

1 0 )2N-C(NRIO)-, RlOC(O)-, RIOOC(O)-, -N(Rl 0 or RIIOC(O)NRIO-, and c) C1I-C6 alkyl substituted by C1I-C6 peffluoroalkyl, R 10 0-, Rl OC(O)NRl (Rlo)2N-C(NRl Oy., R' 0 RIO0C(O)-, -N(RIO)2, or RI IOC(O)NRIO-;

R

9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, ClI-C6 peffluoroalkyl, F, Cl, R 1 0 R IIS(O)m-, RIOC(O)NR 1 CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, RIO0C(O)-, -N(R 1 0 or R1 1 OC(O)NR 10-, and c) ClI -C6 alkyl unsubstituted or substituted by ClI -C6 perfluoroalkyl, F, Cl, R 10 R I 1 R I 0 C(O)NR 1 0 CN, (RIO)2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, -N(R 1 0 )2, or R I I0C(O)NR R 10 is independently selected from hydrogen, ClI -C6 alkyl, benzyl and WO 96/34010 PCT/US96/03975 -34aryl;

R

1 1 is independently selected from C1-C6 alkyl and aryl; Q is selected from: N- -N and -N Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is O, 1 or 2; WO 96/34010 PCT/US96/03975 nis 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; t is 3, 4 or 5; and uis 0orl; or the pharmaceutically acceptable salts thereof.

In a fourth more preferred embodiment of this invention, the prodrugs of the preferred compounds of Formula III are illustrated by the Formula IV:

(R

8 )r R9 Z q SI R 6 Y 0 V A(CR 1 a 2 )nA 2 (CRa 2 W- (CRb2)p.N

O

IV R4a R 4 b wherein: R1a is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R10)2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2; R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: WO 96/340 10 PCTIUS96IrJ3975 36 i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1I-Ci10 alkyl, C2-C 1O alkenyl, C3-C1O cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R 1 1 RIOC(0)NRIO-,

CN,

(RI (b2N-C(NRl Ri 0

R

1 0 N3, -N(R 10)2, R I I0C(0)NR 10- and C I-CIO ailkyl, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or

R

2 and R3 are combined to form (CH2)s or

R

2 or R3 are combined with R 6 to form a ring such that is (HA)

R

3 Rb R4a and R 7 a are independently selected from: a) hydrogen, b) C I -C6 alkyl unsubstituted or substituted by alkenyl, R 100.., R' lS(0)m-, RItOC(0)NRIO-, CN, N3, (RIO)2N-C(NRIO)-, RIOC(0)-, RIO0C(0)-, or RI l0C(0)NRIO-, c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, RI 1 RlOC(0)NRIO-, CN, N02, (RIO)2N- C(NR R I R I N3, -N(R 10)2, or R' IIOC(0)NR 1 and d) CI -6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 1 cycloalkyl; WO 96/34010 W096/4010PCT/US96/03975 37 R4b and R7b are hydrogen; R6 is independently selected from hydrogen or ClI-C6 alkyl; R8 is independently selected from: a) hydrogen, b) Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 peffluoroalkyl, F, Cl, R 1 0 RIOC(O)NRIO-, CN, N02, (Ri 0 )2N-C(NR R 1 Rl 0 -N(Rl 0)2, or R I I0C(O)NR 1 and c) ClI-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 1 0 0-, RI OC(O)NRI (R'0)2N-C(NRl0)-, R 1

OC(O)-,

RIO0C(O)-, -N(RIO)2, or RI I0C(O)NRlO-; R9 is selected from: a) hydrogen, b) C2-C6 aikenyl, C2-C6 alkynyl, ClI-C6 perfinoroalkyl, F, Cl,

R

10 Rl 1 RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, R 1 0

-N(R

10 or R 1 1 0OC(O)NRl10-, and c) ClI -C6 alkyl unsubstituted or substituted by ClI -C6 perfluoroalkyl, F, Cl, R 10 R I 1 R 1 C(O)NR 1 0-, CN, (RI 0 )2N-C(NR R 1

R

1 0 -N(RI 0)2, or R1 1 iOC(O)NR R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl;

R

1 is independently selected from ClI-C6 alkyl and aryl; Q is selected from: WO 96/34010 PCTIUS96/03975 -38-

-N

ib and Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; mis n is p is q is r is t is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1,2, 3 or4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4 or 5; and 0or 1; ITI I II I WO 96/340 10 PCTJUS96/03975 39 or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows: N- H-Lmidazol-4-ylacetyl)-3 (S)-ethylpyrrolidin-2(S)-ylmethyl] prolyl-methionine methyl ester N- H-Imidazol-4-ylacetyl)-3 (S)-ethylpyrrolidin-2(S)-ylmethyl]prolyl-methionine N- [1-[i-(4-Cyanobenzyl)- 1H-imiidazol-5-ylacetyllpyrrolidin-2(S)ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester N- [1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]pyrrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine sulfone isopropyl ester N- [1-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethyl] -3 (S)-ethyl-prolyl-methionine sulfoxide N- -(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine sulfoxide isopropyl ester N- [1-[i-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethyl] -3 (S)-ethyl-prolyl-methionine sulfone [1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]pyrrolidin-2(S)ylmethyl]-3 (S )-ethyl-prolyl-methionine methyl ester N- [1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]pyrrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine N-[i H-Imidazol-4-ylacetyl)-pyrrolidin-2(S )-ylmethyl] -3(S)-ethylprolyl-methionine methyl ester N- H-Imidazol-4-ylacetyl)-pyfrolidin-2(S )-ylmethyl] -3(S)-ethylprolyl-methionine WO 96134010 WO 96/40 10PCTIUS96/03975 N- [1-Glycyl-pyrrolidin-2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester N- [1-Glycyl-pyrrolidin-2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine N- [1H-Imidazol-4-yl]propionyl)-pyrrolidin-2(S)-ylmethyl]-3(S)ethyl-prolyl-methionine methyl ester N- [1H-Imnidazol-4-yllpropionyl)-pyrrolidin-2(S)-ylmethyl]-3 (S ethyl-prolyl-methionine N- 1-(4-Cyanobenzyl)- 1H-imidazol-5-yl)propionyl]pyfrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester N-[i 1-(4-Cyanobenzyl)- 1H-imidazol-5-yl)propionyl]pyffolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine N- 1H-Imidazol-4-ylacetyl-amino)-3 (S)-methylpentyl]-prolylmethionine methyl ester N- [2(S)-(l1H-Imidazol-4-ylacetyl-amino)-3 (S)-methylpentyl]-prolylmethionine N- H-Lmidazol-4-ylacetyl)-pyrrolidin-2(S-)ylmethyl]-prolylmethionine methyl ester N- H-Imidazol-4-ylacetyl)-pyrrolidin-2(S -)ylmethyl] -prolylmethionine N- [1-[l-(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethyl] -prolyl-methionine methyl ester [1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]pyrrolidin-2(S ylmethyl]-prolyl-methionine [1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3 (S ethyl-prolyl-methionine methyl ester WO 96/34010 WO 96/40 10PCTfUS96/03975 -41- N- H-Imidazol-4-ylacetyl)-3 (S)-ethylpyrrolidin-2(S)-ylmethyl]-3 ethyl-prolyl-methionine N- -(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyl]-3 (S)-ethylpyrrolidin- 2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester N- [1-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyl]-3 (S)-ethylpyrrolidin- 2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine N- -(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyl]-3(S)-ethylpyrrolidin- 2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine isopropyl ester N- [1H-Imidazol-4-yllpropionyl)-3 (S)-ethylpyrrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester N- [1H-Imidazol-4-yl]propionyl)-3 (S)-ethylpyrrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine N- [1-Glycyl-3 (S )-ethylpyffolidin-2(S)-ylmethyl] -3 (S)-ethyl-prolylmethionine methyl ester N- [1-Glycyl-3 (S)-ethylpyrrolidin-2(S)-ylmethyl]-3 (S )-ethyl-prolylmethionine N- [1-(4-Nitrobenzyl)-l1H-imnidazol-4-ylacetyllpyrrolidin-2(S)ylmethyl] -3 (S)-ethyl-prolyl-methionine N- -(4-Nitrobenzyl)- 1H-imidazol-5-ylacetyl] pyrrolidin-2(S ylmethyl]-3 (S)-ethyl-prolyl-methionine N-[l (1-Farnesyl)-l1H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyl] 3(S)-ethyl-prolyl methionine WO 96/34010 WO 9634010PCTIUS96/03975 -42- N- -(1-Geranyl)- 1H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyl].

3 (S)-ethyl-prolyl-methionine N- [1-(4-Methoxybenzyl)- 1H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine I[1 [1-(2-Naphthylmethyl)- 1 H-imidazol-5-ylacetyllpyrrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine and N- H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3 (S)-ethylprolyl-(J3-acetylamino)alanine or the pharmaceutically acceptable salts thereof.

Specific examples of compounds of the invention are: N- H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3 (S)-ethylprolyl-methionine

SCH

3 00 1-(1 H-Imidazol-4-ylacetyl)-pyrrolidin-2(S )-ylmethyll-3 (S )-ethylprolyl-methiomne methyl ester WO 96/340 10 PCTJUS96/03975 -43-

SCH

3 00 N- [1H-Imidazol- 4 -yl]propionyl)-pyrrolicin-2(Sy .ylmethyl].3 ethyl-prolyl-methionine

SCH

3 0 N H0

NY

H

N- [1H-Imidazol-4-yllpropionyl)-pyrrolidin-2(Sy..ylmethyl]y3(Sy..

ethyl-prolyl-methionine methyl ester

SCH

3 0 N H 0

NY

H

N-Il-(3-[1 H-Imidazol-4-yllpropionyl (S )-ethylpyrrolidin-2(S)ylmethyl] -3(S )-ethyl-prolyl-methionine WO 96/340 10 PTU9/37 PCTfUS96/03975 -44-

SCH

3 0 0 ~0 N H0

H

N- [1H-lInidazol-4-yllpropionyl)-3 (S)-ethylpyrrolidin-2(S)ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester

SCH

3 o

OCH

3 N H 0

HH

lH-Imidazol-4-ylacetyl-amino)-3(S)-methylpentyl]-prolyl.

methiomine methyl ester

SCH

3 0 H N OH HiNN N No N 0Q lH-Imidazol-4-ylacetyl-amino)-3(S)-methylpentylp-prolylmethionine WO 96/340 PCTIUS96/03975 H N N- -(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]pyfrolidin-2(S).

ylmethyl]-3(S)-ethyl-prolylpmethionine

NC

q SCH 3 00 N- [1-[i-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyllpyrrolidin-2(Sy..

ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester

NC

q SCH 3 N 0 0 0 WO 96/34010 PCT/US96/03975 -46- N- [1 -(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]pyrrolidin-2(S)ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester

NC

SCH

3 N O

NH

N H

O

or the pharmaceutically acceptable salts thereof.

In the present invention, the amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below: Alanine Ala

A

Arginine Arg

R

Asparagine Asn

N

Aspartic acid Asp

D

Asparagine or Aspartic acid Asx

B

Cysteine Cys

C

Glutamine Gln

Q

Glutamic acid Glu

E

Glutamine or Glutamic acid Glx

Z

Glycine Gly

G

Histidine His

H

Isoleucine Ile

I

Leucine Leu L i mwm WO 96/34010 PCT/US96/03975 -47 Lysine Lys

K

Methionine Met

M

Phenylalanine Phe

F

Proline Pro

P

Serine Ser

S

Threonine Thr

T

Tryptophan Trp

W

Tyrosine Tyr

Y

Valine Val

V

The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.

As used herein, "cycloalkyl" is intended to include nonaromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds.

Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like.

As used herein, "aryl" is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.

WO 96/34010 PCTfUS96/03975 -48- The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2 -oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

As used herein, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(CI- C6 alkyl)2, N02, CN, (Cl-C6 alkyl)O-, -OH, (Cl-C6 alkyl)S(O)m-, (Cl- C6 alkyl)C(O)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (CI-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(O)NH- and C1-C20 alkyl.

Irll I CI The following structure: represents a cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring. Examples of such a cyclic amine moiety include, but are not limited to, the following specific structures:

N.

ego.

'00,

S

0* 0100 00 0 0 0 0 0 b 00 9*

S

4 .b 06 0 000* 050 00 09

S.

000 00 *0

B

It is also understood that substitution on the cyclic amine moiety by R 7 a and R 7 b may be on different carbon atoms or on the same carbon atom.

When R 3 and R 4 are combined to form (CH 2 )s cyclic moieties are formed.

Examples of such cyclic moieties include, but are not limited to: When R 5 a and R 5 b are combined to form (CH 2 )s cyclic moieties as described hereinabove for R 3 and R 4 are formed. In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: [R:\LIBAA]07294.doc:TAB i WO 96/34010 PCTIUS96/03975

S

H O O0

S-J

e II 00

S

COR

0 As used herein, the phrase "nitrogen containing C4-C9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be a C5-C7 saturated ring" which defines moiety of the instant invention includes but is not limited to the following ring systems:

J

x The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, from non-toxic inorganic or organic WO 96/34010 PCT/US96/03975 -51acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.

It is intended that the definition of any substituent or variable R10, Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.

Preferably, Ria and Rib are independently selected from: hydrogen, -N(R 8

R

8

C(O)NR

8 or C1-C6 alkyl unsubstituted or substituted by -N(R 8

R

8 0- or R 8

C(O)NR

8 Preferably, R 2 is the sidechain of glycine (hydrogen).

Preferably, R 3 is selected from: a) a side chain of a naturally occurring amino acid, b) substituted or unsubstituted C 1-C20 alkyl, wherein the substituent is selected from F, Cl, Br,

N(R

10 N02, R 10

R

11 R10C(O)NR 10 CN, (R 10 )2N-C(NR10)-, R10C(O)-, R1OOC(O)-, N3,

-N(RO

0 R11OC(O)NR 1 0- and C1-C20 alkyl, and c) C -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C10 cycloalkyl; or

R

3 is combined with R 6 to form pyrrolidinyl ring.

Preferably, R4a, R4b, R7a and R7b are independently selected from: hydrogen, Cl-C6 alkyl, aryl and benzyl.

