AU706150B2 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- AU706150B2 AU706150B2 AU24301/97A AU2430197A AU706150B2 AU 706150 B2 AU706150 B2 AU 706150B2 AU 24301/97 A AU24301/97 A AU 24301/97A AU 2430197 A AU2430197 A AU 2430197A AU 706150 B2 AU706150 B2 AU 706150B2
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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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- A—HUMAN NECESSITIES
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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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- C07D233/54—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
- C07D233/66—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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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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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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- C07D—HETEROCYCLIC COMPOUNDS
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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 97/36901 PCT/US97/05304 -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 GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form Lowy and D.M.
Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in 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-Aaa I-Aaa2-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 97/36901 PCT/US97/05304 -2ation. Other famesylated 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 famesylated. James, et al., have also suggested that there are famesylated 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 ras-dependent tumors in nude mice Kohl et al., Proc. Natl.
Acad. Sci 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl 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 famesyl 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 97/36901 PCT/US97/05304 -3of isoprene biosynthesis.
Inhibitors of faresyl-protein transferase (FPTase) have been described in four general classes Graham, Expert Opinion Ther. Patents, (1995) 5:1269-1285). The first are analogs of faresyl diphosphate (FPP), while a second class of inhibitors is related to the protein substrates Ras) for the enzyme. Bisubstrate inhibitors and inhibitors of famesyl-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 famesyl-protein transferase enzyme, or may be purely competitive inhibitors Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity.
Therefore, a functional replacement for the thiol is desirable.
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of famesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).
It 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 97/36901 PCT/US97/05304 -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 arylheteroarylcontaining compounds which inhibit the famesyl-protein transferase.
Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A:
R
6 a-e
R
3
(R
8 )r f V- A'(CR' 2 )nA 2
(CR
1 2 W (CR 2 )p X -(CR22)p R
A
DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of faresyl-protein transferase and the famesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of faresyl-protein transferase are illustrated by the formula A: WO 97/36901 WO 9736901PCTIUS97/05304 R 6a-e
R
3 -A(l 2 )nA (C Rl 2 W/ (CR 2) X -(CR 2)p R AR
A
wherein: from 1-2 of f(s) are independently N or and the remaining f s are independently CH; R 1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 R I IS(O)m-, R I R I IC(0)0-, (R 1O)2NC(O)-, R 1 0 2N-C(NR10)-, CN, N02, R IOC(O)-, N3, -N(R'1O)2, or R I I 0C(O)NR 1 0-, c) unsubstituted or substituted ClI -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIOO-, RI IS(O)m-, RIOC(O)NRIO-,
(R
1 0 )2NC(O)-,
R
1 02N-C(NRIO)-, CN, RIOC(O)-, N3, and R I IOC(O)-NR
R
3
R
4 and R 5 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, C I -C6 perfluoroalkyl, R 120-, WO 97/36901 WO 97/690 1PCTIUS97/05304 -6- R I IS(O)m-, R I C(O)NR 1 (R 10 R I IC(0)0-, R 1 0 2N-C(NR CN, N02, R I N3, -N(R 1 0)2, or R I IOC(O)NR c) unsubstituted C I -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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 2 RI IS(O)m-, RIOC(O)NRIO-, (RIO)2NC(O)-, RiO02N-C(NR CN, R IOC(O)-, N3, -N(R'1 0 and R I IOC(O)-NR R6a, R6b, R 6 C, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 12 0-, R' IIS(O)m-, R I C(O)NRi10-, (R 10 R' IIC(0)0-, R I 0 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10 )2, or R c) unsubstituted C I -C6 alkyl, d) substituted ClI -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 aikynyl, R 12 R I IS(O)m-, R IOC(O)NR 10-, (R I 0 )2NC(O)-, R 10 2N-C(NR CN, R IOC(O)-, N3, -N(R 10)2, and R I IOC(O)-NR 10-; or any two of R 6 a, R6b, R 6 C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; WO 97/36901 WO 9736901PCTIUS97/05304 -7provided that when R 3
R
4
R
5
R
6 a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 3
R
4
R
5 R6a, R6b, R 6 c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R
7 is selected from: H; CI-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) CI1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) R1 0 f) -S0 2
R
1 g) N(R10)2 or h) CI-4 perfluoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-CI0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 100-., R I R 1 I C(O)NR (RI 0 )2NC(O)-, R 102N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10 or R I I0C(O)NR 10-, and c) C1I-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3 -Ci 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, peffluoroalkyl, F, Cl, Br, R 1 0 R I IS(O)m-, R I C(O)NH-, (R'O0)2NC(O)-,
R
1 02N-C(NRIO)-, CN, RIOC(O)-, N3, or
RIOOC(O)NII-;
WO 97/36901 WO 9736901PCT/US97/05304 -8provided that when R8 is heterocycle, attachment of RS to V is through a substitutable ring carbon;
R
9 is independently selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R I R I IS(0)m-, R IOC(O)NR 10-, (R I 0 R 10 2N-C(NR CN, N02, R I N3, -N(R 10)2, or R I I0C(O)NR 10-, and c) C I-C6 alkyl unsubstituted or substituted by perfiuoroalkyl, F, Cl, Br, R 1 0 R I IS(0)m-, R I C(O)NR (R 1 02NC(0)-, R I 0 2N-C(NR 1 CN, R' I N3, -N(R 10 or R IIOC(0)NR R 1 0 is independently selected from hydrogen, C I-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R
1 is independently selected from C I -C6 alkyl and aryl;
R
12 is independently selected from hydrogen, CI -C6 alkyl, Cj -C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C I -C6 perfluoroalkyl, 2-aminoethyl and 2 ,2,2-trifluoroethyl; A I and A 2 are independently selected from: a bond, -CH=CH-,
-CX=C-,
-C(0)NRIO0, -NR' 0 0, -N(RIO0>, -S(0)2N(R -N(Rl 0 or S(O)m; V is selected from: a) hydrogen, b) heterocycle, c) aryl, WO 97/36901 PCT/US97/05304 -9d) C -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, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 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; X is a bond, -CH=CH-, O, -C(0)NR 7
-NR
7
-C(O)NR
7
-NR
7 -S(0)2N(R 1 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 A:
R
6 a-e
(R
8 )r 1R9 f V A R A2R1, W (CR2)p- X -(CR 2 2 )p f WO 97/36901 WO 9736901PCT/US97/05304 10 wherein: from 1-2 of f(s) are independently N or and the remaining f's are independently
CH;
R 1 is independently selected from: hydrogen, C3 -C 10 cycloalkyl, R 10 -N(R 10)2, F or C I-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, R 1 00., -N(R 10)2, F or C2-C6 alkenyl, c) unsubstituted or substituted C I -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
3
R
4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl -C6 perfluoroalkyl, R 1 2 R I IS(0)m-, R IOC(0)NR 10-, (R 10 R 10 2N-C(NR CN, N02, R I N3, -N(R 1 0 )2, or R I I0C(0)NR 1 0-, c) unsubstituted C I-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 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120.., R I R I OC(0)NR (R 1' 0 R 10 2N-C(NR CN, R I N3, -N(R'1O)2, and R I I0C(0)-NR WO 97/36901 PCTIUS97/05304 -1I1
R
6 a, R6b, R 6 C, R6d and R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C 6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfluoroalkyl, RlO2N-C(NRlO).. CN, N02, RIOC(O)-, N3, -N(R'0)2, or R I c) unsubstituted C I-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 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R I IS(O)m-,
R
1 I C(O)NR 10-, (R 10 R 10 2N-C(NR
CN,
R IOC(O)-, N3, -N(R'O0)2, and R I IOC(O)-NR 10-; or any two of R 6 a, R6b, R 6 c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH., -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3
R
4
R
5
R
6 R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R 3
R
4
R
5 R6a, R6b, R6c, R6d or R 6 e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R
7 is selected from: H; C1-4 alkyl, C3-.6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, WO 97/3690 1 PCTJUS97/05304 12 e)
YR
0 f) _0R g) N(R 10) 2 or h) Cj-4 perfluoroalkyl;
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, CI, R 10 R IOC(0)NR 10O CN, N02, (RlO0)2N-C(NR1)-, R I -N(R 10)2, or R I I0C(0)NR 10-, and C) C I-C6 alkyl substituted by C I -C6 perfluoroalkyl, Ri 100- Ri I C(0)NR 1 (Ri 1%2N-C(NR R 1 0 -N(R 10)2, or R 11 OC(0)NR 1 provided that when R8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C 6 alkynyl, C I-C6 perfinoroalkyl,
F,
Cl, R I 10>, R I IS(0)m-, R IOC(O)NR 10-, (R'I 0 CN, N02, (R 1O)2N-C(NR R IOC(O)-, -N(R 10)2, Or R IIOC(0)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 1 0 R I IS(0)m-, R IOC(0)NR (RI 0 CN, (R I O)2N-C(NR R I OC(O)-, -N(R 10)2, or R IIOC(0)NRi10-; R 1 0 is independently selected from hydrogen, C I -C6 alkyl, benzyl, 2 2 ,2-trifluoroethyl and aryl;
R
1 is independently selected from C I-C6 alkyl and aryl; WO 97/36901 PCT/US97/05304 13
R
12 is independently selected from hydrogen, C -C6 alkyl, Cl -C6 aralkyl, C1-C6 substituted aralkyl, CI-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-,
-CEC-,
-C(O)NR 10O-, 0, -N(R 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) C -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; 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(R -N(RI O)S(0)2- 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; WO 97/36901 PCTIUS97/05304 14qis 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 are illustrated by the formula B: R6a-e I fR V A'(CR 2 )nA 2 (CR'2)-N \J R9b fR 4 B (CR 2 2 )p-X
R
B
wherein: from 1-2 of f(s) are independently N or and the remaining f's are independently
CH;
RI is selected from: hydrogen, C3-CIO cycloalkyl,
R
1 0
-N(R
1 0
F
or C1-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10
-N(R
10
F
or C2-C6 alkenyl, c) unsubstituted or substituted C -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
3 and R 4 are independently selected from: a) hydrogen, WO 97/36901 WO 9736901PCT/US97/05304 15 b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 12 R II R' I C(O)NR (R 1 )2NC(O)., R 10 2N-C(NR1), CN, N02, R IOC(O)-, N3, -N(R 10)2, or R I I OC(O)NR c) unsubstituted C I -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 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120.., R II R' I C(O)NR (R 1 0 RIO02N..C(NRl10), CN, R IOC(O)-, N3, -N(R 1 0 and R I IOC(0).NR
R
6 a, R6b, a) b)
R
6 C, R6d and R 6 e 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 perfluoroalkyl, CN, N02, RIOC(0)-, N3, -N(R' 0 )2, or R I IOC(0)NR unsubstituted C I -C6 alkyl, substituted C I -C6 aikyl wherein the substituent on the substituted C I -C6 aikyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(O)m-, R IOC(O)NR 10-, (R 1 0 RlO2N..C(NR1O)>, CN, RIOC(0)-, N3, -N(R' 0 and R I I C(O)-NR or WO 97/36901 PCT/US97/05304 -16any two of R6a, R6b, R 6 c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3
R
4 R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R 3
R
4 R6a, R6b, R6c, R6d or R6e to the 6 -membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; 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,
R
10 RIOC(O)NR10-, CN, N02, (RI0)2N-C(NR10)_, R
-N(R
10 or RI 1 0C(O)NR 10, and c) C1-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R 1 0 0-, R 1C(O)NR 10-, (R 10)2N-C(NR 10), -N(R10)2, or R 1OC(O)NR10_; provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
R
1 0 is independently selected from hydrogen, CI-C6 alkyl, benzyl, 2, 2 2 -trifluoroethyl and aryl;
R
1 1 is independently selected from Cl-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C1-C6 alkyl, Ci-C6 aralkyl, Ci-C6 substituted aralkyl, C -C6 heteroaralkyl, C -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C -C6 perfluoroalkyl, WO 97/36901 PCT/US97/05304 17- 2-aminoethyl and 2 2 ,2-trifluoroethyl;
A
l and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C -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 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)NR10_, -NRIOC(O)-, -NR 10, 0 or m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; pis 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:
WO 97/36901 WO 9736901PCTIUS97/05304 -18 R 6a-e
(R
8 )r R3 0 N NR 9 a R 3 V A( 2 C Rb (CR 2
)F-XR
