AU721952B2 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- AU721952B2 AU721952B2 AU24326/97A AU2432697A AU721952B2 AU 721952 B2 AU721952 B2 AU 721952B2 AU 24326/97 A AU24326/97 A AU 24326/97A AU 2432697 A AU2432697 A AU 2432697A AU 721952 B2 AU721952 B2 AU 721952B2
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Description
WO 97/36886 PCT/US97/05384 -1- TITLE OF THE INVENTION 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 state, Ras is bound to GDP.
Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTPbound 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 their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa 2 -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 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 catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 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 farnesyl- WO 97/36886 PCT/US97/05384 -2ation. 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 farnesyl-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 faresyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a faresyl 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 by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesylprotein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor WO 97/36886 PCT/US97/05384 -3of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in four general classes Graham, Expert Opinion Ther. Patents, (1995) 5:1269-1285). The first are analogs of farnesyl diphosphate (FPP), while a second class of inhibitors is related to the protein substrates Ras) for the enzyme. Bisubstrate inhibitors and inhibitors of farnesyl-protein transferase that are non-competitive with the substrates have also been described. 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 farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S.
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 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 farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).
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 is, therefore, an object of this invention to develop WO 97/36886 PCT/US97/05384 -4low molecular weight compounds that will inhibit farnesyl-protein transferase and thus, the post-translational farnesylation 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 peptidomimetic arylheteroaryl-containing compounds which inhibit the farnesyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
formula A:
(R
8 )r
V-A'(
The compounds of this invention are illustrated by the
R
6 a.
c A d b R2 R 3 a
I
e
)R
DRa 2 )nA 2
(CR
1 a 2 W (CR2)p- X -(CRb2)p DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula A: WO 97/36886 PCTIUS97/05384 R6a-d bbI 8 R2 R 3 a--I (R r 9) V C (CRlb 2 )p X -(CR2)p R
A
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, 0 or S; Ri1 a and R I b are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIO0-, RIIS(0)m-, Rl 0 C(0)NRIO-,
R
1 1 (RIO)2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RlOC(0)-, N3, -N(RIO)2, or RI 1OC()NRlO-, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 0
R
1 1 Rl 0 C(0)NRIO-, (Rlo)2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(RlO)2, and Rl IOC(0)-NR10-;
R
2
R
3
R
4 and R 5 are independently selected from: a) hydrogen, WO 97/36886 PCTfUS97/05384 -6b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 2 0-, RI IS(O)m-, Rl 0 C(O)NRIO-, (RIO)2NC(O)-, RI 1 C(0)0-,
R
10 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(RlO)2, or RllOC(O)NRIO-, c) unsubstituted Ci1 -C6 alkyl, d) substituted Ci1 -C6 alkyl wherein the sub stituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 RI IS(O)m-, Rl 0 C(O)NRIO-, (Rl 0 )2NC(O)-,
R
1 0 2N-C(NR10)-, CN, RIOC(O)-, N3, -N(RIO)2, and R I IOC(O)-NR provided that when R 2
R
3
R
4 or R 5 is unsubstituted or substituted heterocycle, attachment of R 2
R
3
R
4 or the phenyl ring is through a substitutable heterocycle ring carbon;
R
6 a, R6b, R 6 c and R6d are independently selected from:* a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 12 0-,
R
1 IS(O)m-, Rl 0
C(O)NRI
0 (RIO)2NC(O)-, RI IC(O)O-,
R
10 2N-C(NR 1 0 CN, N02, RIOC(O)-, N3, -N(RIO)2, or RllOC(O)NRIO-, c) unsubstituted C1I-C6 alkyl, d) substituted C1I-C6 alkyl wherein the substituent on the substituted C1I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, WO 97/36886 PCT/US97/05384 -7-
R
1 2
R
1 1 RIOC(O)NR10-, (R 10 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(R 1 0 and RI I*OC(O)-NRIO-;
R
7 is selected from: H; Cl-4 alkyl, C3-6 cycloalcyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)
'YR
0 f) -SO 2
R'
1 g) N(RIO)2 or h) C1-4 perfluoroalkyl;
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, R 11 RIOC(O)NR (RIO)2NC(O)-,
R
1 0 2N-C(NR 10 CN, N02, RIOC(O)-, N3, -N(RIO)2, or R1 1 0C(O)NR 1 and C) C1I-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
R
10 RI I RIOC(O)NH-, (R 10 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, or
RIOOC(O)NH-;
provided that when R 8 is heterocycle, attachment of R8 to v is through a substitutable ring carbon; WO 97/36886 PCTJUS97/05384 -8- R9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Ci -C6 perfluoroalkyl, halogen, R' 110-., R I 1 S R 1 C(0)NR 1 0-,
(R
1 0
R
1 0 2N-C(NR 1 0 CN, N02, RIOC(O)-, N3, -N(RIO)2, or Rl IOC(O)NRIO-, and c) CI -C6 alkyl unsubstituted or substituted by perftuoroalkyl, F, Cl, Br, RIO0-, R 1 IS(0)m-, Rl 0 C(0)NRIO-, (Rl 0
R
1 0 2N-C(NR' CN, R' OC(0)-, N3, -N(RIO)2, or R1 IOC(0)NR10-; R 10 is independently selected from hydrogen, C I -C6 alkyl, 2,2,2trifluoroethyl,benzyl and aryl; R I is independently selected from C1I-C6 alkyl and aryl; R 1 2 is independently selected from hydrogen, C1I-C6 alkyl, C1I-C6 aralkyl, CI -C6 substituted aralkyl, Ci -C6 heteroaralkyl, Ci -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfinoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A and A 2 are independently selected from: a bond, -C(0)NR -NRl 0, -N(RIO0>, -S(0)2N(Rl 0
-N(R
1 0 or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatomn selected from 0, S, and N, and e) C2-C20 alkenyl, WO 97/36886 PCT/US97/05384 -9provided 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; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; W is a heterocycle; X is a bond, -CH=CH-, O, -C(O)NR 7
-NR
7 -C(0)NR 7
-NR
7 -S(0)2N(R 10
-N(R
10 or m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1; or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention is illustrated by the following formula: 6a-d (R")r V Al(CRla 2
),A
2 (CRl (CRib 2 )p X -(CR 1 wherein:
A,
WO 97/36886 WO 9736886PCTIUS97105384 10 a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, 0 or S; Ria is independently selected from: hydrogen, C3-C10 cycloalkyl, RIOO-, -N(RIO)2, F or C1-C6 alkyl; Rl1b is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, RIOO-, -N(RlO)2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl. wherein the substituent on the substituted Ci1 -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, RIOO- and -N(RIO)2;
R
2
R
3
R
4 a) b) and R 5 are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Ci 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfiuoroalkyl,
R
12
R
1 1 RIOC(O)NR10-, (R 1 0 R 1 2N-C(NR CN, N02, RlIOC(O)-, N3, -N(R 10 )2, or R 1 IOC(0)NR10-, unsubstituted C1-C6 alkyl; substituted C I -C6 alkyl wherein the substituent on the substituted ClI -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl., C2-C6 alkenyl, C2-C6 alkynyl,
R
12
R
1 RIOC(0)NRIO-, (R 1 0
R
1 0 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R I IOC(0)-NR WO 97/36886 PCTIUJS97/05384 provided that when R 2
R
3
R
4 or R 5 is unsubstituted or substituted heterocycle, attachment of R 2
R
3
R
4 or the phenyl ring is through a substitutable heterocycle ring carbon;
R
6 a, R6b, a) b)
C)
d)
R
6 C and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Cl 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 RI 1 RIOC(O)NRIO-, (Rl%2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R I IOC(O)NR unsubstituted ClI-C6 alkyl; substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 2 RI IS(O)m-, RIOC(O)NRIO-, (Rl 1 %2NC(O)-,
R
10 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(R 1 0 and
R
1 1 0C(O)-NRIO-;
R
7 is selected from: H; C 1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:a) CI-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)
R
0 f) S0 2 R 1 g) N(RIO)2 or WO 97/36886 PCTfUS97/05384 12 h) Ci1 -4 perifuoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R' RI OC(0)NRl CN, N02, (Ri 0 )2N-C(NRl RlOC(0)-, -N(RIO)2, or RI I0C(0)NRIO-, and c) C1I-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 1 0 0-, RIOC(0)NRIO-, (Rl 0 )2N-C(NRIO)-, RIOC(0)-, 102,or R I I0C(O)NR provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; R9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 peffluoroalkyl, F, Cl, RI RI IS(0)m-, RIOC(0)NR 1 (Rl 0 CN, N02, (RIO)2N-C(NRIO)-, RlOC(0)-, -N(RIO)2, or R I IOC(O)NR 10-, and c) Ci1 -C6 alkyl unsubstituted or substituted by C I -C6 peffluoroalkyl, F, Cl, RIO0-, RI 1 RIOC(0)NRI 0 -N(Ri10)2, or R I IOC(0)NR10-; R 1 0 is independently selected from hydrogen, ClI-C6 alkyl, 2,2,2trifluoroethyl,benzyl and aryl; RI I is independently selected from C1-C6 aikyl and aryl;
R
12 is independently selected from hydrogen, Ci-C6 alkyl, C1-C6 aralkyl, CI-C6 substituted aralkyl, C1-C6 heteroaralkyl, Cl1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfiuoroalkyl, WO 97/36886 PCT/US97/05384 -13 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRIO-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with 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; provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon; W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl; X is a bond, 0, -CH=CH-, -C(0)NR 7
-NR
7
-NR
7 -S(0)2N(RlO)-, -N(R 10 or m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; q is independently 0, 1, 2 or 3; pis 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1; or the pharmaceutically acceptable salts thereof.