Preferably, R5a and R5b are independently selected from: WO 96/34010 PCT/US96/03975 -52a side chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted C1-C6 alkyl Preferably, R 6 is: hydrogen or is combined with R 3 to form pyrrolidinyl ring.

Preferably, R 8 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R 10

R

1 1 CN, N02, R 10 2N-C(NR10)-, R 10

R

10 N3, -N(R 10 or R 1 1 OC(O)NR10- and C1-C6 alkyl.

Preferably, R 9 is hydrogen.

Preferably, R10 is selected from H, C1-C6 alkyl and benzyl.

Preferably, R 12 is selected from C1-C6 alkyl and benzyl.

Preferably, A 1 and A 2 are independently selected from: a bond, -C(O)NR10-, -NR 10 0, -S(0)2N(R 10 and- N(RO0)S(0)2-.

Preferably, Q is a pyrrolidinyl ring.

Preferably, V is selected from hydrogen, heterocycle and aryl.

Preferably, n, p and r are independently 0, 1, or 2.

Preferably t is 3.

The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety conventional chemical methods. Generally, the salts are prepared by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.

The compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1, Academic Press, 1980, or Stewart et al., "Solid Phase Peptide I I I r I i 3 1 I I I WO 96/34010 PCTIUS96/03975 -53- Synthesis", Second Edition, Pierce Chemical Company, 1984. The teachings of these works are hereby incorporated by reference.

Abbreviations used in the description of the chemistry and in the Examples that follow are: Boc

DBU

DMAP

DME

DMF

EDC

HOBT

Et3N EtOAc

FAB

HOOBT

HPLC

MCPBA

MsCI NaHMDS Py

TFA

THF

Acetic anhydride; t-Butoxycarbonyl; 1,8-diazabicyclo[5.

4 .0]undec-7-ene; 4 -Dimethylaminopyridine; 1, 2 -Dimethoxyethane; Dimethylformamide; 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride; 1-Hydroxybenzotriazole hydrate; Triethylamine; Ethyl acetate; Fast atom bombardment; 3-Hydroxy-1, 2 2 -benzotriazin-4(3H)-one; High-performance liquid chromatography; m-Chloroperoxybenzoic acid; Methanesulfonyl chloride; Sodium bis(trimethylsilyl)amide; Pyridine; Trifluoroacetic acid; Tetrahydrofuran.

Compounds of this invention are prepared by employing the reactions shown in the following Reaction Schemes A-J, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Some key bond-forming and peptide modifying reactions are: WO 96/34010 PCT/US96/03975 -54- Reaction A Reaction B Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.

Preparation of a reduced peptide subunit by reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.

Reaction C Deprotection of the reduced peptide subunit Reaction D Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies.

Preparation of a reduced subunit by borane reduction of the amide moiety.

Reaction E Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incorporating acyclic peptide units. It is well understood that such reactions are equally useful when the NHC(RA) moiety of the reagents and compounds illustrated is replaced with the following moiety:

R

7 b These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in the Reaction Schemes.

WO 96/34010 WO 9634010PCT/US96/03975 55 REACTION SCHEME A Reaction A. Coupling of residues to form an amide bond O R A )NO.'IuL,

OH

R 4 b EDO, HOBT or HOOBT Et 3 N, DMF HOI or

TEA

H

0 R 4 b WO 96/34010 WO 9634010PCT/US96103975 56 REACTION SCHEME B Reaction B. Preparation of reduced peptide subunits by reductive alkylation 0 R A C0 2

R

0Kj. N H H 0 NaCNBH 3 0 N 02 R 4 b REACTION SCHEME C Reaction C. Deprotection of reduced p~eptide subunits H C2 0 N 'll TFA c 0 R r R 4 b

HOI

C0 2

R

R 4 b R 4 a WO 96/34010 WO 9634010PCT/US96/03975 57 REACTION SCHEME D Reaction D. Coupling of residues to form an amide bond

H

2

N

0 EDO, HOBT or HOOBT Et 3 N, DMF

R

4 b 0~ HOI or TEA R 4 a, WO 96134010 PCT/US96/03975 -58- REACTION SCHEME E Reaction E. Preparation of reduced dipeptides from peptides

H

0 C0 2

R

J,,

BH3 THF

R

4 b

R

4 a where RA is R 2

R

3 R5a or R5b as previously defined; R4a and R4b are as previously defined; and R is an appropriate protecting group for the carboxylic acid.

Reaction Schemes F M illustrate reactions wherein the nonsulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to an acyclic peptide unit which may be further elaborated to provide the instant compounds. It is well understood that such reactions are equally useful when the NHC(RA) moiety of the reagents and compounds illustrated is replaced with the following moiety:

H

2 )t

R

7 b

I

WO 96/34010 PCT/US96/03975 -59- These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the reactions described in Reaction Schemes A E.

The intermediates whose synthesis are illustrated in Reaction Schemes A and C can be reductively alkylated with a variety of aldehydes, such as I, as shown in Reaction Scheme F. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme The reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide. The product II can be deprotected to give the final compounds III with trifluoroacetic acid in methylene chloride. The final product III is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine III can further be selectively protected to obtain IV, which can subsequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures.

Alternatively, the protected dipeptidyl analog intermediate can be reductively alkylated with other aldehydes such as 1-trityl-4carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as VIII (Reaction Scheme The trityl protecting group can be removed from VIII to give IX, or alternatively, VIII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X. Alternatively, the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.

The imidazole acetic acid XI can be converted to the acetate XIII by standard procedures, and XIII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XIV. Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the WO 96/34010 PCT/US96/03975 presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3ethylcarbodiimide (EDC) leads to acylated products such as XV.

If the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XVI in Reaction Scheme I, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes I, The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XX. In addition, the fully deprotected amino alcohol XXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme or tertiary amines.

The Boc protected amino alcohol XVIII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXIII (Reaction Scheme Treating XVIII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXIII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product

XXIV.

In addition, the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme M. When R' is an aryl group, XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXI. Alternatively, the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXII produced.

Similar procedures as are illustrated in Reaction Schemes F- M may be employed using other peptidyl analog intermediates such as those whose synthesis is illustrated in Reaction Schemes B E.

WO 96/34010 PCTIUS96/03975 -61- Reaction Schemes N-R illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.

WO 96/34010 WO 9634010PCT/1US96/03975 62 REACTION SCHEME F

H

2 N y C0 2

R

R

A

R 4a;:_R 4 b Boc NHI

I

Boc NH CHO NaBH(OAc)3 Et 3 N CICH 2

CH

2

CI

NHBoc

H

Boc NH NH H2

R~

NH2 IC0 2

R

CF

3

CO

2

H

CH

2

CI

2 R 4 b R 4 b

BOC

2 0 0H 2 C1 2

~CHO

NaBH(OAc)3 Et 3 N CICH 2

CH

2

CI

R 4 b WO 96(34010 PCTJUS96/03975 -63 REACTION SCHEME F (continued)

H

BocNH/

N,

HY

NH,

2

N

RA(

CF

3 C0 2 H, CH 2

CI

2 NaHCO 3 R 4 b

NC

AgCN

'R

4 b

R

4 b r WO 96/34010 WO 9634010PCT/US96/03975 -64- REACTION SCHEME G

Y

1- 2

N

RA(

R4a/ C0 2

R

R

4 b NaBH(OAc) 3 Et 3 N CtCH 2

CH

2

CI

(CH

2 )nCHO

N

+r R 4 b Vill

CF

3 00 2 H, CH 2

CI

2

(C

2

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5 3 SiH 1) Ar CH 2 X, CH 3

CN

2) CF 3 00 2 H, CH 2

CI

2

(C

2

H

5 3 SiH C0 2

R

R 4 b R 4 b WO 96/34010 1 WO 9634010PCT1US96/03975 65 REACTION SCHEME H N CH 2 00 2

H

N

H

CH

3 0H

HCI

N- CH 2 00 2

CH

3

N.

H

HOI

(C

6

H

5 3 CBr

(C

2

H

5 3

N

DMF

2) CH 3 OH, reflux xiII Ar- N CH 2

CO

2

CH

3

N

Ar' N-CH 2

CO

2

H

N

2.5N HClaq 55 0

C

WO 96/340 PCT/US96/03975 66 REACTION SCHEME I

A'N-CH

2

CO

2 H

Y

2 N~CO

R

NRA

Q

R~a~ R 4 b EDC -HCI HOBt

DMF

N C0 2

R

xv Ra;a R 4 b WO 96/340 10 PCTfUS96/03975 67 REACTION SCHEME J H2N y C0 2

R

RA Q R~a~ R 4 b NaBH(OAC) 3 Et 3 N ,CICH 2

CH

2

CI

BnOI BocNH CHO

XVI

NHBoc

CO

2 BnO

H

RA Q XVII 4 Pd(OH) 2

H

2

CH

3 0H

CH

3 C0 2

H

CICOCOCI

DMSO

CH

2

CI

2

(C

2

H

5 3

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WO 96/340 PCTfUS96/03975 68 REACTION SCHEME J (CONTINUED) H NHBoc 00 2

OR

H-

R A Q XIX Ra R 4 b 1. R'MgX

(C

2

H

5 2 0 2. TEA, CH 2

CI

2 R 4 b WO 96/340 PCTIUS96/03975 69 REACTION.SCHEME

K

NHBoc

HOH

Fvl

CF

3

CO

2

H

0H 2 C1 2

R

4 b

R'CHO

NaBH(OAc) 3

CICH

2

CH

2

CI

R 4 b R 4 b WO 96/340 PCTfUS96/03975 REACTION SCHEME L H H N ,r=N

N,

R 4 b NaH, DMF 000

R'SH

(PAO)

3 A

CH

3 0H xxiII

R

4 b

XXIV

R 4 b WO 96/340 PCTI/jS9603975 -71- REACTION SCHEME M

H

2 N' 'CO 2

H

xxv LiAIH 4

THE

0-200C 1) Boc 2 O, K 2 C0 3

THF-H

2 0 2) 0H 2

N

2 EtOAc

HO

BocNH CH 2 0H

HO

BocNH C 2

H

xxvi

R'CH

2

X

CS

2

CO

3

DMF

xxvi" pyridie O

DMSO

(C

2

H

53 N BocNH 200C xxix BocNH xxvi"' WO 96134010 PCTfUS96/03975 72 REACTION SCHEME M (continued)

H

2

N

R 4 b

XXIX

NaBH(OAc) 3

CICH

2

CH

2

CI

R'CH

2

O\

1) 20% Pd(OH) 2

CH

3 OH, CH 3

CO

2

H

2) HOI, EtOAc/ R 4 a, HCIEtOAc NqH 2 R 4 b xxxii R 4 b WO 96/340 PCT1US96/03975 73 REACTION SCHEME N

OH

3

H

2 N- N 1) HNO 2 ,Br 2 2) KMnO 4 3) MeOH,H+ MgCI ZnC1 2 NiCI 2 (Ph 3

P)

2 NaBH 4 (excess)

SQ

3 'Py, Et 3 N

DMSO

WO 96/340 PCTIUS96/03975 -74- REACTION SCHEME P

CO

2

CH

3

CN

NaBH 4 N (excess) Zn, CuCN

CO

2

CH

3

NI

Et 3

N

CHO

NI

N

SOTPy, 13 I' MgCI ZnCI 2 NiCI 2 (Ph, NaBH 4 (excess)

SO

3 -Py, Et 3

N

DMSO

WO 96/340 PCTIUS96/0O3975 75 REACTION SCHEME 0 P 0 2

CH

3 Br- 1. LE N 2. Me' CrMgCI ZnCI 2 NiCI 2 (Ph 3

P)

2 002 OH, H+ 9O 2

CH

3 NaBH 4 (excess)

SO

3 -Py, Et 3

N

DMSO

WO 96/340 PCTIUS96/03975 76- REACTION SCHEME R N Br 1. LDA, 002 2. (0HA)SiCHN 2 C0 2 0H 3 Br R 6 _OIBr Zn, NiCI 2 (Ph 3

P)

2 N~ C0 2 0H 3 IN J excess NaBH 4

CH

2 0H

'NJ-

SO

3 -Py, Et 3

N

DMSO

WO 96/34010 PCT/US96/03975 -77 The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras formation neurofibromin (NF-1), neu, scr, abl, Ick, fyn) or by other mechanisms.

The compounds of the instant invention inhibit famesylprotein transferase and the farnesylation of the oncogene protein Ras.

The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.

The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation Indolfi et al. Nature medicine, 1:541-545(1995).

The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease Schaffner et al.

WO 96/34010 PCT/US96/03975 -78- American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).

The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.

The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, saline, at a pH level, 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.

I I Ilr Irrl r

MWMWM

WO 96/34010 PCT/US96/03975 -79- When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.

In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer.

Administration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.

Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl- I II I I I WO 96/34010 PCT/US96/03975 protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by is approximately equal to half of the concentration of the enzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.

The standard workup referred to in the examples refers to solvent extraction and washing the organic solution with 10% citric acid, sodium bicarbonate and brine as appropriate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.

I r I WO 96/34010 PCT/US96/03975 -81- EXAMPLE 1 Preparation of N-[1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)ylmethyl]-prolyl-methionine methyl ester and N-[1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]prolyl-methionine trifluoroacetate Step A: Preparation of Diethyl 1-acetyl-5-hydroxy-3ethylpyrrolidine-2.2-dicarboxylate Sodium (4.02 g, 0.175 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (235.4 g, 1.19 mol) in abs EtOH (1.4 L) at ambient temperature under argon. The reaction mixture was cooled to 0°C, and trans-2-pentenal (100 g, 1.08 mol) was added dropwise maintaining the reaction temperature at <5 0 C. After the addition, the reaction was allowed to warm to room temperature, stirred for 4 h, then quenched with acetic acid (28 mL). The solution was concentrated in vacuo, and the residue dissolved in EtOAc (1.5 L), washed with 10% NaHCO3 solution (2 x 300 mL), brine, and dried (MgSO4). The solution was filtered and concentrated to 700 mL, then heated to reflux and treated with hexane (1 On cooling, the title compound precipitated and was collected, mp 106 109°C. 1H NMR 8 5.65 1H, J= 5 Hz), 4.1 4.25 4H), 2.7-2.8 1H), 2.21 3H), 2.10 (dd, 1H, J 6, 13, Hz),1.86- 1.97 2H), 1.27 3H, J= 7 Hz), 1.23 3H, J= 7 Hz), 1.1- 1.25 1H), 0.97 3H, J= 7 Hz).