wherein: from 1-2 of f(s) are independently N or and the remaining f's are independently CH; R I is selected from: hydrogen, C3-CI10 cycloalkyl, R 1 0 -N(R'10)2, F or CI-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 1 0
-N(R'
0
F
or C2-C6 alkenyl, c) unsubstituted or substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(RIO)2;
R
3 and R 4 are independently 'selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Ci 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfinoroalkyl, RIO2N..C(NRlOY, CN, N02, RIOC(O)-, N3, -N(R 1 0 )2, or R I I0C(0)NR10-, c) unsubstituted ClI -C6 alkyl, WO 97/36901 WO 9736901PCTIUS97/05304 19 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 1 20, R I R 1 I C(O)NR 10-, (R I Q2NC(O)-, R 10 2N-C(NR CN, R I N3, -N(R'10)2, and R I I0C(O)-NR R6a, R6b, a) b)
R
6 c, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfluoroalkyl, R 12 R I IS(O)m-, R I C(O)NR 1 CN(R I 0 )2NC(O)-, R 1 0 2N-C(NR CN, N02, R I N3, -N(R 10 )2, or R I IOC(O)NR 1 0-, 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 alkynyl, R 1 20-, R I S R I OC(O)NR 10-, (R 1 0 )2NC(O)-, R 10 2N-C(NR CN, R IOC(O)-, N3, -N(R 10)2, and R I IOC(O)-NR 10-; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3
R
4
R
6 a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 3
R
4 R6a, R6b, R 6 c, R6d or Reto the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; "WO 97/36901 PTU9/50 PCT/US97/05304 20 RS is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Ci -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 10 R IOC(0)NR 10-, CN, N02, (R 10 )2N-C(NR10)-, R IOC(O)-, -N(R 10 or R' I IC(0)NR 10-, and C) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 00,
R
1 OC(0)NRI10., (RIO)2N-C(NRI10>, R 1 0 -N(R 10 or R' I IC(O)NR 1 0 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, C I -C6 alkyl, trifluoromethyl and halogen; R 10 is independently selected from hydrogen, C I-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R
1 1 is independently selected from ClI -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen, C I -C6 alkyl, ClI -C6 aralkyl, C1I-C6 substituted aralkyl, C I -C6 heteroaralkyl, C I -C6 substituted heteroaraikyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C I -C6 perfluoroalkyl, 2-amirnoethyl and 2,2,2-trifluoroethyl;
A
1 I and A 2 are independently selected from: a bond, -CH=CH-, -C(0)NR 10-, 0, -N(R 1 or S (O)m; V is selected from: a) hydrogen, WO 97/36901 PCT/US97/05304 -21 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 A 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-, -NRIOC(0)-, -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, provided that p is not 0 if X is a bond or O; 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 famesyl-protein transferase are illustrated by the formula
D:
R 6a-e wherein: I WO 97/36901 WO 9736901PCTJUS97/05304 22 from 1-2 of f(s) are independently N or and the remaining f s are independently CH; RI is selected from: hydrogen, C3-CI0 cycloalkyl or C1-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, RIO0-, -N(R 1 O)2, F or C2-C6 alkenyl, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, RIOO-, or -N(Rl 0)2;
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI-C6 perfluoroalkyl, R 1 2 R I IS(O)m-, R I C(O)NR 10-, (R I 0 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 10 )2, or R' I IC(O)NR 1 0-, c) unsubstituted C I -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 1 20-, R I R I OC(O)NR 1 (RI 0 )2NC(O)-, R 10 2N-C(NR CN, R I N3, -N(R 10 and R I I0C(O)-NR
R
4 is selected from H, halogen, CI -C6 alkyl and CF3; R6a, R6b, R6c, R6d and R6e are independently selected from: WO 97/36901 WO 9736901PCTIUS97105304 23 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl, R 12 R I IS(0)m-, R I C(0)NR 10-, (R I 0 R 10 2N-C(NR'10)-, CN, N02, R I N3, -N(R'O0)2, or R Il OC(0)NR c) unsubstituted C I -C6 alkyl, d) 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-CiO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 R I
R
1 I C(0)NR (R I 0 R 10 2N-C(NR CN, R I N3, -N(R 10)2, and R I I0C(0)-NRl10-; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CFI=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3
R
6 a, R6b, R6c, R 6 d or R6e is unsubstituted or substituted heterocycle, attachment of R 3
R
6 a, R6b, R 6 c, R6d or R 6 e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -C6 perfluoroalkyl, F, Cl, R 10 R I C(0)NR 10-, CN, N02, (R 10 )2N-C(NR R I 0 -N(R 10 or R I I C(0)NR 1 and WO 97/36901 PCT/US97/05304 -24c) C -C6 alkyl substituted by C1-C6 perfluoroalkyl, R 1 0 0-, RI OC(O)NR 10-, (R 10)2N-C(NR RI OC(O)-, -N(R10)2, or R110C(O)NR10_; 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;
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R11 is independently selected from CI-C6 alkyl and aryl; R1 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, CI-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C -C6 perfluoroalkyl, 2-aminoethyl and 2 ,2,2-trifluoroethyl; Al is selected from: a bond, O, or S(O)m; X is a bond, -CH=CH-, -C(O)NR10-, -NR -NR10-, O or n is 0 or 1; provided that n is not 0 if Al is a bond, 0, or S(O)m; m is 0, 1 or 2; and pis 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula E: I WO 97/36901 WO 9736901PCTfUS97/05304 25 d
A(CR
1
R
8 f \N wherein: from 1-2 of f(s) are independently N or and the remaining f's are independently CH; RI is selected from: hydrogen, C3-CIO cycloalkyl, RIO0-, -N(R' 0
F
or Ci -C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, RIO0-,
F
or C2-C6 alkenyl, c) CI-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, RIO0-, or
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfluoroalkyl, R 1 R I R' I C(O)NR 1 0, (R 1 0 )2NC(O)-, RlO02N-C(NR CN, N02, R IOC(O)-, N3, -N(R 1 0 )2, or R I I0C(O)NR c) unsubstituted C1I-C6 alkyl, WO 97/36901 WO 9736901PCTIUS97/05304 26 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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R' IIS(O)m-, R I C(O)NR 10-, (R I 0 )2NC(O)-, R 10 2N-C(NR 1 CN, R IOC(O)-, N3, -N(R 1 0 and R I IOC(O)-NR
R
4 is selected from H, halogen, C I-C6 alkyl and CF3;
R
6 a, R6b, a) b)
R
6 C, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 20, R I S R 1
I
0 C(O)NR 1 (Ri 102NC(O)-, R 10 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10)2, or R I IOC(O)NR 1 0-, unsubstituted C I-C6 alkyl, substituted C I -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 aikenyl, C2-C6 aikynyl,
R
12 RI IS(O)m-, RIOC(O)NRIO-, (R 1 0 )2NC(O)-, R I 0 2N-C(NR 1 CN, R IOC(O)-, N3, -N(R 10 and R I IOC(O)-NR 10-; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3
R
6 a, R6b, R 6 C, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 3
R
6 a, R6b, R 6 c, R6d or Reto the 6-membered heteroaryl WO 97/36901 WO 9736901PCTfUS97OS304 27 ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ClI -C6 perfiuoroalkyl, F, Cl, R 10 R I C(O)NR 10-, CN, N02, (R 1%2N-C(NRl10)-, R I -N(R 10 or R I I0C(O)NR 10-, and c) C I-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 10 0-,
R
1 I C(O)NR 10-, (R I 0 )2N-C(NRl 10), R I OC(O)-, 102,or R' I IC(O)NR 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, C I -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R
1 is independently selected from C I -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen, ClI-C6 alkyl, C I -C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, ClI-C6 perfinoroalkyl, 2-aminoethyl and 2 2 ,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NR 10-, -NR I -NR 10-, 0 or n is 0Oor 1; M is 0, 1 or 2; and p is 0, 1, 2 3 or 4 ,provided that pis not 0if Xis abond orO0; 'WO 97/36901 PCT/US97/05304 -28 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-e wherein: from 1-2 of f(s) are independently N or and the remaining fs are independently
CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl or Cl-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 1 0
-N(R
10 )2 or
F,
c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R 10 or -N(R 10 )2;
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 R lS(O)m-, RIOC(O)NR10-, (R O)2NC(O)-,
R
10 2N-C(NR10)-, CN, N02, R10C(O)-, N3, -N(R 10 )2, or R 1 0OC(O)NR10-, WO 97/36901 WO 9736901PCTIUS97/05304 29 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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(O)m-, R I C(O)NR 10-, (R 102NC(O)-, R 10 2N-C(NR CN, R IOC(O)-, N3, -N(R'10)2, and R I I0C(O)-NR 1 0-;
R
4 is selected from H, halogen, CH3 and CF3;
R
6 a, R6b, a) b) c) d)
R
6 c, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl,
R
1 0 2N-C(NR'O)-, CN, N02, RIOC(O)-, N3, -N(R 1 0 )2, or R I I 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-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(O)m-, R I C(O)NR 10-, (R 1 0 )2NC(O)-, R 10 2N-C(NR CN, R I N3, -N(R 10 and R I IOC(O)-NR 10-; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3 R6a, R6b, R 6 c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R 3 WO 97/36901 PCT/US97/05304 R6a, R6b, R 6 c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R
9 a and R9b are independently hydrogen, halogen, CF3 or methyl;
R
10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R
1 1 is independently selected from C -C6 alkyl and aryl;
R
12 is independently selected from hydrogen, CI-C6 alkyl, Cl-C6 aralkyl, C1-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-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)NR 10-, -NR -NR10-, O or m is 0, 1 or 2; and pis O, 1, 2, 3 or 4; 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:
R
6 a-e b N R9a \0f R \f NC- \R 9 R 4
A
1
(CR
1 2 )n R 2 'WO 97/36901 WO97/3901PCTJUS97/05304 31 wherein: from 1-2 of f(s) are independently N or and the remaining f s are independently
CH;
R I is selected from: hydrogen, C3-C 10 cycloalkyl, R 10 -N(R'10)2, F or C1I-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-ClO cycloalkyl, c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, RIO0-, or -N(R 10)2;
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 a Ikenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl,
R
10 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(R'O)2, or R I I0C(O)NR 1 0c) unsubstituted C I -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-Cl10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 R I R 1 I C(0)NR (R I
R
1 0 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(RIO)2, and R I IOC(0)-NR
R
4 is selected from H, halogen, CH3 and CF3; WO 97/36901 WO 9736901PCTIUS97/05304 32 R6a, R6b, R 6 c, R6d and R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 2 R I IS(O)m-, R I C(O)NR 10-, (R I 0 )2NC(O)-, R 10 2N-C(NR CN, N02, R I N3, -N(R 10)2, or R I I0C(O)NR c) unsubstituted C I -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-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R' IIS(O)m-, R I OC(O)NRI 10, (R 10 R 1 0 2N-C(NR 1
CN,
R IOC(O)-, N3, -N(R 1 0 and R I I0C(O)-NR 10-; or any two of R6a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3 R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R 3 R6a, R6b, R6c, R6d or R 6 e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R
9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 1 0 is independently selected from hydrogen, C I -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R I Iis independently selected from C I-C6 alkyl and aryl; WO 97/36901 WO 9736901PCT/US97/05304 33 R 12 is independently selected from hydrogen, C I-C6 alkyl, C I-C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaraikyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C I -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; AIis selected from: a bond, 0, -N(R or S(O)m; m is 0,i1or 2;and n is 0Oorl1; or the pharmaceutically acceptable salts thereof.
Preferred compounds of the invention are: I -(2-Phenylpyrid-5 -ylmethyl)-5 4 -cyanobenzyl)imidazole 1-2Pey--xprd5ymty)5(-ynbny~mdzl 1 -Phenylpyrid-6-ylmethyl)-5 4 -cyanobenzyl)imidazole I -(3-Phenyl -N-Oxopyrid-6-ylmethyl)-5 4 -cyanobenzyl)imidazole I -Trifluoromethoxyphenyl)-pyrid..s-ylmethyi)-5-(4cyanobenzyl)imidazole 1 2 -Trifluoromethylphenyl )-pyrid-5 -ylmethyl cyanobenzyl)imidazole 1 -Phenyl-2-Chioropyrid-6.yimethyl>5 4 -cyanobenzyl)imidazole I WO 97/36901 WO 9736901PCT/US97/05304 34 1 -Phenyl-4-chloropyrid-6-ylmethyl 5 4 -cyanobenzyl)imidazole and l-( 2 -Amino- 3 -phenylpyrid-6-ylmethy>..5.(4..cyanobenzyl)imidazole or a pharmnaceutically acceptable salt thereof.
Specific examples of the compounds of the instant invention are: I -(2-Phenylpyrid-5 -ylmethyl 4 -cyanobenzyl)imidazole 1 2 -(2-Trifluoromethylphenyl )-pyrid-5-ylmethyl)-5-(4cyanobenzyl)imidazole 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 WO 97/36901 PCT/US97/05304 isomers, being included in the present invention. When any variable aryl, heterocycle, R 1
R
2 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, faresyl, geranyl, geranylgeranyl and the like.
"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 aroyl and aralkyl, 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 IWO 97/36901 PCT/US97/05304 -36- 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.