WO 97/36886 PCT/US97/05384 -14- A preferred embodiment of the compounds of this invention are illustrated by the formula B: R6a-d
(R
8 )r
V-I
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; Ria is independently selected from: hydrogen, C3-C10 cycloalkyl,
R
10
-N(R
10 F or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10
-N(R
10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(R10)2;
R
2 and R 3 a) are independently selected from: hydrogen, i, WO 97/36886 WO 9736886PCT/US97/05384 15 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl, R 1 2 R 1 1 S RI OC (O)NR 1 0 (R I 0 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R1 1 0C(O)NR 1 0-, c) unsubstituted C I-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted CI -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIO cycloalkyl, C2-C6 aikenyl, C2-C6 alkynyl, R 12 R1 1 R I C(O)NR 10 (R I 0 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(RlO)2, and R I IOC(O)-NR provided that when R 2 or R 3 is unsubstituted or substituted heterocycle, attachment of R 2 or R3to the phenyl ring is through a substitutable heterocycle ring carbon; R6a, R6b, a) b)
R
6 c and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Ci 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 RI 1 Rl 0
C(O)NR
10
(R
1
R
1 0 2N-C(NR 1 CN, N02, RIOC(O)-, N3, -N(Rlo)2, or RI 1 0C(O)NR10-, unsubstituted C1I-C6 alkyl, substituted Ci -C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 2
R
1 IS(O)m-, Rl 0
C(O)NR
10
(R
10 )2NC(O)-,
R
10 2N-C(NR 1 CN, RIOC(O)-, N3, -N(R 1 0 and
R
1 WO 97/36886 PCT1TJ597/05384 R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci -C6 perfluoroalkyl, F, Cl, RIO00, R 1 OC(O)NRIO0., CN, N02, (Rl 0 )2N-C(NRl RIOC(O)-, -N(RIO)2, or R1 I0C(O)NRIO-, and C) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R 1 0 0-,
R
1
OC(O)NR
1 (RI 0 )2N-C(NR 1 R 10 -N(R 10 or R1 1 OC(O)NR provided that when R 8 is heterocycle, attachment of R 8 to v is through a substitutable ring carbon;
R
9 a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen; R 1 0 is independently selected from hydrogen, C 1-C6 alkyl, 2,2,2trifluoroethyl,benzyl and aryl; R 11 is independently selected from C I -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen, Cl1-C6 alkyl, C 1-C6 aralkyl, C1-C6 substituted araikyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfinoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;.
A
1 I and A 2 are independently selected from: a bond, -CH=CH-, -C=RC-, -C(O)NRIO-, -NRIOC(O)-, 0, or S(O)m; V is selected from: a) hydrogen, WO 97/36886 PCT/US97/05384 17b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with 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; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(0)NR10-, -NRO1C(O)-, -NR10-, O or m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
Another preferred embodiment of the compounds of this invention are illustrated by the formula C: R6a-d bC31 b 1
(R
8 )r 2 2 V Ala(CR' 2 )nA 2 (CR a2)N N S R 9 b (CR 1 b2 wherein: a is N or C; WO 97/36886 WO 9736886PCTIUS97/05384 -18 from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, 0 or 8; R I a is independently selected from: hydrogen, C3-C 10 cycloalkyl, RIO0-, -N(R 1 0 F or C1-C6 alkyl; R l b is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, RIO0-, -N(R 1 0 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted Ci -C6 alkyl. wherein the substituent on the substituted CI -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RIO0- and -N(RIO)2;
R
2 and R 3 a) b) are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R
12
R
1 IS(0)m-, RIOC(O)NRIO-, CN(RIO)2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R1 1 'OC(O)NR unsubstituted C I -C6 alkyl, substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl., C2-C6 aikynyl,
R
1 2
R
1 1 RIOC(0)NRIO-, (RIO)2NC(O)-,
R
10 2N-C(NR10)-, CN, RlOC(0)-, N3, -N(RIO)2, and RI IOC(0)-NRlO-; WO 97/36886 PCTIUS97/05384 -19 provided that when R 2 or R 3 is unsubstituted or substituted heterocycle, attachment of R 2 or R3to the phenyl ring is through a substitutable heterocycle ring carbon;
R
6 a', R6b, a) b)
R
6 c and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroaikyl,
R
1 2
R
1 1 RIOC(O)NR10-, CN(R 1 0 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or RI unsubstituted C1-C6 ailkyl, substituted Ci1 -C6 alkyl wherein the substituent. on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 2
R
1 1
R
1 0
C(O)NR
10 (Rl%2NC(O)-,
R
10 2N-C(NRIO)-, CN, R1OC(O)-, N3, -N(Rl 0 and
R
1
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycleC I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 peffluoroalkyl, F, Cl, R100-, RlOC(O)NR 1 0-, CN, N02, (R 1 0 )2N-C(NRIO)-, RlOC(O)-, -N(R 10 or
R
1 IOC(O)NRIO-, and c) ClI-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 10 0-,
R
1 OC(O)NRl (Ri 0 )2N-C(NR 1
R
1
OC(O)-,
-N(IO2,or R 1 1 0C(O)NR10-; provided that when R8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon; WO 97/36886 PCT/US97/05384 R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen; R1 0 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2trifluoroethyl,benzyl and aryl;
R
1 1 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-,
-C(O)NRO
1 O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with 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; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(0)NRO 1 -NR1OC(O)-, -NR10-, O or WO 97/36886 PCT/US97/05384 -21 m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond,
-NR
1
-NRO
1 or 0; and r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula
D:
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; Rla is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; Rlb is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10
-N(R
10 )2, F or C2-C6 alkenyl, WO 97/36886
R
2 is PCTIUS97/05384 22 C) Ci -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, RIO0-, or NR02 selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
1 2
RI
1 RIOC(O)NRIO-, (R 1 0 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(RIO)2, or Rl 1 c) unsubstituted C1-C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted Ci1 -C6 alkyl is selected from unsubstituted. or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12
R
1 1 RlGC(O)NR 10 (Rl 1 %2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(Rl 0 and R1 1 OC(O)-NR provided that when R 2 is unsubstituted or substituted heterocycle, attachment of R 2 to the phenyl ring is through a substitutable heterocycle ring carbon;
R
3 is selected from H, halogen, C1-C6 alkyl and CF3; R6a, R6b, a) b)
R
6 c and R6d are independently selected from: hydrogen, unsubstituted. or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perftuoroalkyl,
R
1 2
RI
1 Rl 0
C(O)NR
10
(R
10 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(R 1 0 )2, or R 1
OC(O)NR
1 0-, WO 97/36886 PCT/US97/05384 23 c) unsubstituted C I-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Ci -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 2
R
1 IS(O)m-, RI 0 C(O)NRIO-, (Rlo)2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and
R
1 lOC(O)-NRIO-; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RIO0-, Rl 0 C(O)NRIO-, CN, N02, (Rl 0 )2N-C(NR 1 RIOC(O)-, -N(RIO)2, or R' 1 0C(O)NRlO-, and c) C1-C6 alkyl substituted by C1-C6 perifuoroalkyl, RIO0-,
R
1
OC(O)NR
1 (RI1O)2N-C(NR 1
R
1
OC(O)-,
-N(lO2,or R 1 lOC(O)NRIO-;, provided that when R8 is heterocycle, attachment of R 8 to v is through a substitutable ring carbon; R9a and R9b are independently hydrogen, halogen, CF3 or methyl; RIO is independently selected from hydrogen, C1-C6 alkyl, 2,2,2trifluoroethyl,benzyl and aryl; R 1 1 is independently selected from C1I-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1I-C6 alkyl, Cl1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; WO 97/36886 PCT/US97/05384 -24- Al is selected from: a bond, O, -N(RlO)- or S(O)m; X is a bond, -CH=CH-, -C(0)NR10-, -NR1OC(O)-, O or n is m is p is 0 or 1; provided that n is not 0 if Al is a bond, 0, or S(O)m; 0, 1 or 2; and 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
R
9 b wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; Rla is independently selected from: hydrogen, R100-, -N(R 10
F,
C3-C10 cycloalkyl or C1-C6 alkyl; WO 97/36886 WO 9736886PCTIUS97/05384 25 Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, RIO0-, -N(RIO)2, F or C2-C6 ailkenyl, C) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, R 10 0-, or NRO2
R
2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 12 R1 1 R I C(O)NR 10 (R I 0 )2NC(O)-,
R
10 2N-C(NR 1 0 CN, N02, RlOC(O)-, N3, -N(RIO)2, or RI 1 0C(O)NRIO-, c) unsubstituted C I -C6 alkyl, d) substituted Ci -C6 alkyl wherein the sub stituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 2
RI
1 RIOC(O)NRIO-, (Rl 0 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(Rl 0 and
R
1 provided that when R 2 is unsubstituted or substituted heterocycle, attachment of R 2 to the phenyl ring is through a substitutable heterocycle ring carbon;
R
3 is selected from H, halogen, CI-C6 alkyl and CF3;
R
6 a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, WO 97/36886 WO 9736886PCTIUS97/05384 -26b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 atkynyl, halogen, C1-C6 perfluoroalkyl,
R
1 2
R
11
R
1 0 C(O)NRIO-, (R 10 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(RIO)2, or R 1 1 0C(O)NR 10 c) unsubstituted. C1I-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R1 1 R 1 C(O)NR 10 (R 10 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(Rlo)2, and R I IOC(O)-NR
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R
10 RlOC(O)NR10-, CN, N02, (RIO)2N-C(NRIO)-, RIOC(O)-, -N(RIO)2, or R 1 1OC(O)NRIO-, and C) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RIO0-, RlOC(O)NRIO-, (R'O)2N-C(NRIO)-, RlOC(O)-, -N(RIO)2, or RI 1
OC(O)NRIO-;
provided that when R 8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R