Step B: Preparation of Diethyl 1-acetyl-3-ethylpyrrolidine-2,2dicarboxvlate To a solution of diethyl 1-acetyl-5-hydroxy-3ethylpyrrolidine-2,2-dicarboxylate (287 g, 0.95 mol) and triethylsilane (228 mL, 1.43 mol) in CH2C12 (3 L) under argon was added trifluoroacetic acid (735 mL, 9.53 mol) dropwise with stirring while maintaining the internal temperature at 25 OC by means of an ice bath.

After stirring for 3 h at 23°C, the solution was concentrated in vacuo, the residue diluted with CH2C12 (1.5 then treated with H20 (1 L) and II I

MENNEN

WO 96/34010 PCT/US96/03975 -82solid Na2CO3 with vigorous stirring until the solution was basic. The organic layer was separated, dried (Na2SO4), filtered, then concentrated to give the title compound as a yellow oil which was used without further purification.

Step C: Preparation of 3-Ethylproline hydrochloride (Cis:Trans Mixture) Diethyl 1-Acetyl-3-ethylpyrrolidine-2,2-dicarboxylate (373 g, 0.95 mol) was suspended in 6N HCI (2 L) and HOAc (500 mL) and heated at reflux for 20 h. The reaction mixture was cooled, washed with EtOAc then concentrated in vacuo to give an oil which crystallized upon trituration with ether to give the title compound. 1 H NMR (D20) 4.23 1H, J= 8 Hz), 3.84 1H, J= 8 Hz), 3.15- 3.4 4H), 2.33- 2.44 1H), 2.19-2.4 1H), 2.02- 2.15 2H), 1.53- 1.72 3H), 1.23- 1.43 2H), 1.0- 1.15 1H), 0.75 0.83 6H).

Step D: Preparation of N-[(tert-Butyloxy)carbonyl]-cis:trans-3ethylproline methyl ester 3-Ethylproline hydrochloride (Cis:Trans Mixture) (20 g, 0.11 mol) was dissolved in CH30H (200 mL), and the solution was saturated with HCI gas, then stirred at 23 0 C for 24 h. Argon was bubbled through the solution to remove excess HC1. The solution was treated with NaHCO3 (>84 g) to a pH of 8, then di-tert-butyl dicarbonate (25.1 g, 0.115 mol) dissolved in CH30H (20 mL) was added slowly. After stirring for 18 h at 23 0 C, the mixture was filtered, the filtrate concentrated, and the residue triturated with EtOAc, filtered again, and concentrated to give the title compound as an oil.

Step E: Preparation of N-[(tert-Butyloxy)carbonyl]-trans-3ethylproline and N-[(tert-Butyloxy)carbonyl]-cis-3ethylproline methyl ester N-[(tert-Butyloxy)carbonyl]-cis, trans-3-ethylproline methyl ester (29.1 g, 0.113 mol) was dissolved in CH30H (114 mL) with cooling to 0°C, then treated with 1 N NaOH (114 mL). After stirring for 20 h at I~ II I I

I,

WO 96/34010 PCT/US96/03975 -83- 23 0 C, the solution was concentrated to remove the CH30H and then extracted with EtOAc (3 The organic layers were combined, dried (MgSO4), filtered, and concentrated to give 12.8 g of N-[(tert- Butyloxy)carbonyl]-cis-3-ethylproline methyl ester as an oil. The aqueous layer was acidified with solid citric acid and extracted with EtOAc (2 the organic layers combined, dried (MgSO4), filtered, and concentrated to give N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline as an oil. 1H NMR (CD30D) 5 3.86 and 3.78 (2 d, 1H, J 6 Hz), 3.33 3.58 2H), 2.01 2.22 2H), 1.5 1.74 2H), 1.33 1.5 1H), 1.45 and 1.42 (2 s, 9H), 0.98 3H, J= 8 Hz).

Step F: Preparation of 3(S)-Ethvl-2(S)-proline hydrochloride N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline (15.5 g, 0.064 mol), S-a-methylbenzylamine (9.03 mL, 0.070 mol), HOBT (10.73 g, 0.70 mol), and N-methylmorpholine (8 mL, 0.076 mol) were dissolved in CH2C12 (150 mL) with sitrring in an ice-H20 bath, treated with EDC (13.4 g, 0.070 mol) stirred at 23 0 C for 48 h. The reaction mixture was partitioned between EtOAc and 10% citric acid solution, the organic layer washed with satd NaHCO3 solution, brine and dried (MgSO4), filtered, and concentrated to give an oil. This oil was dissolved in a minimum amount of ether (10 mL) to crystallize the desired S,S,S diastereomer (4.2 mp 118-121 0 C. A solution of this product in 8N HCl (87 mL) and glacial acetic acid (22 mL) was heated at reflux overnight. The solution was concentrated on a rotary evaporator, and the residue taken up in and extracted with ether. The aqueous layer was concentrated to dryness to give a 1:1 mixture of 3 (S)-ethyl-2(S)-proline hydrochloride and amethylbenzylamine.

3(S)-Ethyl-2(S)-proline containing a-methylbenzylamine g, 0.0128 mol) was dissolved in dioxane (10 mL) and H20 (10 mL) with stirring and cooling to 0°C. N,N-diisopropylethylamine (2.2 mL, 0.0128 mol) and di-tert-butyl-dicarbonate (2.79 g, 0.0128 mol) were added and stirring was continued at 23 0 C for 48 h. The reaction mixture was partitioned between EtOAc (60 mL) and H20 (30 mL), the organic layer washed with 0.5N NaOH (2 x 40 mL), the aqueous layers f.

WO 96/34010 PCT/US96/03975 -84combined and washed with EtOAc 30 mL) and this layer back-extracted with 0.5 N NaOH (30 mL). The aqueous layers were combined and carefully acidified at 0°C with 1N HC1 to pH 3. This mixture was extracted with EtOAc (3 x 40 mL), the organics combined, dried (MgSO4), filtered and concentrated to give N-[(tert-Butyloxy)carbonyl- 3(S)-ethyl-2(S)-proline as a colorless oil. N-[(tert-Butyloxy)carbonyl- 3(S)-ethyl-2(S)-proline was dissolved in EtOAc (50 mL) and the solution was saturated with HCI gas with cooling in an ice-H20 bath. The solution was stoppered and stirred at 0°C. for 3 hr. Argon was bubbled through the solution to remove excess HC1, and the solution was concentrated to dryness to give 3(S)-ethyl-2(S)-proline hydrochloride.

Step G: N-[(tert-Butvloxy)carbonyll-3(S)-ethyl-2(S)-prolinol 3(S)-Ethyl-2(S)-proline hydrochloride containing amethylbenzylamine (2.0 g, 0.0128 mol) was dissolved in dioxane mL) and H20 (10 mL) with stirring and cooling to 0°C. N,Ndiisopropylethylamine (2.2 mL, 0.0128 mol) and di-tert-butyldicarbonate (2.79 g, 0.0128 mol) were added and stirring was continued at 23 0 C for 48 h. The reaction mixture was partitioned between EtOAc (60 mL) and H20 (30 mL), the organic layer washed with 0.5N NaOH (2 x 40 mL), the aqueous layers combined and washed with EtOAc 30 mL) and this layer back-extracted with 0.5 N NaOH (30 mL). The aqueous layers were combined and carefully acidified at 0°C with IN HCI to pH 2. This mixture was extracted with EtOAc (3 x 40 mL), the organics combined, dried (MgSO4), filtered and concentrated to give N-[(tert- Butyloxy)carbonyl--3(S)-ethyl-2(S)-proline as a colorless oil which was used without purification.

N-[(tert-Butyloxy)carbonyl]-3(S)-ethyl-2(S)-proline (1.6 g, 6.58 mmol) was dissolved in dry THF (10 mL) and treated with borane (IM in THF, 12.5 mL, 12.5 mmol) with stirring at 0 oC for 2 h, then 23°C for 1 h. The solution was cooled to 0°C, treated with H20 (20 mL), and extracted with EtOAc (2 x 30 mL). The organics were washed with brine, satd NaHCO3, H20, dried (MgSO4), filtered and concentrated to give a viscous oil. The oil was dissolved in CH2C12. filtered through dry Si02,

I.

WO 96/34010 PCT/US96/03975 and the filtrate concentrated to give the title compound as an oil. 1H NMR (CDC13) 6 4.97 1H, J= 7 Hz), 3.71 1H, J 8 Hz), 3.51-3.62 3H), 3.18 3.26 1H), 1.9 2.0 1H), 1.53-1.7 2H), 1.47 (s, 9H), 1.26 1.43 2H), 0.95 3H, J 7 Hz).

Step H: N-[(tert-Butyloxv)carbonvll-3(S)-ethvl-2(S)-prolinal N-[(tert-Butyloxy)carbonyl-3(S)-ethyl-2(S)-prolinol (0.638 g, 2.78 mmol) and Et3N (1.4 mL, 9.74 mmol) were dissolved in dry CH2C12 (10 mL) with stirring and cooling to -10 0 C and treated dropwise with a solution of S03.pyr (1.33 g, 8.35 mmol) in dry DMSO (5 mL) keeping the reaction mixture temperature at 0°C. The mixture was stirred at 0°C. for 20 min then at 5 0 C for 20 min, and at 15 0 C for 1 h, then poured into ice-cold 0.5 N HC1 and the layers separated. The aqueous layer was extracted with CH2C12 (3 x 20 mL), organics combined, washed with H20, aq satd NaHCO3 solution, brine, and dried (Na2SO4).

Filtration and concentration to dryness gave the title compound which was used without purification.

Step I: N-[(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)ylmethyll-proline methyl ester N-[(tert-Butyloxy)carbonyl]-3(S)-ethyl-2(S)-prolinal (0.315 g, 0.0014 mol) and proline methyl ester hydrochloride (0.233 g, 0.0014 mol) were dissolved in MeOH (5 mL) at ambient temperature under argon with cooling in an ice-H20 bath, and treated with sodium cyanoborohydride (0.131 g, 0.002 mol) with stirring. After 18 h the mixture was poured into 5% NaHCO3 solution (20 mL), the removved and the aq layer washed with EtOAc (3 x 30 mL), the organics combined, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound as a colorless oil after chromatography (SiO2, hexane: EtOAc, 1 H NMR (CDC13) 5 3.70 3H), 3.1 5H), 2.2 2.65 4H), 1.7 2.15 5H), 1.5 1.65 1H), 1.46 9H), 1.2 1.5 2H), 0.93 3H, J 7 Hz).

WO 96/34010 PCT1US96/03975 86 Step J: N- [(tert-Butyloxy)carbonyl-3 (S)-ethylpyrrolidin-2(S)ylmethyll-proline N- [(tert-Butyloxy)carbonyl-3 (S)-ethylpyrrolidin-2(S)ylmethyl]-proline methyl ester 0.08 1 g, 0.238 minol) was dissolved in CH30H (2 mL), cooled to 0 0 C and treated with IN NaOH solution (0.952 mL, 0.952 nimol). After stirring at 23TC for 3h, the solution was neutralized with IN HCl (0.952 niL, 0.952 nimol), concentrated to remove the CH3OH, then lyophilized and the residue used as is.

Step K: N- [(tert-Butyloxy)carbonyl-3 (S)-ethylpyrrolidin-2(S)ylmethyll-prolvl-methionine methyl ester N- [(tert-Butyloxy)carbonyl-3 (S)-ethylpyrrolidin-2(S)ylmethyl]-proline (0.238 mniol), HOBT (0.048 g, 0.262 mmol), EDC (0.068 g, 0.0357 imnol), and methionine methyl ester hydrochloride (0.048 g, 0.238 nimol) were dissolved in CH2CL2 (10 niL) and stirred at 23TC for 18 h. EtOAc (100 mlL) was added, and the mixture washed with satd NaHCO3 solution, H20, brine, and dried (MgSO4). Filtration and concentration to dryness gave 0.085 g of title compound. IH NM (CD3OD) 8 (major rotamer) 4.63 1H, J 7 Hz), 3.73 3H), 3.55 3.7 (in, 1H), 3.0-3.5 (in, 4H), 2.3 2.7 (in, 5H), 1.9 2.2 (in, 3H), 2.08 (s, 3H4), 1.6 1.9 (in, 4H1), 1.46 9H), 1.3 1.45 (mn, 2H), 0.92 1.02 (in, 3H).

Step L: N- [3(S)-Ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester hydrochloride HC1 gas was bubbled into a solution of N-[tertbutyloxy)carbonyl-3 (S)-ethylpyrrolidin-2(S)-ylmethyl]-prolyl methioninine methyl ester (0.08 5 g, 0. 18 minol) in EtOAc (5 niL) with stirring and cooling in an ice-H-20 bath until saturation. The solution was stoppered and stirred at 0OC for 2 h, then purged with Ar and concentrated to give the title compound as a yellow foam.

Step M: N- H-Imidazol-4-ylacetyl)-3 (S )-ethylpyrrolidin-2(S ylmethvll1-prolvl-methionine methyl ester WO 96/34010 PCTIUS96/03975 -87- N-[3(S)-Ethylpyrrolidin-2(S)-ylmethyl]-proly methionine methyl ester hydrochloride (0.075 g, 0.169 mmol), 1H-imidazol-4ylacetic acid (0.052 g, 0.253 mmol), HOBT (0.34 g, 0.253 mmol), EDC (0.49 g, 0.253 mmol) and Et3N (0.176 mL, 1.27 mmol) were dissolved in DMF (4 mL) and stirred at 23 0 C for 18 h. The solvent was removed in vacuo, EtOAc (60 mL) was added, and the solution was washed sequentially with satd NaHCO3 solution, H20, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography (SiO2, 5 10% CH30H/CH2C12). 1

H

NMR (CD30D) 5 (major rotamer) 7.62 1H), 6.93 1H), 4.6 4.67 1H), 4.1-4.16 1H), 3.74 3H), 3.65 2H), 3.5 3.68 2H), 3.2 3.25 1H), 3.04 3.1 1H), 2.44 2.7 5H), 2.05 2.26 (m, 4H), 2.08 3H), 1.68 1.87 4H), 1.26 1.5 3H), 0.99 3H, J 7 Hz). FAB MS 480 (M 1).