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, SWO 97/36901 PCT/US97/05304 -37tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
As used herein in the definition of R 3
R
4
R
5 and R6a-e, the term "the substituted group" is intended to mean a substituted Ci-8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s)
R
3
R
4
R
5 and R6a-e are selected.
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 substituents 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, CI, Br, CF3, NH2, N(Cl-C6 alkyl)2, N02, CN, (Cl-C6 alkyl)O-, -OH, (C1-C6 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl-C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(CI-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 3
R
4 Q etc.) means that the indicated bond may be attached to any of the substitutable ring carbon atoms.
The substituent illustrated by the structure CQ7 R 6a-e is a simplified representation of a phenyl ring having five substituents (hydrogens and/or non-hydrogens) and may also be represented by the structure WO 97/36901 PCT/US97/05304 -38-
R
6 b
R
6a
R
6 c R6d R6e The moiety described as R 6a-e where any two of R 6 a, R6b, R 6 C, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH, -CH=CH-CH-, -(CH2)4- and -(CH2)4- includes the following structures: q I
I
It is understood that such fused ring moieties may be further substituted by the remaining R 6 a, R6b, R 6 c, R6d and/or R 6 e as defined hereinabove.
The moiety designated by the following structure f represents an aromatic 6-membered heterocyclic ring and includes the following ring systems: 'WO 97/36901 PCTJUS97/05304 -39- N~fL
N
0 The moiety designated by the following structure ~frepresents an aromatic 6-membered heterocyclic ring and includes the following ring systems:
N/N
N
i
N
N -\N
"N
N-"
0 HN NH N" 0. L.
wherein it is understood that one of the ring carbon atoms is substituted with R 6a-e ?i: WO 97/36901 WO 9736901PCT/US97/05304 40 Preferably, the aromatic 6-membered heterocyclic ring is a pyridyl ring.
Preferably, R 1 and R 2 are independently selected from: hydrogen, R I IC(0)0-, -N(R 1 0 R I C(O)NR 1 R 10 0- or un substituted or substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 10 R 1 0 0- and R IOC(O)NR 1 0-.
Preferably,
R
3 is selected from: a) hydrogen, b) C3-C 10 cycloalkyl, halogen, ClI-C6 perfluoroalkyl, R 1 2 0-, CN, N02, R IOC(O)- or 02 c) unsubstituted C I -C6 alkyl, d) substituted C 1 -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 1 2 R I 1 S(O)m R I C(O)NR 10-, (R'I 0 )2NC(O)-, RiO02N-C(NR'10)-, CN, R IOC(O)-, N3, -N(R 10 and R I I0C(O)-NR Preferably, R 4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C I -C6 alkyl.
Preferably, R 5 is hydrogen.
Preferably,
R
6 a, R6b, R 6 c, R6d and R 6 e are independently selected from: a) hydrogen, b) C3-CIO cycloalkyl, halogen, CI-C6 perfluoroalkyl,
R
1 2 0-, R' IIS(O)m-, CN, N02, R IOC(O)- or 02 c) unsubstituted C I -C6 alkyl; d) substituted ClI -C6 alkyl wherein the substituent on the substituted C I-C6 alkyl is selected from unsubstituted or substituted aryl, C3 -Cl10 cycloalkyl, R 12 0 R I 1 S(O)m- R IOC()-or -N(R 10)2; or WO 97/36901 PCT/US97/05304 -41 any two of R6a, R6b, R 6 c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-.
Preferably, R8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 perfluoroalkyl or CN.
Preferably, R 9 is hydrogen, halogen, CF3 or methyl.
Preferably, R 10 is selected from H, C1-C6 alkyl and benzyl.
Preferably, A1 and A 2 are independently selected from: a bond, -C(O)NRlO-, -NRIOC(O)-, 0, -S(0)2N(R10)- and- N(R 0 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 (R8)Cp V A'(CR'2)nA2 (CR'2)n Wt (CR22)p X -(CR 2 2 )p is selected from: WO 97/36901 PCTIUS97/05304 -42- R9a
R
9b \rN N N R9b e9a b and N
R
CH
2 CH2\ NC
NC
It is intended that the definition of any substituent or variable R R2, R 9 n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule.
Thus, -N(R 10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be 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.
WO 97/36901 PCT/US97/05304 -43 Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-21, 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 3
R
6 and R 8 as shown in the Schemes, represent the substituents R 3
R
4
R
5
R
6 a, R6b, R 6 c, R6d, R 6 e and R 8 although only one such R 3
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 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. The reactions described in the Schemes are illustrative only and are not meant to be limiting. 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 1-21: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Schemes 1-12 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 phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl.
Chem., 63:419 (1991)) with a suitably substituted halogenated nicotinic acid, such as 4-bromonicotinic acid, to provide the arylheteroaryl carboxylic acid II. The acid may be reduced and the triflate of the WO 97/36901 PCT/US97/05304 -44intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
Schemes 2-4 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 methyl nicotinate boronic acid and the "terminal" phenyl moiety employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 3.
Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the arylheteroaryl component of the instant compounds, as shown in Scheme 4. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted heteroaryl 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 5 illustrates the preparation of a suitably substituted biphenylmethyl bromide which could also be utilized in the reaction with the protected imidazole as described in Scheme 1.
As illustrated in Scheme 6, the sequence of coupling reactions may be modified such that the aryl-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 phenyl boronic acid.
Scheme 7 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
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.
WO 97/36901 PCT/US97/05304 Scheme 8 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl 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.
Compounds of the instant invention wherein the AI(CR12)nA 2 (CR 12)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 9.
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 10 illustrates an analogous series of reactions wherein the (CR 2 2)pX(CR 2 2)p linker of the instant compounds is oxygen. Thus, a suitably substituted halopyridinol, such as 3-chloro- 2-pyridinol, 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 aryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the A1(CR12)nA 2
(CR
1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 11. 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 R 1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.
WO 97/36901 PCT/US97/05304 -46- Addition of various nucleophiles to an imidazolyl aldehyde may also be employed to form a substituted alkyl linker between the biheteroaryl and the preferred W (imidazolyl) as shown in Scheme 12.
Thus an aryllithium can be reacted with pyridine to form the 2substituted N-lithio-l,2-dihydropyridine XXa. Intermediate XXa can then react with a aldehyde to provide a suitably substituted instant compound. Similar substituent manipulation as shown in Scheme 11 may be performed on the fully functionalized compound which incorporates an R 2 hydroxyl moiety.
SCHEME 1 N Br
(HO)
2
B
HO
HR
2 Pd(PPh 3 4 0 NR LiAIH 4
HO
RR
2 0 II
N
HO,
WO 97/36901 WO97/3901PCTIUS97/05304 47 SCHEME I (continued) Tr Tr NiCI 2 (PPh 3 2
-N]
ZnBr R8
IV
N ,4R HO,
R
2 (0F 3 S0 2 2 0, -78-C NEtiPr 2
CH
2 C1 2 -78 0 C-20 0
C
5500, CH 3 0H N X +R R 2 7- V WO 97/36901 WO 9736901PCTIUS97/05304 48 SCHEME 2 N B(OH) 2 R6 I Br 0e Pd(PPh 3 4 N MeO I LAIH 4
NR
HO"
WO 97/36901 WO 9736901PCTIUS97/05304 49 SCHEME 3 N B(OH) 2
R
3 SiO R 6 Br Pd(PPh 3 4 N BU 4
NF
R
3 SiO" c R 2
N
HO
R 2R W BrR6
R
3 SiO J
(HO)
2
B
R 2 Pd(PPh 3 4 N BU 4
NF
R
3 SiO R WO 97/36901 WO 9736901PCTIUS97/05304 50 SCHEME 4 N I
R
3 SiO R 2
N
R
3 SiO BrZn NiCI 2 (PPh 3 2 L 6
BU
4
NF
-R 6 R 6 Br" NIC12 (pPh 3 2 R 6
BU
4
NF
N Znl
R
3 SiO
H
H
6
NR
HO,
I WO 97/36901 WO 9736901PCTIUS97/05304 51 SCHEME 2. LiAIH 4 (HO)2 B Pd(PPh 3 4 KMnO 4
NR
H0 2 C0
R
6
NR
HO0, LiAIH 4 WO 97/36901 WO 9736901PCTIUS97/05304 52 SCHEME 6 Tr R. 2 BrN ii. MeOH ref lux
(HO)
2 B
I
Pd(PPh 3 4 Vill WO 97/36901 WO 9736901PCT/US97/05304 53 SCHEME 7
N
R 9 b
~T
ix Nal, NaHCO 3 ,1 2
N
R 9 b TrCl, NEt 3
N
R 9 b NiC1 2 (PPhQ) 2 Tr
N
R
Tr
N
Ra< OPf 1. -78OC-200C ii. MeOH, reflux I WO 97/36901 WO 9736901PCTIUS97105304 54 SCHEME 8 0--Y 0 i. R8Br ii. EtOH,80 0 C, NH 2
NH
2 XII
N
8N N" H 2
N
acylation, sulfonylation
N-N
or alkylation R 8
N
N
RK~
N
N
R~j WO 97/36901 WO 9736901PCTIUS97/05304 55 SCHEME 9 NC
-H
xIV i, Na, MeOH ii. 120C KN
N
N C Tr Tr~l, NEt 3 N
NC
XV'
Tr
NCN
i. -78 0 C-20 0
C
ii. MeOH ref lux OTf
XVI
RH
2
N
'N
NC-o I WO 97/36901 W097/6901PCT/US97OS3O4 56 SCHEME
N
/\OH
i, Na, MeOH ii. 120 0
C
H3C, 0cI K N R 2
XVI
Tr TrCI, NEt 3
-T
N0 N 2~ CR 0
N-
R 2 XVII OTf i. -78 0 ii. MeCH reflux
B(OH)
2
R
6 DMF, Pd(PPh 3 4
K
3 P0 4 80 0
C
1. WO 97/36901 WO 9736901PCT/US97/05304 57 SCHEME 11 EtMgBr Rs0 T r, K OH R8
XIX
XVIII
AC
2 O, PY N6 HO0
(CF
3
SO
2 2 0, -78OC NEtiPr 2 ,0H 2
CI
2 J LiOH
SOC'
2 OAc
XX
WO 97/36901 WO 9736901PCT/US97/05304 58 SCHEME 11I (continued)
NH
3 MeOH
NH
2 *WO 97/36901 PCTIUS97/05304 59 SCHEME 12 R 6 Li
N
N
H 0
N
R 6 RR6
N\
OH
R
8 I WO 97/36901 PCTIUS97/05304 Schemes 13-21 illustrate reactions wherein the moiety (R 8 )r V- A1(CR1 2 )nA2(CR1 2 n (CRp-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.
Lithioheteroaryl chemistry may be utilized, as shown in Scheme 13, to incorporate the arylheteroaryl moiety. Thus, a suitably substituted arylheteroaryl N-lithio 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 14, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 14, 15). 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 I WO 97/36901 PCT/US97/05304 -61 alkyl lithium reagents, 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 15), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as XXXIII (Scheme 16). 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 17. 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 18-21 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 97/36901 W097/6901PCTIUS97/05304 62 SCHEME 13 Boc
NHI
BcNH'CHO 1. catalytic hydrogenation 2. CF 3 C0 2
H
CH
2 01 2 Boc NH xx'
NH
2 BocNH
NH
2
XXI
BOC
2 0
CH
2
CI
2
~CHO
NaB H (Ac) 3 Et 3 N ClCH 2
CH
2
CI
NH
2
XXIII
WO 97/36901 WO 9736901PCT/US97/05304 63 SCHEME 13 (continued) -N R R 6 BocNH
CF
3
CO
2 H, CH 2
C
2 NH NaHCO 3
XXIV
-N NC6
NH
2
NC
NH AgON A:
-NN
XXV
WO 97/36901 WO 9736901PCTIUS97/05304 64 SCHEME 14 Et 2
O
BnO HO -N
R-
NHBoc HO .J:N R A 6 BnOI BocNH CHO
XXVI
20% Pd(OH) 2
H
2
CH
3 0H
CH
3 C0 2
H
CICOCOCI
DMSO
CH
2
CJ
2
(C
2
H
5 3
N
NHBoc xi WO 97/36901 WO 9736901PCTIUS97/05304 65 SCHEME 14 (continued) -IN -R 6 R'MgX NHBoc
XXIX
R NHBoc
XXX
'.WO97/36901 PCTIUS97/05304 66 SCHEME
-INRO
NHBoc
CF
3
CO
2
H
0H 2 C1 2 xxviII
R'CHO
NaBH (OAC) 3 ClCH 2
CH
2
CI
NH
2
XXXI
HO
R'CH
2 Xxxii .WO 97/36901 PCTIUS97/05304 67 SCHEME 16 H H
RH
6 S 5 02 NaH, DMF 000 NHBoc xxviII
RA
2 -IN R 6
N
H
R"SH
(0 2
H
5 3 N
A
CH
3 0H xxxiII R 2 Rits -I R 6
NIH
2 xxxiv .WO 97/36901 PCT/US97/05304 68 SCHEME 17 1) Boc 2 O, K 2 00 3
THF-H
2 0 2) CH 2
N
2 EtOAc
HO
BocNH C0 2 0H 3 xxxv i
H
2 N- -CO 2
H
xxxv LiAIH 4
THF
0-200C
HO
BocNH
CH
2 0H R CH 2
X
DMF
xxxv"l R CH 2 0 BocNH
CH
2 0H xxxv"'l pyridine -SO~
DMSO
(C
2
H
5 3
N
0
C
R"'CH
2
O
BocNH
CHO
IXL
.WO 97/36901 PCTIUS97/05304 69 SCHEME 17 (continued) 'j.