9 a. and R9b are independently hydrogen, halogen, CF3 or methyl;
R
10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2trifluoroethyl,benzyl and aryl; R 1 1 is independently selected from C1I-C6 alkyl and aryl; WO 97/36886 PCT/US97/05384 -27-
R
12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, C1-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NR 10 -NRO1C(O)-, O or nis 0 or 1; m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O; or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula F:
R
6 a-d N R 2 a-e la N 9b (CRlb 2
X
3 NC
F
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; il WO 97/36886 WO 9736886PCT[US97/05384 -28- Ria is independently selected from: hydrogen, C3-C10 cycloalkyl or ClI-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 1 0 -N(Rl 0 )2 or
F,
c) Ci1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R 10 or NRO2
R
2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Cl0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 R I R I C(O)NR 1 (R 10 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(RIO)2, or R11OC(O)NRIO-, c) unsubstituted C I -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I S R 1OC(O)NR 1 (R I 0 )2NC(O)-, R102N-C(NRIO)-, CN, RIOC(O)-, N3, -N(Rlo)2, and
R
1 provided that when R 2 is unsubstituted or substituted heterocycle, attachment of R 2 to the phenyl ring is through a substitutable heterocycle ring carbon;
R
3 is selected from H, halogen, CH3 and CF3;
R
6 a, R6b, R6c and R6d are independently selected from: a) hydrogen, WO 97/36886 PCTIUS97/05384 29 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci -C6 perfluoroalkyl,
R
1 2
R
1 1 Rl 0 C(O)NRIO-, (R 10 )2NC(O)-,
R
1 0 2N-C(NR10)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R 1 lOC(O)NRIO-, c) unsubstituted C1I-C6 alkyl, d) substituted CI -C6 alkyl wherein the sub stituent on the substituted Ci -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 2
R
11 R1 0 C(O)NRlO-, (RIO)2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(Rl 0 and
R
1 1 0C(O)-NRIO-;
R
9 a and R9b are independently hydrogen, halogen, CF3 or methyl; RIO is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2trifluoroethyl,benzyl and aryl; R" is independently selected from C I -C6 alkyl and aryl;
R
1 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1I-C6 substituted aralkyl, C 1-C6 heteroaralkyl, Ci -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C I -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NR 1 0 -NRlOC(O)-, 0 or mnis 0,l1or 2;and p is 0, 1, 2, 3or4; WO 97/36886 PCT/US97/05384 or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula G: R6a-d
R
2 'dga R d R 9b e NCN Rib R 3 NC A-(CR1a 2 )n Rb
R
3
G
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; Rla is independently selected from: hydrogen, R 1 0
-N(R
10
F,
C3-C10 cycloalkyl or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 or -N(R10)2;
R
2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 WO 97/36886 PCTIUS97/05384 -31 alkenyl, C2-C6 aikynyl, halogen, Ci -C6 perfluoroalkyl,
R
1 2 R' 1
RIOC(O)NR
10
(R]
0 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or Rl 1 0C(O)NRIO-, c) unsubstituted CI-C6 alkyl, d) substituted C 1 -C6 alkyl wherein the sub stituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R1 1 R I C(O)NR 10 (R 1 0 )2NC(O)-,
R
1 0 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and Rl 1
OC(O)-NRIO-;
provided that when R 2 is unsubstituted or substituted heterocycle, attachment of R 2 to the phenyl ring is through a substitutable-heterocycle ring carbon;
R
3 is selected from H, halogen. CH3 and CF3; R6a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alcynyl, halogen, C1-C6 perfluoroalkyl,
R
1 2
R
1 1 RIOC(O)NRIO-, (RIO)2NC(O)-,
R
10 2N-C(NR 10 CN, N02, RIOC(O)-, N3, -N(RIO)2, or RI I0C(O)NR 1
O-,
c) unsubstituted C1-C6 alkyl, d) substituted Ci -C6 alkyl wherein the substituent on the substituted Cl -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12
R
1 1
R
1 0 C(O)NRIO-,
R
10 2N-C(NR 1 CN, RlOC(O)-, N3, -N(RIO)2, and R I IOC(O)-NR WO 97/36886 PCT/US97/05384 -32-
R
9 a and R9b are independently hydrogen, haldgen, CF3 or methyl;
R
10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2trifluoroethyl,benzyl and aryl;
R
1 1 is independently selected from C1-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al is selected from: a bond, O, or S(O)m; m is 0, 1 or 2; and n is 0 or 1; or the pharmaceutically acceptable salts thereof.
Specific examples of the compounds of the invention are: 1-(4-(1,2,3-Thiadiazolyl)-phenylmethyl)-5-(4-cyanobenzyl) imidazole
NC
WO 97/36886 PCT/US97/05384 -33 1-(4-[Thien-3-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole
NC
N
S
or the pharmaceutically acceptable salts thereof.
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. When any variable aryl, heterocycle, Rla, Rib etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
As used herein, "alkyl" and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
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.
WO 97/36886 PCT/US97/05384 -34 "Alkynyl" groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl," and the aryl portion of aralkyl and aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11 -membered bicyclic heterocyclic 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, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
WO 97/36886 PCTUS97/05384 As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, 0, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
As used herein in the definition of R 7 the substituted C1-8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituent s in addition to the point of attachment to the rest of the compound.
As used herein, when no specific substituents are set forth, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(C1-C6 alkyl)2, N02, CN, (C1-C6 alkyl)O-, -OH, (C1-C6 alkyl)S(O)m-, (C1-C6 alkyl)C(O)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(C1-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl.
Lines drawn into the ring systems from substituents (such as from R 2
R
3
R
4 etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
WO 97/36886 PCT/US97/05384 -36- The moiety designated by the following structure b
I
acrepresents an aromatic 5-membered heterocyclic ring and includes the following ring systems:
N
I N 0> 0/y
N'S,
N N I N NW
N
NKN
N
I N
S
N'
VS
N
N
IN N
N
IIN
N'
,S
N-O
Is
WO
Preferably the aromatic 5-membered heterocyclic ring is selected from:
N
O 0 0/
S
N!
0
N
WS
I!
WO
NU
1/ WO0 97/36886 PCT/US97/05384 -37- Preferably, R1a and R 1 b are independently selected from: hydrogen, R11C(O)O-, -N(R 10 RO1C(O)NR10-, R 10 0- or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 10
R
10 0- and RO1C(O)NRIO-.
Preferably, R 2 is selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, CN, N02, R10C(O)- or-N(R10)2, 0 c) unsubstituted C1-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12
R
1 1 R10C(O)NR 10
(R
10 )2NC(O)-,
R
10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R 1 0 and
R
1 1OC(O)-NR10-.
Preferably, R 3 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C1-C6 alkyl.
Preferably, R 4 and R 5 are hydrogen.
Preferably, R6a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, R 12 0-,
R
1 1 CN, N02, R10C(O)- or -N(R10)2, c) unsubstituted C1-C6 alkyl; d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, C3-C10 cycloalkyl, R 12
R
1 1 S(O)m-, R10C(O)- or -N(R 10 )2.
Preferably, R 8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 perfluoroalkyl or CN.
WO 97/36886 PCT/US97/05384 -38 Preferably, R 9 is hydrogen, halogen, CF3 or methyl.
Preferably, R10 is selected from H, C1-C6 alkyl and benzyl.
Preferably, Al and A 2 are independently selected from: a bond, -C(O)NR 10 -NR10C(O)-, O, -S(0)2N(R 10 and
-N(R
10 Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
Preferably, n and r are independently 0, 1, or 2.
Preferably s is 0.
Preferably t is 1.
Preferably, the moiety (R )r (R )9 V A(CRa 2 )nA 2 (CRla) W (CRb 2 p X-(CR1b 2 is selected from: R9a
R
9 b
N
N R 9 b a N R9a and N/ C H C H 2 NC
NC
It is intended that the definition of any substituent or variable Rla, Rib, R 9 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 WO 97/36886 PCT/US97/05384 -39of 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 synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
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 acids. 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.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either 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.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-22, 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. Substituents R 2
R
6 and R 8 as shown in the Schemes, represent the substituents R 2
R
3
R
4
R
5 R6a, R6b, R 6 c, R6d and R 8 although only one such R 2
R
6 or R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents.
These reactions may be employed in a linear sequence WO 97/36886 PCT/US97/05384 to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G.
Sammes, Oxford (1979) and references therein. Aryl-aryl coupling is generally described in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, Pergamon Press (1995).
Synopsis of Schemes 1-22: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Schemes 1- 13 illustrate synthesis of the instant arylheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain. Thus, in Scheme 1, for example, a arylheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted heteroaryl boronic acid, such as a suitably substituted thienyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated benzoic acid, such as 4iodobenzoic acid, to provide the arylheteroaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1. Thus, Scheme 2 illustrates the analogous series of arylheteroaryl alcohol forming reactions starting with the halogenated arylaldehyde.