Step N: 1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidinvlmethyll-prolvl-methionine trifluoroacetate N-[1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)ylmethyl]-prolyl-methionine methyl ester (0.020 g, 0.042 mmol) was dissolved in CH30H (2 mL) at OOC and treated with 1N NaOH solution (0.167 mL, 0.167 mmol) with stirring. After 5 h at 23 0 C IN HCI (0.167 mL, 0.167 mmol) was added and the mixture was purified by preparative RP HPLC on a Vydac column eluting with 0.1% TFA/CH3CN: 0.1% TFA/ H20 gradient to give the title compound.

1 H NMR (CD30D) 8 8.88 1H, J 1Hz)), 7.43 1H, J 1Hz), 4.53 4.58 1H), 4.25-4.31 1H), 3.96 (ABq, 2H), 3.7 3.85 3H), 3.58 3.66 1H), 3.50 (dd, 1H, J 3, 14 Hz), 3.39 (dd, 1H, J 3, 14 Hz), 3.23 3.42 1H), 2.45 2.67 3H), 2.12 2.28 4H), 2.08 3H), 1.98 2.05 3H), 1.54 1.68 2H), 1.26 1.4 1H), 1.03 3H, J 7 Hz). FAB MS 466 (M 1).

WO 96/34010 PCT/US96/03975 -88- EXAMPLE 2 Preparation of N-[l-[l-(4-Cyanobenzyl)-1H-imidazol-5ylacetyl]pyrrolidin- 2 (S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester Step A: N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)ethvl-proline 3(S)-Ethyl-2(S)-proline hydrochloride (from Example 1, Step F) (2.33 g, 0.013 mol) was dissolved in CH30H (20 mL), treated with 3A molecular sieves (2 g) and KOAc (1.27 g, 0.013 mol) to adjust the pH of the reaction mixture to 4.5-5, then N-[(tert- Butyloxy)carbonyl-prolinal (Pettit et al., J. Org. Chem. (1994) 59, [21] 6287-95) (3.36 g, 0.017 mol) was added, and the mixture was stirred for 16 hrs at room temperature. The reaction mixture was filtered, quenched with aq satd NaHCO3 (5 mL) and concentrated to dryness. The residue was extracted with CHCl3. The extract was dried (MgSO4), filtered, and concentrated to give the title compound and inorganic salts.

Step B: N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)ethyl-prolyl-methionine isopropvl ester N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)ethyl-proline (2.4 g, 0.008 mol), methionine isopropyl ester hydrochloride (2.21 g, 0.0097 mol), HOBT (1.49 g, 0.0097 mol) and EDC (1.86 g, 0.0097 mol) were dissolved in DMF (15 mL) at room temperature and treated with N-methylmorpholine (3 mL, 0.024 mol). The reaction mixture was stirred overnight at room temperature, then concentrated and partitioned between EtOAc and H20. The organic layer was washed with aq satd NaHCO3 solution, brine, and dried (MgS04). The crude product was chromatographed on a flash silica gel column eluting with hexane: EtOAc, 7:3 to give N-(t-butyloxycarbonyl)-pyrrolidin-2(S)ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester.

WO 96/34010 PCTIUS96/03975 -89- Step C: N-(Pyrrolidin-2(S)-ylmethyl)-3(S)-ethyl-prolyl methionine isopropyl ester hydrochloride N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)ethyl-prolyl-methionine isopropyl ester (1.38 g, 0.0028 mol) was dissolved in EtOAc (40 mL), cooled to -20 0 C, saturated with HCI gas, and stirred at 0°C. for 1.25 hr, and room temperature for 0.25 hr.

Concentration to dryness gave the title compound.

Step D: 1H-Imidazole-4- acetic acid methyl ester hydrochloride A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature (RT) for 18hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.

1 H NMR(CDC13, 400 MHz) 8 8.85(1H, s),7.45(1H, 3.89(2H, s) and 3.75(3H, s) ppm.

Step E: 1-(Triphenylmethyl)-1 H-imidazol-4-ylacetic acid methyl ester To a solution of 1H-Imidazole-4- acetic acid methyl ester hydrochloride (24.85g, 0.141mol) in dimethyl formamide (DMF) (115ml) was added triethylamine (57.2 ml, 0.412mol) and tribenzyl bromide(55.3g, 0.171mol) and the suspension was stirred for 24hr. After this time, the reaction mixture was diluted with ethyl acetate (EtOAc) (1 1) and water (350 ml). The organic phase was washed with sat. aq.

NaHCO3 (350 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (Si02, 0-100% ethyl acetate in hexanes; gradient elution) to provide the title compound as a white solid.

IH NMR (CDC13, 400 MHz) 7.35(1H, 7.31(9H, 7.22(6H, m), 6.76(1H, 3.68(3H, s) and 3.60(2H, s) ppm.

Step F: [1-(4-Cyanobenzyl)- 1H-imidazol-5-yl]acetic acid methyl ester WO 96/34010 PCTIUS96/03975 To a solution of l-(Triphenylmethyl)-1H-imidazol-4ylacetic acid methyl ester (8.00g, 20.9mmol) in acetonitrile (70 ml) was added bromo-p-toluonitrile (4.10g, 20.92 mmol) and heated at 55 0 C for 3 hr. After this time, the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration.

The filtrate was heated at 55 0 C for 18hr. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting white precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc).

The solid was treated with sat aq NaHCO3 (300ml) and CH2C12 (300ml) and stirred at room temperature for 2 hr. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid 1HNMR(CDC13, 400 MHz) 8 7.65(1H, d, J=8Hz), 7.53(1H, 7.15(1H, d, J=8Hz), 7.04(1H, 5.24(2H, 3.62(3H, s) and 3.45(2H, s) ppm.

Step G: [1-(4-Cyanobenzvl)-lH-imidazol-5-vllacetic acid A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester (4.44g, 17.4mmol in THF (100ml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1 M HC1 (17.4 ml) was added and the THF was removed by evaporation in vacuo.

The aqueous solution was lyophilized to afford the title compound containing lithium chloride as a white solid.

1 H NMR(CD30D, 400 MHz) 6 8.22(1H, 7.74(1H, d, J=8.4Hz), 7.36(1H, d, J=8.4Hz), 7.15(1H, 5.43(2H, s) and 3.49(2H, s) ppm.

Step H: -[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester [1-(4-Cyanobenzyl)- 1H-imidazol-5-yl]acetic acid LiCl (0.416 g, 1.47 mmol), N-(pyrrolidin-2(S)-ylmethyl)-3(S)-ethyl-prolyl- WO 96/34010 PCT/US96/03975 -91methionine isopropyl ester hydrochloride (Step I) 0.63 g, 1.33 mmol), HOOBT (0.239 g, 1.47 mmol), and EDC (0.281 g, 1.47 mmol) were dissolved in degassed DMF (20 mL) with stirring at room temperature, N-methylmorpholine (0.8 mL, 5.32 mmol) was added to achieve a pH of 7, and stirring was continued overnight. The reaction mixture was concentrated to remove most of the DMF, and the residue was partitioned between EtOAc and aq satd NaHCO3 solution. The aq layer was washed with EtOAc, the organics combined, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography on silica gel eluting with CH2Cl2:CH30H, 95:5.

Anal. calcd for C33H46N604S 0.7 H20: C, 62.38; H, 7.52; N, 13.23; found: C, 62.40; H, 7.17; N, 13.11.

FAB MS 623 (M+1) Following the procedures outlined above, but substituting methionine sulfone isopropyl ester for methionine isopropyl ester, the following compound was prepared: N-[l-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin-2(S)ylmethyll-3(S)-ethyl-prolyl-methionine sulfone isopropyl ester Anal. calcd for C33H46N606S 0.9 H20: C, 59.07; H, 7.18; N, 12.52; found: C, 58.99; H, 6.87; N, 12.86.

FAB MS 655 (M+1) EXAMPLE 3 Preparation of N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine sulfoxide To a solution of N-[l-[1-(4-Cyanobenzyl)-lH-imidazol-5ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine (0.15 g, 0.186 mM) in 3 mL of MeOH:H20 1:1 was added sodium periodate (0.048 g, 0.223 mM). The mixture was stirred for 1 h, diluted with 3 mL WO 96/340 10 PCTIUS96/03975 92 of H20 and purified by prep HPLC (Delta-pak, C- 18). The pure fractions were pooled and lyophillized to yield the title compound.

Anal. calcd for C3OH4ON6OS- 4.2 CF3CO2H 0.5 C, 42.52; H, 4.20; N, 7.75; found: C, 42.51; H, 4.21; N, 8.11.

FAB MS 597 (M+1) Following the procedure above the following compound was prepared: N- [1-[i-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyl]pyrrolidin-2(S)vlmethyll-3(S)-ethvl-prolvl-methionine sulfoxide isopropyl ester Anal. calcd for C33H46N605S 1.0 C, 60.34; H, 7.37; N, 12.80; found: C, 60.32; H, 7.19; N, 12.42.

EXAMPLE 4 Preparation of 1-[1 -(4-Cyanobenzyl)- ylacetyllpyrrolidin-2(S)-ylmethyll-3 (S)-ethyl-prolvl-methionine sulfone To a solution of 1- [1-(4-Cyanobenzyl)- ylacetyllpyrrolidin-2(S)-ylmethyl].3 (S)-ethyl-prolyl-methionine (0.15 g, 0. 186 mM) in 5 mL of MeOH:H20 1:1 was added Oxone 1 g, 0.372 mM). After stirring for 0.5 h, the mixture was partially evaporated and diluted with 5 mL of H20 and purified by prep HPLC (Vydac, C- 18).

The pure fractions were pooled and lyophilized to yield the title compound.

Anal. calcd for C30H40N606S -3.2 CF3CO2H 1.2 C, 43.75; H, 4.60; N, 8.41; found: C, 43.75; H, 4.59; N, 8.45.

FAB MS 613 (M+1) WO 96/34010 PCT/US96/03975 93 EXAMPLE Preparation of N-[i -(4-Cyanobenzyl)- ylacetyllpyrrolidin- 2 (S)ylmethyl3(S)ethybprolyl-methionine methyl ester and N- [1-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyl]pyrrolidin- 2(S )-ylmethvll-3 (S)-ethyl-prolyl-methionine Step A: N- -(4-Cyanobenzyl)- pyrrolidin-2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester Following the procedures described for Example 2, but substituting methionine methyl ester hydrochloride for methionine isopropyl ester hydrochloride in Step B, the title compound was prepared.

Anal. calcd for C31JH42N604S 3.7 CF3CO2H 0.3 C, 45.13; H, 4.57; N, 8.22; found: C, 45. 10; H, 4.53; N, 8.39.

Step B: N- -(4-Cyanobenzyl)-l1H-imidazol-5-l)acetyl]pyrrolidin.

2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methiomne trifluoroacetate N- [1-(4-Cyanobenzyl)- ylacetyl]pyrrolidin-2(S)-ylmethyly3 (S)-ethyl-prolyl-methionine methyl ester (0.016 g, 0.02 mmol) was dissolved in CH30H (1 mL) and H20 (I mL) at ambient temperature and treated with 1 N NaOH (0.3 mL, 0.3 mmol) with stirring. After 1 hr the reaction mixture was neutralized with 1N HCl 3 mL) and purified on a VYDAC preparative RP HPLC column and lyophilized to give the title compound.

Anal. calcd for C30H40N604S 3.9 CF3CO2H 0.6 C, 43.8 1; H,4.39; N, 8.11; found: C, 43.79; H, 4.39; N, 8.27.

Following the procedures outlined in Examples 2 and 3, but substituting the appropriate carboxylic acid in Example 2, Step H; the following compounds were prepared: WO 96/34010 PCTJUS96/03975 -94- N--i H-Imidazol-4-ylacetl)-yrrolidin2(S-)vlmethll..3 (S)-ethylprolvi-methionine methyl ester IH NMR (CD3OD) 8 8.88 1H), 7.43 1H), 4.64 4.71 (in, 1H), 4. 19-4.27 (mn, 1H), 3.94 2H), 3.75 3.88 (in, 2H), 3.74 3H), 3.57 3.61 (in, 2H), 3.34 3.5 (in, 3H), 3.15 3.25 (mn, 1H), 2.45 2.67 (in, 2H), 1.98 2.37 (in, 6H), 2.08 3H), 1.83 1.98 (mn, 3H), 1.4 1.56 (mn, 1H), 1.01 3H, J 7 Hz).

Anal. calcd for C23H37N504S 2.8 CF3CO2H e 1.3 C, 41.88; H, 4.96; N, 8.54; Found: C, 41.85; H, 4.95; N, 8.54.

FAB MS 480 (M 1).

N-[i -(1H-Imidazol-4-ylacetylb-pyrrolidin-2(S).ylme hv 1-3(S)-ethylp2rolyl-methionine 1 H NMR (CD3OD) 8 8.87 1H), 7.43 1H), 4.61 4.71 (in, 1H), 4.2-4.3 (in, 1H), 3.94 (brs, 2H), 3.75 3.88 (in, 2H), 3.6 3.73 (in, 1H), 3.16 3.48 (in, 5H), 2.5 2.7 (in, 2H), 2.0 2.3 8 (mn, 6H), 2. 10 3H), 1.83 1.98 (mn, 3H), 1.4 1.55 (in, 1H), 1.01 3H, J 7 Hz).

Anal. calcd for C22H35N504S 2.8 CF3CO2H: C, 42.24; H, 4.85; N, 8.92; Found: C, 42.18; H, 4.86; N, 8.95.

FAB MS 466 (M 1).

N-ri -Glycyl-p2yrrolidin-2(S )-vlmethyll -3 (S)-ethvl-12rolvl-methionine methyl ester FAB MS 429 (M 1).

N-ri -Glycyl-pvyrrolidin-2(S )-ylmethyl] -3(S )-ethyl-prLvlY-methionine Anal. calcd for Cl9H34N4045 3.0 CF3CO2H 0.5 C, 39.22; H, 5.00; N, 7.32; Found: C, 3 9.2 1; H, 5.02; N, 7.68.

FAB MS 415 (M 1).

WO 96/34010 PCTIUS96/03975 95 N-ri -(3-ri H-Imidazol-4-yllpropionyl-prrolidin2(Svethy!L 3 ethyl-prolvl-methiofife methyl ester Anal. caicd for C24H39N50 4 S 0.75 C, 56.84; H, 8.05; N, 13.81; Found: C, 56.79; H, 7.95; N, 13.90.

FAB MS 494 (M 1).

N-ri -(3-ri H-Imidazol-4ylpropionvl)prrolidin2(S-)vlmethyll- 3 ethyl-prolyl-methionine FAB MS 480(M 1).

N-ri- r3-' 1-( 4 -Cyanobenzyl)- 1H-imidazol-5-vlD-ppionyllpyoidin-2(S ylmethyll-3 (S -ethyl-prolyl-methionine mthyl ester Anal. calcd for C32HM4N6O4S 2.0 HC1 0.4 C, 55.79; H, 6.85; N, 12.20; Found: C, 55.86; H, 6.85; N, FAB MS 609 (M 1).

N-ri- r3-' i-(4-Cyanobenzyl)- 1H-imidazol-5-yI)p1ro-Pionyllpyrrolidin.2(S)ylmethyll-3 (S)-ethvl-p2rolyl-methionine Anal. caicd for C31IH42N6O4S 2.9 CF3CO2H 0. 8 C, 47.03; H, 4.99; N, 8.94; Found: C, 47.05; H, 4.96; N, 9.3 1.

FAB MS 595(M 1).

EXAMPLE 6 Preparation of N- 1H-Imidazol-4-ylacetylamino).3 methylpentyi]-prolylpmethionine methyl ester and N-r2(s)-(iH.

Imidazol-4-vlacetvl.amino).3 (S )-methVIpentyll1-prolvl-methionine Step A:

N-[

2 (S)-(iH-Imidazol4ylacetyl-amino)-3(S)methylp~entyl 1-prolvi-methionine methyl ester WO 96/340 10 PCTIUS96/03975 96 Following the methods outlined in Example 1, but substituting N-(t-Butyloxycarbonyl).isoleucinaI for N-[t- Butyloxy)carbonyl-3(S..ethyl.2(S)-.prolinal in Step 1, the title compound was prepared.

Anal. calcd for C22H37N504S 0.5 H20: C, 55.43; H, 8.04; N, 14.69; Found: C, 55.75; H, 7.82; N, 14.36.

FAB MS 468(M 1).

Step B: N- 1H-Imidazol-4-ylacetyl-anino)-3 methylpeniyll-prolyl-methionine The title compound was prepared following the method dscribed in Example 1, Step N.

Anal. calcd for C21H35N504S 2.5 CF3CO2H: C, 42.27; H, 5.12; N, 9.48; Found: C, 41.9 1; H, 5.17; N, 9.5 1.

FAB MS 454 (M 1).

EXAMPLE 7 Preparation of N- H-Imidazol-4-ylacetyl)-pyrrolidin.2(S)yylmethyl] prolyl-methionine methyl ester and N- H-Imidazol-4-ylacetyly..

pyr-rolidin-2(S )-vlmethvll-prolyl-methionine Step A: N- H-Imidazol- 4 -ylacetyl)-pyrrolidin-2(S).ylmethyl..

prolyl-methionine methyl ester Following the methods outlined in Example 1, but substituting N-(t-Butyloxycarbonyl).prolinal for N- [t- Butyloxy)carbonyl-3(S)-ethyl-2(S)-.prolinal in Step 1, the title compound was prepared.

Anal. calcd for C21H33N504S 1.9 CF3CO2H 2.2 HCl: C, 39.80; H, 5.00; N, 9.36; Found: C, 39.82; H, 5.01; N, 9.33.

FAB MS 452 1).

WO 96/34010 PCTIUS96/039 7 97 Step B: Iiao-4yaey)pyrldn2S)ymty] prolyl-methionine The title compound was prepared following the method dscribed in Example 1, Step N.

Anal. calcd for C20H3lN50 4 S 2.6 CF3CO2H.- 1.1 HCL: C, 40.15; H, 4.79; N, 9.29; Found: C, 40.15; H, 4.85; N, 9.02.

FAB MS 438(M 1).

Following the procedures outlined in Examples 1, 2, and 7, the following compounds were prepared: N- 4 -Cyanobenzyl)- lH-imidazol-5-ylacetylpyffolidin-2(S)ylmethyl1-prolyl-methionine mtl ester Anal. calcd for C29H38N604S 1.2 H20: C, 59.20; H, 6.92; N, 14.28; Found: C, 59.25; H, 6.8 1; N, 14.14.

FAB MS 567 (M 1).

N- 4 -Cyanobenzyl)- lH-imnidazol-5-ylacetyllpyffolidin.2(S)ylmethvll-prolyl..methionine Anal. calcd for C28H36N60 4 S 3.4 CF3CO2H 1.0 C, 43.61; H, 4.35; N, 8.77; Found: C, 43.59; H, 4.35; N, 8.91.

FAB MS 553 (M 1).

EXAMPLE 8 Using the procedures described in Example 1, but substituting 3(S)-Ethyl- 2 (S)-proline hydrochloride for proline methyl ester in Step 1, the following compounds were prepared: N- H-Imidazol-4.ylacetyly.3 (S)-ethylpyrrolidin-2(S).ylmethyl-3 (S ethyl e s te r Anal. calcd for C25H41N5O4S H20: C, 50.93; H, 7.52; N, 11.88; Found: C. 50.,90; H, 7.38; N, 11.87.

WO 96/340 10 PCT1LUS96/03975 98 N- H-Imidazol-4-ylacetyly.3 (S)-ethylpyrrolidin-2(S)y lymethyl]3 ethyl-proly-l-methionine trifluoroacetate Anal. calcd for C24H39N504S 2.95 CF3CO2H: C, 43.27; H, 5.09; N, 8.44; Found: C, 43.17; H, 5.16; N, 8.54.

N- [1 -[1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyly3 (S)-ethylpyrrolidin.

2 (S)-ylmethyl1-3(S').ethyl-prolimethofnine methyl ester Anal. calcd for C33H46N60 4 S: C, 63.63; H, 7.45; N, 13.50; Found: C, 63.53; H, 7.36; N, 13.39.

[1 -(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyly3 (S)-ethylpyrrolidin.

2(S )-vlmethyl -3 (S)-ethvl-prolvl-methionine triflonrcte Anal. calcd for C32H44N604S 3.2 CF3CO2H 0.6 C, 46.85; H, 4.96; N, 8.54; Found: C, 46.86; H, 4.96; N, 8.78.

N- [1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl-3 (S)-ethylpyrrolidin- 2(S)-vlmethyl-3 (S)-ethyl-prolyl-methionine isppl ester Anal. caled for C35H50N604S 0.25 H-20: C, 64.14; H, 7.77; N, 12.812; Found: C, 64.16; H, 7.73; N, 12.82.

N- [1H-Imidazol-4.yllpropionyly.3 (S)-ethylpyrrolidin..2(S)vlmethyll-3(S)-e hylp1rolyl-methionine methyl ester FAB MS 522 1).

N- H-Imidazol-4.-yllpropionyl)-3(S)-ethylpyrrolidin-2(Sy..

vlmethvI1-3( )-ethyl-prolylmethQoj 1 1 trifluoroacetate FAB MS508 (M N- [1-Glycyl-3 (S )-ethylpyrrolidin..2(S)..ylmethyly3 (S )-ethyl-prolylmethionine methyl ester WO 96/340 10 PCTIUS96/03975 99 N- [1-Glycyl-3 (S)-ethylpyrrolidin-2(S).ylmethyly3 (S)-ethyl-prolylmethionine trifluoroacetate EXAMPLE 9 Preparation of N- -(4-Nitrobenzyl)- 1H-imidazol-4ylacetyllpyrrolidin-2(S).ylmethyly3 (S)-ethyl-prolyl-methionine bis trifluoroacetate and 1-(1 -(4-Nitrobenzyl)- pyrrolidin- 2 (S)-ylmethyl]-3(S)-ethyl.prolyl.metiopjne bis trifluoroacetate.

Step A: 1 -(4-Nitrobenzyl)-l1H-imidazol-4-ylacetic acid methyl ester and 1 -(4-Nitrobenzyl)- 1H-imidazol-5-ylacetic acid methyl ester (3:1 mixture) To a solution of sodium hydride (60% in mineral oil, 99 mg, inmol) in dimethylformnamide (2 ml) cooled to 0 0 C was added, via cannula, a solution of lH-imidazole-4-acetic acid methyl ester hydrochloride (200 mg, 1. 13 mmol) in dimethylformamide (3 ml). This suspension was allowed to stir at OTC for 15 mmn. To this suspension was added 4-nitrobenzyl bromide (244 mg, 1. 13 mmol) and stirred at room temperature for 2 h. After this time, the mixture was quenched with sat.

aq. sodium bicarbonate (15 ml) and water (20 ml) and extracted with methylene chloride (2 x 50 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4), filtered and the solvent was evaporated in vacuc. The residue was purified by flash chromatography using acetonitrile as eluent to give the title compounds as a yellow oil.

1 H NMR (CDCl3, 400 MHz) 8 8.20 (2H, d, J=8.5 Hz), 7.49 (1H, 7.27 (2H, d, J=8.5 Hz), 7.03 (0.25H, 6.87 (0.75H, 5.28 (0.5H, 5.18 3.70 (2.25H, 3.65 (1.5H, 3.61 (0.75H, s) and 3.44 s) ppm.

Step B: 1 -(4-Nitrobenzyl)- 1 H-imidazol-4-ylacetic acid hydrochloride and 1 -(4-Nitrobenzyl)- I acid 1mixture) mm WO 96/34010 1 PCT/US96/03975 -100- To a solution of a mixture of 1-(4-Nitrobenzyl)-1Himidazol-4-ylacetic acid methyl ester and 1-(4-Nitrobenzyl)-1Hacid methyl ester mixture, 216 mg, 0.785 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) under argon was added M sodium hydroxide (1.18 ml, 1.18 mmol) and stirred for 18 h. After this time, 1.0 N hydrochloric acid (2.36 ml, 2.36 mmol) was added and the mixture evaporated in vacuo to give the title compounds.

1H NMR (CDC13, 400 MHz) 6 9.04 (0.75H, 8.83 (0.25H, 8.28 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.54 (0.75H, 7.43 (0.25H, 5.61 (0.5H, 5.58 (1.5H, 3.84 (0.5H, s) and 3.82 (1.5H, s) ppm.

Step C: N-[1-(1-(4-Nitrobenzyl)-1H-imidazol-4-ylacetyl]pyrrolidin- 2 (S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester bis trifluoroacetate and N-[l-(1-(4-Nitrobenzyl)-1H-imidazol-5ylacetyl]pyrrolidin-2(S)-ylm ethyl]-3(S)-ethylproly methionine methyl ester bis trifluoroacetate To a solution of 1-(4-nitrobenzyl)-1H-imidazol-4-ylacetic acid hydrochloride and 1-(4-nitrobenzyl)-1H-imidazol-5-ylacetic acid hydrochloride (3:1 mixture, 0.392 mmol), N-[pyrrolidin-2(S)-ylmethyl]- 3(S)-ethyl-prolyl methionine methyl ester hydrochloride (0.392 mmol), prepared as described in Example 1, Steps A-L (but utilizing the substitutions described in Example 2, Step and 3-hydroxy-1,2,3benzotriazin-4(3H)-one (HOOBT, 0.39 mmol) in methylene chloride ml) are added 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.392 mmol) and triethylamine (1.57 mmol) and the mixture is stirred overnight at room temperature. After this time, sat. aq.

sodium bicarbonate (10 ml) is added and the mixture is extracted with methylene chloride. The combined extracts are washed with sat. aq.

sodium bicarbonate (10 ml) and the solvent evaporated in vacuo. The regioisomers are separated by preparative HPLC using a Nova Prep 5000 Semi preparative HPLC system and a Waters PrepPak cartridge (47X300mm, C18, 15gtm, 100 A) eluting with 5-95% acetonitrile/water TFA) at 100 ml/min (chromatography method A) to give the title compounds after lyophilization.

WO 96/34010 PCTfUS96/03975 101 Ste D: N- -(4-Nitrobenzyl)-l1H-imidazol-4-ylacetyl]pyrrolidin-.

2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine bis trifluoroacetate To a solution of N-[l-(1-(4-nitrobenzyl)-lH-inmidazol-4 ylacetyllpyrrolidin-2(S)-ylmethyl] -3 (S)-ethyl-prolyl methionine methyl ester bis trifluoroacetate (0.023 minol) in methanol (1 ml at room temperature is added L.ON lithium hydroxide (135 p.1, 0. 135 nunol). This solution is stirred for 4 h and treated with trifluoroacetic acid (100 p.1).

This mixture is purified by preparative HPLC using chromatography method A to give the title compound.

Step E: N- -(4-Nitrobenzyl)- 2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine bis trifluoroacetate To a solution of 1-(1 -(4-nitrobenzyl)- ylacetyllpyrrolidin-2(S)-ylmethyly3 (S)-ethyl-prolyl methionine methyl ester bis trifluoroacetate (0.031 nmmol) in methanol (1 ml is added 1LON lithium hydroxide (187 p.1, 0. 187 mmol This solution is stirred for 4 h and treated with trifluoroacetic acid (100 This mixture is purified by preparative HPLC using chromatography method A to give the title compound.

EXAMPLE Preparation of N- -(1-Farnesyl)- 2(S )-ylmethyll-3 (S)-ethyl-p2rolvI methionine bis trifluoroacetate Step A: l-(l-Fanesyl)-H-imidazol-5..lacetic acid methyl ester To a solution of 1 -(tribenzyl)- 1 H-imidazol-4-ylacetic acid methyl ester (200 mg, 0.523 mmol) in acetonitrile (5 ml) was added trans, trans-farnesyl bromide (156 p.1, 0.575 mmol) and heated at 55'C for 16 h.

After this time, the reaction was heated at 80'C for 3 h and then the WO 96/340 PCTIUS96/03975 -102reaction mixture was evaporated in vacuc. The residue was dissolved in methanol (5 ml and heated to reflux for 30 min and then evaporated in vacuc. The residue was purified by flash chromatography (2-4% methanol/methylene, chloride gradient elution) to provide the title compound.

I H NMR (CDCl3, 400 MHz) 8 7.50 (1iH, 6.92 (1 H, 5.24 (1iH, t, J=5.9 Hz), 5.09 (2H, in), 4.49 (2H, d, J=6.9 Hz), 3.69 (3H, 3.60 (2H, 1.91-2.15 (8H, in), 1.72 (3H, 1.65 (3H, 1.59 (3H, s) and 1.57 (3H, s) ppm.

Step B: N- -Farnesyl)- 2 (S)-ylmethyl]-3 (S)-ethyl-prolyl methionine methyl ester bis trifluoroacetate, Following the procedure described in Example 9, Steps C-D, but using I-farnesyl- IH-imiclazols...ylacetic acid methyl ester described in Step A in place of l-( 4 -nitrobenzyl)-1H-inmidazol-5.ylacetic acid methyl ester provides the title compound.

Step C: N-[i -(1-Famesyl)- 2 (S)-ylinethyl]-3(S)-ethyl-prolyl inethionine bis trifluoroacetate Following the procedure described in Example 1, Step N, but using the methyl ester prepared as described in Step B provides the title compound.

EXAMPLE 1I Preparation of N-[i -(1-Geranyl)- 2(S )-ylinethyl-3 (S )-ethyl-proly-1-methionine bis trifluoroacetate Step A: N- -(1-Geranyl)- 2(S)-ylmethyl]-3 (S )-ethyl-prolyl-methionine methyl ester bis trifluoroacetate i WO 96/34010 PCTIUS96/03975 -103- Following the procedure described in Example 10, Steps A- B, but using trans-geranyl bromide in place of farnesyl bromide provides the title compound.

Step B: -Geranyl)- ylacetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolylmethionine bis trifluoroacetate Following the procedure described in Example 1, Step N, but using the methyl ester prepared as described in Step A provides the title compound.

EXAMPLE 12 Preparation of -(4-Methoxybenzyl)- ylacetyl)pyrrolidin-2(S)-ylmethyl-3(S)-ethyl-prolyl-methionine bis trifluoroacetate Step A: 4 -Methoxybenzyl)- 1 yl)acetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolylmethionine methyl ester bis trifluoroacetate Following the procedure described in Example 9, Steps B-D, but using 4 -methoxybenzyl chloride in place of 4 -nitrobenzylbromide provides the title compound.

Step B: N-[1-(1-(4-Methoxybenzyl)- ylacetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolylmethionine bis trifluoroacetate Following the procedure described in Example 1, Step N, but substituting the methyl ester from Step A provides the title compound.

II II I- I WO 96/34010 PCT/US96/03975 -104- EXAMPLE 13 Preparation of N- -(2-Naphthylmethyl)-l1H-imidazol-5ylacetyllpyrrolidin-2(S)-ylmethyly3 (S)-ethyl-prolyl-methionine bis trifluoroacetate Step A: N- -(2-Naphthylmethyl)- 1H-imidazol-5-ylacetyl]3 etypfoii-()ymehl-rllmtinn methyl ester bis trifluoroacetate Following the procedure described in Example 9, Steps B-D, but using 2 -(bromomethyl)naphthylene in place of 4 -nitrobenzylbromide provided the title compound.

Step B: 1-(1 -(2-Naphthylmethyl)- ylacetyl]pyrrolidin-2(S)-ylmethyl]y3(S).ethyl-prolyl.

methionine bis trifluoroacetate Following the procedure described in Example 1, Step N, but using the methyl ester prepared as described in Step A provided the title compound.

EXAMPLE 14 Preparation of N- H-Imidazol-4-ylacetyl)-pyffolidin-2(S).ylmethyl] 3 (S)-ethyl-12rolvl-(13-acetvlanino)alanine trifluoroacetate Step A: Methyl 2 (S)-benzloxvcarbonlamino3.amn prponate A solution of 2 (S)-benzyloxycarbonylaniino-3aminopropionic acid (2.4 g) in methanol at 0' C was saturated with HCl gas. After stir-ring for 2 h at 200 C the solution was evaporated to obtain the title compound. I 1 HNMR (300 MHz, CD30D 8 7.35 (5H, in), 5.13 (2H, 4.50 (1H, mn), 3.77 (3H, 3.45 in), 3.22 (1H, in).

Step B: Methyl 2(S )-benzyloxycarbonylamino-3-acetylamino.

propionate WO 96/34010 PCTIUS96/03975 -105- To a solution of methyl 2 (S)-benzyloxycarbonylamino-3amino propionate (2.5 g) in methylene chloride was added pyridine mL) and acetic anhydride (5 mL). After stirring for 2 h the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted w/ 50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Upon evaporation pyridine hydrochloride precipitated and was removed by filtration. The filtrate was evaporated to obtain the title compound. 1 HNMR (300 MHz, CDC13 8 7.28 (5H, 6.14 (1H, s), 5.97 (1H, 5.10 (2H, 4.41 (1H, 3.78 (3H, 1.93 (3H, s).

Step C: Methyl 2(S)-amino-3-acetvlaminopropionate To a solution of methyl 2(S)-benzyloxycarbonylamino-3acetylamino-propionate (2.2 g in ethanolic HC1 was added 10% Pd/C 0.3 g) under nitrogen atmosphere. Hydrogen was applied to the mixture at 60 psi for 16 h. The mixture was filtered and concentrated in vacuo.

The residue was triturated with diethyl ether to obtain the product.

1 HNMR (300 MHz, CD30D) 8 4.20 (1H, 3.88 (3H, 3.82 (1H, m), 3.60 (1H, 1.99 (3H, s).

Step D: N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]- 3 (S)-ethyl-prolyl-(3-acetylamino)alanine methyl ester trifluoroacetate Following the procedures outlined in Examples 1 and 2, but substituting the methyl 2 (S)-amino-3-acetylaminopropionate of Step C for methionine methyl ester hydrochloride in Example 1, Step K, the title compound is prepared.

Step E: N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]- 3 (S)-ethvl-prolvl-(-acetylamino)alanine trifluoroacetate The title compound is prepared following the method described in Example 1, Step N.

i I I I Il WO 96/34010 PCT/US96/03975 -106- EXAMPLE In vitro inhibition of ras famesvl transferase Assays offaresyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and RAS- CAIL) were prepared as described by Schaber et al., J. Biol. Chem.

265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively.

Bovine FPTase was assayed in a volume of 100 pl containing 100 mM N- (2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM 3 H]-farnesyl diphosphate 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 gg/ml FPTase at 310C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.

Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB (3plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the 3 H]-FPP was utilized during the reaction period. Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay.

Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% polyethylene glycol 20,000, 10 IM ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 pl of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.

The compounds of the instant invention were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of 10 pM.

WO 96/34010 PCT/US96/03975 -107- EXAMPLE 16 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Rati or NIH3T3 cells, which expressed viral Ha-ras p21. The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37 0

C,

the cells are labelled in 3 ml methionine-free DMEM supple-meted with regular DMEM, 2% fetal bovine serum and 400 mCi[ 3 5 S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer NP40/20 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)).

Following a 2 hour antibody incubation at 4 0 C, 200 ml of a suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1 M NaC1) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.

-i WO 96/34010 PCT/US96/03975 -108- EXAMPLE 17 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Rat cells transformed with either a vras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

I- a I

Claims (5)

1. 2. A prodrug of a compound which inhibits farnesyl- protein transferase, the prodrug which is illustrated by the formula IL: (R 8 )r (R9 6 N 5 R12 V lCla 2 (CRla H x R~a R 4 b wherein: RlIa and RlIb are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, ailkenyl, alkynyl, R 10 0-, R 1 1S(O)m-, R I C(O)NR 1 CN, N02, (R 1 0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or R 1 OC(O)NRIO-, c) ClI -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RIO0-, R I S R I OC(O)NR 10-, CN, (R 10 )2N-C(NR RIOC(O)-, R 10 N3, -N(RIO)2, or R 1 1 C(O)- R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, WO 96/340 10 PTU9137 PCT/US96/03975 -114- b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 1 0 N02, R 1 0 R 1 1S(O)m-, RIOC(O)NRIO-, CN, (R 10 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, N3, -N(RlO)2, RI 1 0C(O)NRIO- and Cl-C20 alkyl, and d) Cl -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- Gb1 cycloalkyl; or R 2 and R3 are combined to form (CH2)s or R2or R3are combined with R 6 to form a ring such that R6 is (HA) R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) ClI-C6 alkyl unsubstituted or substituted by alkenyl, Rl100-, RI IS(O)m-, RIOC(O)NRlO-, CN, N3, (RIO)2N-C(NR 10 RlOC(O)-, RIO0C(O)-, -N(RIO)2, or R 1 1 0C(O)NR10-, c) aryl, heterocycle, cycloalkyl, alkenyl, RIO0-, R I IS(O)m-, R I C(O)NRlO0-, CN, N02, (RI 0 )2N- C(NRlO)-, RlOC(O)-, R 1 0 N3, -N(RIO)2, or R I I0C(O)NR 1 and WO 96/34010 PCTfUS96/03975 -115- d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl; R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, (R 0 N02, RIO-, R 1 1 S(O)m-, R1OC(O)NR10-, CN, (R1 0 )2N-C(NR10O)-, RIOC(O)-, R 1 0 0oC(O)-, N3, -N(R 1 0 R 1 1 OC()NR10- and C1-C20 alkyl, d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CO10 cycloalkyl; or and R5b are combined to form (CH2)s wherein one of the carbon atoms is optionally replaced by a moiety selected from: 0, S(O)m, and R6 is independently selected from hydrogen or C1 -C6 alkyl; R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 S(O)m-, R 10 C(0)NR 10 CN, N02, R 10 2N-C(NR 1 R 1 OC(O)-, R 1 0 0IC(0)-, N3, -N(R 1 0 or R11 OC()NRIO-, and WO 96/34010 WO 96/40 10PCT/US96/03975 -116- c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, periluoroalcyl, F, Cl, Br, RIO0-, Rl 1 Rl 0 C(O)NH-, CN, H2N- RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, peffluoroalkyl, F, Cl, Br, R 10 0-, RIIS(O)m-, RIOC(O)NR1 0 CN, N02, (RIO)2N-C- (NRIO)-, RIOC(O)-, R10OC(O)-, N3, -N(R 1 0 or Ri 11OC(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 Ri11S (O)m7, RIOC(O)NRIO-, CN, (R 1 0 )2N-C(NRIO)-, RlOC(O)-, RIO0C(O)-, N3, -N(R 1 0 )2, or Ri iOC(O)NRi0-; R 10 is independently selected from hydrogen, C1I-C6 ailkyl, benzyl. and aryl; R 1 1 is independently selected from C I-C6 alkyl and aryl; R 1 2 is a) substituted or unsubstituted ClI -C8 alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted ailkyl, cycloallcyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C I-C6 alkyl, 2) aryl, 3) heterocycle, 4) -N(R 1 1 )2, -OR 10 or WO 96/34010 PCTIUS96/03975 -117- R' 3 O O R14 R 13 is independently selected from hydrogen and C1-C6 alkyl; R1 4 is independently selected from C1-C6 alkyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, O, -N(R1O)-, -S(0)2N(R 1 -N(R10)S(0)2-, or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; m is 0, 1 or 2; nis 0, 1,2, 3 or4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; WO 96/34010 PCTIUS96/03975 -118- s is 4 or t is 3, 4or u is 0Oorl1; or a pharmaceutically acceptable salt thereof.
2. 3. A compound which inhibits farnesyl-protein transferase having the Formula III: HOCH 2 (CH 2 (R )r (R9 R6Y Z -Al(CRla 2 2 (CRla Rl 2)Py 1N (CH 2 y U H 0 R2R 3 Q RIaI R 4 b wherein: R Ia and R Ib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R100-, R IIS(0)m-, RIOC(0)NRIO-, CN, N02, (RIO)2N- C(NRIO)-, RIOC(0)-, RIO0C(O)-, N3, -N(RIO)2, or R 1 1 OC(0)NR 1 0-, c) ClI -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlO0-, RI IS(0)m-, RIOC(O)NRIO-, CN, (R 10 )2N-C(NRIO)-, RIOC(0)-, RIO0C(0)-, N3, -N(RlO)2, or RI R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or WO 96/34010 WO 9634010PCTIUS96/03975 119 ii) methionine sulfone, and c) substituted or unsubstituted C1I-C20 alkyl, C2-C20 alkenyl, C3-CIO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RIO)2, N02, RIO0-, Rl 1 RIOC(0)NRIO-, CN, (Rl 0 )2N-C(NRIO)-, Rl 0 RIOOC(0)-, N3, -N(RIO)2, RI 1 0C(0)NRIO- and CI-C20 alkyl, and d) Ci -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R 2 and R 3 are combined to form (CH2)s or R2or R 3 are combined with R 6 to form a ring such that Nis (HA) R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) Ci1 -C6 alkyl unsubstituted or substituted by alkenyl, R 1 00.., Ri RIOC(0)NRO-, CN, N3, (RIO)2N-C(NRIO)-, R IOC(0)-, R IOOC(0)-, -N(R 1 0 or R1 1 iOC(0)NR c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 0-, R1 1 S R I C(0)NR 1 0 CN, N02, (R 1 O)2N- C(NRlO)-, RIOC(0)-, RlOOC(0)-, N3, -N(RIO)2, or R 1 I0C(0)NRIO-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C 10 cycloalkyl; R 6 is independently selected from hydrogen or C 1 -C6 alkyl; WO 96/340 10 PCTIUS96/03975 -120- R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, peffluoroalcyl, F, Cl, Br, R 10 R1 1 Ri OC(O)NRIO0., CN, N02, Ri 0 2N-C(NR 1 R 1 0 N3, -N(RIO)2, or RI IOC(O)NR10-, and c) C1I-C6 ailkyl unsubstituted or substituted by aryl, heterocycle, cycloallcyl, ailcenyl, alkynyl, peffluoroalkyl, F, Cl, Br, R 10 R 1 1 Rl 0 C(O)NH-, CN, H2N- RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or R9 is selected from: a) hydrogen, b) alkenyl, alcynyl, perfluoroalkyl, F, Cl, Br, RIOO-, R 1 1 RlOC(O)NRIO-, CN, N02, (RIO)2N-C- (NRIO)-, RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or R 1 OC(O)NR 1 0 and c) Ci1 -C6 ailkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R1 0 Rl IS(O)m-, RIOC(O)NRI 0 CN, (Ri O)2N-C(NR 1 RI R 1 OOC(O)-, N3, -N(RI 0)2, or RI R 10 is independently selected from hydrogen, C1I-C6 ailkyl, benzyl and aryl; R 1 1 is independently selected from C1I-C6 alkyl and aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C=EC-, -C(O)NRIO-, -NRIOC(O)-, 0, -N(RIO)-, -S(0)2N(RIO)-, -N(RI 0 or S(O)m; WO 96/34010 PCT/US96/03975 -121- Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; mis nis p is q is r is s is tis u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 4 or 3, 4 or 5; and 0or 1; or a pharmaceutically acceptable salt thereof.
3. 4. A prodrug of a compound which inhibits farnesyl- protein transferase, the prodrug which is illustrated by the formula IV: C I WO 96/340 10 PCTfUS96/03975 -122- (R 8 )r R VAl(CRla 2 )nA 2 (CRlaOn W/u- IV R 4 b wherein: R Ia and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, aikynyl, R 1 0 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (RIO)2N- RlOC(O)-, RIO0C(O)-, N3, -N(RIO)2, or R 1 1 OC(O)NRIO-, c) C1.-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloallcyl, alkenyl, alkynyl, RIO0-, RI 1 RI 0 C(O)NRIO-, CN, 0 )2N-C(NR 1 RIOC(O)-, RIOOC(O)-, N3, -N(R 1 0 or RI 1 0C(O)- R2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I -C20 alkyl, C2-C20 alkenyl, C3-CIO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R 10 N02, R 10 R I IS(O)m-, R I C(O)NR 10 CN, (Rl 0 )2N-C(NRIO)-, RlOC(O)-, RIOOC(O)-, N3, -N(R 1 0)2, R I I0C(O)NRl10- and ClI-C20 alkyl, and WO 96/340 10 PCT1US96/03975 -123- d) C I -C6 alkyl substituted with an unsubstituted substituted group selected from aryl, heterocycle aiid C3- C 10 cycloalkyl; or R 2 and R3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that Nis (HA) R2R 3 R Rb R4a, R4b, R 7 a and R7b are independently selected from: a) hydrogen, b) Cl1-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, R' 1 Rl 0 C(O)NRlO-, CN, N3, (R' 0 )2N-C(NRIO)-, RIOC(O)-, RIO0C(O)-, -N(RIO)2, or RI 1 0C(O)NRIO-, c) aryl, heterocycle, cycloalkyl, ailkenyl, RIO0-, RI 1 iS(O)m-, RIOC(O)NRiO-, CN, N02, (RiO)2N- R IOC(O)-, R I N3, -N(R'10)2, or R I IOC(O)NR 10-, and d) C I -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-ClO cycloalkyl; R 6 is independently selected from hydrogen or ClI -C6 alkyl; R 8 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, ailkynyl, perfluoroalkyl, F, Cl, Br, R 10 R1 1 S(O)m-r, RIOC(O)NR 1 CN, N02, R 10 2N-C(NRlO)-, RIOC(O)-, RIOOC(O)-, N3, -N(RiO)2, or RI I0C(O)NRIO-, and WO 96/34010 PCTJUS96/03975 -124- c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, peffluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m,, RIOC(O)NH-, CN, H2N- RIOC(O)-, RIO0C(O)-, N3, -N(RlO)2, or RIOOC(O)NH-; R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalcyl, F, Cl, Br, R 1 0 0-, RI 1 RIOC(O)NRIO-, CN, N02, (RIO)2N-C- (NRIO)-, RIOC(O)-, RIO0C(O)-, N3, or RI IOC(O)NRIO-, and c) C1I-C6 alkyl unsubstituted or substituted by perfluoroalcyl, F, Cl, Br, R 100-, R1 1 RIOC(O)NR10-, CN, (Ri 0 )2N-C(NR R 1 0 RI OOC(O)-, N3, -N(Rl 0)2, or RI 1 OC(O)NRIO-; R 1 0 is independently selected from hydrogen, ClI-C6 ailkyl, benzyl and aryl; R 1 is independently selected from C1I-C6 alkyl and aryl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C=RC-, -C(O)NRIO-, -NRIOC(O)-, 0, -N(RIO)-, -N(RlO)S(0)2-, or S(O)m; Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C5-C7 saturated ring; V is selected from: a) hydrogen, b) heterocycle, c) aryl, WO 96/34010 PCTIUS96/03975 -125- d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle; X, Y and Z are independently H2 or O; mis 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or t is 3, 4 or 5; and uis 0orl; or a pharmaceutically acceptable salt thereof. The compound according to Claim 1 of the formula I: (R 8 )r R a S.R6 Y N OH V A(CR a 2 )nA 2 (CR 1 a 2 )n W (CRIb 2 N H X SR4a/ wherein: Ra is independently selected from: hydrogen or C1-C6 alkyl; Rlb is independently selected from: WO 96/34010 PCT/US96/03975 -126- a) hydrogen, b) aryl, heterocycle, cycloalkyl, R100-, -N(R10)2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(R10)2; R 2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO2, R 10 R 1 1 R 10 C(O)NR10-, CN, (R 1 0 )2N-C(NR10)-, R10C(O)-, R100C(O)-, N3, -N(R 10 R11OC(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; or R 2 and R3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that R 6 X3 R R 7 b R4a and R 7 a are independently selected from: a) hydrogen, I WO 96/340 10 PCT/US96/03975
4. 127- b) C1I-C6 alkyl unsubstituted or substituted by alkenyl, R 100-., R 1 R' 0 C(O)NRl CN, N3, (RI (b2N-C(NRl Oy., RIOC(0)-, RIO0C(O)-, or RI 1 0C(0)NR 1 0-, c) aryl, heterocycle, cycloallcyl, aikenyl, RIO0-, R I IS(0)m-, R I C(O)NR 10-, CN, N02, (RI 02N- C(NR RI R 1 0 N3, -N(R 10)2, or R 1 1 OC(O)NR 10-, and d) C1I-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- Cio0cycloalkyl; ROb and R7b are hydrogen; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C I-C 10 alkyl, C2-C 10 ailkenyl, C3-Cl10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, RIO0-, RI IS(0)m-, RIOC(0)NR10-, (Ri 0 CN, (RI O)2N-C(NRi RI OC(O)-, RIO0C(O)-, N3, -N(RlO)2, RI 1OC(0)NRIO- and C I -C20 alkyl, and d) ClI -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 1 cycloalkyl; is selected from: a) hydrogen, and b) C I-C3 alkyl; WO 96/340 10 PCTfUS96/03975 -128- R 6 is independently selected from hydrogen or C I -C6 alkyl; R8 is independently selected from: a) hydrogen, b) ClI-C6 alkyl, C2-C6 alkenyl, C2-C6 ailkynyl, C 1-C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (Ri 0 )2N-C(NRl R 1 0 Rl OOC(O)-, -N(Rl 0)2, or RI I0C(O)NR 1 and c) C1I-C6 alkyl. substituted by ClI-C6 perfluoroalkyl, R 1 0 0-, RI OC(O)NRI (Rl (b2N-C(NR RI 0 RIOOC(O)-, or RI 1 OC(O)NRIO-; R 9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, ClI-C6 perfluoroalkyl, F, Cl, R 1 0 RI IS(O)m-, RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NRIO)-, RlOC(O)-, RIO0C(O)-, -N(R 1 0 or R 1 iOC(O)NRIO-, and c) C1I-C6 alkyl unsubstituted or substituted by ClI-C6 peffluoroalkyl, F, Cl, R 1 0 R II 1 R I C(O)NR CN, (R I 0 )2N-C(NR Ri 1 R I OOC(O)-, -N(R 10)2, or R IIOC(O)NR R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl and aryl; R 1 is independently selected from ClI-C6 alkyl and aryl; Q is selected from: i~ WO 96/34010 PCT/US96/03975 -129- 'N N and A 1 and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is 0, 1 or 2; nis 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; t is 3, 4 or 5; and u is 0or 1; WO 96/34010 PCT/US96/03975 -130- or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 2 of the formula II: R(a R 5 b (R )r R 9 Z OR 1 2 1 1 R6 Y N" V A(CRla 2 )nA 2 (CRRa 2 b2) H 11 NYR 2 R 2 Y Q x R 4 a R 4 b wherein: Ra is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R 1 0 )2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R100-, or -N(R10)2; R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R 1 1 R 10 C(O)NR 10 CN, (R 10 )2N-C(NR10)-, R10C(O)-, R100C(O)-, N3, -N(R10)2, R 1 1 OC(O)NR 10 and C1-C20 alkyl, and WO 96/34010 PCT/US96/03975
5. 131- d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- CIO cycloalkyl; or R 2 and R3 are combined to form (CH2)s or R2 or R3 are combined with R 6 to form a ring such that R6 Ny is H 2 )t RR 2 3 R7a R7b R4a and R 7 a are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R 10 0-, R1 1 R10C(O)NR10-, CN, N3, (R10)2N-C(NRl0)-, R10C(O)-, R10OC(O)-, -N(R 10 or R 1 1 c) aryl, heterocycle, cycloalkyl, alkenyl, R100-, R11S(O)m-, R10C(O)NR 10 CN, N02, (R 10 )2N- C(NRlO)-, R10C(O)-, R 10 N3, -N(R 1 0 )2, or R11OC(O)NR10-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- C 10 cycloalkyl; R4b and R7b are hydrogen; is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or WO 96/34010 WO 9634010PCTIUS96/03975 -132- ii) methionine sulfone, and c) substituted or unsubstituted C I-C 10 alkyl, C2-C 1O alkenyl, C3-ClO cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 1 0 RI 1 RIOC(O)NR1 0 -,1 (Ri 0 CN, (RI 0 )2N-C(NR 1 R 1 0 R 1OOC(O)-, N3, -N(R 10 R 1 1 0OC(O)NR 1 0- and alkyl, and d) C I -C6 alkyl. substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; is selected from: a) hydrogen, and b) C1-C3 alkyl; R6 is independently selected from hydrogen or C I -C6 alkyl; R8 is independently selected from: a) hydrogen, b) C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 peffluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (RI O)2N-C(NR 1 R 1 R 1 OOC(O)-, -N(Ri 0)2, or R1 1 iOC(O)NR 10-, and c) C I -C6 alkyl. substituted by C I -C6 perfluoroalkyl, R 100.., RiOC(0)NRO.., (RIO)2N-C(NRIO)-, RlOC(0)-, -N(RlO)2, or RI R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Ci1-C6 peffluoroalkyl, F, Cl, R 1 0 R I IS(O)m-, R IOC(0)NR 10-, CN, N02, (RI 0 )2N- C(NRIO)-, RIOC(O)-, RIO0C(0)-, -N(RIO)2, or R I I0C(O)NR 10 and WO 96/34010 WO 9634010PCTIUS96/03975 133 c) C 1-C6 alkyl unsubstituted or substituted by C I-C6 perfluoroalkyl, F, Cl, R 1 0 R1 1 R 1 C(O)NR CN, (R 10 )2N-C(NR 1 R' R' OOC(O)-, -N(Rl 0)2, or R 1 R 10 is independently selected from hydrogen, C1I-C6 alkyl, benzyl and aryl; R I is independently selected from C1I-C6 alkyl and aryl; R 1 2 is a) substituted or unsubstituted C 1 -C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from: 1) aryl, 2) heterocycle, 3) -N(R 1 1 )2, 4) -0R 10 or b) ''R1 R 13 is independently selected from hydrogen and C1I-C6 ailkyl.; R 14 is independently selected from C1I-C6 ailkyl; Q is selected from: N and +N WO 96/34010 PCT/US96/03975 -134- Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR1O-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is 0, 1 or 2; nis 0, 1, 2, 3 or 4; pis 0,1,2, 3 or4; r is 0 to 5, provided that r is 0 when V is hydrogen; t is 3, 4 or 5; and uis 0or 1; or the pharmaceutically acceptable salts thereof. 7. The compound according to Claim 3 of the formula WO 96/34010 PCTIUS96/03975 -135- HOCH 2 (CH 2 )q (R )r R9 V- A'(CRla 2 )nA 2 (CR a 2 n III wherein: Ra is independently selected from: hydrogen or C1-C6 alkyl; Rlb is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 10 -N(R 10 )2 or alkenyl, 0 c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 10 or -N(RIO)2; R2 and R 3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, "0 C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R 1 R 10 C(O)NR10-, CN, (R0O)2N-C(NR10)-, R10C(O)-, R 10 N3, -N(R10)2, R 1 1 0C(O)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl; or WO 96/34010 WO 96/40 10PCTIUS96/03975 -136- R2 and R 3 are combined to form (CH2)s or R2or R 3 are combined with R 6 to form a ring such that R2R HA) R~a" R 7 b R4a and R 7 a are independently selected from: a) hydrogen, b) C1I-C6 alkyl unsubstituted or substituted by alkenyl, R 1 0 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (Rlo)2N-C(NRIO)-, RIOC(O)-, R 1 0 -N(Rl 0 or RI 1OC(O)NR1O-, c) aryl, heterocycle, cycloallcyl, ailkenyl., RIO0-, RI 1 RIOC(O)NRIO-, CN, N02, (RIO)2N- C(NRIO)-, RIOC(O)-, R 10 N3, -N(R 1 0 )2, or R IIOC(O)NR 10-, and d) C I -C6 ailkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- CIO cycloalcyl; R4b and R7b are hydrogen; R6 is independently selected from hydrogen or C Il-C6 alkyl; R 8 is independently selected from: a) hydrogen, b) ClI-C6 alkyl, C2-C6 ailcenyl, C2-C6 alkynyl, C 1-C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NRlO-, CN, N02, (Rl 0 )2N-C(NRl R 1 R 1 0 -N(Rl 0)2, or R I I0C(O)NR 10-, and WO 96/34010 PCTIUS96/03975 137 c) C1I-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 1 0 0-, R 1 OC(O)NR 1 (Ri 0 )2N-C(NRl R 1 OC(O)-, RIO0C(O)-, -N(R 1 0 or RI 1OC(O)NRIO-; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 1 0 RIIS(O)m-, Rl 0 C(O)NR10-, CN, N02, (RIO)2N- C(NRIO)-, RlOC(O)-, RIO0C(O)-, -N(Rl 0 or RI IOC(O)NRIO-, and c) C I -C6 alkyl. unsubstituted or substituted by C I -C6 perfluoroalcyl, F, Cl, R 1 0 R II 1 R I C(O)NR 1-, CN, (RI 0 )2N-C(NR RI 0 RI OOC(O)-, -N(RI 0)2, or RI is independently selected from hydrogen, C I-C6 alkyl, benzyl and aryl; R 11 is independently selected from C I-C6 alkyl and aryl; Q is selected from: N ~and +N b A 1 I and A 2 are independently selected from: a bond, -CH=CH-, -CE-C-, -C(O)NRIO-, 0, or S(O)m; V is selected from: a) hydrogen, WO 96/34010 PCTIUS96/03975 -138- b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is nis p is qis r is t is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4 or 5; and 0or 1; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 4 of the formula Formula IV: WO 96/34010 PCT/US96/03975 -139- (R 8 )r 9 V A'(CRla 2 )nA 2 (CRa 2 )n IV wherein: R1a is independently selected from: hydrogen or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, R 1 0 -N(R 10 )2 or alkenyl, 0LO c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R 1 0 or -N(R10)2; R 2 and R3 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C10 alkyl, C2-C10 alkenyl, !0 C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 R 1 R 10 C(O)NR10-, CN, (R10)2N-C(NR10)-, R 1 R 1 0 N3, -N(R 10 R1 1 0C(O)NR10- and CI-C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- cycloalkyl; or WO 96/34010 PCT1US96103975 -140- R 2 and R3 are combined to form (CH2)s or R2or R3are combined with R 6 to form a ring such that R6~ R4a and R7a are independently selected from: a) hydrogen, b) C1I-C6 ailkyl unsubstituted or substituted by alkenyl, R 10 0-, RI IS(O)m-, RIOC(O)NRIO-, CN, N3, (RIO)2N-C(NR 1 RIOC(O)-, R 10 -N(Rl 0 or Rl 1 c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 0-, R 1 1 Rl 0 C(O)NR1 0 CN, N02, (Rl 0 )2N- C(NR 1 0 R 1 R 1 0 N3, -N(R 10)2, or Ri 11OC(O)NR 10-, and d) C1-C6 alkyl. substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- Cl1O cycloalkyl; ROb and R7b are hydrogen; R6 is independently selected from hydrogen or C1I-C6 alkyl.; R8 is independently selected from: a) hydrogen, b) Cl1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 peffluoroalcyl, F, Cl, RIOO-, RIOC(O)NR 10 CN, N02, (Rl O)2N-C(NR 1 RI R 1 OOC(O)-, -N(Rl 0)2, or R I I0C(O)NR 10 and WO 96/340 10 WO 9634010PCTIUS96/03975 141 c) C 1-C6 alkyl substituted by C1I-C6 peffluoroalkyl, R 10 0-, RI OC(O)NRIO0, (RlO)2N-C(NRIO0>, Ri OC(O)-, -N(RIO)2, or RI IOC(O)NRIO-; R 9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 perfluoroalcyl, F, Cl, R 10 RI 1 RIOC(O)NR1 0 CN, N02, (R 1 0 )2N- C(NRIO)-, RIOC(O)-, R 10 -N(RIO)2, or R1 1OC(O)NRIO-, and c) C1I-C6 alkyl unsubstituted or substituted by C1I-C6 peffluoroalcyl, F, Cl, R 1 0 R I 1 RIOC(O)NRIO-, CN, (RIO)2N-C(NRIO0>, R' R' 0 -N(Rl 0)2, or RI 1 0C(O)NRlO-; R 10 is independently selected from hydrogen, C1I-C6 alkyl, benzyl and aryl; R 1 1 is independently selected from C1I-C6 ailkyl and aryl; Q is selected from: aSW N N D and +N A 1 I and A 2 are independently selected from: a bond, -CH=CH-, -C.EC-, C(O)NRIO-, 0, or S(O)m; V is selected from: a) hydrogen, WO 96/34010 PCT/S96/03975 -142- b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z are independently H2 or O; m is n is p is qis r is t is u is 0, 1 or 2; 0, 1, 2, 3 or 4; 0, 1, 2, 3 or 4; 0, 1 or 2; 0 to 5, provided that r is 0 when V is hydrogen; 3, 4 or 5; and 0or 1; or a pharmaceutically acceptable salt thereof. 9. A compound which inhibits farnesyl-protein transferase which is: N-[l-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]- prolyl-methionine methyl ester H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)-ylmethyl]- prolyl-methionine WO 96/34010 WO 9634010PCT/US96/03975 -143- [1-(4-Cyanobenzyl)- 1 H-imidazol-5-ylacetyl]pyrrolidin-2(S)- ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester 1- [1-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyr-rolidin-2(S)- ylmethyl]-3(S)-ethyl-prolyl-methionine sulfone isopropyl ester N- -(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyllpyrrolidin-2(S)- ylmethyl]-3 (S)-ethyl-prolyl-methionine sulfoxide N- -(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyl]pyrrolidin-2(S)- ylmethyl]-3 (S)-ethyl-prolyl-methionine sulfoxide isopropyl ester N- [1-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)- ylmethyl]-3 (S)-ethyl-prolyl-methionine sulfone N- [1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]pyffolidin-2(S)- ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester N- -(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)- ylmethyl]-3 (S)-ethyl-prolyl-methionine N- H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl- prolyl-methionine methyl ester N- H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl- prolyl-methionine N- [1-Glycyl-pyrrolidin-2(S)-ylmethyl] -3 (S)-ethyl-prolyl-methiomne methyl ester N-[i -Glycyl-pyrrolidin-2(S)-ylmethyl] -3 (S)-ethyl-prolyl-methionine N-[i -(3-ri H-Imidazol-4-yllpropionyl)-pyrrolidin-2(S)-ylmethyl]-3 ethyl-prolyl-methionine methyl ester N-[i H-Imidazol-4-yllpropionyl)-pyrrolidin-2(S)-ylmethyl]-3(S)- ethyl-prolyl-methionine WO 96/34010 WO 9634010PCTIUS96/03975 -144- N- [1-[3-(l1-(4-Cyanobenzyl)-l1H-imidazol-5-yl)propionyllpyrrolidin-2(S)- ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester 1-(4-Cyanobenzyl)- 1H-imidazol-5-yl)propionyllpyrrolidin-2(S ylmethyl]-3 (S)-ethyl-prolyl-methionine N- [2(S)-(l1H-Imidazol-4-ylacetyl-amino)-3 (S)-methylpentyl]-prolyl- methionine methyl ester N- [2(S)-(l1H-Lmidazol-4-ylacetyl-amino)-3 (S)-methylpentyl]-prolyl- methionine N- H-Imidazol-4-ylacetyl)-pyrrolidin-2(S-)ylmethyl]-prolyl- methionine methyl ester N- H-Imidazol-4-ylacetyl)-pyffolidin-2(S-)ylmethyl]-prolyl- methionine N- [1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyllpyffolidin-2(S)- ylmethyl]-prolyl-methionine methyl ester N- [1-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)- ylmethyl]-prolyl-methionine N- H-Lmidazol-4-ylacetyl)-3 (S)-ethylpyrrolidin-2(S)-ylmethyl]-3 ethyl-prolyl-methionine methyl ester N- H-Imidazol-4-ylacetyl)-3 (S)-ethylpyrrolidin-2(S)-ylmethyl]-3 ethyl-prolyl-methionine N- -(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl] -3 (S)-ethylpyrrolidin- 2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester N-[i -(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl] -3 (S)-ethylpyrrolidin- 2(S)-ylmethyl]-3 (S )-ethyl-prolyl-methionine WO 96/34010 WO 9634010PCT/US96/03975 -145- N- [1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]-3 (S)-ethylpyrrolidin- 2(S)-ylmethyl]-3 (S)-ethyl-prolyl-methionine isopropyl ester N- [1H-Imidazol-4-yl]propionyl)-3 (S)-ethylpyrrolidin-2(S)- ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester N- [1H-Imidazol-4-yl]propionyl)-3 (S)-ethylpyrrolidin-2(S)- ylmethyl]-3(S)-ethyl-prolyl-methionine N- [1-Glycyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3 (S)-ethyl-prolyl- metbionine methyl ester N- [1-Glycyl-3(S)-ethylpyrrolidin-2(S)-ylmethyl]-3 (S )-ethyl-prolyl- methionine N- [1-(4-Nitrobenzyl)-l1H-imidazol-4-ylacetyllpyrrolidin-2(S)- ylmethyl]-3(S)-ethyl-prolyl-methionine N- [1-(4-Nitrobenzyl)-l1H-imidazol-5-ylacetyl] pyrrolidin-2(S)- ylmethyl]-3(S)-ethyl-prolyl-methionine N- -(1-Farnesyl)- 1H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyl]- 3 (S)-ethyl-prolyl methionine N- -(1-Geranyl)- 1H-imidazol-5-ylacetyl)-pyrrolidin-2(S)-ylmethyl] 3(S)-ethyl-prolyl-methionine N- [1-(4-Methoxybenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)- ylmethyl]-3 (S )-ethyl-prolyl-methionine N- [1-(2-Naphthylmethyl)- 1H-imidazol-5-ylacetyl]pyrrolidin-2(S ylmethyl]-3(S)-ethyl-prolyl-methionine or N- H-Imidazol-4-ylacetyl)-pyrrolidin-2(S )-ylmethyll-3 (S)-ethyl- prolyl-(P-acetylamino)alanine WO 96/34010 WO 96/40 10PCTfUS96/03975 -146- or a pharmaceutically acceptable salt thereof. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethYl]-3 (S)-ethyl- prolyl-methionine methyl ester SCH 3 p~H OCH 3 HN H0 or a pharmaceutically acceptable salt thereof. 11. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- [(1H-Imidazol-4-ylacetyl-2(S)-amino)-3 (S)-methylpentyl] -prolyl- methionine methyl ester SCH 3 0 HN H -N 0 0O WO 96/34010 PCT/US96I03975 -147- or a pharmaceutically acceptable salt thereof. 12. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- lH-Imidzol- 4 -yl]propionyl).pyffolidin-.2(Sy..ylmethyl]-3(S)- ethyl-prolyl-methionine methyl ester SCH 3 0 H N 0 H or a pharmaceutically acceptable salt thereof. 13. The compound according to Claim 9 which inhibits famesyl-protein transferase which is: N- [1H-Imidazol-4-yllpropionyl)-3(S)-ethylpyrrolidin-2(S)- ylmethyl] -3 (S)-ethyl-prolyl-methionine methyl ester SCH 3 0 N HZ 0 N H or a pharmaceutically acceptable salt thereof. I /I 149 16. The compound according to claim 9 which inhibits farnesyl-protein transferase which is: N-[1-[1-(4-Cyanobenzyl)-lH-imidazol-5-ylacetyl]pyrrolidin-2(S)-ylmethyl]- 3 ethyl-prolyl-methionine isopropyl ester NC q SCH 3 N o HON NN N 17. A compound which inhibits farnesyl-protein transferase or a prodrug thereof S substantially as hereinbefore described with reference to any one of the Examples. 18. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of any one of claims 10 to 17. 19. A method for inhibiting farnesylation of Ras protein which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 17 or of a composition of claim 18. 20. A method for treating cancer which method comprises administering to a S 15 mammal a therapeutically effective amount of a compound of any one of claims 1 to 17 or of a composition of claim 18. 21. A method for treating neurofibromin benign proliferative disorder which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 17 or of a composition of claim 18. 22. A method for treating blindness related to retinal vascularization which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 17 or of a composition of claim 18. 23. A method for treating infections from hepatitis delta and related viruses which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 17 or of a composition of claim 18. 24. A method for preventing restenosis which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 17 or of a composition of claim 18. [N:\LBaa]01343:ABN WO 96/340 10PCUSIr37 PCTfUS96/03975 148 14. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- [1-(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)- ylmethyl] -3 (S)-ethyl-prolyl-methionine or a pharmaceutically acceptable salt thereof. The compound according to Claim 9 which inhibits farnesyl-protein transferase which is: N- -(4-Cyanobenzyl)-l1H-imidazol-5-ylacetyllpyrrolidin-2(S)- ylmethyl]-3 (S)-ethyl-prolyl-methionine methyl ester NC SCH 3 0 q OCH, or a pharmaceutically acceptable salt thereof. 150 A method for treating polycystic kidney disease which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 17 or of a composition of claim 18. 26. The use of a compound of any one of claims 1 to 17 for the medicament for inhibiting farnesylation of Ras protein. 27. The use of a compound of any one of claims 1 to 17 for the medicament for treating cancer. 28. The use of a compound of any one of claims 1 to 17 for the medicament for treating neurofibromin benign proliferative disorder. 29. The use of a compound of any one of claims 1 to 17 for the medicament for treating blindness related to retinal vascularization. The use of a compound of any one of claims 1 to 17 for the manufacture of a manufacture of a manufacture of a manufacture of a manufacture of a S.. *4 S S S *5 I medicament for treating infections from hepatitis delta and related viruses. 31. The use of a compound of any one of claims 1 to 17 for the manufacture of a 15 medicament for preventing restenosis. 32. The use of a compound of any one of claims 1 to 17 for the manufacture of a medicament for treating polycystic kidney disease. 33. A compound of any one of claims 1 to 17 or of a composition of claim 18 when used for inhibiting farnesylation of Ras protein. 34. A compound of any one of claims 1 to 17 or of a composition of claim 18 S when used for treating cancer. 35. A compound of any one of claims 1 to 17 or of a composition of claim 18 S when used for treating neurofibromin benign proliferative disorder. 36. A compound of any one of claims 1 to 17 or of a composition of claim 18 when used for treating blindness related to retinal vascularization. 37. A compound of any one of claims 1 to 17 or of a composition of claim 18 when used for treating infections from hepatitis delta and related viruses. 38. A compound of any one of claims 1 to 17 or of a composition of claim 18 when used for preventing restenosis. 39. A compound of any one of claims 1 to 17 or of a composition of claim 18 when used for treating polycystic kidney disease. Dated 9 September, 1998 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON -z' [N:\LIlaaju0134-.:AIN I Ir