BocNH_
CHO
Et 2
O/
2. 2
C
NHBoc 0Q% Pd(OH) 2
H
2
~H:
3 H, CH 3 C0 2
H
3. HCJ, EtOAc ryl 2. 20% Pd(OH) 2
H
2
CH
3 OH, CH 3 00 2
H
2) HO!, EtOAc
NH
2
XLII
XLl
NH
2 .WO 97/36901 PCTIUS97/05304 70
CH
3
H
2 N" N 1) HNO 2 ,Br 2 2) KMnO 4 3) MeGH, H+ C0 2 0H 3 Br'
N
MgcI ,C0 2
CH
3 ZnC1 2 ,NiC[ 2 (Ph 3
P)
2 NaBH 4 (excess) R 6
SCH
2 0H
SO
3 'Py, Et 3
N
DMSO
I
"WO097/36901 PTU9/50 PCTIIJS97/05304 71 SCHEME 19 1. EtO(CO)CI 2. R 6 Br Zn, CuON 3. S, xylene, heat C0 2 0H 3
(NY
C0 2
CH
3 NaBH 4 (excess)
SO
3 -Py, Et 3
N
CH
2 0H DMSO
N'
R 6
CHO
N
3 MgCI ZnCI 2 NiCI 2 (Ph 3 p) 2 ,C0 2
CH
3 NaBH 4 (excess)
.CH
2 OH
SO
3 -Py, Et 3
N
DMSO
CHO
WO 97/36901 WO 9736901PCT/US97105304 72 SCHEME
N
LDA, CO 2 2. MeGH, HI
CO
2
CH
3 Br
N
R 6 MgCI ZnC! 2 NiCI 2 (Ph 3
P)
2 2
CH
3 NaB H 4 (excess) R 6
SO,
3 Py, Et 3
N
DMSO
WO 97/36901 WO 9736901PCTIUS97/05304 73 SCHEME 21 a**IN Br 1. LDA, C0 2 2. (CH 3 3
SICHN
2
CO
2
CH
3 Br R 6 B r
,CO
2
CH
3 Zn, NiCI 2 (Ph 3
P)
2 excess NaBH 4 N CH 2 0H
SO
3 'Py, Et 3
N
DMSO
R 6 N
CHO
.WO 97/36901 PCT/US97/05304 -74- The instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity neurofibromin neu, scr, abl, Ick, fyn) or by other mechanisms.
The compounds of the instant invention inhibit faresylprotein transferase and the famesylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease Schaffner et al.
WO 97/36901 PCT/US97/05304 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.
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 WO 97/36901 PCTIUS97/05304 -76kidney 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 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 WO 97/36901 PCT/US97/05304 -77 quantity of farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl 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 famesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques.
Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesylprotein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl 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 97/36901 PCT/US97/05304 -78
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-( 2 -Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: l-Trityl-4-(4-cyanobenzvl)-imidazole To a suspension of activated zinc dust 3 .57g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon at 20 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 .4g, 3.64 mmol) and 4 -iodo-l-tritylimidazole (15.95g, 36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739 (1991)) were added in one portion.The resulting mixture was stirred 16 hours at 20 0 C and then quenched by addition of sat. aq. NH4C 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 in CH2C12 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, and 3.93(2H, s)ppm.
WO 97/36901 PCT/US97/05304 -79- Step B. 2 A mixture of 2 -bromo-5-methylpyridine (2.00 g, 11.63 mmol), phenylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50g, 17.4 mmol), DME (80 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenylphosphine)palladium(0) (672 mg, 0.58 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. HCI. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with 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.
IH NMR (CDC13, 400MHz) 6 8.52 (1H, 7.96(2H, d, 7.63(1H, d, J=8.0Hz), 7.55(1H, brd, J=8.0Hz), 7.50-7.35(3H, m), and 2.37(3H, s) ppm.
Ste C: 2 A suspension of 2 -phenyl-5-methyl pyridine (1.03g, 6.09 mmol) and potassium permanganate 2 8 9g, 18.3 mmol), in water (25 mL) was heated at reflux for 2 hours. The reaction was allowed to cool to ambient temperature and filtered through celite to remove the solids. Acetic acid (1 mL) was added to the colourless filtrate and the product was collected as a white solid by filtration.
1H NMR (CD30D, 400MHz) 5 9.18(1H, 8.41(1H, dd, 2.2 and 8.2Hz), 8.08-8.02(2H, 7.97(1H, dd, J=8.2 and 0.7Hz) and 7.56- 7.46(3H, m) ppm.
Step D: To a solution of 2 -phenyl-5-carboxypyridine (520 mg, 2.61 mmol) in tetrahydrofuran (10 mL) at 0°C was added 1.0 M lithium aluminum hydride in tetrahydrofuran (2.61 mL, 2.61 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours, cooled to 0°C, and quenched by dropwise
I
WO 97/36901 PCT/US97/05304 addition of water (0.20 mL), 4 N aq. NaOH (0.20 mL), and water (0.60 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 0-5% MeOH in CH2C12) to afford the title compound.
1H NMR (CDC13, 400MHz) 6 8.66(1H, 7.97(2H, d, J=7.9Hz), 7.82-7.70(2H, 7.52-7.38(3H, 4.77(2H, s) and 1.89(IH, brs) ppm.
Step E: 1-( 2 -Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt To a solution of 2 (264 mg, 1.43 mmol) and diisopropylethylamine (0.522 mL, 3.00 mmol) in dichloromethane (10 mL) at -78 0 C was added trifluoromethanesulfonic anhydride (0.252 mL, 1.50 mmol) and the mixture stirred at -78 0 C for 15 minutes. To this mixture was added a solution of l-trityl- 4 -(4-cyanobenzyl)imidazole (608 mg 1.43 mmol) in dichloromethane (9 mL). The mixture was allowed to warm to ambient temperature and stirred for 16 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in 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, 0-5% NH40H in CH2C12). The amine was converted to the HCI salt by treatment with 1.OM HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
FAB MS 351 (MH+) IH NMR (CD30D, 400MHz) 8 8.38(1H, d, J=2.4Hz),7.97(2H, m), 7.64(1H, d, J=8.2Hz), 7.60(1H, 7.56-7.40(5H, 7.28-7.20(1H, 7.17(2H, d, J=8.0Hz), 6.97(1H, 4.96(2H, s) and 3.89(2H, s) ppm.
EXAMPLE 2 I WO 97/36901 PCT/US97/05304 -81 1-(2-Phenyl-N-Oxopyrid-5-y lmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt 1-( 2 -Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl) imidazole hydochloride (66.7mg, 0.159 mmol) was partitioned between CH 2 Cl 2 (mL) and sat. aq. Na 2
CO
3 (1 mL). The organic layer was separated, dried, (MgSO 4 and the solvent evaporated in vacuo. The residue was dissolved in CH 2
CI
2 (2 mL), 3-chloroperbenzoic acid (109 mg, 0.506 mmol) was added and the solution stirred at ambiant temperature for 16 hours. The reaction was partitioned between CH 2
C
2 (5mL) and sat. aq. Na 2
CO
3 (2mL) and the organic layer separated, dried, (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel 4-10% MeOH in CH 2 0 2 The amine was converted to the HCI salt by treatment with I.OM HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
IH NMR (CD30D, 400MHz) 8 9.18(1H, 8.13(1H,s), 7.80- 7.20(12H,m), 5.53(2H,s) and 4.28(2H,s) ppm.
EXAMPLE 3 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 3-Phenvl-6-carboxvpvridine A suspension of 3-phenyl-6-methyl pyridine (1.99g, 11.78 mmol) and potassium permanganate (7.65, 48.6 mmol), in water (50 mL) was heated at reflux for 16 hours. The reaction was allowed to cool to ambient temperature and filtered through celite to remove the solids. Acetic acid (2 mL) was added to the colourless filtrate and the product was collected as a white solid by filtration.
1H NMR (CD30D, 400MHz) 8 8.86(lH, 8 .15(2H,m), 7.70(2H,d, J=6.7Hz) and 7.60-7.30(3H,m) ppm.
Step B: 3-Phenyl-6-hydrox vmethylpyridine WO 97/36901 PCT/US97/05304 -82- To a solution of 3 -phenyl-6-carboxypyridine (1.05g, 5.27 mmol) in tetrahydrofuran (25 mL) at 0°C was added 1.0 M lithium aluminum hydride in tetrahydrofuran (10.0 mL, 10.0 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 6 hours, cooled to 0°C, and quenched by dropwise addition of water (0.50 mL), 4 N aq. NaOH (0.50 mL), and water mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 0-5% MeOH in CH 2 C2) to afford the title compound.
1 H NMR (CDC13, 400MHz) 8 8.79(1H, d, J=1.0Hz), 7.88(1H, dd, J=8.6 and 1.5Hz), 7.58(2H,d, J=6.7Hz), 7.49(2H,t, 7.41(IH,t, J=7.0Hz), 7.33(1H,d, J=7.6Hz), 4.83(2H,s) and 3.75(1H,brs) ppm.
Step C: 1-( 3 -Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt To a solution of 3-phenyl-6-hydroxymethylpyridine (192 mg, 1.04 mmol) and diisopropylethylamine (0.360 mL, 2.07 mmol) in dichloromethane (8 mL) at -78 0 C was added trifluoromethanesulfonic anhydride (0.180 mL, 1.07 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 (441 mg 1.04 mmol) in dichloromethane (9 mL). The mixture was allowed to warm to ambient temperature and stirred for 4 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 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, EtOAc and then 5% MeOH in CH2C12). The amine was converted to the HCI salt by treatment with 1.OM HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
WO 97/36901 PCT1US97/05304 83 FAB HRMS exact mass calcd for C23H1I9N4 351.160972
(MHI+);
found 351.161206.
1 H NMR (CD30D, 400MHz) 6 9.20(111, d, J=1.4Hz), 8.75(1H, d, J=2.2Hz), 8.16(1H, d, J=8.20), 7.66 (2H, d, J=8.4Hz), 7.60-7.40(7H, 7.26(2H, d, J=8.0Hz), 5.73(2H, s) and 4.27(2H, s) ppm.
Anal. Calcd. for C23H18N4-2.00 HC-0.80 C, 63.11; H, 4.97; N, 12.80.
Found: C, 63.10; H, 4.97; N, 12.95.
EXAMPLE 4 1-( 3 -Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl) imidazole hydochloride (100.0mg, 0.
2 36mmol) was partitioned between
CH
2 C0 2 (2mL) and sat. aq. Na 2
CO
3 (lmL). The organic layer was separated, dried, (MgSO 4 and the solvent evaporated in vacuo.
The residue was dissolved in CH 2
CI
2 (2 mL), 3 -chloroperbenzoic acid (143mg, 0.472 mmol) was added and the solution stirred at ambient temperature for 16 hours. The reaction was partitioned between CH 2
C
2 (5mL) and sat. aq. Na 2
CO
3 (2mL) and the organic layer separated, dried, (MgSO 4 and the solvent evaporated in vacuo.
The residue was chromatographed (Silica gel 4-10% MeOH in CH2Cl2The amine was converted to the HCI salt by treatment with 1.OM HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
1H NMR free base (CDCI3, 400MHz) 8 8.44(1H, d, J= 7.63(JH,s), 7.60-7.20(10OH,m), 7.03(1H,s), 6.35(lH,d, J=8.2Hz), 5.29(2H,s) and 3.96(2H,s) ppm.
EXAMPLE 1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4cyanobenzyl)imidazole hydrochloride salt WO097/36901 PCT/US97/05304 84 Step A: 2 3 To a solution of 3 -bromotrifiuoromethoxybenzene (0.590m-L, 4.00 mmol) in THIF (12 mL) at -78'C was added t-butyl lithium (4.7 lmL, of a 137M solution in pentane, 8.00 mmol. After minutes zinc chloride(4.OmL, of a 1 M solution in diethylether, 4.00 mmol) was added. The reaction was stirred for 10 minutes at -78'C and then allowed to warm to 0 0 C and stirred for 3 0minutes.