Scheme 3 illustrates the reaction wherein the "terminal" heteroaryl moiety is employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible WO 97/36886 PCTIUS97/05384 -41 when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 4.
Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the arylheteroaryl component of the instant compounds, as shown in Scheme 5. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted phenyl halide in the presence of nickel (II) to provide the arylheteroaryl VII. The heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
Scheme 6 illustrates the utilization of a suitably substituted arylheteroarylmethyl bromide in the reaction with the protected imidazole as described in Scheme 1.
As illustrated in Scheme 7, the sequence of coupling reactions may be modified such that the phenyl-heteroaryl bond is formed last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII. Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted heteroaryl boronic acid.
Scheme 8 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the preferred W moiety, imidazolyl. Thus, a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
Scheme 9 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the arylheteroaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII, wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown.
WO 97/36886 PCT/US97/05384 -42- Compounds of the instant invention wherein the Al(CRla2)nA 2 (CRla2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme The suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
Scheme 11 illustrates an analogous series of reactions wherein the (CRlb2)pX(CRlb2)p linker of the instant compounds is oxygen. Thus, a suitably substituted haloaryl alcohol, such as 4-bromophenol and the like, is reacted with methyl N-(cyano) methanimidate to provide intermediate XVI. Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a heteroaryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the Al(CR a2)nA 2 (CRla2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 12. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 1) provides the instant compound XX. If other RIa substituent s are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.
Grignard chemistry may also be employed to form a substituted alkyl linker between the arylheteroaryl and the preferred W (imidazolyl) as shown in Scheme 13. Similar substituent manipulation as shown in Scheme 12 may be performed on the fully functionalized compound which incorporates an R lb hydroxyl moiety.
WO 97/36886 WO 9736886PCT1US97/05384 43 SCHEME I
(HO)
2
B."
HO
0 Pd(PPh 3 4
R
6 HO RKR 6 LAIH4 0
HO,
WO 97/36886 PCTIUS97/05384 -44 SCHEME 1 (continued) Tr Tr NiCI 2 (PPh 3 2 "I
R
8 ZnBr R R8
IV
HO
(0F 3 S0 2 2 0, -78-C NEtiPr 2
CH
2
CI
2 -780C-200C -R2 550C, CH 3 0H \N R 6 A- V WO 97/36886 WO 9736886PCTIUS97/05384 45 SCHEME 2 0R
S
(HO0) 2 BR6 Pd(PPh 3 4 -s AlR 6 NaBH 4 6 SCHEME 3
B(OH)
2 ~NTr Pd(PPh 3 4 MeG.
N ~NTr MeG I
LAIH
4 0N NTr
HO
L.
WO 97/36886 WO 9736886PCTIUS97/05384 -46- SCHEME 4 Br"'al Pd(PPh 3 4
BU
4
NF
Br
R
3 SiO Kj'd (HO)2 BX,-'a e Pd(PPh 3 4 .R 6
BU
4
NF
HO
R 2 WO 97/36886 WO 9736886PCT[US97/05384 47 SCHEME
R
3 SiO R 2 BrZn' ez N iC1 2 (PPh 3 2
BU
4
NF
R
3 SiO ZnI X R 2 NiCI 2 (PPh 3 2 e BU 4
NF
HOl WO 97/36886 PCTIUS97/05384 48 SCHEME 6
R
6 Tr Br e +NI
R
8 WO 97/36886 WO 9736886PCTIUS97/05384 49 SCHEME 7 ii. MeGH ref lux
(HQ)
2
B
Pd(PPh 3 4 Vill t.
WO 97/36886 PCTIUS97/05384 50 SCHEME 8
H
N
R 9 b l ix Nal, NaHCO 3 ,1 2
H
N
R 9 b Tr~t, NEt, 3
N
R 9 b
N
NiCI 2 (PPh 3 2 ZnBr OTf L. -78OC-200C ii. MeOH, reflux R 6 7 L- e WO 97/36886 WO 9736886PCT/US97/05384 51 SCHEME 9 0 0R i. Br
N
55 0 C,CH3CN N N ii. EIOH,80 0 C, NH 2
NH
2 0 x~l
N
N NH 2
R
8 X11I acylation, sulfonylation I", or alkylation N'
R
8 -i\
N
R
8 f
V
WO 97/36886 WO 9736886PCTIUS97/05384 52 SCHEME NC 'aO xIv i, Na, MeOH ii. 1200C H3C.. 0 KN
N
H
NC
Tr Tr~l, NEt 3 N NCor XVi
R
6 b'9 a -e' NC R 2 OTf i. -78OC-20oC ii. MeOH reflux
XVI
NC WO 97/36886 PCTIUS97/05384 53 SCHEME 11
\OH
Br i, Na, MeOH ii. 1200C 13C, 0 Br KN
'N
0 -0 R 2
XVI
Tr TrO, NEt 3
N
Br0 OTf i. -78OC-2O0C ii. MeOH reflux (H0)2 e DMF, Pd(PPh 3 4
K
3 P0 4 8000
XVII
0 R6I~ 0- WO 97/36886 WO 9736886PCTfUS97/05384 54 SCHEME 12 Tr
\N
AC
2 O, PY' EtMgBr 0 R 8 Tr,
\N
O H R8
XIX
R
R
2
(CF
3
SO
2 2 0, -780C NEtiPr 2
,GH
2 01 2 /R 6 e LIOH
CR
6 ez SOC12
OH
WO 97/36886 WO 9736886PCTJUS97/05384 55 SCHEME 12 (continued)
NH
3 MeOH
NH
2 R6 b-c/ Il ll u ct- e .1 OMe WO 97/36886 WO 9736886PCTIUS97/05384 56 SCHEME 13 R 2 0 N' CH, Br
NH
H
2
NKAH
2150C Br R 2 0 NBS Br Bsr R 2 N=r\ NH TrOl, Et 3
N
NNH
N"
KI
Mg R8 Et 2 0 I NTr
OH
WO 97/36886 PCT/US97/05384 -57 Schemes 14-22 illustrate reactions wherein the moiety (R r (R 9) V A(CRla 2 )nA 2 (CRa 2 n W (CRb 2 )p-X.
incorporated in the compounds of the instant invention is represented by other than a substituted imidazole-containing group.
Thus, the intermediates whose synthesis are illustrated in Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. 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. Grignard chemistry may be utilized, as shown in Scheme 14, to incorporate the arylheteroaryl moiety. Thus, a suitably substituted arylheteroaryl Grignard reagent is reacted with an aldehyde to provide the C-alkylated instant compound XXI. Compound XXI can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII. The final product XXII may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures.
If the arylheteroaryl subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme 15, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 15, 16). 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 WO 97/36886 PCT/US97/05384 -58reagents, to obtain secondary alcohols such as XXX. In addition, the fully deprotected amino alcohol XXXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXII (Scheme 16), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as XXXIII (Scheme 17). Treating XXVIII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXIII The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ringopened product XXXIV In addition, the arylheteroaryl subunit reagent can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 18. When R' is an aryl group, XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI. Alternatively, the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII produced.
Schemes 19-22 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 97/36886 WO 9736886PCTIUS97/05384 59 SCHEME 14 6Boo
NH
1 I Boc NH CHO BrMg' HOe/ Boc NH e NHBoc
NH
2 e
NH
2 2 61. catalytic hydrogenati on 2. CF 3 C0 2
H
CH
2 Cl 2 Boc 2 0
CH
2
CI
2
~CHO
NaBH(OAc) 3
EI
3 N ClCH 2
CH
2
CI
NH
2
XXIII
1' WO 97/36886 PCTIUS97/05384 60 SCHEME 14 (continued) e-d F 3 00 2 H, CH 2
CI
2 NaHCO 3
NH
XXIV
a" b, 6NC AgON L
NH
XXV
WO 97/36886 WO 9736886PCTIUS97/05384 61 SCHEME BrMgti Et 2
O
BnOI BocNH CHO xxvi Bno O b 20% Pd(OH) 2
H
2
CH
3 0H NHBoo
OH
3 CO 2 \/ac-R6 DMSO CH 2
CI
2 NHBoc
(C
2
H
5 3
N
XXVII
1.
WO 97/36886 PCTIUS97/05384 62 SCHEME 15 (continued) 0 a~~R6 R-MgX e-d H NHBoc XXI X R 2 -b, HO a~ R 6 e-d R' NHBoc
XXX
WO 97/36886 PCTIUS97/05384 63 SCHEME 16 HO- Z,
CF
3 00 2
H
e-d CH 2 01 2 NHBoc
XXVIII
R 2 HO/b,
RCHO
e- d NaBH(OAc) 3
NH
2
XXXI
HO -I c e-d
NH
CICH
2
CH
2
CI
R'CH
2
XXXII
WO 97/36886 WO 9736886PCT/US97/05384 64 SCHEME 17
HO
NHBoc H H N, NN 02 NaH, DMF 0 0
C
XXVIII
-I-R R6 R"SH (0 2
H
5 3 N
A
CH
3 0H xxxiII R 2 HIS R 6
NH
2 xxxiv 1, WO 97/36886 WO 9736886PCT[US97105384 65 SCHEME 18
HO
H
2 N C0 2
H
1) Boc 2 O, K 2 C0 3
THF-H
2 0 2) CH 2
N
2 EtoAc H- -CO 2
CH
3 xxxv' xxxv LiAIH 4
THE
0-20 0
C
HO
BocNH CH 2 0H
R"'CH
2
X
CS
2 00 3
DMF
xxxv"l R"'0H 2 0 pyridn Sa
I
DMSO 1
(C
2
H
5 3 N BocNH iCHO 200C BooN H -CH 2
OH
xxxvi"' WO 97/36886 WO 9736886PCTfUS97/05384 66 SCHEME 18 (continued) BocNH_ -CHO Et 2 0 e Pd(OH) 2
H
2
CH
3 OH, CH 3
CO
2
H
3. HOI, EtOAc ryl
XL
1) 20% Pd(OH) 2
H
2
CH
3 OH, CH 3 00 2
H
2) HOI, EtOAc
R"'H
2
C
HO~ ac R6 a-R6 e-d
NH
2
XLII
WO 97/36886 WO 9736886PCTIUS97/05384 67 SCHEME 19 1) HNO 2 ,Br 2 2) KMnO 4 3) MeOH, H+
OH
3
H
2
NN
BrN MgCI .00 2
CH
3 ZnC 12, N 1C 2 (Ph 3
P)
2 NaBH 4 (excess)
SO
3 -Py, Et 3 N R
CHO
JN
DMSO
WO 97/36886 WO 9736886PCT/1JS97/05384 68 SCHEME 1. EtO(CO)CI 2.
CrBr Zn, CuON 3. S, xylene, heat 00 2
CH
3
N
-C00H, No NaBH 4 (excess) S03aPy, Et 3
N
CHO
CH
2 0H DMSO ZnCI 2 NiCI 2 (Ph 3
P)
2 NaBH 4 (excess) ,CH2HS 3 Py, Et 3
N
DMSO
WO 97/36886 WO 9736886PCTIUS97/05384 69 SCHEME 21
N
1. LDA, 002 2. MeGH, H' C0 2 0H 3 Br
NI
ZnCI 2 NiCI 2 (Ph 3
P)
2 NaBH 4 (excess)
SO
3 'Py, Et 3
N
DMSO
WO 97/36886 PCTIUS97/05384 SCHEME 22 N Br 1. LDA, C02 2. (CH 3 3 SiCHN 2 CO2CH 3 Br
N
R6 Br Zn, NiCI 2 (Ph 3
P)
2 excess NaBH 4
R
6
CH
2 0H
N.)
S0 3 Py, Et 3
N
DMSO
R6
CHO
NN.
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 WO 97/36886 PCT/US97/05384 -71 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 activity neurofibromin neu, scr, abl, Ick, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesylprotein 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.
American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
The instant compounds may also be useful for the treatment of fungal infections.
1.
WO 97/36886 PCT/US97/05384 -72- 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 compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range WO 97/36886 PCT/US97/05384 -73 described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
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 blood-stream by local bolus injection.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
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 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 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 famrnesyl-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 WO 97/36886 PCT/US97/05384 -74of 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 faresylate 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 faresyl-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 faresyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and faresyl 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 50% is approximately equal to half of the concentration of the enzyme in that particular sample.
WO 97/36886 PCT/US97/05384 75
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.
EXAMPLE 1 1-(4-(1,2,3-Thiadiazolyl)-phenylmethyl)-5-(4-cyanobenzyl) imidazole trifluoroacetate salt Step A: 1-Trityl-4-(4-Cyanobenzyl)-imidazole To a suspension of activated zinc dust (3.57g, 54.98mmol) in THF (50 mL)was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred for 45 minutes under argon at 0 C. The suspension was cooled to 0°C and a-bromo-p-tolunitrile (9.33g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20 0
C
for 6 hours and bis(triphenylphosphine)Nickel II chloride (2.40g, 3.64 mmol) and 4-iodo-l-tritylimidazole (15.95g, 36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739 (1991)) was added in one portion. The resulting mixture was stirred 16 hours at 20 0
C
and then quenched by addition of saturated NH4C1 solution (100 mL) and the mixture stirred for 2 hours. Saturated aq. NaHCO3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2 x 250 mL), dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc inCH2Cl2) to afford the title compound as a white solid.
1 H NMR (CDC13 400MHz) 8 7.54 (2H, d, J=7.9Hz), 7.38(1H, s), 7.36-7.29 (11H, 7.15-7.09(6H, 6.58(1H, s) and 3.93(2H, s) ppm.
WO 97/36886 PCT/US97/05384 -76- Step B: 1-(4-(1,2,3-Thiadiazolyl)-phenylmethyl)-5-(4cvanobenzyl) imidazole trifluoroacetate salt To 1-Trityl-4-(4-Cyanobenzyl)-imidazole (199 mg 0.468 mmol) in acetonitrile (1 mL) was added 4-(4-bromomethylphenyl)-l,2,3-thiadiazole (122 mg, 0.478 mmol) and the mixture heated at 55°C for 16 hours. The residue was dissolved in methanol mL) and heated at reflux for 30 minutes, cooled and evaporated to dryness. The residue was partitioned between sat. aq. NaHCO3 solution and CH2C12. The organic layer was dried, (NaSO4) and the solvent evaporated in vacuo. The residue was chromatographed (silica gel, 3% methanol in CH2C12) and further purified by preparative HPLC, (gradient elution, 95 :5 to 5:95% water:acetonitrile containing 0.1% trifluoroacetic acid) to afford the title compound.
FAB MS 358(MH+) 1H NMR (CD30D 400MHz) 8 9.28(1H, 9.08(1H, d, 8.04(2H, d, J=8.4Hz), 7.55(2H, d, J=8.4Hz), 7.44(1H, 7.27(2H, d, J=8.4Hz), 7.26(2H, d, J=8.4Hz), 5.47(2H, s) and 4.18(2H, s) ppm.
EXAMPLE 2 1-(4-[Thien-3-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: Methyl (4-thien-3-yl)benzoate A mixture of methyl 4-iodobenzoate(0.451 g, 1.72 mmol), 3-thienylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME (8 mL) and water mL) was purged with dry argon. Tetrakis(triphenyl-phosphine) palladium(0) (99.0 mg, 0.086 mmol) was added, and the resultant solution was stirred at 80 "C for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1M aq. HC1. The aqueous extract was separated, and extracted with EtOAc. The organic extracts WO 97/36886 PCT/US97/05384 -77 were combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S203, dried, (Na2SO4) filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, CH2C12) to afford the title compound.
1 H NMR (CDC13 400MHz) S 8.06(2H, d, J=8.4Hz), 7.67(2H, d, J=8.4Hz), 7.57(1H, dd, J=1.6 and 2.8Hz), 7.45-7.40(2H, m) and 3.93(3H, s) ppm.
Step B: 4-Thien-3-yl-benzyl alcohol To a solution of methyl (4-thien-3-yl)benzoate (552 g, 1.60 mmol) in THF (5 mL) at 0°C was added 1.0 M lithium aluminum hydride in diethyl ether (1.60 mL, 1.60 mmol) over minutes. The reaction was allowed to stir at ambient temperature for 3 hours, cooled to 0°C, and quenched by dropwise addition of water (0.10 mL), 4 N aq. NaOH (0.10 mL), and water (0.30 mL).
The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The title compound was obtained as an oil and was used without furthur purification.
1 H NMR (CDC13 400MHz) 5 7.60(2H, d, J=8.2Hz), 7.46(1H, t, J=2.2Hz), 7.44-7.36(3H, 7.30-7.23(1H, 4.72(2H, d, J=5.9Hz) and 1.63(1H, t, J=5.9Hz) ppm.
Step C: 1-(4-[Thien-3-yl]phenylmethyl)-5-(4cyanobenzyl)imidazole hydrochloride salt To a solution of 4-thien-3-yl-benzyl alcohol (253 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -78 0 C was added trifluoromethanesulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -78 0 C for 1 hour. To this mixture was added a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566mg, 1.33 mmol) in dichloromethane (5 mL). The mixture was allowed to warm to ambient temperature and stirred for 2 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol mL), heated at reflux for 1 hour, and the solvent evaporated in WO 97/36886 PCT/US97/05384 -78 vacuo. The residue was partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (silica gel, 2% MeOH in CH2C12) and the amine was converted to the HCI salt by treatment with 1.OM HC1 in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
Anal. Calcd for C22H17SN3-1.00 HC1*0.40 EtOAc: C, 66.36; H, 5.00; N, 9.84.
Found: C, 65.97; H, 4.64; N, 9.61.
FAB MS 356(MH+) 1 H NMR (CD30D, 400MHz) 8 9.00(1H, d, J=1.5Hz), 7.70- 7.56(4H, 7.45(1H, dd, J=5.1 and 2.9Hz), 7.43(1H, dd, J=1.5 and 5.2Hz), 7.39(1H, 7.27(2H, d, J=8.4Hz), 7.16(2H, d, J=8.4Hz), 5.39(2H, s) and 4.16(2H, s) ppm.
WO 97/36886 PCT/US97/05384 -79- EXAMPLE 3 In vitro inhibition of ras farnesvl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et a, 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 p1 containing 100 mM N-(2hydroxy 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 lig/ml FPTase at 31 C 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 P-plate 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 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% (w/v) polyethylene glycol 20,000, 10 |tM ZnC12 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 described in the above Examples 1-2 were tested for inhibitory activity against human WO 97/36886 PCT/US97/05384 FPTase by the assay described above and were found to have IC50 of gM.
EXAMPLE 4 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl 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°C, the cells are labelled in 3 ml methionine-free DMEM supplemented with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[ 3 5 S]methionine (1000 Cilmmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml 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.