This solution was added via cannula to a solution of methyl pyridine and bis(triphenylphosphine) Nickel 11 chloride. The reaction stirred for 1 hour at 0 0 C and then at ambient temperature for a furthur I hour. Saturated ammonium hydroxide solution (3 mL) was added and the mixture stirred until homogenous, extracted with Et 2 O and the organic extracts washed with saturated brine, dried (MgSO 4 and evaporated in vacuo. The residue was chromatographed (Silica gel, 25-50% CH 2
CI
2 in hexanes).
IH NMR (CD3OD, 400MHz) 8 8.48(1H, s),7.93(IH, brd, J=8.OHz), 7.87(1H, 7.79(2H, d, J=8.OHz), 7.74(2H, d, J=8.OHz), '7.56(lH, t, 7.32(IH, brd, J=8.OHz) and 2.40(3H, s) ppm.
StepB 2-(3 -Trifluoromethoxyphe-nvh -5 croyprdn A solution of 2 3 methylpyridine 2 .35g, 2.22 mmol) and tetrabutylam-monium permanganate (1.904, 0.01 2mol), in pyridine (8 mL) was heated at 75'C for 16 hours. The cooled reaction was filtered through celite to remove the solids. The solid was washed with EtOAc and MeOH and the filtrate evaporated in vacuo to afford the title compound of sufficient purity to be used in the next step.
Step C: 2 3 hydroxymethylIyriding To a solution of 2 3 -trifluoromethoxyphenyl) carboxy pyridine (2.0 g, 7.06 mmol) in tetrahydrofuran (15 mL) at 0 0 C was added 1.0 M lithium aluminum hydride in tetrahydrofuran WO 97/36901 PCT/US97/05304 (7.07 mL, 7.07 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 4 hours, cooled to 0°C, and quenched by dropwise addition of saturated Na 2
SO
4 (1.0 mL). The reaction was diluted with diethylether, filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 50% EtOAc in hexanes) to afford the title compound.
1 H NMR (CD30D, 400MHz) 6 8.62(1H, d, J=l.0Hz), 8.00- 7.84(H,m), 7.57(1H, t, J=8.0Hz), 7.33(1H,brd, J=8.0Hz) and 4.84(2H,s) ppm.
Step D: 1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)- 4 -cvanobenzvl)imidazole hydrochloride salt To a solution of 2 3 hydroxymethylpyridine (66 mg, 0.25 mmol), diisopropylethylamine (0.085 mL, 0.49 mmol), and 1-trityl- 4 -(4-cyanobenzyl)imidazole (105 mg 0.25 mmol) in dichloromethane (1.4 mL) at -78°C was added trifluoromethanesulfonic anhydride (0.041 mL, 0.25 mmol) and the mixture stirred at -78 0 C for 1 hour. The reaction was allowed to warm to ambient temperature and stirred for 4 hours.
The solvent was evaporated in vacuo. The residue was dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and sat. aq. Na 2
CO
3 solution. The organic layer was dried, (Na2SO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 3% MeOH in CH 2 C1 2 The amine was converted to the HCI salt by treatment with 1.OM HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
1 H NMR (CD30D, 400MHz) 6 9.23(1H, 8.67(1H,s), 8.18- 8.04(2H, 8.00-7.90(2H,m), 7.74(1H, t, J=7.9Hz), 7.62-7.50(4H, 7.31(2H, d, J=7.9Hz), 5.71(2H, 4.29(2H, s) ppm.
WO 97/36901 PCT/US97/05304 86- FAB HRMS exact mass caled for C24H1I8sN 4
OF
3 435.143271 found 435.144474.
Anal. Calcd. for C24H 1 7
N
4
OF
3 -2.00 HC1: C, 56.82; H, 3.77; N, 11.04.
Found: C, 56.50; H, 3.88; N, 10.86.
EXAMPLE 6 I1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4cvanobenzvl)imidazole hydrochloride salt Step A: 2 To a solution of 2 bromo-5-methyl pyridine (1.
8 1g, 10.53 mmol) and barium hydroxide (4.97 g, 15.78 mmol) in water (15 mL) was added DME (80 mL). This mixture was treated sequentially with 2 -(trifluoromethyl)phenylboronic acid (2.00g, 10.53 mmol) and palladium tetrakis(triphenylphosphine) (553 mg, 0.48 mmol) and the mixture warmed to 80 0 C for 48 hours.
Water (100mL) was added and the pH of the solution was adjusted to 10 and extracted with EtOAc (3X200mL).
The organic extracts were combined, washed with brine, dried (MgSO4), and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 50% -100% CH 2 Cl 2 in hexanes) to afford the title compound.
1 H NMR (CDCI3, 400MHz) 8 8.52(1H, 7.75(1H, d, J=7.9Hz), 7.64-7.44(4H, min), 7.32(1H, d, J=7.9Hz) and 2.40(3H,s) ppm.
Step B: 2 2 A suspension of 2 2 methylpyridine (0.40g, 1.68 mmol) and potassium permanganate (1.60g, 10.1 mmol), in water (10 mL) was heated at reflux for 16 hours. The reaction was filtered hot through celite to remove the solids. Acetic acid was added to the colourless filtrate to yield a pH of 5 and the resulting suspension was extracted with CH2Cl2.washed
MMWMM
WO 97/36901 PCTIUS97/05304 87 with water (10 mL), dried, (MgON), and the solvent evaporated in vacuo to afford the title compound.
I H NMR (CD3OD, 400MHz) 6 9.34(JH, 8.41(lH,d, J=8.2Hz), 7.80(IH,d, J=7.9Hz) and 7 7 0-7.50(4H,m) ppm.
Step C: 2 2 -Trifluoromethlphenl)-5-.h drox meth ~yIdn To a solution of 2 2 -Trifluoromethylphenyl)y (220 mg, 1.23 mmol) in tetrahydrofuran m.L) at 0 0 C was added 1.0 M lithium aluminum hydride in tetrahydrofuran (1.23 mL, 1.23 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours, cooled to 0 0 C, and quenched by dropwise addition of water (0.05 mL), 2.5 N aq. NaOH (0.05 mL), and water (0.15 mL). Sodium sulfate was added, the reaction filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, CH 2
CI
2 then EtOAc) to afford the title compound.
I H NMR (CDC]I3, 400MHz) 8 8.63 (11H, 7 8
O-
7 4 0(6H,m) and 4.77(2H, s) ppm.
Step D: l-( 2 2
S-(
4 -cvanobenz I imidazole- hdrocride salt The title compound was prepared using the procedure described for Example 5, step D using 2 2 -trifluoromethylphenyl) from Step C in place of 2-(3-trifluoro- 11H NMR (CD3OD, 400MHz) 6 9.17(l H, 8.42(l 8.00- 7.40011H, in), 5.60(2H1, 4.26(2H, s) ppm.
FAB MIS 419 (MH+) Anal. Calcd. for C24H1 7
N
4
F
3 -2-95 HCL. 0.6 EtOAc: C, 54.78; H, 4.3 1; N, 9.68.
Found: C, 54.79; H, 4.18; N, 9.68.
EXAMPLE 7 WO 97/36901 PCT/US97/05304 88 l-( 3 -Pheny12Chloropyrid6...etyl)5meyan)5(4cyl).midaz hydrochloride s alt Step A: 3 -Phenvi-6-methylpyridine N-oxide A solution of 3 -phenyl-6-methyl pyridine 2 3 6g, 13.95 mmol), in CH 2
CI
2 (40 mL) at 0 0 C was treated with MCPBA 3 .58g, 13.95 mmol) for 1 hour. Saturated aq. Na 2
CO
3 (50 mL) was added and the reaction was extracted with CH2CI 2 (20 mL). The organic extracts were dried (MgSO 4 and the solvent evaporated in vacuo to afford the title compound.
I H NMR (CDCI3, 400MHz) 6 8.53 (1H, 7 .60-7.20(7H, m) and 2.57(3H-, s) ppm.
Step B: 3 -Phenyl-2-chloro-6-.methylpyridine and 3-phenyl-4chi oro-6-methylpvyridine A solution of 3 -phenyl-6-methyl pyridine-N-Oxide (1.42g, 7.66 mmol), in P 2 0 5 (50 mL) at 0 0 C was at 80'C for 3 hours. The reaction was allowed to cool to room temperature and then poured over ice (400g). Saturated aq. Na 2
CO
3 was -added until the pH of the solution was 8 and the reaction was extracted with
CH
2
CI
2 (3X250 mL). The organic extracts were dried (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (silica gel, 10-20% EtOAc in CH 2 Cl 2 to afford 3 -Phenyl-2-chloro- 6 -methylpyridine (First eluted) 1j-H NMR (CDCI3, 400MHz) 6 7.56(11-H, d, J=7.6Hz), 7.60- 7 30 7.15(IH,d, J=7.6Hz) and 2.59(3H, s) ppm.
3 -Pheny-4-chloro-.6-methylpyridine (Second eluted).
IH NMR (CDCI3, 400MHz) 5 8.43(IH, 7 6
O-
7 .40(5H,m), 7 .29(1H,s) and 2.59(3H, s) ppm.
Step C: 3 -Phenyl-2-chloro-6bromoMethjpridl, A solution of 3 -Phenyl-2-chloro-6.methylpyridine (0.0 9 4g, 0.462 mmol), NBS (0.0 8 6g, 0.485 mmol) and AJBN (0.008g, O.O46mmol) in CC1 4 (3 mL) were heated at reflux for WO 97/36901 PCT/US97/05304 89 2 hours. The solvent was evaporated and the residue chromatographed(Silica gel, 100% CH 2
CI
2 to afford the title compound.
1 H NMR (CDCl3, 400Miz) 5 7.68(H, d, J=7.6Hz), 7.60- 7.40(6H,m), and 4.56(2H, s) ppm.
Step D: 1-( 3 -Phenyl-2-chloropyrid-6-ylmethyl)-5-(4cvanobenzy)imidazole hdrochloride salt To I-trityl-4-(4-Cyanobenzyl)-imidazole 8 8 .4mg, 0.208 mmol) in acetonitrile (1 mL) was added 3 -phenyl-2-chloro- 6 -bromomethylpyridine 5 3 .5mg, 0.189 mmol) and the mixture heated at 65 0 C for 16 hours. The residue was dissolved in methanol (3 mi) and heated at reflux for 2 hours, cooled and evaporated to dryness. The residue was partitioned between sat. aq. Na 2
CO
3 solution and CH 2
CI
2 The organic layer was dried, (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 2.5-3% MeOH in CH 2
CI
2 to afford the free base which was converted to the HCI salt by treatment with one equivalent of HCI in aqueous acetonitrile. Evaporation of solvent in vacuo afforded the title compound as a white powder.
1 H NMR (CD30D, 400MHz) 6 9.11(1H, 7.64(lH,d, J=7.7Hz), 7.55(2H,d, J=8.2Hz), 7 .51(1H,s), 7 .50-7.34(5H,m), 7 .32-7.20(3H, 5.56(2H, 4.27(2H, s) ppm.
Anal. Calcd. for C23H 17 C1N 4 -1.00 HC1. 0.6 EtOAc: C, 54.78; H, 4.31; N, 9.68.
Found: C, 54.79; H, 4.18; N, 9.68.
EXAMPLE 8 1-(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt The title compound was prepared using the procedure described for Example 7, steps C and D using 3-phenyl-4-chloro-6-methylpyridine in place of 3 -phenyl-6-methyl pyridine.
WO 97/36901 PCT/US97/05304 Anal. Calcd. for C24H 17
N
4 C1-1.00 HCI. 0.30 C, 64.74; H, 4.39; N, 13.13.
Found: C, 64.82; H, 4.52; N, 12.93.
EXAMPLE 9 1-(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 2-Amino-3-Phenvl-6-methvl vri dine A solution of 3 -phenyl-6-methyl pyridine (0.815 g, 4.82 mmol), and sodium amide 7 52mg, 19.3mmol) in diethylaniline (IOmL) was heated at 180'C for 72 hours. The reaction was cooled and quenched with ice (100g), and the mixture extracted with EtOAc. The organic extract was washed with brine (50 mL) dried (MgSO 4 silica gel (100g) was added and the solvent evaporated in vacuo.
The material was loaded onto a column and chromatographed (Silica gel, eluting with 0-100% EtOAc in CH 2
CI
2 to afford the title compound.