WO 97/36886 PCT/US97/05384 -81 EXAMPLE 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 Ratl cells transformed with either a v-ras, 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.
Claims (3)
- 82- WHAT IS CLAIMED IS: 1. A compound which inhibits farnesyl-protein transferase of the formula A: R6a-d bI R 3 a (R8) r R I K I Vl- a (CR lb -(CR lb) R V A(CRa2)nA2(CRa2) n (CRb2) p X -(CR 1 )p R A wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; Ria and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100-, R 1 lS(O)m-, R10C(O)NR 1 O-, R11C(0)0-, (R 10 R102N-C(NR10)-, CN, N02, R1OC(O)-, N3, -N(R 10 or R 1 1 OC(O)NR 10 c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, WO 97/36886 WO 9736886PCT/US97/05384 83 R 10 R' 1 RlOC(O)NR (R 1 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(R 1 0 and R 1 1OC(O)-NR10-; R 2 R 3 R 4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 peffluoroalkyl, R 12 0-, R1 1 R I C(O)NR 1 0 (R 1 02NC(O)-, R' IIC(0)0-, R 10 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(Rl 0 )2, or RI c) unsubstituted C I-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 RI IS(O)m-, RIOC(O)NRIO-, (R 10 )2NC(O)-, R 10 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(R 1 0 and provided that when R 2 R 3 R 4 or R 5 is unsubstituted or substituted heterocycle, attachment of R 2 R 3 R 4 or the phenyl ring is through a substitutable heterocycle ring carbon; R6a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 peffluoroalkyl, R 12 0-, R 1 1 Rl 0 C(O)NR 10 (RIO)2NC(O)-, R 1 1 C(O)O-, R102N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(RIO)2, or R I IOC(O)NR c) unsubstituted ClI-C6 alkyl, t. WO 97/36886 PCT[US97/05384 -84- d) substituted Ci -C6 alkyl wherein the sub stituent on the substituted C 1 -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R 11 R 10 C(O)NRIO-, (R 1 0 )2NC(O)-, R 1 0 2N-C(NR 1 CN, RIOC(O)-, N3, -N(RlO)2, and R 1 lOC(O)-NRIO-; R 7 is selected from: H; Cl1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) R 0 N(RIO)2 or Ci -4 perfluoroalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, R 11 RIOC(O)NRIO-, (R 10 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(RIO)2, or R11OC(O)NRIO-, and C) C 1-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI 1 Rl 0 C(O)NH-, (R 1 0 )2NC(O)-, WO 97/36886 WO 9736886PCTIUS97/05384 85 R1 0 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(R 1 0 or RI OOC(O)NH-; provided that when R8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon; R 9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Ci1 -C6 perfluoroalkyl, ha logen, RI 10-, RI IS(O)m-, RI 1 OC(O)NRIO-, (RIO)2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, Rl 0 N3, -N(R 10 or R I I0C(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R 1 1 R 1 C(O)NR 1 0 (R 1 0 R 10 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(R 1 0 or RlIOC(O)NRIO-; R 10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl,benzyl and ary'l; Rll is independently selected from Cl-C6 alkyl and aryl; R 12 is independently selected from hydrogen, ClI-C6 alkyl, C I-C6 aralkyl, C1I-C6 substituted aralkyl, ClI-C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, CI -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRIO-, -NRIOC(O)-, 0, -N(RlO)-, -S(O)2N(R' 0 -N(RIO)S(O)2- or S(O)m; V is selected from: a) hydrogen, b) heterocycle, 86 c) aryl, d) ClI-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, 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 A 1 I is a bond, n is- 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R 8 and to A I is through a substitutable ring carbon;- is an unsubstituted. or substituted heterocycle; X is a bond, 0, -C(O)NR 7 -NR 7 -C(O)NR 7 -NR 7 -S (O)2N(R -N(RIO)S(0)2- or-S= m- mnis 0,l1or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0, 1, 2or 3; 20 r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0Oor 1; or a pharmaceutically acceptable salt thereof. *Vso 87 2. A compouand which inhibits feaesyl-protein. trarisferase of the formula A: V Al(CRla 2 X(CRa 1 (CR lb 2 x wherein: i. 5 a is Nor C; from 0-4 of b, c, d and e are independently N, NH, 0 and and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, 0 or S; [0 R Ia is independently selected from: hydrogen, C3-C 10 cycloalkyl, R 100-, -N(R 10 F or Cl1-06. alkyl; Rib is independently selected from: [5 a) .hydrogen., b) aryl, heterocycle, C3-ClO cycloallcyl-, RIO0-, -N(R 1 0 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1I-C6 alkyl. is selected from to unsubstituted or substituted aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, RIOO- and -N(RIO)2; R 2 R0, R 4 and R 5 are independently selected from: a) hydrogen-, WO 97/36886 WO 9736886PCTJUS97/05384 88 b) unsubstituted. or substituted aryl, unsubstituted. or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 120-., RI 1 R 1 0 C(O)NRI (Ri 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or RIIOC(O)NRlO-, c) unsubstituted C1-C6 alkyl; d) substituted C I -C6 alkyl wherein the substituent on the substituted Ci -C6 alkyl is selected from unsubstituted. or substituted aryl, unsubstituted or substituted heterocyclic, cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R 1 iOC(O)-NRIO-; provided that when R 2 R 3 R 4 or R 5 is unsubstituted or substituted heterocycle, attachment of R 2 R 3 R 4 or the phenyl ring is through a substitutable heterocycle ring carbon; R6a, R6b, a) b) R 6 c and R6d. are independently selected from: hydrogen, unsubstituted. or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl -C6 perfluoroalkyl, R 12 RlI RlOC(O)NR10-, (R 1 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RlO)2, or RI I0C(O)NRIO-, unsubstituted. C I -C6 alkyl; substituted C I -C6 alkyl wherein the substituent on the substituted Ci-C6 alkyl is selected from unsubstituted. or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, WO 97/36886 PCT/US97/05384 89 R 1 20-, R 11 R 1 0 C(O)NRIO-, (RI O)2NC(O)-, R 10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R I IOC(O)-NR R 7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) 'YR 0 f) -SO 2 R" g) N(Rl 0 )2 or h) Cp-4 perfluoroalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, CI1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci -C6 peffluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (R' 0 )2N-C(NR10)-, RlOC(O)-, -N(RIO)2, or R 1 I0C(O)NRIO-, and c) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 0 RIOC(O)NR 1 (R 1 0 )2N-C(NRIO)-, RlOC(O)-, -N(IO2,or R 1 I0C(O)NRIO-; provided that when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon; R9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RI RI IS(O)m-, Rl 0 C(O)NRIO-, (R 1 0 )2NC(O)-, WO 97/36886 PCT/US97/05384 CN, N02, (R 10 )2N-C(NR 1 RIOC(O)-, -N(R 1 0 or R 1 OC(O)NR10-, and c) C1 -C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, C1, R 1 0 R 11 R 1 0 C(O)NR 1 0-, (Ri 0 CN, (RIO 0 )2N-C(NR 1 RIOC(O)-, -N(R10)2, or R 11OC(O)NR10-; R 1 0 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl,benzyl and aryl; Rll 1 is independently selected from C1 -C6 alkyl and aryl; R1 2 is independently selected from hydrogen, C1 -C6 alkyl, C1 -C6 aralkyl, C1-C6 substituted aralkyl, C1 -C6 heteroaralkyl, C1 -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Ci -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -CEC-, -C(O)NRIO-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with 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; provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon; 91 W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl; X is a bond, 0, -C(O)NR 7 -NR 7 -NR 7 -S(0)2N(R 1 -N(Rl O)S or M is 0,l1or 2; n is independently 0, 1, 2, 3 or 4; q is independently 0, 1, 2 or 3; p is 0, 1,2, 3or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0Oorl1; S or a pharmaceutically acceptable salt thereof. .5 3. A ccfnpound which inhibits farnesyl-protein transferase. of the formula B: R6a-d (RL a VAl(CRla )nA 2 (CRla2)FN. R 9b R B (CR' bAPX wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, 0 or S; WO 97/36886 PCTIUS97/05384 92 RIa is independently selected from: hydrogen, C3-ClO cycloalkyl, R 1 0 -N(R 1 0 F or ClI-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, R 10 -N(R 1 0 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C 1 -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(R 1 0 )2; R 2 and R 3 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci -C6 perfluoroalkyl, R 1 2 R 11 RIOC(O)NRIO-, (RIO)2NC(O)-, RlO2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or RI lOC(O)NRIO-, c) unsubstituted. C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C I -C6 alkyl. is selected from unsubstituted. or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R 11 RIOC(O)NR 1 (RIO)2NC(O)-, R102N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R 1 iOC(O)-NRIO-; provided that when R 2 or R 3 is unsubstituted or substituted heterocycle, attachment of R 2 or R3to the phenyl ring is through a substitutable heterocycle ring carbon; R 6 a, R6b, R 6 c and R6d are independently selected from: WO 97/36886 WO 9736886PCT1LJ597/05384 93 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI1-C6 perfluoroalkyl, R 12 Rl IS(0)m-, RIOC(0)NRIO-, R 10 2N-C(NRIO)-, CN, N02,'RIOC(0)-, N3, -N(RlO)2, or RI 1 0C(O)NRIO-, c) unsubstituted C 1-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 RI 1 RIOC(0)NRIO-, (R 10 R 1 0 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(RlO)2, and R I IOC(O)-NR R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 peffluoroalkyl, F, Cl, R 1 R 1 OC(0)NR 1 CN, N02, (R 1 0 )2N-C(NR 1 RIOC(O)-, -N(R 1 0 or RI I0C(O)NRIO-, and c) C I-C6 alkyl substituted by ClI-C6 periluoroalkyl, R 10 0-, R 1 