1 H NMR (CDCI3, 400MHz) 7.50-7.20(6H, m) 6.61(1 H,d, J=7.OHz), and 2.42(3H, s) ppm.
WO 97/36901 PCTIUS97/05304 91 Step B: N-bis t-Butoxycarbonyl2-Amino-3-Phenyl-6methylpyridine A solution of 2 -amino-3-phenyl-6methyl pyridine (1.21 g, 6.57 mmol), di t-butylcarbonate(3.58g, 16.4 mmol), triethylamine (2.29 mL, 16.4 minol) and DMAP (0.803g, 6.57 mmol) in CH 2
CI
2 (2OmL) were heated at 65 0 C for 16 hours. The reactionwas diluted with sat. aq. Na 2
CO
3 and extracted with CH 2
CI
2 The solvent was evaporated in vacuo. and the residue chromatographed (Silica gel, eluting with 20% EtOAc in CH 2
CI
2 to afford the title compound.
1 H NMR (CDCI3, 400MHz) 6 7.62(lIH, d, J=7.7Hz), 7.41-7.30(5H, in), 7.19(1H, d, J=7.7Hz), 2.59(3H, s) and 1.28(18H, s) ppm.
Step C: 2-(bis t-butoxycarbonylamino)-3phenyl6methvlpvridine-N-oxide A solution of N-bis t-butoxycarbonyl2amino-3phenyl.
6 -methylpyridine (0.
2 15g, 0.56 minol), in CH 2
CI
2 (4 mL) at 0 0 C was treated with MCPBA (0.
2 20g 0.727 mmol) for I hour. Saturated aq. Na 2
CO
3 (50 mL) was added and the reaction was extracted with
CH
2 Cl 2 (2X50 mL). The organic extracts were dried (MgSO 4 and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, eluting with 100% EtOAc to afford the title compound.
I H NMR (CDCI3, 400MHz) 5 7 4 4 -7.36(6H,n), 7.13(lIH, d, J=7.7Hz), 2.56(3H, s) and 1.3 1(18H, s) ppm.
Step D: N-bis t-Butoxycarbonyl.2-.amino-.3-.phenyl-6 1cetoxymethylpvridine A solution of 2-(bis t-butoxycarbonylamino)3phenyl- 6 -methylpyridine.N.oxide (0.
2 2 3g, 0.557 mmol), in acetic anhydride mL) was heated at 65'C for 24 hours, The solvent was evaporated in vacuo and the residue chromatographed 3 O-50%EtOAc in hexanes) to afford the title compound.
I H NMR (CDCI3, 400MHz) 6 7.74(l H, d, J=7.7Hz), 7.50-7.30(6H, mn), 5.25(2H, 2.17(3H, s) and 1.28(18H, s) ppm.
WO097/36901 PCTfUS97/05304 92 Step E: N-bis t-Butoxycarbonyl-2-amino.3pheny..6 hydroxymethylpyridine A solution of 2- (bis t-butoxycarbonylamino)-3 -phenyl- 6 -acetoxymethylpyridin-e (0.0 4 0g, 0.09 mmol), THF (1.3 mL) was treated with Lithium hydroxide (1IM solution in water 0.271 ml, 0.27 1 mmol) at room temperature for 16 hours. The reaction was diluted with water and extracted with CH 2
CI
2 The organic extracts were dried (MgSO4),and the solvent evaporated in vacuo to afford the title compound.
1 H NMR (CDCl3, 400MHz) 6 7.74(111, d, J=7.8 Hz), 7.44-7.33(5H-, in), 7.3 1(IH,brd, J=7.8Hz), 4.8 1(2H, and 1.29(18H, s) ppm.
Step F: 1 -(2-Amino-3 cyanobenzyl )imidazole hydrochloride salt The title compound was prepared using the procedure described for Example 3 step C using N-bis t-butoxycarbonyl-2.amino-.3-phenyl- 6 -hydroxymethylpyridine in place of 3 -phenyl 6 -hydroxymeihyl pyridine. In this case the free base was treated with TFA and triethylsilane to effect cleavage of the t-butoxycarbonyl groups which was followed by its conversion to the hydrochloride salt.
III NMR (CD3OD, 400MHz) 6 9.23(11-, 7.80-7.20(H, in), 6.96(1H,s), 6.65(1H,d, J=7.6Hz), 5.66(2H, 4.33(2-, s) ppm.
Anal. Calcd. for C23Hi 9
N
5 1.00 HCI. 0.95 H20 0.35 EtOAc: C, 60.26; H, 5.33; N, 14.40.
Found: C, 60.04; H, 5.10; N, 14.45.
EXAMPLE In vitro ihibition of ras famesyl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-C VIM and Ras-CAIL) were prepared as described by Schaber et al., J. Biol.
Chem. 265:14701-14704 (1990), Pompliano, etal., 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 41
I
WO 97/36901 PCT/US97/05304 -93containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM 3 H]-famesyl diphosphate 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 gg/ml FPTase at 31 0 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 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10 JM ZnC1 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 gl of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compound of the instant invention described in the above Examples 1-9 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of gM.
EXAMPLE 11 In vivo ras famesylation assay The cell line used in this assay is a v-ras line derived from either Rati or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is performed essentially as described in DeClue, J.E. et al.
Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% WO 97/36901 PCTIUS97/05304 -94confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37 0 C, the cells are labelled in 3 ml methionine-free DMEM supplemeted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer NP40/20 mM HEPES, pH 7.5/5 mM MgC12/1mM 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. I M NaCI) 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 nonfaresylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
EXAMPLE 12 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
I
WO 97/36901 PCT/US97/05304 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 (9)
1. A compound which inhibits farnesyl-protein. transferase of the formula A: (R 8 )r (R 9 )q V 'C'2n -R2 W (CR 2 )p X -C -f A wherein: from 1-2 of f(s) are independently N or N->O0, and the remaining f's are independently CH; R I and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 R I IS(O)m-, R I R I IC(0)0-, (R I 0 R I 0 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10 or R I I0C(O)NR 1 0-, c) unsubstituted or substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0 R I IS(O)m-, R IOC(O)NR 1O-, (R'I 0 )2NC(O)-, R 10 2N-C(NR CN, R IOC(O)-, N3, -N(R 10)2, and R I I0C(O)-NR R 3 R 4 and R 5 are independently selected from: I WO 97/36901 W097/6901PCT/US97/05304 97 R 6 a, R6b, a) b) c) d) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1I-C6 perfluoroalkyl, R 1 2 0-, R I IS(O)m-, R 1 I C(O)NRl 10, (R 1 02NC(O)-, R I C(0)0-, R 10 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 1 0)2, or R I IOC(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 alkynyl, R 12 R' IIS(O)m-, R I C(O)NR 10-, (R I 02NC(O)-, R 10 2N-C(NR CN, R IOC(O)-, N3, -N(R 10 and R 6 C, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfiuoroalkyl, R 1 2 0-, R I S (O)m R I OC(O)NR (R 1 0%2NC(O) R I C(0)O0 R 10 2N-C(NR CN, N02, R I N3, -N(R 1 0 )2, or R I I0C(O)NR 1 0-, 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-CI10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R I IS(O)m-, R I C(O)NR 10-, (R 10 )2NC(O)-, R 1 0 2N-C(NR CN, R IOC(O)-, N3, -N(R 1 0 and R I IOC(O)-NRl10-; or WO W97/36901 PCTIUS97/05304 98 any two of R 6 a, R6b, R 6 C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-., -CH=CH-CH 2 -(CH2)4- and -(CH2)3-; provided that when R 3 R 4 R5, R6a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 3 R 4 R 5 R 6 a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R 7 is selected from: H; CI-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) S 2 1 g) N(R 1 0)2 or h) CIA4 perfluoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R I R I OC(O)NR
10-, (R 10 )2NC(O)-, RlO02N-C(NRl10)-, CN, N02, R IOC(O)-, N3, -N(R'10)2, or R I IOC(O)NR10-, and c) C I -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, WO W97/36901 PCTIUS97/05304 99 R 10 RI I S(0)mn-, R IOC(0)NHi-, (R 10)2NC(0>, R1O2N-C(NRO).. CN, RIOC(0)-, N3, -N(RlO) 2 or RI 0 0C(0)NH-; 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) alkenyl, alkynyl, perfiluoroalkyl, F, Cl, Br, R R I IS(0)m-, R I C(0)NR 10., (R I R 102N-C(NR 10Oy CN, N02, R IOC(0)-, N3, -N(R 10) 2 or R I OC(O)NRI 10, and c) CI-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 RI I R IOC(0)NR (R I 0 RI 0 2N-C(NR CN, R I OC(0)-, N3, -N(R 10) 2 or RI I 0C(0)NR R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl, 2 2 2 -trifluoroethy1 and aryl; R I 1 is independently selected from Cl -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen, C1I-C6 alkyl, C I-C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C I -C6 perfluoroalkyl, 2 -aminoethyl and 2 2 2 -trifluoroethyl; A 1 I and A 2 are independently selected from: a bond, -CU=CH-, -C(0)NRIO., -NRIOC(O)., 0, -S (0)2N(R -N(RJ l)S or S(O)m; V is selected from: a) hydrogen, I WO 97/36901 PCT/US97/05304
100- b) heterocycle, c) aryl, d) C -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, 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; W is a heterocycle; X is a bond, -CH=CH-, O, -C(0)NR 7 -NR 7 -C(O)NR 7 -NR 7 -S(O)2N(R -N(RIO)S(0)2- or-S(=O)m-; 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 tis 0or 1; or a pharmaceutically acceptable salt thereof. 2. The compound according to Claim I of the formula A: IWO 97/36901 PCT/US97/o5304 101 R 6a-e (RB)r V-A 1 (CR (CR 2 2 )p X -(CR 2 wherein: from 1-2 of f(s) are independently N or and the remaining f's are independently CH-; R I is independently selected from: hydrogen, C3-CI10 cycloalkyl, R 10 -N(R 10)2, F or C1I-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, RIO0-, -N(R] 0 F or C2-C6 alkenyl, c) unsubstituted or substituted C I -C6 alkyl wherein the substituent on the substituted ClI -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(RIO)2; R 3 R 4 and a) b) R5are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, .WO 97/36901 PCTIUS97/0j5304 102 c) d) RlO02N-C(NR 10>, CN, N02, R IOC(Oy-, N3, -N(R 10)2, or R I IOC(O)NR unsubstituted C I -C6 alkyl; 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-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 0-, R I S (O)m R I OC(O)NR (RI 102NC(O)-, R 1024.. C(NR CN, R IOC(O)-, N3, -N(R 10)2, and R I I0C(O)- Rba, R6b, R 6 C, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Cj 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R102N-C(NRIOy.., CN, N02, RIOC(O)-, N3, -N(RIO)2, or R'IlIOC(O)NRJO0- c) unsubstituted C I-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 -C cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R I IS(O)m-, R I OC(O)NR 1 0, (R I 0 R 1O2N-C(NR 1 CN, RIOC(o)-, N3, and RI IOC(O)-NRIO-; or any two of R6a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH-=CH-CHCH-, -CH=CH--CH 2 -(CH2)4- and -(CH2)3-; provided that when R 3 R 4 R 5 R 6 a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R 3 R 4 R 5 R6a, R6b, R6c, R6d or R6e to the 6 -membered .WO 97/36901 PCTIUS97/05304 103 heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R 7 is selected from: H; CI-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted. or substituted with: a) Ci1 -4 alkoxy, b) aryl or heterocycle, c) halogen, D d) HO, e) "YR 0 f) -S0 2 R 11 g) N(R'1O)2 or h1) C1I-4 perfluoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ClI -C6 perfluoroalkyl, F, Cl, R 10 R IOC(O)NR 10, CN, N02, (R 'O)2N-.C(NRl10)-, R I -N(R 10)2, or R I OC(O)NR 10t., and C) C1I-C6 alkyl substituted by CjI -C6 perfluoroalkyl, R 10 0-, Rl 0 C(O)NR (RI 0 )2N-C(NR lOy., R 1 0 -N(R'1O)2, or R I I provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R I 1 R I R I OC(O)NR 1 (R 1 *WO 97/36901 PCT/US97/05304 104 CN, N02, (R 1O)2N..C(NR10)-, R IOC(O)-, -N(Rl1O) 2 or R I IOC(O)NRO10., and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 10 R II R IOC(O)NR (R I 0 CN, (R 10 )2N-C(NR Ri I -N(R 10)2, or R I I0C(O)NR R 1 0 is independently selected from hydrogen, C I -C6 alkyl, benzyl, 2 2 2 -trifluoroethyl and aryl; Ri is~ independently selected from Cl1 -C6 alkyl and aryl; Ri1 2 is independently selected from hydrogen, C I -C6 alkyl, ClI -C6 aralkyl, C I -C6 substituted aralkyl, ClI -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, ClI -C6 perfluoroalkyl, 2 -aminoethyl and 2 2 2 -trifluoroethyl; A and A 2 are independently selected from: a bond, -CH=CH-, CEC-, -C(O)NR1-, 0, -N (R or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, qumnolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if AlI is S(O)m and V is not hydrogen if AlI is a bond, n isO0 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; .WO 97/36901 PCT/US97/05304 105 W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridiriyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl; X is a bond, 0, -CH=CH-, -C(0)NR 7 -NR 7 C(oj.. -NR 7 -S(O)2N(RI10>, -N(R 1 0 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; q is 0,1, 2 or 3; 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. 3. The compound according to Claim I of the formula B: R 6 a-e R 8 r 9 a R 3 1 I X-N R 3 f-P- V -Al(CR 2 )nA 2(C R 2 N, f R 9 b'fR\ B (CR 2 9 -X wherein: from 1-2 of f(s) are independently N or and the remaining fs are independently CH; RI is selected from: hydrogen, C3-CIO cycloalkyl, RlO0-, F or Cj -C6 alkyl; IWO 97/36901 PCTIUS97/05304 106 R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, RIO0-, -N(RiO) 2 F or C2-C6 alkenyl, c)0 unsubstituted or substituted C I -C6 alkyl wherein the substituent on the substituted ClI -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-Cj 0 cycloalkyl, C2-C6 alkenyl, R 1 0 0- and -N(R'O)2; R 3 and R 4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 R I R' I C(0)NR (R I 0 R 1O2N..C(NR10)-, CN, N02, R I C(0y, N3, -N(R 1O) 2 or R I I OC(0)NR 10- c) unsubstituted C I -C6 alkyl, d) substituted C1I-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 I 1 R'IOC(0)NR 10-, (R RlO02N-C(NR CN, R I N3, -N(R 10)2, and R I R 6 a, R6b, a) b) R6c, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfiluoroalkyl, R 1 R I S R 1 I 0 C(0)NR (R I 0 R'1 0 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 1 0 )2, or R I'IOC(0)NR WO097/36901 PCTUS97/05304 107 c) unsubstituted C I -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-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 aikynyl, R 120., R I R 1 I C(0)NR (R I 0 RlO02N-C(NRi10)-, CN, R I N3, -N(R 10)2, and RI I 0C(0)-NR 10-; or any two of R6a, R6b, R 6 c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH.., -CFI=CH-CH 2 -(CH2)4- and -(CH2)3-; provided that when R 3 R 4 R 6 a, R6b, R6c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 3 R 4 R 6 a, R6b, R 6 c, R6d or R 6 e to the 6 -membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 aikenyl, C2-C6 alkynyl, CI -C6 perfiuoroalkyl, F, Cl, R 10 R IOC(0)NR 10., CN, N02, (R 1O)2N..C(NR R I -N(R 10)2, or R I OC(O)NRI 10, and C) ClI-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 1 0 0-, R IOC(0)NR (RlO0)2N..C(NR 10), R IOC(O)-, -N(R 10)2, or R I I0C(0)NRO0-; 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, CI -C6 alkyl, trifluoromethyl and halogen; SWO 97/36901 PCT/US97/05304