OC(0)NRIOft, (RI 0 )2N-C(NR 1 R 1 OC(0)-, -N(Rl 0 or R1 1OC(O)NRIO-; provided that when R 8 is heterocycle, attachment of R8 to v is through a substitutable ring carbon; R 9 a and R9b are independently hydrogen, C1I-C6 alkyl, trifluoromethyl and halogen; R 10 is independently selected from hydrogen, C I -C6 alikyl, 2,2,2- trifluoroethyl,benzyl and aryl; WO 97/36886 PCT/US97/05384 -94- R 1 1 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, Cl-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, -NR 1 O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with 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; provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(0)NR10-, -NRO1C(O)-, -NR10-, O or m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 4. A compound which inhibits famesyl-protein transferase of the formula C: R 6 a-d (R 8 )r V- Al(CRl'fA 2 (CR 2 n R 9 b' S S a wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the 10 remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1a is independently selected from: hydrogen, C3-C10 cycloalkyl, R 10 -N(R 10 F or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 -N(R 10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(R 10 )2; R 2 and R 3 a) are independently selected from: hydrogen, WO 97/36886 PCTIUS97/05384 96 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl, R 12 RI 1 RIOC(O)NRIO-, CN(R 1 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RlO)2, or RI 1 OC(O)NRIO-, c) unsubstituted C I -C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted Ci1 -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R 11 Rl 0 C(O)NR 1 0 (RIO)2NC(O)-, R 10 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(RIO)2, and R 1 lOC(O)-NRIO-; provided that when R 2 or R 3 is unsubstituted or substituted heterocycle, attachment of R 2 or R3to the phenyl ring is through a substitutable heterocycle ring carbon; R 6 a, R6b, R6c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl, R 12 R 11 S R I C(O)NR 10 CN(R 1 %2NC(O)-, R102N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or RI IOC(O)NRIO-, c) unsubstituted C1I-C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted CI -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, ~R 1 2 R 1 I RIOC(O)NRIO-, (R 10 )2NC(O)-, R102N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R I I0C(O)-NR 1 0-; WO 97/36886 PCT1US97/05384 -97- R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 1 0 RIOC(O)NR10-, CN, N02, (R10)2N-C(NR10)-, RlOC(O)-, -N(R 1 0 or R11 OC(O)NRIO-, and c) C1 -C6 alkyl substituted by C1 -C6 perfluoroalkyl, R100-, R10C(0)NR10-, (R10)2N-C(NR10)-, RIOC(0)-, -N(R 10 or R110C(O)NRO-; provided that when R8 is heterocycle, attachment of RS to V is through a substitutable ring carbon; R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen; is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl,benzyl and aryl; R 11 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -CRC-, -C(O)NR10-, O, or S(O)m; V is selected from: a) hydrogen, -98- b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with 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 A 1 is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(0)NR 10 -NRO1C(O)-, -NR 10 O or m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, -NR 10 -NR 10 or 0; and 20 r is 0 to 5, provided that r is 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. A compound which inhibits famesyl-protein transferase of the formula D: 5. R6a-d 1 b 9a R R 2 e NCRlb2) XQ R 8 D wherein: WO 97/36886 WO 9736886PCT/US97/05384 99 a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, 0 or S; Ri a is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, RIO0-, -N(Rl 0 )2, F or C2-C6 alkenyl, C) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, RIO0-, or NRO2 R 2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted. or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci -C6 peffluoroalkyl, R 1 2 R 1 1 S(0)rn-, RIOC(0)NR 1 0 (Rl 0 R102N-C(NRIO)-, CN, N02, RlOC(0)-, N3, -N(Rl 0 )2, or RI 1 OC(0)NR10-, c) unsubstituted C 1-C6 alkyl, d) substituted CI-C6 alkyl wherein the substituent on the substituted C1I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R 11 Rl 0 C(0)NR 10 R102N-C(NRIO)-, CN, R1OC(O)-, N3, -N(Rl 0 and R 1 lOC(0)-NR10-; WO 97/36886 PCT/US97/05384 100 provided that when R 2 is unsubstituted or substituted heterocycle, attachment of R 2 to the phenyl ring is through a substitutable heterocycle ring carbon; R 3 is selected from H, halogen, C1I-C6 alkyl and CF3; R6a, R6b, a) b) R6c and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C 1 -C6 perfluoroalkyl, R1 2 RI IS(O)m-, RIOC(O)NRIO-, (RIO)2NC(O)-, R102N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or Rll0C(O)NRIO-, unsubstituted C1I-C6 alkyl, substituted C1-C6 alkyl wherein the substituent on the substituted Ci -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 RI 1 RIOC(O)NR1 0 (RIO)2NC(O)-, R102N-C(NR 10 CN, RIOC(O)-, N3, -N(RIO)2, and R1 1 OC(O)-NR R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycleCl1-C6 alikyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 1 0 RIOC(O)NRIO-, CN, N02, (RIO)2N-C(NR 1 RIOC(O)-, -N(R 1 0 or RI IOC(O)NRIO-, and c) C1I-C6 alkyl substituted by C 1-C6 perfluoroalcyl, R 1 0 0-, RlOC(O)NR (RIO)2N-C(NRIO)-, RlOC(O)-, -N(IO2,or RI IOC(O)NRIO-;, WO 97/36886 PCT/US97/05384 -101 provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; R9a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl,benzyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C -C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al is selected from: a bond, O, -N(R10)- or S(O)m; X is a bond, -CH=CH-, -C(O)NR 10 -NRO1C(O)-, O or n is m is pis 0 or 1; provided that n is not 0 if Al is a bond, 0, or S(O)m; 0, 1 or 2; and 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. WO 97/36886 PCT/US97/05384
- 102- 6. The compound according to Claim 4 of the formula E: wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1a is independently selected from: hydrogen, R 1 0 -N(R 10 F, C3-C10 cycloalkyl or Cl-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 -N(R 10 F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, R 10 or -N(R10)2; R 2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 WO 97/36886 PCTIUS97/05384 103 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 12 R1 1 R I C (O)NR 10-, (R 1 0 )2NC(O)-, R 1 0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RlO)2, or R I IOC(O)NR c) unsubstituted C1I-C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 RI 1 Rl 0 C(O)NRIO-, (R 10 )2NC(O)-, R 10 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(RlO)2, and R 1 1 0C(O)-NR10-; provided that when R 2 is unsubstituted or substituted heterocycle, attachment of R 2 to the phenyl ring is through a substitutable heterocycle ring carbon; R 3 is selected from H, halogen, Cl1 -C6 alkyl and CF3; R6a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1.-C6 perfluoroalkyl, R 1 2 RI IS(O)m-, RIOC(O)NRIO-, (R 1 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(R 1 0 )2, or RllOC(O)NRIO-, c) unsubstituted C1-C6 alkyl, d) substituted Cl -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 2 RIIS(O)m-, RIOC(O)NRIO-, (R 10 )2NC(O)-, R102N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R' lOC(O)-NRIO-; WO 97/36886 PCTIUS97/05384 104 R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl1-C6 perfluoroalkyl, F, Cl, R 1 0 Rl 0 C(O)NRIO-, CN, N02, (R 1 0 )2N-C(NR10)-, RIOC(O)-, -N(R 1 0 or RI IOC(O)NRIO-, and C) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, RIO0-, R 1 OC(O)NR 1 (Ri 0 )2N-C(NR 1 R lOC(O)-, -N(RIO)2, or R11OC(O)NR10-; provided that when R8 is heterocycle, attachment of R8 to v is through a substitutable ring carbon; R 9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, C Il-C6 alkyl, 2,2,2- trifluoroethyl,benzyl and aryl; R 1 1 is independently selected from C1I-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, Cl -C6 substituted aralkyl, Cl -C6 heteroaralkyl, Ci -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, CI -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NRIO-, -NRlOC(O)-, 0 or n is 0Oorl1; m is 0,l1or 2;and p is 0, 1, 2, 3or 4,provided that pis not 0if Xis abond or 0; or a pharmaceutically acceptable salt thereof. WO 97/36886 PCT/US97/05384 105 7. The compound according to Claim 5 of the formula F: wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1a is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 -N(R 10 )2 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R 10 or -N(R10)2; R 2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 WO 97/36886 PCT1US97/05384 -106 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 12 R 1 1 RIOC(O)NRIO-, (R 10 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RlOC(O)-, N3, -N(R 1 0 )2, or RllOC(O)NRIO-, c) unsubstituted Ci1 -C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R1 2 RI 1 Rl 0 C(O)NRIO-, (RIO)2NC(O)-, R 10 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(RIO)2, and R 1 1 0C(O)-NRIO-; provided that when R 2 is unsubstituted or substituted heterocycle, attachment of R 2 to the phenyl ring is through a substitutable heterocycle ring carbon; R 3 is selected from H, halogen, CH3 and CF3; R6a, R6b, R6c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C 1 -C6 perfluoroalkyl, R 1 2 R 1 1 Rl 0 C(O)NRIO-, (R 10 )2NC(O)-, R 1 0 2N-C(NRIO)-, CN, N02, R1OC(O)-, N3, -N(R 1 0 )2, or R1 1 OC(O)NR c) unsubstituted C1.-C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R- 12 R 11 Rl 0 C(O)NR1 0 (R 10 )2NC(O)-, R 10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RlO)2, and R1 1 OC(O)-NR WO 97/36886 PCT/US97/05384