108- R 10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2, 2 -trifluoroethyl and aryl; S R11 is independently selected from Cl-C6 alkyl and aryl; R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, CI-C6 substituted aralkyl, Ci-C6 heteroaralkyl, Cl-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)NRIO-, O, or S(0)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) C -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 A1 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-, -NRIOC(O)-, -NR10-, 0 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 SWO 97/36901 PCT/US97/05304 -109- r is 0 to 5, provided that r is 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 4. The compound according to Claim 1 of the formula C: R 6 a-e (R )rR3 I ,Nk<R 9 a f V- A'(CR'2)nA2(CR' 2 C R 9 b (CR 2 2 )p-X R4 wherein: from 1-2 of f(s) are independently N or and the remaining fs are independently CH; RI is selected from: hydrogen, C3-C10 cycloalkyl, R 10 -N(R 10)2, F or C1-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 -N(R10)2, F or C2-C6 alkenyl,. c) unsubstituted or substituted C -C6 alkyl wherein the substituent on the substituted C -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 3 and R 4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C 6 WO 97/36901 PCTIUS97/05304 -110- R 6 a, R6b, a) b) alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 120-, R I IS(O)m-, R I OC(O)NR 10>, CN(R 1 0 )2NC(O)-, RlO02N-C(NR 10O> CN, N02, R IOC(O)-, N3, -N(R 10)2, or RI 1 C(O)NRIO-, unsubstituted C I -C6 alkyl, substituted C I -C6 alkyl wherein the substituent on the substituted C1I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIO02N-C(NR10)., CN, R IOC(O)-, N3, -N(R 10)2, and R I I OC(O)-NR R 6 C, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 R' IIS(O)m-, R I OC(O)NR 10-, CN(R 1 0 )2NC(O)-, RlO02N-C(NR 10)- CN, N02, R IOC(O)-, N3, -N(R 10)2, or R I unsubstituted C I -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-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1O2N-C(NR10)-, CN, R IOC(O)-, N3, -N(R 10)2, and R II OC(O)-NR or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH±=CH-CH2-, and -(CH2)3-; WO 97/36901 PCT/US97/05304 -111- provided that when R 3 R 4 R6a, R6b, R 6 c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R 3 R 4 R 6 a, R6b, R 6 c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cj -C6 perfluoroalkyl, F, Cl, R 1 0 RiOC(O)NR 10-, CN, N02, (R10)2N-C(NR R 10 -N(R 10)2, or RIIOC(O)NR 10-, and c) Ci-C6 alkyl substituted by Cl -C6 perfluoroalkyl, R 10 0-, R 1 OC(O)NR 10-, (R 1 0 )2N-C(NR R 10 -N(R10)2, or R I provided that when R8 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, Ci -C6 alkyl, benzyl, 2 2 ,2-trifluoroethyl and aryl; R1 is independently selected from C1-C6 alkyl and aryl; R 1 2 is independently selected from hydrogen, Cj -C6 alkyl, C -C6 aralkyl, Ci-C6 substituted aralkyl, CI-C6 heteroaralkyl, Ci-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)NRi10-, O, -N(R or S(O)m; I I WO 97/36901 PCT/US97/05304
112- 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) C -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 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)NR10-, -NR1OC(O)-, -NR 10-, 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 or O; and r is 0 to 5, provided that r is 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. The compound according to Claim 3 of the formula D: R9a R 6 a-e R 3 R 9 b (CR 2 2 )p-X R4 WO W97/36901 PCTIUS97/05304 113 wherein: from 1-2 of f(s) are independently N or and the remaining f's are independently CH; R I is selected from: hydrogen, C3 -C 10 cycloalkyl or C I -C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, RlO0-, -N(R 10)2, F or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CI10 cycloalkyl, C2-C6 alkenyl, R 1 0 or -N(R 10)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CI0 cycloalkyl, C2-C6 alkenyl, C2-C6 aikynyl, halogen, C I -C6 perfluoroalkyl, RlO02N-C(NR 10)- CN, N02, R IOC(O)-, N3, -N(R 10 )2, or R I'IOC(O)NR c) unsubstituted C I -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 120-., RI 1 I R 1 I C(0)NR 1 (R 1 0 RlO02N-C(NR CN, R IOC(0)-, N3, -N(R 10)2, and R I I0C(O)-NR R 4 is selected from H, halogen, C1I-C6 alkyl and CF3; I WO 97/36901 WO 9736901PCTIUS97/05304 -114- R 6 a, R6b, R 6 c, R6d and R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl, R 120., R I R 1 I C(0)NR (R I 0 R 1 0 2N-C(NR CN, N02, R I N3, -N(R 1 0 )2, or R I IOC(0)NR 1 0-, c) unsubstituted C I -C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted C1I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 R I IS(O)m-, R 1 I C(0)NR 10-, (R 1 0 R'1 0 2N-C(NR CN, R IOC(0)-, N3, -N(R'1 0 and R I I0C(0)-NR 10-; or any two of R6a, R6b, R 6 c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and provided that when R 3 R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R 3 R 6 a, R6b, R6c, R6d or R 6 e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alikynyl, C I -C6 perfluoroalkyl, F, CI, R 1 00., R 1 I C(0)NR CN, N02, (Ri O)2N-C(NR R IOC(0)-, -N(Ri1O)2, or R' I IC(0)NR 10-, and WO 97/36901 PCT/US97/05304
115- c) CI-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, R 1C(O)NR 10_, (R 10)2N-C(NR 10), R OC(O)-, -N(R10)2, 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; R 9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R11 is independently selected from C1-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, Cl-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; X is a bond, -CH=CH-, -C(0)NR10-, -NR10C(O)-, -NR10-, O or n is 0 or 1; provided that n is not 0 if A 1 is a bond, 0, or S(O)m; m is 0, 1 or 2; and pis 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 4 of the formula E: I WO 97/36901 W097/6901PCT/US97/05304
116- 6 a-e Ni R 9 b C22)fR4 wherein: from 1-2 of f(s) are independently N or and the remaining f's are independently CH; R I is selected from: hydrogen, C3-C 10 cycloalkyl, R 100-, -N(R 10)2, F or C I -C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, R 100-, -N(R 10 F or C2-C6 alkenyl, c) C1I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, R 10 or -N(R 10)2; R 3 is 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, R 120-, R I R 1 I C(O)NR 10-, (R 1 0 )2NC(O)-, R 1 02N-C(NR'O)-, CN, N02, RIOC(O)-, N3, -N(R 1 0 )2, or R I I0C(O)NR 1 0-, c) unsubstituted C I -C6 alkyl, I WO 97/36901 W097/6901PCTIUS97105304
117- 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, cycloalcyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R I IS(O)m-, R I C(O)NR 10-, (R I 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(R 1 0 and R 4 is selected from H, halogen, ClI-C6 alkyl and CF3; R 6 a, R6b, R 6 c, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CI0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 10 2N-C(NR 1 CN, N02, R I N3, -N(R 1 0 )2, or R I IOC(O)NR 1 0-, c) unsubstituted C I -C6 alkyl, d) substituted ClI -C6 alkyl wherein the substituent on the substituted ClI-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 IS(O)m-, R I C(O)NR 1 (R 10 )2NC(O)-, R 10 2N-C(NR 1 CN, R I N3, -N(R 1 0 and R I IOC(O)-NR 10-; or any two of R 6 a, R6b, R 6 c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH--, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3 R 6 a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 3 R6a, R6b, R 6 c, R6d or Reto the 6-membered heteroaryl WO 97/36901 PCT/US97/05304 -118- ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, CI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RI 0 R10C(O)NR10-, CN, NO2, (RI0)2N-C(NR1O)-, -N(R 10 or R 1 1 OC(O)NR 10 and c) CI-C6 alkyl substituted by C -C6 perfluoroalkyl, R 1 0 0-, R 10C(O)NR10-, (R 10)2N-C(NR10)-, R OC(O)-, -N(R10)2, or R 1 1 0C(O)NR10-; 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; is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R 1 1 is independently selected from Cl-C6 alkyl and aryl; R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C -C6 substituted aralkyl, C1-C6 heteroaralkyl, C -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)NR1O-, -NRIOC(O)-, -NR10-, 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; I WO 97/36901 WO 9736901PCTIUS97/05304
119- or a pharmaceutically acceptable salt thereof. 7. The compound according to Claim 5 of the formula F: R 6 a-e CR12-N_, R~ 9 b F wherein: from 1-2 of f(s) are independently N or and the remaining fs are independently CH; R I is selected from: hydrogen, C3-C 10 cycloatkyl or C1I-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C1O cycloalkyl, RIOO-, -N(RIO)2 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3 -C 10 cycloalkyl, R 10 or -N(R 10)2; R 3 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, C I -C6 perfluoroalkyl, R 1 2 R I 1 R I C(O)NR 10-, (R I )2NC(O)-, R 10 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10 )2, or R I I0C(O)NR 1 0-, WO 97/36901 WO 9736901PCT1US97/05304 120 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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20., R I R 1 I C(0)NR (R 1 0 R 10 2N-C(NR10)-, CN, R I N3, -N(R 10 and R I IOC(0)-NR R 4 is selected from H, halogen, CH3 and CF3; R6a, R6b, a) b) c) d) R 6 c, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 R II R 1 I C(0)NR 1 (R 1 0%2NC(0)-, R 10 2N-C(NR CN, N02, R IOC(0)-, N3, -N(R 10 )2, or R I I0C(0)NR 1 0-, unsubstituted ClI -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-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 R I R I OC(0)NR (R 10 R 10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(R 1 0 and R I I C(0)-NR 10-; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3 R 6 a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 3 WO 97/36901 PCT/US97/05304 121 R6a, R6b, R 6 c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R 9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, C -C6 alkyl, benzyl, 2,2,2-trifluoroethyl 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, C -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NRIO-, -NRlOC(O)-, -NRIO-, O or m is 0, 1 or 2; and pis 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 6 of the formula G: R Q R6a-e R 3 9b NR4 R9a f NC^. fR2 R I WO 97/36901 WO 9736901PCTIUS97/05304 122 wherein: from 1-2 of f(s) are independently N or and the remaining f s are independently CH; R I is selected from: hydrogen, C3 -C 10 cycloalkyl, R 10 -N(R 10 )2, F or C I-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-CIO cycloalkyl, c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, RIO0-, or -N(R 10)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 R I R 1 I C(0)NR (R 1 0 R 1 0 2N-C(NR 10 CN, N02, R I N3, -N(R 10 )2, or R I IOC(0)NR 1 0-, c) unsubstituted C I -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-C1 0 cycloalkyl, C2-C6 aikenyl, C2-C6 aikynyl, R 1 2 R I IS(O)m-, R I 0 C(0)NR 1 (R I 02NC(0)-, R 10 2N-C(NR CN, R IOC(0)-, N3, -N(R 10 and R I I0C(O)-NR R 4 is selected from H, halogen, CH3 and CF3; WO 97/36901 W097/6901PCTIUS97/05304 123 R 6 a, R6b, R 6 C, R6d and R 6 e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 1 2 R I IS(O)m-, R I C(O)NR 10-, (R I %2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R I IOC(O)NR c) unsubstituted ClI -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' IIS(O)m-, R I C(O)NR 1 (R I 02NC(O)-, R 10 2N-C(NR CN, R I N3, -N(R 10 and R I I0C(O)-NR 10-; or any two of R 6 a, R6b, R 6 c, R6d and R 6 e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; provided that when R 3 R6a, R6b, R6c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 3 R 6 a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon; R 9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, ClI-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R' is independently selected from ClI-C6 alkyl and aryl; WO 97/36901 WO 9736901PCT/US97/05304 -124- R 1 2 is independently selected from hydrogen, C1I-C6 alkyl, C1I-C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C I -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al is selected from: a bond, 0, or S(O)m; m is n is 0, 1 or 2; and 0 or 1; or a pharmaceutically acceptable salt thereof. 9. A compound which inhibits famnesyl-protein transferase which is: 1 -(2-Phenylpyrid-5 -ylmethyl)-5 -(4-cyanobenzyl)imidazole 1 2 -Phenyl-N-0xopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1 -Phenylpyrid-6-ylmethyl)-5 -(4-cyanobenzyl)imidazole 1 -Phenyl-N-0xopyrid-6-yhmethyl)-5-.(4-cyanobenzyl )imidazole 1 -Trifluoromethoxyphenyl)-pyrids...ylmethyl)s..(4. cyanobenzyl)imidazole 1 2 2 -Trifluoromethylphenyl)-pyrid--ylmethyl).5.(4. cyanobenzyl)imidazole 1 (-hnl2Clrpri--lehl--4eynbny~mdzl WO 97/36901 WO 9736901PCT/US97/05304 125 1 -Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-..yanobenzyl)imidazole or 1 -(2-Amino- 3-phenylpyrid-6-ylmethy1)-5-(4-cyanobenzyl)jmidazole or a pharmaceutically acceptable salt thereof. The compound according to Claim 9 which is: 1 2 -Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole NC 1z NN or a pharmaceutically acceptable salt thereof. 11. The compound according to Claim 9 which is: i 2 2 -Trifluoromethylphenyl)-pyrid-s -ylmethyl)-5 cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof. 12. A compound which inhibits farnesyl-protein transferase, substantially as hereinbefore described with reference to any one of the examples. 13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of any one of claims 1 to 12. 14. A pharmaceutical composition made by combining the compound of any one of claims 1 to 12 and a pharmaceutically acceptable carrier. A process for making a pharmaceutical composition comprising combining a compound of any one of claims 1 to 12 and a pharmaceutically acceptable carrier. 16. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 12 or of a composition of claim 13 or claim 14. 17. A compound according to any one of claims 1 to 12 or a composition according to claim 13 or claim 14 when used in inhibiting farnesyl-protein transferase. 18. The use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for inhibiting farnesyl-protein transferase. 19. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 12 or of a composition of claim 13 or claim 14. A compound according to any one of claims 1 to 12 or a composition according to claim 13 or claim 14 when used in treating cancer. 21. The use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for treating cancer. 22. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 12 or of a composition of claim 13 or claim 14. 23. A compound according to any one of claims 1 to 12 or a composition according to claim 13 or claim 14 when used in treating neurofibromin benign proliferative disorder. 24. The use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for treating neurofibromin benign proliferative disorder. A method for treating blindness related to retinal vascularisation which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any ,-one of claims 1 to 12 or of a composition of claim 13 or claim 14. C04206 127 26. A compound according to any one of claims 1 to 12 or a composition according to claim 13 or claim 14 when used in treating blindness related to retinal vascularisation. 27. The use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament for treating blindness related to retinal vascularisation. 28. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 12 or of a composition of claim 13 or claim 14. 29. A compound according to any one of claims 1 to 12 or a composition according to claim 13 or claim 14 when used in treating infections from hepatitis delta and related viruses. S 10 30. The use of a compound according to any one of claims 1to 12 for the manufacture of a medicament for treating infections from hepatitis delta and related viruses. 31. A method for preventing restenosis which comprises administering to a mammal in need thereof a, therapeutically effective amount of a compound of any one of claims 1 to 12 or of a S composition of claim 13 or claim 14. 32. A compound according to any one of claims 1 to 12 or a composition according to claim 13 or claim 14 when used in preventing restenosis. 33. The use of a compound according to any one of claims 1 to 12 for the manufacture of a S medicament for preventing restenosis. S S34. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 12 or of a composition of claim 13 or claim 14. 0e•° 35. A compound according to any one of claims 1 to 12 or a composition according to claim 13 or claim 14 when used in treating polycystic kidney disease. S° 36. The use of a compound according to any one of claims 1 to 12 for the manufacture of a 25 medicament for treating polycystic kidney disease. Dated 22 October 1998 MERCK Co., INC. Patent Attorneys for the Applicant/Nominated Person SPRUSON&FERGUSON C04206
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 | ||
| US2264796P | 1996-07-24 | 1996-07-24 | |
| US60/022647 | 1996-07-24 | ||
| GB9617277 | 1996-08-16 | ||
| GBGB9617277.0A GB9617277D0 (en) | 1996-08-16 | 1996-08-16 | Inhibitors of farnesyl-protein transferase |
| PCT/US1997/005304 WO1997036901A1 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2430197A AU2430197A (en) | 1997-10-22 |
| AU706150B2 true AU706150B2 (en) | 1999-06-10 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU24301/97A Ceased AU706150B2 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0891361A1 (en) |
| JP (1) | JP2000507590A (en) |
| AU (1) | AU706150B2 (en) |
| CA (1) | CA2249607A1 (en) |
| WO (1) | WO1997036901A1 (en) |
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| US6015817A (en) * | 1996-12-05 | 2000-01-18 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US6093737A (en) * | 1996-12-30 | 2000-07-25 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US5939439A (en) * | 1996-12-30 | 1999-08-17 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US6127390A (en) * | 1997-10-02 | 2000-10-03 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
| EP1045846B1 (en) | 1997-11-28 | 2003-05-02 | Lg Chemical Limited | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
| CA2312366A1 (en) * | 1997-12-04 | 1999-06-10 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| JP2002518387A (en) * | 1998-06-16 | 2002-06-25 | ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス | Imidazolyl derivatives |
| US6420555B1 (en) | 1998-06-16 | 2002-07-16 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Imidazolyl derivatives |
| JP2002543074A (en) * | 1999-04-13 | 2002-12-17 | エルジー シーアイ リミテッド | Fanesyl transferase inhibitor having pyrrole structure and method for producing the same |
| EP1420015A1 (en) * | 1999-06-11 | 2004-05-19 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Imidazolyl derivatives |
| IL153123A0 (en) | 2000-06-30 | 2003-06-24 | Bristol Myers Squibb Co | N-ureidoheterocycloalkyl-piperidine derivatives and pharmaceutical compositions containing the same |
| US7211595B2 (en) | 2000-11-30 | 2007-05-01 | Abbott Laboratories | Farnesyltransferase inhibitors |
| US20020115640A1 (en) * | 2000-11-30 | 2002-08-22 | Claiborne Akiyo K. | Farnesyltransferase inhibitors |
| EP1521582A1 (en) | 2002-07-02 | 2005-04-13 | F. Hoffmann-La Roche Ag | 2,5-substituted pyrimidine derivatives as ccr-3 receptor antagonists |
| CA2574600C (en) | 2004-07-23 | 2010-08-31 | Pfizer Inc. | Pyridine derivatives |
| CA2672373C (en) | 2006-12-19 | 2011-08-30 | Pfizer Products Inc. | Nicotinamide derivatives as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases |
| UY30892A1 (en) | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | AKT ACTIVITY INHIBITORS |
| EP2132196A1 (en) | 2007-02-26 | 2009-12-16 | Pfizer Products Inc. | Nicotinamide derivatives as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases |
| AR067354A1 (en) | 2007-06-29 | 2009-10-07 | Sunesis Pharmaceuticals Inc | USEFUL COMPOUNDS AS INHIBITORS OF RAF QUINASA |
| US7968536B2 (en) | 2007-06-29 | 2011-06-28 | Millennium Pharmaceuticals, Inc. | Heterocyclic compounds useful as RAF kinase inhibitors |
| KR101406433B1 (en) | 2008-09-22 | 2014-06-13 | 카이맨 케미칼 컴파니 인코포레이티드 | Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases |
| TW201100398A (en) | 2009-03-31 | 2011-01-01 | Arqule Inc | Substituted indolo-pyridinone compounds |
| AU2014201037B9 (en) * | 2010-04-06 | 2015-11-19 | Nippon Soda Co., Ltd. | Nitrogen-containing heterocyclic compound and method for producing same |
| EP2842944B1 (en) * | 2010-04-06 | 2017-03-15 | Nippon Soda Co., Ltd. | Method for producing nitrogen-containing heterocyclic compound |
| US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| MX2021012208A (en) | 2013-10-04 | 2023-01-19 | Infinity Pharmaceuticals Inc | Heterocyclic compounds and uses thereof. |
| CA2943075C (en) | 2014-03-19 | 2023-02-28 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds for use in the treatment of pi3k-gamma mediated disorders |
| EP3180325B1 (en) * | 2014-07-28 | 2019-03-20 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
| US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
| PL3319959T3 (en) | 2015-07-06 | 2022-02-14 | Alkermes, Inc. | Hetero-halo inhibitors of histone deacetylase |
| US10421756B2 (en) | 2015-07-06 | 2019-09-24 | Rodin Therapeutics, Inc. | Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase |
| US10160761B2 (en) | 2015-09-14 | 2018-12-25 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same |
| US10759806B2 (en) | 2016-03-17 | 2020-09-01 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors |
| WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| JP6756925B2 (en) | 2017-01-11 | 2020-09-16 | ロダン・セラピューティクス，インコーポレーテッド | Bicyclic inhibitor of histone deacetylase |
| JP7152471B2 (en) | 2017-08-07 | 2022-10-12 | ロダン・セラピューティクス，インコーポレーテッド | Bicyclic inhibitor of histone deacetylase |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2162513B (en) * | 1984-06-25 | 1988-01-20 | Toyama Chemical Co Ltd | Dihydropyridine derivatives |
| US5159083A (en) * | 1990-12-28 | 1992-10-27 | Neurogen Corporation | Certain aminomethyl phenylimidazole derivatives; a class of dopamine receptor subtype specific ligands |
| US5633376A (en) * | 1990-12-28 | 1997-05-27 | Neurogen Corporation | Certain aminomethyl phenylimidazole derivatives; and 4-aryl substituted piperazinyl and piperidinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype ligands |
| IT1255802B (en) * | 1992-08-07 | 1995-11-16 | Luso Farmaco Inst | IMIDAZOLIC DERIVATIVES FOR ACTIVITY A II ANTAGONIST |
-
1997
- 1997-04-01 JP JP9535534A patent/JP2000507590A/en active Pending
- 1997-04-01 WO PCT/US1997/005304 patent/WO1997036901A1/en not_active Application Discontinuation
- 1997-04-01 AU AU24301/97A patent/AU706150B2/en not_active Ceased
- 1997-04-01 EP EP97920000A patent/EP0891361A1/en not_active Withdrawn
- 1997-04-01 CA CA002249607A patent/CA2249607A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU2430197A (en) | 1997-10-22 |
| JP2000507590A (en) | 2000-06-20 |
| WO1997036901A1 (en) | 1997-10-09 |
| CA2249607A1 (en) | 1997-10-09 |
| EP0891361A1 (en) | 1999-01-20 |
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