- 107- R 9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, C -C6 alkyl, 2,2,2- trifluoroethyl,benzyl and aryl; R 11 is independently selected from Ci-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, O or m is p is 0, 1 or 2; and 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 6 of the formula G: R6a-d R 9 b. NC /Ca A(cR1a 2 aR b Rilb wherein: WO 97/36886 PCTIUS97/05384 -108 a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d. or e is independently N, NH, 0 or S; Ria is independently selected from: hydrogen, RIO0-, -N(RIO)2, F, C3-ClO cycloalkyl. or Cl-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C I -C6 alkyl. unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, RIO0-, or NRO2 R 2 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl, R 12 R 1 1 RIOC(0)NR 10 (RIO)2NC(O)-, R 1 0 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or RI 1OC(0)NR10-, c) unsubstituted C I -C6 alkyl, d) substituted C1-C6 alkyl. wherein the substituent on the substituted C I-C6 alkyl. is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R1 1 RI 0 C(0)NR 10 (Rl 0 R 10 2N-C(NR 1 CN, RIOC(O)-, N3, -N(RIO)2, and R 1 iOC(0)-NRIO-; WO 97/36886' PCTIUS97/05384 109 provided that when R 2 is unsubstituted or substituted heterocycle, attachment of R 2 to the phenyl ring is through a substitutable heterocycle ring carbon; R 3 is selected from H, halogen. CH3 and CF3; R 6 a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, k 12 RI IS(O)m-, RIOC(O)NR 1 0 (R 10 )2NC(O)-, R 1 0 2N-C(NR10)-, CN, N02, RIOC(O)-, N3, -N(R 1 0 )2, or R I IOC(O)NR c) unsubstituted C1I-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R I IS(O)m-, R I C(O)NRI 0 (R 10 )2NC(O)-, R1O2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(Rl 0 and R1 1 OC(O)-NR R9a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is. independently selected from hydrogen, C1I-C6 alkyl, 2,2,2- trifluoroethyl,benzyl and aryl; R 1 1 is independently selected from Cl-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C I-C6 alkyl, C1I-C6. aralkyl, C1I-C6 substituted aralkyl, C 1-C6 heteroaralkyl, WO 97/36886 PCTIUS97/05384 110 C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C I -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A 1 is selected from: a bond, 0, or S(O)m; mnis n is 0, 1 or 2; and 0 or 1; or the pharmaceutically acceptable salts thereof. 9. A compound which inhibits farnesyl-protein transferase which is: 1 1,2,3-Thiadiazolyl)-phenylmethyl)-5- (4-cyanobenzyl) imidazole NC N -S or a pharmaceutically acceptable salt thereof. A compound which inhibits famesyl-protein transferase which is: 1 [Thien-3-Yllphenylmethyl)-5-(4-cyanobenzyl)imidazole 111 N=C N or a pharmaceutically acceptable salt thereof. 11. A compound which inhibits farnesyl protein transferase, substantially as hereinbefore described with reference to any one of the examples. 12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of any one of claims 1 to 11. 13. A pharmaceutical composition made by combining the compound of any one of claims 1 to 11 and a pharmaceutically acceptable carrier. 14. A process for making a pharmaceutical composition comprising combining a compound of any one of claims 1 to 11 and a pharmaceutically acceptable carrier. A method for inhibiting farnesyl-protein transferase, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13. 16. A compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13 i when used in inhibiting famesyl-protein transferase. S: 17. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for inhibiting farnesyl-protein transferase. 18. A method for treating cancer, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 11 or of a composition of 20 claim 12 or claim 13. 19. A compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13 when used in treating cancer. 20. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for treating cancer. 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 11 or of a composition of claim 12 or claim 13. 22. A compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13 when used in treating neurofibromin benign proliferative disorder. 23. The use of a compound according to any one of claims 1 to 11 for the manufacture of a 2 medicament for treating neurofibromin benign proliferative disorder. [R:\LIBAA]07786.doc:tab 112 24. A method for treating blindness related to retinal vascularisation, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13. A compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13 s when used in treating blindness related to retinal vascularisation. 26. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for treating blindness related to retinal vascularisation. 27. 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 11 or of a composition of claim 12 or claim 13. 28. A compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13 when used in treating infections from hepatitis delta and related viruses. 29. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for treating infections from hepatitis delta and related viruses. 30. 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 11 or of a composition of claim 12orclaim 13. 31. A compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13 when used in preventing restenosis. 20 32. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for preventing restenosis. 33. 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 11 or of a composition of claim 12 or claim 13. 25 34. A compound of any one of claims 1 to 11 or of a composition of claim 12 or claim 13 when used in treating polycystic kidney disease. 35. The use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for treating polycystic kidney disease. Dated 16 December, 1999 Merck Co., Inc. Patent Attorneys for the ApplicantlNominated Person SPRUSON FERGUSON [R:\LBAA07786.do:tab
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1459296P | 1996-04-03 | 1996-04-03 | |
| US60/014592 | 1996-04-03 | ||
| GBGB9613462.2A GB9613462D0 (en) | 1996-06-27 | 1996-06-27 | Inhibitors of farnesyl-protein transferase |
| GB9613462 | 1996-06-27 | ||
| US2233296P | 1996-07-24 | 1996-07-24 | |
| US60/022332 | 1996-07-24 | ||
| GBGB9617254.9A GB9617254D0 (en) | 1996-08-16 | 1996-08-16 | Inhibitors of farnesyl-protein transferase |
| GB9617254 | 1996-08-16 | ||
| PCT/US1997/005384 WO1997036886A1 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2432697A AU2432697A (en) | 1997-10-22 |
| AU721952B2 true AU721952B2 (en) | 2000-07-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU24326/97A Ceased AU721952B2 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
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| Country | Link |
|---|---|
| EP (1) | EP0891343A1 (en) |
| JP (1) | JP2000507593A (en) |
| AU (1) | AU721952B2 (en) |
| CA (1) | CA2249645A1 (en) |
| WO (1) | WO1997036886A1 (en) |
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| US6627629B2 (en) | 2000-06-30 | 2003-09-30 | Bristol-Myers Squibb Pharma | N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity |
| US6992087B2 (en) | 2001-11-21 | 2006-01-31 | Pfizer Inc | Substituted aryl 1,4-pyrazine derivatives |
| CA2480497A1 (en) | 2002-04-26 | 2003-11-06 | Pharmacia & Upjohn Company | Substituted pyrazine derivatives |
| BRPI0409505A (en) | 2003-05-09 | 2006-04-18 | Pharmacia & Upjohn Co Llc | compounds as crf1 receptor antagonists |
| JP4928949B2 (en) | 2003-12-23 | 2012-05-09 | アステックス、セラピューティックス、リミテッド | Pyrazole derivatives as protein kinase modulators |
| EP1902032A1 (en) | 2005-06-22 | 2008-03-26 | Astex Therapeutics Limited | Pharmaceutical compounds |
| WO2006136837A2 (en) | 2005-06-23 | 2006-12-28 | Astex Therapeutics Limited | Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators |
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| WO2010114896A1 (en) | 2009-03-31 | 2010-10-07 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
| US9828345B2 (en) | 2013-02-28 | 2017-11-28 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors |
| AR094929A1 (en) | 2013-02-28 | 2015-09-09 | Bristol Myers Squibb Co | DERIVATIVES OF PHENYLPIRAZOL AS POWERFUL INHIBITORS OF ROCK1 AND ROCK2 |
| AU2016295693B2 (en) | 2015-07-17 | 2020-05-21 | Sunshine Lake Pharma Co., Ltd. | Substituted quinazoline compounds and preparation and uses thereof |
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Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU557755A3 (en) * | 1968-08-19 | 1977-05-05 | Янссен Фармасьютика Н.В. (Фирма) | Method for preparing imidazole derivatives |
| DE2059949C3 (en) * | 1970-12-05 | 1979-12-13 | Bayer Ag, 5090 Leverkusen | Thienyl fatty acid derivatives, processes for their preparation and their use as pharmaceuticals |
| DE3228266A1 (en) * | 1982-07-29 | 1984-02-02 | A. Nattermann & Cie GmbH, 5000 Köln | Imidazolylalkylthiophenes, process for their preparation and pharmaceutical preparations containing them |
| AT395425B (en) * | 1991-04-04 | 1992-12-28 | Laevosan Gmbh & Co Kg | NEW THIOPHEN-2-CARBONIC ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
-
1997
- 1997-04-01 JP JP9535554A patent/JP2000507593A/en active Pending
- 1997-04-01 EP EP97920032A patent/EP0891343A1/en not_active Withdrawn
- 1997-04-01 AU AU24326/97A patent/AU721952B2/en not_active Ceased
- 1997-04-01 CA CA002249645A patent/CA2249645A1/en not_active Abandoned
- 1997-04-01 WO PCT/US1997/005384 patent/WO1997036886A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0891343A1 (en) | 1999-01-20 |
| WO1997036886A1 (en) | 1997-10-09 |
| AU2432697A (en) | 1997-10-22 |
| JP2000507593A (en) | 2000-06-20 |
| CA2249645A1 (en) | 1997-10-09 |
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| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |