AU716381B2 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- AU716381B2 AU716381B2 AU26058/97A AU2605897A AU716381B2 AU 716381 B2 AU716381 B2 AU 716381B2 AU 26058/97 A AU26058/97 A AU 26058/97A AU 2605897 A AU2605897 A AU 2605897A AU 716381 B2 AU716381 B2 AU 716381B2
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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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- 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
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Description
WO 97/36881 PCTUS97/05514 -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-Aaal-Aaa 2 -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes faresyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C1 5 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 97/36881 PCT/US97/05514 -2ation. Other fanesylated 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 famesyl-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 famesyl-protein transferase blocks the growth of rasdependent tumors in nude mice Kohl et al., Proc. Natl. Acad.
Sci 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Famesyl-protein transferase utilizes farnesyl 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 farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesylprotein transferase would be more specific and attended by fewer side WO 97/36881 PCT/US97/05514 -3effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in four general classes Graham, Expert Opinion Ther. Patents, (1995) 5:1269-1285). The first are analogs of farnesyl diphosphate (FPP), while a second class of inhibitors is related to the protein substrates Ras) for the enzyme. Bisubstrate inhibitors and inhibitors of 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 farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).
It has recently been reported that famesyl-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 97/36881 PCT/US97/05514 -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 arylheteroaryl-containing 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 Q
R
6a -e
R
3
Q
(R
8 )r 9b T d S 2 2 R 4 V A(CR2)nA2(CR2) W (CR2)p X -(CR 2)p WO 97/36881 PCT/US97/05514 DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula A: R R 6 a-e
(R
8 )r
R
9 b d 2122/ a. e R V A(CR 1 2 )nA 2
(CR
2 W (CR 2 2 )p X-(CR2)p
A
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1 and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10
R
1 lS(O)m-, R10C(O)NR 10 R11C(O)O-, (R 10 R1 0 2N-C(NR10)-, CN, NO2, R1OC(O)-, N3, -N(R 10 or R llOC(O)NR 10 c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted C -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, WO 97/36881 WO 9736881PCT/UJS97/05514
R
3
R
4 and a) b) -6- R 100.., R I S R I OC(0)NR 1 0 (R I %2NC(O>-, R'1 0 2N-C(NR'1 0 CN, R IOC(0)-, N3, -N(R 10 and R I IOC(0)-NR
IR
5 are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl.-C6 perfluoroalkyl, R 12 0-, R I IC(0)0-, R I 1 R I C(0)NR 10 (R I 0 )2NC(O)-, R102N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R I IOC(0)NR unsubstituted C I -C6 alkyl, substituted C I -C6 alkyl wherein the sub stituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R'1 0 2N-C(NR 1 CN, R 1OC(0)-, N3, -N(R 10 and R I IOC(0)-NR 10
R
6 c, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfluoroalkyl, R 12 0-, R I IS(0)m-, R I C(0)NR 10 (R I 0 R I IC(0)0-.,
R'
0 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R I IOC(0)NR 1 0 unsubstituted C I -C6 alkyl, 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
6 a, R6b, a) b) WO 97/36881 WO 9736881PCTIUS97/05514 -7 R 1 R I R I OC(0)NR (R 1 R 102N-C(NR CN, R IOC(0)-, N3, -N(R 10 and R I IOC(0)-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 R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R 6 c, R6d or R6e to Q is through a substitutable 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, e)
"YR
0 f) -SO 2
R'
1 g) N(R 1 0 )2 or h) CI-4 perfluoroalkyl;
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R1 1 R I C(O)NR 10 (R I 0
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R I I0C(O)NR 10 and c) C I -C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3 -CI 0 cycloalkyl, WO 97/36881 WO 97/688 1PCT/US97/05514 8- C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R I IS(O)m-, R I C(O)NH-, (R I 02NC(O>-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, or
R
1
OOC(O)NII-;
provided that when R 8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R
9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 peffluoroalkyl, F, Cl, Br, RI RI IS(0)m-, RIOC(0)NRIO-, (Ri R 1 0 2N-C(NRIO0>, CN, N02, R lOC(0)-, N3, -N(R 10 or R I OC(0)NR 1 and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 perfiucroalkyl, F, Cl, Br, R 10 R I IS(0)m-,
R
1 OC(0)NRIO0, (R 10 R102N-C(NRIO0>, CN, R IOC(0)-, N3, -N(R 10 or R I IOC(0)NR R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R' is independently selected from Ci -C6 alkyl and aryl; R 12 is independently selected from hydrogen, C I -C6 alkyl, ClI -C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C I -C6 perfluoroalkyl, 2-amninoethyl and 2,2,2-trifluoroethyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -C(0)NRIO-, -NRIOC(Oj-, 0, -N(RIO)-, -S(0)2N(RIO0>, -N(R 1 0 or S(O)m; V is selected from: -9a) hydrogen, b) heterocycle, c) aryl, d) Cl -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(0)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 15 -C(0)NR 7
-NR
7 -S(0)2N(R 10 S. -N(R 10 or provided that if a is N, then X is not 0, -C(0)NR 7 -C(0)NR 7 -S(0)2N(RIO)- or-NR7-; 20 m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; 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 25 tis 1; or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention is illustrated by the following formula A: WO 97/36881 PCT/US97/05514
R
6 a-e
(R
8 )r V A 1
(CR
1 2
),A
2
(CR
1
(CR
2 2 )p X -(CR 2 wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R100-, -N(R 10 F or C1-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10
-N(R
10 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted Cl-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 1 0 0- and -N(R10)2;
R
3
R
4 and a) b)
R
5 are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R
12 R1S(O)m-, R 1 C(O)NR10-, (R 1 0)2NC(O)-, WO 97/36881 WO 9736881PCTIVS97/05514 11 R6a, R6b, a) b) R 1 2N-C(NR 1 0 CN, N02, R IOC(0)-, N3, -N(R 10)2, or R' IIOC(0)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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20., R I S R I OC(0)NR 1 0 (R 10
R
10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(RIO)2, and R I IOC(0)-NR
R
6 c, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1I-C6 perfluoroalkyl, R 1 R I RI1 OC(O)NR 1G0., (Ri 10)2NC(O)-, R 10 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10 )2, or R I I0C(0)NR 1 0-, 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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R 1 R I C(0)NR 1 (R 1 0 R1 0 2N-C(NR'O)-, CN, RIOC(0)-, N3, -N(Rl 0 and R' IIOC(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 -(CH2)3-; provided that when R 6 a, R6b, R 6 c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R6c, R6d or R6e to Q is through a substitutable ring carbon; WO 97/36881 WO 9736881PCTIUS97/05514 12
R
7 is selected from: H; Cl1-4 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, e)
YR
0 f) -S0 2
R
11 g) N(R 10 )2 or h) CI-4 perfluoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (R 1 0 )2N-C(NRIO)-, R I -N(R 10 or R I IOC(O)NR 10-, and c) C I-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 10 0-,
R
1 I C(O)NR (Ri 0 )2N-C(NR R I OC(O)-, 102,or R I IOC(O)NR provided that when R 8 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-C6 alkynyl, ClI-C6 perfiuoroalkyl, F, Cl, R I R' IIS(O)m-, R I C(O)NR 1 (R I 0 )2NC(O)-, CN, N02, (RIO)2N-C(NRIO)-, RIOC(O)-, -N(RIO)2, or R I I0C(O)NR 10-, and WO 97/36881 PCT/US97/05514 13 c) C -C6 alkyl unsubstituted or substituted by C -C6 perfluoroalkyl, F, Cl, R 10
R
1 1
R
10
C(O)NR
10 (R 0)2NC(O)-, CN, (R 0 )2N-C(NR 10
RIOC(O)-,
-N(R10)2, or R 1
IOC(O)NR
10
R
1 0 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, C1-C6 aralkyl, Cl-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-,
-C(O)NR
10 O, -N(R 10 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 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon; S 14- 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(O)NR 7
-NR
7
-NR
7 -S(0)2N(R 1 -N(RIO)S(0)2- or provided that if a is N, then X is not 0, -C(0)NR 7 -,-S(0)2N(R 10 or -NR7-; mis 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 15 tis 1; p or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B: 2B (R8 r R 9 R3 raw N b" 2 f::r V A'(CR2), A2(CR'2 j d (CR22)pX 0 20
B
I wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; WO 97136881 WO 9736881PCTIUS97/05514 15 RI is independently selected from: hydrogen, C3-CIO cycloalkyl, RIO0-, -N(R 1 0 F or CI-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, RIO0-, -N(RIO)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-CIO cycloalkyl, C2-C6 alkenyl, RIO0- and -N(R 1 0 )2;
R
3 and R 4 a) b) are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl, R 1 2 R I 1 R I C(O)NR 1 0 (R I 0 )2NC
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 10 )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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1
RI
1 RIOC(0)NRIO-, (R 1 0
R
10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(Rlo)2, and R I I OC(O)-NR R6a, R6b, R 6 c, R6d and R6e are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C 10 cycloalkyl, C2-C6 WO 97/36881 PTU9/51 PCTIUS97/05514 16 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfluoroalkyl, R 120-., R I R I OC(0)NR (R 10 R 10 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10)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 1 2 R I IS(0)m-, R I C(O)NR 1 0 (R 1Q2NC(0)-,
R
10 2N-C(NRIO)-, CN, RlOC(O)-, N3, -N(R 1 0 and R I I0C(0)-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 R6a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 6 a, R6b, R6c, R6d or R 6 e to Q is through a substitutable ring carbon;
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 peffluoroalkyl, F, Cl, R 10 R I C(0)NR 10-, CN, N02, (R 10 )2N-C(NR 10 R IOC(0)-, -N(R 10 or R I IOC(0)NR 10-, and c) C1I-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 10 0-,
R
1 OC(0)NRI10., (R 10 )2N-C(NRI10>, R 10 102,or R I I0C(0)NR provided that when RS 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; WO 97/36881 PCT/US97/05514 17-
R
10 is independently selected from hydrogen, CI-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R
11 is independently selected from CI-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, CI-C6 alkyl, Cl-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-,
-C(O)NR
10 O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(0)NRO 1 -NR10C(O)-, -NR 10 O or provided that if a is N, then X is not -C(O)NR 10
-NR
10 or O; m is 0, 1 or 2; WO 97/36881 PCT/US97/05514 18 n is independently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
Another preferred embodiment of the compounds of this invention are illustrated by the formula C:
(R
8 )r R 3
Q
N R a b.c V A'(CR'2)nA2(CR) d C Rb (CR2 2 )p-X wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1 is independently selected from: hydrogen, C3-C10 cycloalkyl,
R
10 -N(R10)2, F or C1-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, R100-, -N(RIO)2, F or C2-C6 alkenyl, c) unsubstituted or substituted Cl -C6 alkyl wherein the substituent on the substituted C1 -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-CO1 cycloalkyl, C2-C6 alkenyl, R 1 0 0- and -N(RO 1 )2;
R
3 and R 4 are independently selected from: WO 97/36881 WO 9736881PCTIUS97/05514 19
R
6 a, R6b, a) b) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R' RI R 1 OC(0)NRI10., CN(R 1
R
1 0 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R I I0C(0)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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(0)m-, R I C(0)NR 10 (R I 02NC(0)-,
R
10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(RIO)2, and R I IOC(0)-NR
R
6 c, R6d and R 6 e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Ci 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 peffluoroalkyl, R 120., R I R I OC(O)NR 1 0O, CN(R 1 0Q2NC(0)-,
R
10 2N-C(NRIO)-, CN, N02, RlOC(0)-, N3, -N(R 1 0 )2, or R1 1 0C(0)NR unsubstituted C I -C6 alkyl, substituted C I -C6 alkylI 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 R I S R I OC(O)NR (R 1 R 10 2N-C(NR 1 CN, R I N3, -N(R 10 and R I IOC(0)-NR WO 97/36881 PCT/US97/05514
R
8 is provided that when R6a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 6 a, R6b, R 6 c, R6d or R 6 e to Q is through a substitutable ring carbon; independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 perfluoroalkyl, F, Cl,
R
1 00 RO 1 C(O)NR10-, CN, N02, (R 10 RlOC(O)-, -N(R 10 or R 1 1
OC(O)NR
1 and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 10 0-, RIO0C(O)NR10-, (R 10)2N-C(NR10)-, -N(R 10)2, or Rl provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R
10 is independently selected from hydrogen, C1-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, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR10-, O, or S(O)m; V is selected from: WO 97/36881 PCT/US97/05514 -21 a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(0)NRlO-, -NRIOC(O)-, -NR 10 O or provided that if a is N, then X is not -C(0)NR 10
-NR
10 or O; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond,
-NR
10 or 0; and r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula
D:
R
9 a 3
R
6 a-e R R3 N b" "'c A'(CR'2)-N J d
R
9 b (CR 2 )p -X
R
8 n WO 97/36881 WO 97/688 1PCT/US97/05514 22 wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NIE, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, 0 or S R I is independently selected from: hydrogen, C3 -C 10 cycloalkyl or C1I-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-ClO cycloalkyl, RIOO-, -N(RIO)2, F or C2-C6 alkenyl, C) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, RIOor NRO2
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 peffluoroalkyl, R 1 R I S R I OC(O)NR 10 (R'O0)2NC(0)-, R102N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R I IOC(0)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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R' IIS(0)m-, R I C(0)NR 10 (R'IQ02NC(0)-, R 1 0 2N-C(NR 10 CN, R IOC(0)-, N3, -N(R 10)2, and R I IOC(0)-NR WO 97/36881 WO 9736881PCT1US97/05514 23
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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, ClI-C6 perfluoroalkyl, R 1 20-, R I S R I OC(O)NR (R I 0 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, 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 C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3 -Cl0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 20-, RI 1 R 1 OC(O)NR (R 1 0 )2NC(O)-, R102N-C(NRIO)-, CN, RIOC(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 6 a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R 6 c, R6d or R 6 e to Q is through a substitutable ring carbon; R9 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ClI-C6 perfluoroalkyl, F, Cl, R I -N(R 10 or R' IIOC(O)NR 10-, and c) ClI-C6 alkyl substituted by C I-C6 perfluoroalkyl, WO 97/36881 PCT/US97/05514 -24- RO1O-, ROC(O)NR1O-, (R O)2N-C(NR RIOC(O)-, -N(R10)2, or R I1OC(O)NRIO-; provided that when R 8 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; RI 1 is independently selected from CI-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, Cl-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 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(O)NRIO-, -NR10C(O)-, -NR 1 O or provided that if a is N, then X is not -C(0)NR 10
-NR
1 0 or O; n is 0 or 1; provided n is not 0 if Al is a bond, 0, -N(R 10 or S(O)m; m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula E: WO 97/36881 WO 9736881PCT/US97105514 25 HR 6 a-e N R 9 a b' c. A(CR1 2 )n ~N a R 9 b (CR 2 2)p-~X
E
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NI-, 0 or S; RI is independently selected from: hydrogen, RIOO-, -N(RIO)2, F, cycloalkyl or Cl-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3 -C 10 cycloalkyl, R 100-, -N(R 10 )2, F or C2-C6 alkenyl, C) CI -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Cl10 cycloalkyl, C2-C6 alkenyl, R 10 0-, or 02
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, C1I-C6 perfluoroalkyl, R1 2 RI IS(0)m-, RIOC(0)NRlO-, (RIO)2NC(O>-, WO 97/36881 WO 9736881PCT/US97/05514 26 R1O2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RlO)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 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 1 (R I 0 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R I IOC(O)-NR
R
4 is selected from H, halogen, C I-C6 alkyl and CF3;
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, C1I-C6 peffluoroalkyl, R 1 R I S R 1 I C(0)NR 1 (R 10 R 10 2N-C(NR CN, N02, R IOC(0)-, N3, -N(R 10 )2, or R I I OC(0)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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(O)m-, R I C(0)NR 10-, (R I 0 )2NC(O)-,
R
10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(RIO)2, and R' lOC(0)-NRIO-; provided that when R 6 a, R6b, R6c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R 6 c, R6d or R6e to Q is through a substitutable ring carbon;
R
8 is independently selected from: WO 97/36881 WO 9736881PCTIUS97/05514 27 a) hydrogen, b) aryl, substituted aryl, heterocycle, C1I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CLI-C6 perfluoroalkyl, F, Cl, R 100.., R I OC(0)NR CN, N02, (Ri 0 )2N-C(NR R IOC(0)-, -N(R 10 or R I IOC(0)NR 1 0 and c) C I-C6 alkyl substituted by C1I-C6 perfinoroalkyl, R 10 0-, R I OC(0)NR 1 (R 1 0%2N-C(NR R I OC(0)-, -N(R102,or R' I IC(0)NR 10 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, 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 12 is independently selected from hydrogen, C I-C6 alkyl, C I-C6 aralkyl, C I-C6 substituted aralkyl, C1I-C6 heteroaraikyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, ClI -C6 peffluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NRI 0 -NRIOC(0)-, -NRI 0 0 or provided that if a is N, then X is not -C(0)NRIO-, -NRIO- or 0; n is 0Qori1; m is 0,i1or 2;and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, -NR IOC(0)-, -NR 10 or 0; or the pharmaceutically acceptable salts thereof.
WO 97/36881 PCT/US97/05514 28 In a further embodiment of this invention, the inhibitors of faresyl-protein transferase are illustrated by the formula F: c9aR 3 Q" >R 6 a-e R L
Q
C1 2 N 9c CR 2 R 9 -b d Sae
R
(CR 2 )p-X NC
F
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1 is independently 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 10
-N(R
10 )2 or F, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R1OO-, or -N(R10)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, Cl-C6 perfluoroalkyl,
R
12 R 1 lS(O)m-, R 10 C(O)NR10-, (R 0 WO 97/36881 WO 9736881PCTIUS97/05514 29
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 1 0 )2, or R I IOC(O)NR 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 aIlkenyl, C2-C6 alkynyl, R102N-C(NRIO)-, CN, RIOC(O)-, N3, N(R 10 and R 1 1OC(O)-NR 10
R
4 is selected from H, halogen, CH3 and CF3;
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, C I -C6 perfluoroalkyl,
R
12 RI IS(O)m-, R 1 0 C(O)NRIO-,
R
10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R I IOC(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-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
12 RI I RIOC(O)NRIO-, (RIO)2NC(O)-, R102N-C(NRIO)-,CN, RIOC(O)-, N3, -N(R 10 and R1 1 OC(O)-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 -(CH2)3-; WO 97/36881 PCT/US97/05514 provided that when R6a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R 6 c, R6d or R6e to Q is through a substitutable ring carbon;
R
9 a and R9b are independently hydrogen, halogen, CF3 or methyl;
R
10 is independently selected from hydrogen, C1-C6 alkyl, 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, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, O or provided that if a is N, then X is not -C(0)NR 10 or O; m is 0, 1 or 2; and pis 0,1,2, 3 or4; or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula G: WO 97/36881 PCT/US97/05514 31
R
6 a-e
RNC
NC A wherein: a is C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that at least one of b, c, d or e is independently N, NH, O or S; RI is independently selected from: hydrogen, R 1 0
-N(R
10
F,
C3-C10 cycloalkyl or Cl-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 0-, or -N(R1O)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, Cl-C6 perfluoroalkyl,
R
12 R1 1
RIOC(O)NR
10
(R
10 WO 97/36881 WO 9736881PCT1US97/05514 32 R1O2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 1 O)2, or R1 1 OC(O)NR 10 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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20-, R I 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 I IOC(O)-NR
R
4 is selected from H, halogen, CH3 and CF3; 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 perfinoroalkyl, R 1 20-, R I R I OC(O)NR (R 1 02NC(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 ClI -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I R 1 I C(O)NR 1 0 (R I 0 )2NC(O>-, R102N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RI 0 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 formn a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-; WO 97/36881 PCT/US97/05514 33 provided that when R 6 a, R6b, R 6 c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R 6 c, R6d or R 6 e to Q 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 is independently selected from CI-C6 alkyl and aryl;
R
1 2 is independently selected from hydrogen, C1-C6 alkyl, Cl -C6 aralkyl, C1 -C6 substituted aralkyl, Ci -C6 heteroaralkyl, Ci -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A
1 is selected from: a bond, O, -N(R 10 or S(O)m; m is 0, 1 or 2; and nis 0 or 1; or the pharmaceutically acceptable salts thereof.
The preferred compounds of this invention are as follows: 1- [1-(4-Cyanobenzyl)- 1 H-imidazol-5-yl]ethyl -4-phenyl-imidazole 1- 1-(4-Cyanobenzyl)- I H-imidazol-5-yl)methyl I -4-phenylimidazole 1- 1-(4-Cyanobenzyl)- 1 H-imidazol-5-yl)methyl -4-(2-methyl)phenyl imidazole WO 97/36881 WO 9736881PCT/(JS97/05514 34 1 -Phenyl-5 -isoxazolylmethyl)-5 -(4-cyanobenzyl) imidazole 1 -(3-Phenyl-isoxazol-5 -ylacetyl)-5-(4-cyanobenzyl) imidazole 1 -(4-Cyanobenzyl)-5 -(4-Phenyl -thiazol-2-ylmethyl)imidazole 1 -(4-Cyanobenzyl (2-methylphenyl)-thiazol-2 -ylmethyl)imnidazole 1 -(4-Cyanobenzyl)-5 -chlorophenyl)-thiazol-2-ylmethyl)imidazole I -(4-Cyanobenzyl) -5 -(4-(naphth-2-yl)-thiazol-2-ytmethyl)imidazole 1 (2-methylphenyl)-5-methylthiazole-2-ylmethyl)-5 -(4-cyanobenzyl) imidazole 1- ((4-(2-methylphenyl)thiazole-2-ylethy1)-5 -(4-cyanobenzyl) imidazo le or the pharmaceutically acceptable salts or optical isomers thereof.
Specific examples of the compounds of the invention are: 1- I 1 -(4-Cyanobenzyl)- I H-imidazol-5 -yl)methyl I -4-phenylimidazole
NC
1 -(3-Phenyl-5 -isoxazolylmethyl)-5 -(4-cyanobenzyl) imidazole WO 97/36881 PCT/US97/05514
NC
<N
1-(4-Cyanobenzyl)-5-(4-(2-methylphen)-ao--y yl)imidazole
NC
H
3
C
NN
s-y 1-((4-(2-methylphenyl)thiazole-2-ylethyl)-5-(4-cyanobenzyl) imidazole
NC
N
H
3
C
or the pharmaceutically acceptable salts thereof.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. 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.
WO 97/36881 PCT/US97/05514 -36- 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, farnesyl, 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 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, WO 97/36881 PCTIUS97/05514 37 dihydrobenzofuryl, dihydrobenzothieny1, 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, tetrahydroisoquinolinyl, 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" intended to mean a substituted Ci -8 alkyl, substituted C2- alkenyl, substituted C2g8 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 C 1-8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl- WO 97/36881 PCT/US97/05514 38 sulfonyl 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, Cl, Br, CF3, NH2, N(C1-C6 alkyl)2, N02, CN, (CI-C6 alkyl)O-, -OH, (Cl-C6 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3,(C1-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl.
The moiety designated by the following structure cd a--e represents an aromatic 5-membered heterocyclic ring and includes the following ring systems: WO 97/36881 PCT/US97/05514
N
I N 0
NN
I N
N
7
S
N--O N
N-N
39
N'N
,N
N"U
N
N
NN N
N'S\
N1 N
N'N
NS
Is NL)
N-O
L Preferably the aromatic 5-membered heterocyclic ring is selected from: N- N N
N
N-
N
u\J 0 0
ND/
IS
NU
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 or nitrogen atoms.
The substituent illustrated by the structure RGa-e WO 97/36881 PCT/US97/05514 is a simplified representation of a phenyl ring having five substituents (hydrogens and/or non-hydrogens) and may also be represented by the structure
R
6 d The moiety described as SR6a-e where 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-CH-, -(CH2)4- and -(CH2)4- includes the following structures:
~N
11 1 LZZ 00 III WO 97/36881 PCT/US97/05514 -41 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.
Preferably, RI1 and R 2 are independently selected from: hydrogen, R 1 1
-N(R
1 0 RIOC(0)NRIO-, R 1 0 0- or unsubstituted or substituted C1 -C6 alkyl wherein the substituent on the substituted Ci -C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 10
R
10 0- and R10C(0)NR10-.
Preferably, R 3 is selected from: a) hydrogen, b) C3-CO10 cycloalkyl, halogen, C1-C6 perfluoroalkyl, R 12 0-, CN, N02, RIOC(0)- or-N(R10)2, c) unsubstituted Ci -C6 alkyl, d) substituted C -C6 alkyl wherein the substituent on the substituted Cl -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CO10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
1 20-, R 1 1 R1 0 C(0)NR 10 (R 10)2NC(0)-,
R
1 0 2N-C(NR 1 0 CN, RIOC(0)-, N3, -N(R 1 0 and
R
1 OC(0)-NR10-.
Preferably, R 4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C -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-CO10 cycloalkyl, halogen, C1-C6 perfluoroalkyl,
R
1 2
R
1 1 CN, N02, R 1 OC(0)- or -N(R10)2, c) unsubstituted Cl -C6 alkyl; d) substituted C -C6 alkyl wherein the substituent on the substituted Ci -C6 alkyl is selected from unsubstituted or WO 97/36881 PCT/US97/05514 -42substituted aryl, C3-C10 cycloalkyl, R 12 R 11S(O)m-, or -N(R10)2; 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 -(CH2)3-.
Preferably, R8 is independently selected from: a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, CI-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, Al and A 2 are independently selected from: a bond, -C(O)NRO1-, -NRO1C(O)-, O, -S(0)2N(R 10 and- N(R10)S(0)2-.
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.
It is intended that the definition of any substituent or variable R a, 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.
WO 97/36881 PCT/US97/05514 -43- The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-25, 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 R6a, R6b, R6c, R6d, R6e and R 8 although only one such 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. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive WO 97/36881 PCT/US97/05514 -44- 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 1-25: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Schemes 1- 15 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 phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated heteroaryl moiety, such as 2-bromothienyl-4-carboxylic acid, to provide the arylheteroaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1. Thus, Scheme 2 illustrates the analogous s eries of arylheteroaryl alcohol forming reactions starting with the halogenated heteroarylaldehyde.
Scheme 3 illustrates the reaction wherein the "terminal" phenyl moiety is 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 4.
Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the arylheteroaryl component of the instant compounds, as shown in Scheme 5. Thus, a zinc bromide adduct, WO 97/36881 PCT/US97/05514 such as phenyl zinc bromide, may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the arylheteroaryl VI. The heteroaryl halide, phenyl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
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 heteroarylmethyl halide to provide intermediate VII. Intermediate VII can then undergo Suzuki type coupling to a suitably substituted heteroaryl boronic acid.
Scheme 7 illustrates the synthesis of a thiazole containing instant compound from the acyclic precursors. Further substitution on the thiazole ring may be accomplished as illustrated in Scheme 7a.
Similar strategies may be utilized to prepare other bisheteroatom moieties.
Schemes 8 and 9 illustrate synthetic strategies that utilize the nucleophilicity of an imidazolyl moiety in the arylheteroaryl. Thus, as shown in Scheme 8, the commercially available 4-phenylimidazole may be reacted with a suitably substituted imidazolyl methyl halide to provide the instant compound VIII. If a particular substituted aryl imidazole is not commercially available, it may be synthesized as illustrated in Scheme 9.
Scheme 10 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.
Scheme 11 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the arylheteroaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII, wherein the primary amine is protected WO 97/36881 PCT/US97/05514 -46as 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 A (CR 2)nA 2
(CR
1 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 12.
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 13 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 haloheteroaryl alcohol, such as 4-bromo-2-thienol, 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 suitably substituted phenyl boronic acid by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the Al (CR 1 2)nA 2 (CR 12)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 14. 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 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.
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 15. Thus a bishalogenated five membered heteroaryl, such as WO 97/36881 PCT/US97/05514 -47- 2,4-dibromothiophene, may undergo metal halogen exchange followed by reaction with a suitably substituted imidazolyl aldehyde and acteylation to form a regioisomeric mixture of the acetyl intermediates. The halogenated regioisomeric mixture may be chromatographically separated at this stage, if convenient. Suzuki coupling with a suitably substituted 6-membered heteroaryl boronic acid affords the instant acetoxy compound, which can be treated with lithium hydroxide to remove the acetyl group. Then, similar substituent manipulation as shown in Scheme 14 may be performed on a fully functionalized compound which incorporates an R 2 hydroxyl moiety.
SCHEME 1 (HO) 2 B A
I
HO_ Br Pd(PPh 3 4 0 A LiAIH 4
HO
A
R6
A
III
HO
WO 97/36881 WO 9736881PCTIUS97/05514 48 SCHEME 1 (continued) NiOI 2 (PPh 3 2
R
A
HO/
ZnBr
(CF
3 S0 2 2 0,-~78-C NEtiPr 2
CH
2
CI
2 NIv -780C-200C R 6
CH
3 0H WO 97/36881 WO 9736881PCTIUS97/05514 49 SCHEME 2
A
Br (HO)2 Bl Pd(PPh 3 4
A-
\~6 0 NaBH 4
A
HO, 1/ 6J SCHEME 3 YEA Br MeO 7B(OH) 2 PdPh) 0 e A R 6
AIH
4 0
A-
HO, 1K 6 WO 97/36881 PTU9/51 PCT/US97/05514 50 SCHEME 4 A Br R3S'o" x BOH)2Pd(PPh 3 4 A
BU
4
NF
R
3 SiO R/ 6
A-
HO 1/ \R 6
R
3 SiO A Br(HO)2
B
Pd(P Ph 3 4 A -BU 4
NF
R
3 SiO"" R/ 6 A -0 HOJ 1/,/KR 6 WO 97/36881 PTU9/51 PCTfUS97105514 51 SCHEME A BrZn
R
3 SiO 'B 0 x Br NiCI 2 (PPh 3 2 IA
BU
4
NF
R
3 SiO
,/R
vi
A-
HO, 1/ 6 WO 97/36881 PTU9/51 PCT[US97/05514 52 SCHEME 5 (continued)
_H
6 Br R3S' x Zn~r NiCI 2 (PPh 3 2 A uNF
R
3 SiO" 1/
_U
A 6 WO 97/36881 WO 9736881PCT[US97/05514 53 SCHEME 6
A
L. Br Br-, ii. MeGH ref tux Tr Nz
A
/Br R 8 i 4~6 (HO)2 B"Q Il Pd(P Ph 3 4 WO 97/36881 WO 9736881PCTJS97/05514 54 SCHEME 7 R 8
N
0000i- N D
NH
3 /EtOH /RT Lawesson' s Reagent 1 ,4-dioxane 800C
OONH
2 N D R 8
N
CSNH
2
N
WO 97/36881 WO 9736881PCTIUS97/05514 55 SCHEME 7 (continued)
R
3 Py. HBr. Br 2
R
H3C Br 0 0
N
N:
NH
2
N
N N WO 97/36881 WO 9736881PCTIUS97/05514 56 SCHEME 7a REtMgBr (1M) NC
THF
H
3 0 0 Py.HBr.Br 2 or H R6 PhCH 2
(CH,)
3 N.HBr.Br 2 Br
NH
2 R8 WO 97/36881PC/J7051 PCT/US97/05514 57 SCHEME 8 N H N N NaDM C I
N:
NR8
NN
SCHEME 9 R 6 0
H
2 N
RH
3 R 6 HN/Yo
N
N)-
WO 97136881 WO 9736881PCT/US97/05514 58 SCHEME
N
R 9 b Nal, NaHOO 3 1
N
R 9 b TO, NEt 3 R 9 b R 9 b.
NiC1 2 (PPh 3 2 ZnBr R 8 1 Tr
\N
b-C Id Ke OTf i. -78 0 C-20 0
C
ii. MeGH, reflux WO 97/36881 WO 9736881PCTfUS97/05514 59 SCHEME I11
N
N]
R
8 to i. I Br 55-C,CH3CN ii. EtOH,80 0 0, NH 2
NH
2 XII
N
Nl
NH
2
N
acylation, sulfonylation or alkylationR-.L\
N
R/
N
R
8 WO 97/36881 WO 9736881PCT/US97/05514 60 SCHEME 12 NC
O
xIV iNa, MeOH ii. 120C
KN,
H Tr IN TrC, NE 3
IN
NC -0NCor XV
XVI
NCN
XIP'
R
OTf i. -78OC-200C ii. MeOH ref lux NC WO 97/36881 WO 9736881PCTIUS97/05514 61
\OH
BrF TrCi, NEt 3 Br' 0 Br SCHEME 13 i, Na, MeGH ii. 1200C
H
R
3
N
Br xv' t R 3
N
0-s OTf i. -78 0 0-20 0
C
ii. MeOH reflux
B(OH)
2 DMF, Pd(P Ph 3 4
K
3 P0 4 xv"l 0 R6< WO 97/36881 WO 9736881PCTIUS97/05514 62 SCHEME 14 Tr xviII EtMg Br R 8 Tr
OH
R
8 l Tr
AC
2 O, py_
N
OAc b -c
C.-
HO,, R 3
(CF
3
SO
2 2 0, -78 0
C
NEtiPr 2 ,0H 2 01 2 N cLiOH N a Y\ OAc R8
XX
SOCd 2
OH
WO 97/36881 WO 9736881PCT[US97OS514 63 SCHEME 14 (continued)
NH
3 MeOH
NH
2 OMe WO 97/36881 PTU9/51 PCTfUS97/05514 64 SCHEME Br t ,Br BuLi Br Li Br t ,Li
N
D-i 0 QAc 2. AcCI
LIGH
Pd(P Ph 3 4 WO 97/36881 PCT/US97/05514 65 Schemes 16-20 illustrate reactions wherein the moiety (R 8) V A(CR'2)nA2CR'2- W (CR 2 2 )p-Xincorporated 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, as shown in Scheme 16. 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. Metal halogen exchange chemistry (Scheme may be employed when manipulating the aldehydes. Alternatively, Grignard chemistry may be utilized, as shown in Scheme 16. Thus, Suzuki coupling provides, for example, the pyrrole containing biheteroaryl XXI. Reaction of the intermediate XXI with a Grignard reagent provides the N-pyrrylmagnesium derivative XXIa, which is then reacted with an aldehyde to provide the C-alkylated instant compound XXII. The product XXII 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 XXIIa. 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.
Scheme 17 illustrates the use of in situ formation of a lithium anion of a suitably substituted N-alkyl pyrrole to provide the C-alkylated compound of the instant invention.
WO 97/36881 PCT/US97/05514 66 If the arylheteroaryl subunit is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme 18, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 18, 19). The alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as 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 19), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as XXXIII (Scheme 20). 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 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 21. 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 22-25 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 97/36881 WO 97/688 1PCTIUS97/05514 67 SCHEME 16 Pd(PPh 3 4 +R6
(HO)AB
N
H
R 6 N i
H
EtMg Br XXIa BrMg WO 97/36881 WO 9736881PCTIUS97/05514 68 SCHEME 16 (continued) Boc
NHI
Boc NH 'CHO Et 2
O
BrMg NHBoc
XXII
1. catalytic hydrogenation 2. CF 3 C0 2
H
CH
2
CI
2 B0C20
CH
2
CI
2 cIIJ~CHO NaBH(OAc), 3 Et 3 N ClCH 2
CH
2
CI
NH
2 )0(IlIa BocN'
NH
2
XXIII
WO 97/36881 WO 9736881PCT/US97/05514 69 SCHEME 16 (continued) BocNH
NH
CF
3
CO
2 H, CH 2
CI
2 NaHCO 3
XXIV
NC
AgON L N' N
XXV
WO 97/36881 WO 9736881PCTIUS97/05514 70 SCHEME 17 Br Pd(PPh 3 4 S+ Zia R 6 dN
(HO)
2
B
aly Boc NH 6 BuLi Boo NH CHO TMEDA Et 2
O
N
atkyl
R
HO
Boo NH al ky I WO 97/36881 WO 9736881PCT[US97/05514 71 SCHEME 18 Et 2
O
BrMg- BnO BooN H CHO 620% Pd(OH) 2
H
2
CH
3 0H
CH
3
CO
2
H
HO
NHBoc R 6
CICOCOCI_
DMSO CH 2
CI
2 (02 HF) 3
N
XXVII
WO 97/36881 WO 9736881PCTIUS97/05514 72 SCHRME ISX (CONTINUED) R'MgX NHBoc
XXIX
HO
R'
NHBoc
XXX
WO 97/36881 WO 9736881PCTfUS97/05514 73 SCHEME 19
HO
NHBoc R 6
OF
3 00 2
H
CH
2 01 2
XXVIII
HO
NH
2
RCHO
NaBH(OAo) 3
CICH
2
CH
2
CI
xxxi
XXXII
WO 97/36881 WO 9736881PCTIUS97/05514 74 SCHEME H
H
R 02 NaH, DMF 0'C HO a NHBoc
XXVIII
<N
H
R"SH
(0 2
H
5 3 N A
CH
3 0H
XXXIII
R"S
NH
2
XXXIV
WO 97/36881 WO 9736881PCT[US97/05514 75 SCHEME 21
HO-
1) BoC 2 O, K 2 00 3 TH F-H 2 0 2) CH 2
N
2 EtOAc
H
2 N- CO 2
H
BocNH' -CO 2
CH
3 XXXV i XXXV LiAIH 4
THF
0-200C
R"'CH
2
X
CS
2 00 3
DMF
BocNH
XXXVII
R 0H 2 0 BocNH CH 2 0H
XXXVIII
R"...CH
2 0 pyride O
DMSO
(0 2
H)
3 N BocNH CHO 200C lx,' WO 97/36881 WO 9736881PCTfUS97/05514 76 SCHEME 21 (continued) R"'C H 2 0 BocNH CHO
IXL
BrMg \d
R
3 1. Et 2
O\
2. 20% Pd(OH) 2
H
2
CH
3 0H, CH 3 00 2
H
not aryl Et 2
O
3. HOI, EtOAc R CH 2 0 NHBoc
AL-
1) 20% Pd(OH) 2
H
2
CH
3 OH, CH 3
CO
2
H
2) HCt, EtOAc
HO'
NH
2
XLII
WO 97/36881 WO 9736881PCTIUS97/05514 77 SCHEME 22
OH
3
H
2 N' N I 1) HNO 2 ,Br 2 2) KMnQ 4 3) MeOH,Hl C0 2 C H 3 Br' N ZnCI 2 ,NiCI 2 (Ph 3
P)
2 NaBH 4 (excess)
,CH
2 0H
-CHO
SO
3 gPy, Et 3
N
DMSO
WO 97/36881 PTU9/51 PCT/US97/05514 78 SCHEME 23 Br C0 2 0H 3
N
1. EtO(CO)CI 2.
I MgCI Zn, CuCN 3. S, xylene, heat C0 2 0K 3
N
NaBH 4 (excess)
SOS
3 Py, Et 3
N
,CH
2 0H DMSO MgCI ZnCI 2 NiCI 2 (Ph 3
P)
2
-CO
2
CH
3 NaBH 4 (excess) S0 3 ?Py, Et 3
N
,CH
2
OH
DMSO
-CHO
0 PCTIUS97105514 WO 97/36881 79 SCHEME 24 q0 2
CH
3 Br
N
1. LDA, 002 2. MeCH, H' MgCI q0 2
CH
3 ZnCI 2 NiC1 2 (Ph 3
P)
2 NaB H 4 (excess)
H
2 0H S0 3 'Py, Et 3
N
DMSO
CHO
WO 97/36881 WO 9736881PCTfUS97/05514 -gSo- SCHEME N B r 1. LDA, 002 2. (CH 3 3 SiCHN 2 C0 2
CH
3 Br R 6 IBr Zn, NLCI 2 (Ph 3
P)
2 excess NaBH 4 R 6 N C0 2
CH
3
SO
3 -Py, Et 3
N
DMSO
CHO
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 WO 97/36881 PCT/US97/05514 -81 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 famesylprotein transferase and the farnesylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease Schaffner et al.
American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
WO 97/36881 PCT/US97/05514 -82- 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-i, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
WO 97/36881 PCTUS97/05514 83 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 quantity of famrnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two WO 97/36881 PCT/US97/05514 84portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quantitating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesylprotein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.
WO 97/36881 PCT/US97/05514 85
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- [1 -(4-Cyanobenzyl)-1 H-imidazol-5-yl]ethyl} -4-phenyl-imidazole bishvdrochloride salt Step A: 1H-Imidazole-4-acetic acid methyl ester hydrochloride A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 mL) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature for 18 hours. The solvent was evaporated in vacuo to afford the title compound as a white solid.
1 H NMR (CDC13, 400MHz) 8 8.85(1H, 7.45(1H, 3.89(2H, s) and 3.75(3H, s) ppm.
Step B: 1-(Triphenylmethyl)- H-imidazol-4-ylacetic acid methyl ester To a solution of the product from Step A (24.85g, 0.141 mol) in DMF (115 mL) was added triethylamine (57.2 mL, 0.412 mol) and triphenylmethyl bromide (55.3g, 0.171 mol) and the suspension was stirred for 24 hours. After this time, the reaction mixture was diluted with EtOAc and water. The organic phase was washed with sat. aq. NaHCO3, dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 0-100% EtOAc in hexanes) to provide the title compound as a white solid.
1 H NMR (CDC13, 400MHz) 6 7.35(1H, 7.31(9H, 7.22(6H, 6.76(1H, 3.68(3H, s) and 3.60(2H, s) ppm.
WO 97/36881 PCT/US97/05514 86- Step C: [1 -(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester To a solution of the product from Step B (8.00g, 20.9 mmol) in acetonitrile (70 mL) was added 4-cyanobenzyl bromide (4.10g, 20.92 mmol) and heated at 55°C for 3 hours. The reaction was cooled to room temperature and the resulting imidazolium salt was collected by filtration. The filtrate was heated at 55 0 C for 18 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 mL) and the resulting precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 mL) and heated to reflux for 30 minutes. After this time, the solvent was removed in vacuo. The resulting residue was suspended in EtOAc (75 mL) and the solid isolated by filtration and washed with EtOAc.
The solid was treated with sat. aq. NaHCO3 solution (300 mL) and CH2C12 (300 mL) and stirred at room temperature for 2 hours. The organic layer was separated, dried, (MgSO4) and evaporated in vacuo to afford the title compound as a white solid.
1 HNMR (CDCl3,400MHz) 6 7.65(1H, d, J=8Hz), 7.53(1H, s), 7.15(1H, d, J=8Hz), 7.04(1H, 5.24(2H, 3.62(3H, s) and 3.45(2H, s) ppm.
Step D: 5-f1 -(4-Cvanobenzyl)-1 H-imidazolyllethanol To a stirred solution of the ester from example step C, (1.50g, 5.88 mmol), in methanol (20 mL) at 0°C, was added sodium borohydride (1.00g, 26.3 mmol) portionwise over 5 minutes. The reaction was stirred at 0°C for 1 hour and then at room temperature for 1 hour. The reaction was quenched by the addition of sat. aq.
NH4Cl solution and the methanol evaporated in vacuo. The residue was partitioned between EtOAc and sat. aq. NaHCO3 solution and the organic extracts dried, (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (Silica gel, 4-10% methanol in CH2C12) to afford the title compound as a white solid.
WO 97/36881 PCTUS97/05514 87 1 H NMR (CDC13 400MHz) 8 7.64(2H, d, J=8.2Hz), 7.57(1H, s), 7.11(2H, d, J=8.2Hz), 6.97(1H, 5.23(2H, 3.79(2H, t, J=6.2Hz), 2.66(2H, t, J=6.2Hz) ppm.
Step E: 5-(1 -(4-Cyanobenzyl)-imidazolyl)ethylmethanesulfonate A solution of 5-[1-(4-cyanobenzyl)-lH-imidazolyl] ethanol (0.500 g, 2.20 mmol) in CH2Cl2 (6 mL) at 0°C was treated with Hunig's base (0.460 mL, 2.64 mmol) and methanesulfonyl chloride (0.204 mL, 2.64 mmol). After 2 hours, the reaction was quenched by addition of saturated NaHCO3 solution (50 mL) and the mixture extracted with CH2C12 (50 mL), dried, (MgSO4) and the solvent evaporated in vacuo. The title compound was used without further purification.
1 H NMR (CDC13 400MHz) 5 7.69 (1H, s) 7.66(2H, d, J=8.2Hz), 7.15 (2H, d, J=8.2Hz), 7.04(1H, 5.24(2H, 4.31(2H, t, J=6.7Hz), 2.96(3H, and 2.88(2H, t, J=6.6Hz)ppm.
Step F: 1- [1 -(4-Cyanobenzyl)-1 H-imidazol-5-yl]ethyl phenvl-imidazole bis hydrochloride salt To a suspension of sodium hydride (14.2mg, dispersion in mineral oil, 0.356 mmol) in DMF (0.30 mL) at 0 C was added 4-phenylimidazole (48.8mg, 0.339 mmol), and stirred for 20 minutes. A solution of the mesylate from step E (100mg, 0.339 mmol) in DMF (0.50 mL) was added to the solution and stirring continued at 0°C for 1 hour and then at room temperature for 16 hours. The reaction was quenched with sat. aq. ammonium chloride solution (0.10 mL), and the solvent evaporated in vacuo.
The residue was purified by chromatography (Silica gel, acetonitrile). The resulting material was converted to the HCI salt by treating an EtOAc solution of the imidazole with gaseous HC1 and evaporation of the solvent in vacuo.
Anal. Calcd for C22H 19N5-2.00HCI* .50H20: C, 58.29; H, 5.34; N, 15.45.
Found: C, 58.24; H, 5.47; N, 15.48.
WO 97/36881 PCT/US97/05514 88 FAB HRMS exact mass calcd for C22H20N5 354.171871 found 354.171948.
1 H NMR (CD30D 400MHz) 6 8.93 (1H, 8.75(1H, 7.86(1H, 7.76(2H, d, J=7.9Hz), 7.69(2H, d, 7.1Hz), 7.65-7.35(6H, m), 5.61(2H, s) and 4.53(2H,m)ppm.
EXAMPLE 2 1- 1 -(4-Cyanobenzyl)-1 H-imidazol-5-yl)methyl} -4-phenylimidazole bis hydrochloride salt Step A: 1-Triphenvlmethyl-4-(hydroxymethyl)imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in dry DMF (250 mL) at room temperature was added triethylamine (90.6 mL, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL) was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Step B: 1-Triphenylmethyl-4-(acetoxymethyl)imidazole The alcohol from Step A (260 mmol, prepared above) was suspended in pyridine (500 mL). Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into EtOAc, washed sequentially with water, 5% aq. HCI solution, sat. aq. NaHCO3, solution, and brine. The organic extracts were dried, (Na2SO4), and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction.
WO 97/36881 PCT/US97/05514 89 Step C: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide A solution of the product from Step B (85.8 g, 225 mmol) and 4-cyanobenzyl bromide (50.1 g, 232 mmol) in EtOAc (500 mL) was stirred at 60 oC for 20 hours, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume (200 mL), heated at 60 °C for 2 hours, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to a volume (100 mL), heated at 60 oC for 2 hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in methanol (500 mL), and warmed to 60 After 2 hours, the solution was concentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble by products. Removal of residual solvents in vacuo provided the titled product as a white solid which was used in the next step without further purification.
Step D: 1-(4-Cvanobenzvl)-5-(hydroxvmethvl)imidazol To a solution of the acetate from Step C (50.4 g, 150 mmol) in 3:1 THF/water (1.5 L) at 0 OC was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After 1 hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
WO 97/36881 PCT/US97/05514 Step E: 1-(4-Cyanobenzvl)-5-(chloromethyl)imidazole A solution of 1-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole (1.00g, 4.70 mmol), in thionyl chloride (5 mL), was stirred at 70 0 C for 16 hours. The solvent was evaporated in vacuo and the resulting solid suspended in CH2C12, collected by filtration and dried in vacuo. The material was sufficiently pure for use in the next step without further purification.
1 H NMR (CD30D 400MHz) 8 9.06 (1H, 7.83(2H, d, 7.77(1H, 7.55(2H, d, J=8.0Hz), 5.67(2H, s) and 4.78(2H, s) ppm.
Step F: 1- [1 -(4-Cyanobenzyl)-1H-imidazol-5-yl]ethyl -4phenyl imidazole bis hydrochloride salt To a solution of the chloride from step E (500mg, 1.65 mmol) in DMF (10 mL) at 0°C was added sequentially, 4-phenylimidazole (238mg, 1.65 mmol) and sodium hydride (145mg, dispersion in mineral oil, 3.62 mmol). Stirring was continued at 0 C for 1 hour and then at room temperature for 16 hours. The reaction was quenched with water (50 mL), and extracted with CH2C12. The organic extracts were dried, (MgSO4), and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, NH40H: acetonitrile). The imidazole was converted to the hydrochloride salt by treating an EtOAc solution of the resulting material with gasseous HC1 and evaporation of the solvent in vacuo.
Anal. Calcd for C21H17N5*2.00HCl* 1.75H20*0.30EtOAc: C, 56.70; H, 5.34; N, 14.89.
Found: C, 56.71; H, 5.22; N, 14.91.
1 H NMR (CD30D 400MHz) 8 9.32 (1H, d, J=1.4Hz), 8.87(1H, s), 8.07(IH, 7.69(1H, d, J=1.6Hz), 7.60-7.45(7H, 7.24(2H, d, J=8.6Hz), 5.75(2H, s) and 5.72(2H, s)ppm.
WO 97/36881 PCT/US97/05514 91 EXAMPLE 3 1 1-(4-Cyanobenzyl)-1 H-imidazol-5-yl)methyl -4-(2-methyl)phenyl imidazole bis hydrochloride salt Step A: 4-(2-Methvl)phenyl imidazole A solution of I -(2-methyl)phenyl-2-bromoethanone (1.97g, 9.24 mmol) in formamide (12 mL), was heated at 215°C for 2 hours. The reaction was cooled to room temperature and 0.2M aq. HC1 (120 mL) was added and the resulting solid removed by filtration. The filtrate was treated with sat. aq. NH40H to pH and extracted with EtOAc The organic extracts were washed with brine, dried, (MgS04) and evaporated in vacuo. The residue was purified by chromatography (Silica gel, EtOAc) to afford the title compound.
Step B: 1- [1-(4-Cyanobenzyl)-1 H-imidazol-5-yl]ethyl methyl)phenl)imidazole bis hydrochloride salt The title compound was prepared using the protocol described in Example 2, Step F using 4-(2-methyl)phenyl imidazole.
Anal. Calcd. for C22H19N5-2.15HCl- 1.75H20- C, 57.03 H, 5.36N, 15.12.
Found: C, 57.02; H, 5.35; N, 15.29.
1H NMR (CD30D, 400MHz) 8 9.25(1H, 8.89(1H, 8.03(1H, 7.68(2H, d, J=8.2Hz), 7.58(1H, d, J=1.6Hz), 7.45-7.25(6H, m), 5.76(2H, 5.73(2H, s) and 2.35(3H, s) ppm.
EXAMPLE 4 1-(3-Phenyl-5-isoxazolylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt WO 97/36881 PCT/US97/05514 92- Step A: 1-Tritvl-4-(4-cyanobenzyl)-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 for 45 minutes under argon at 20 0
C.
The suspension was cooled to 0°C and a-bromo-p-toluinitrile (9.33g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 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-iodotritylimidazole (15.95g, 36.6 mmol) were added in one portion.The resulting mixture was stirred 16 hours at 20 0 C and then quenched by addition of saturated NH4C1 solution (100 mL) and the mixture stirred for 2 hours. Saturated aq. NaHCO3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2 x 250 mL), dried, (MgSO4) and the solvent evaporated in vacuo.
The residue was chromatographed (Silica gel, 0-20% EtOAc in CH2C12) to afford the title compound as a white solid.
1 H NMR 8 CDC13 (7.54 (2H, d, J=7.9Hz), 7.38(1H, 7.36-7.29 (1 H, 7.15-7.09(6H, 6.58(1H, and 3.93(2H, s)ppm.
Step B: 1-(3-Phenyl-5-isoxazolylmethyl)-5-(4cyanobenzyl)imidazole hydrochloride salt A suspension of 1-(bromomethyl)-3-phenylisoxazole (31.3mg, 0.13 mmol), 1-trityl-4-(4-cyanobenzyl)-imidazole (60 mg, 0.13 mmol) in acetonitrile (0.20 mL) was stirred at 55 0 C for 16 hours. The solvent was evaporated in vacuo and the residue dissolved in methanol (5 mL) and stirred at reflux for 1 hour. The solvent was evaporated in vacuo and the residue partitioned between CH2C12, and aq. NaHCO3. The organic extract was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 0-3%MeOH in CH2C12), and converted to the hydrochloride salt by treatment with hydrochloric acid in EtOAc. Evaporation of the solvent in vacuo afforded the title compound.
Anal. Calcd. for C21Hl6N40 1.00 HC1.
WO 97/36881 WO 9736881PCTIUS97/05514 93 C, 66.93 H, 4.55 N, 14.87.
Found: C, 66.84; H, 4.39; N, 14.5 1.
I
1 H NMR (CD3OD, 400MHz) 6 9.21 (1 H, 7.5 1(2H, in), 7.58(2H, d, 7.54-7.43(4H, in), 7.33(2H, d, J=8.OHz), 6.62(1H, s), 5.70(2H, s) and 4.3 1(2H, s) ppm.
EXAMPLE 1 -(3-Phenyl-isoxazol-5-ylacetyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in Example 4, Step B using 5-(bromoacetyl)-3-phenyl isoxazole.
Anal. Calcd. for C22H 1 6N4O2-2.55HCL.0.5OH2O- C, 60.65 H, 4.50 N, 12.41.
Found: C, 60.72; H, 4.51; N, 12.16.
IH NMR (CD3OD, 400MHz) 6 8.95(lH, d, J=1.5Hz), 8.00- 7.90(2H, in), 7.73(1H, 7.64(2H, d, J=8.4Hz), 7.58-7.50(3H, in), 7.48-7.40(3H, nm), 5.85(2H, 4.23(2H, s) ppm.
EXAMPLE 6 1 -(4-Cyanobenzyl)-5-(4-Phenyl-thiazol-2-ylmethyl)imidazole hydrochloride salt Step A: 4-[5-(Aminocarbonylmethyl)imidazol- 1 ylmethyll beuzonitrile To a 100 mL glass pressure vessel with a stirring bar was added I-(4-cyanobenzyl)-1IH-imidazol-5-yl] acetic acid methyl ester (6.00 g, 23.5 minol) and absolute ethanol (50 mL). This well stirred solution was cooled to -78'C and 50 mL of anhydrous ammonia was condensed in. The vessel was sealed and the mixture warmed to ambient temperature. This solution was stiffed 24 hours WO 97/36881 PCT/US97/05514 -94at ambient temperature. The excess ammonia was allowed to evaporate and the ethanol was removed in vacuo. The solid residue was triturated with EtOAc and collected on a frit. This material was dried in vacuo to give the title compound as a white solid.
1 H NMR (DMSO-d6, 400MHz) 6 3.25(s, 2H), 5.32(s, 2H), 6.88(s, 1H), 6.96(s,lH), 7.24(d, j=8Hz,2H), 7.42(s,1H), 7.68(s,lH), 7.83(d, j=8Hz, 2H).
Step B: 1-(4-Cyanobenzyl)- carbonvlmethyl To a 50 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added methyl)imidazol-1-ylmethyl]benzonitrile (0.36g, 1.49 mmol), Lawesson's reagent (0.73g, 1.8 mmol) and 1,4-dioxane (10 mL).
O
This well stirred mixture was heated at 80 C for 24 hours. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed (silica gel, 10% 2-propanol in ammonia saturated CHC13). The title compound was obtained as a yellow, crystalline solid.
1 H NMR (DMSO-d6, 400MHz) 8 3.66(s, 2H), 5.41(s, 2H), 6.85(s, IH), 7.24(d, j=8Hz,2H), 7.70(s,lH), 7.82(d, j=8Hz, 2H), 9.21(s, 1H), 9.56(s, 1H).
Step C: 1-(4-Cyanobenzyl)-5-(4-phenyl-thiazol-2vlmethyl)imidazole hydrochloride salt To a 25 mL round bottomed flask with a stirring bar reflux condenser and an argon inlet was added 1-(4-Cyanobenzyl)- (0.12g, 0.468 mmol), dry THF (10 mL), and a-bromoacetophenone (0.098g, 0.491 mmol). This mixture was heated at 50 0 C for 7 hours. The cooled reaction mixture was diluted with EtOAc and washed sucessively with aq. NaHCO3 water, and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed (silica gel, 3% 2-propanol in ammonia saturated WO 97/36881 PCT/US97/05514 CHC13). The purified product was converted into the hydrochloride salt with 4M HCI in 1,4-dioxane. This material was triturated with EtAOc and collected on a frit. The product was dried in vacuo at 500C.
mp: 245-247 0 C (HCI salt).
1 H NMR (CDC13, 400MHz, free base) 6 1.70(br s, 1H), 4.23(s, 2H), 5.27(s, 2H), 7.04(d, j=8Hz, 2H), 7.14(s,lH), 7.29(s, 1H), 7.35 7.44 2H), 7.49(d, j=8Hz, 2H), 7.56(s, 1H) and 7.78 (d, j=8 Hz, 2H) ppm.
EXAMPLE 7 1-(4-Cyanobenzyl)-5-(4-(2-methylphenyl)-thiazol-2-ylmethyl)imidazole hydrobromide salt Step A: 1-(2-Methvl)phenyl-2-bromoethanone To a 500 mL round bottomed flask with a stirring bar and an argon inlet was added CHC13 (200 mL), THF (100 mL), 2-methylacetophenone (10 mL, 76.46 mmol), and pyridinium bromide perbromide (26.85g, 84.11 mmol). This solution was stirred at ambient temperature for 24 hours. The reaction mixture was washed with 5% aqueous HC1, H20, and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was vacuum distilled at 15 torr to give 1-(2-methyl)phenyl-2-bromoethanone, bp: 143-148 0 C as a green oil.
1H NMR (CDC13, 400MHz) 8 2.51(s, 3H), 4.41 2H), 7.22 (m, 2H), 7.41 1H), 7.66 j=7Hz, 1H).
WO 97/36881 PCTUS97/05514 -96- Step B: 1-(4-Cyanobenzyl)-5-(4-(2-methylphenyl)-thiazol-2ylmethvl)imidazole hydrobromide salt To a 25 mL round bottomed flask with a stirring bar reflux condenser and an argon inlet was added 1-(4-cyanobenzyl)- 1H-imidazol-5-yl] aminothiocarbonylmethyl (0.15 g, 0.585 mmol), dry THF (10 mL), and 1-(2-methyl)phenyl-2-bromoethanone (0.274 g, 1.28 mmol). This mixture was heated at 50 0 C for 2.5h. The cooled reaction mixture was concentrated in vacuo. The material was triturated with EtOAc and collected on a frit. The product was dried in vacuo at mp: 215-216 0 C (HBr salt).
1H NMR (DMSO-d6) 6 2.36(s, 3H), 4.53(s, 2H), 5.63(s, 2H), 7.25(m, 3H), 7.34(d, j=8Hz, 1H), 7.45(d, j=8Hz, 1H), 7.62 (s,1H), 7.70 (br s, 2H), 7.72(d, j=8Hz, 2H), 9.15(s, 1H).
EXAMPLE 8 1-(4-Cyanobenzyl)-5-(4-(3-chlorophenyl)-thiazol-2-ylmethyl)imidazole hydrochloride salt Step A: 1-(3-Chloro)phenl-2-bromoethanone To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 3-chloroacetophenone (0.60g, 3.85 mmol), CHCl3 (20 mL), and benzyltrimethylammonium bromide perbromide (180g, 4.62 mmol). This suspension stirred at ambient temperature for 48 hours. The reaction mixture was diluted with EtOAc and this solution was washed with H20 and brine. Drying (MgSO4), filtration and removal of the solvent gave an oil. This material was chromatographed (Silica gel, 5% EtOAc in hexanes).
The title compound was obtained as an oil.
1H NMR (CDCI3,400MHz) 8 4.42(s, 2H), 7.47 j=8Hz, 1H), 7.58 j=8Hz, 1H), 7.86 j=8Hz, 1H) and 7.97 1H) ppm.
WO 97/36881 PCT/US97/05514 -97 Step B: 1-(4-Cyanobenzyl)-5-(4-(3-chlorophenyl)-thiazol-2ylmethylimidazole hydrochloride salt To a 50 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet, was added 1-(4-cyanobenzyl)-lHimidazol-5-yl]aminothiocarbonylmethyl (0.15g, 0.585 mmol), THF mL), and 1-(3-chloro)phenyl-2-bromoethanone (0.18g, 0.77 mmol). This mixture was heated at 50 0 C for 3 hours. The cooled mixture was concentrated in vacuo and the residue was partitioned between EtOAc and aq. NaHCO3 solution. The layers were separated and the organic phase was washed with brine, dried, (MgSO4) filtered and concentrated in vacuo. This material was chromatographed (Silica gel, 2% CH30H in EtOAc). The main chromatographic product was repurified by liquid chromatogrphy (0.1%TFA in H20:CH3CN gradient 95:5 to 5:95) to provide two compounds as TFA salts. The TFA salt material thus obtained was converted into the HCI salts with 4M HCI in 1,4-dioxane. The title compound, isolated as the major component, was triturated with EtOAc and collected on a frit. The product was dried in vacuo at 50°C. mp: 245-246°C.
1H NMR (DMSO-d6, free base) 5 4.56(s, 2H), 5.67(s, 2H), 7.32(d, j=8Hz, 2H), 7.43(m, 2H), 7.65(d, j=8Hz, 2H), 7.74 (br s,lH), 7.80 (br s, 1H), 8.11(s, lH), 9.33(s, 1H).
The minor component was isolated: (3-{4-[4-(3-chlorophenyl)-thiazol- 2-yl]-3-H-imidazol-4-yl)acetonitrile, hydrochloride.
mp:219-220°C 1H NMR (DMSO-d6) 8 4.18(s, 2H), 5.49(s, 2H), 7.43(d, j=8.3Hz, 2H), 7.48(d, j=7.5Hz, 2H), 7.63(s, 1H), 7.99(d, j=7.5Hz, 2H), 8.05(d, j=8.3Hz, 2H), 8.35(s, 1H), 8.97(br s, 1H).
WO 97/36881 PCT/US97/05514 98 EXAMPLE 9 1-(4-Cyanobenzyl)-5-(4-(naphth-2-yl)-thiazol-2-ylmethyl)imidazole hydrochloride salt To a 35 mL round bottomed flask with a stirring bar, condenser and an argon inlet was added 1-(4-cyanobenzyl)-IH- (0.15g, 0.585 mmol), THF mL), and I-(2-naphthalenyl)-2-bromoethanone (0.175g, 0.70 mmol). The well stirred mixture was heated at 50 0 C for 2 hours.
The mixture was cooled to room temperature and allowed to stir over night. The solvent was removed in vacuo and the residue was partitioned between EtOAc and aq. NaHCO3 solution. The layers were separated and the organic phase was washed with H20 and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed (Silica gel, 2% 2-propanol in ammonia saturated CHC13). The product was converted into the hydrochloride salt with 4M HCI in 1,4-dioxane.
The HCI salt was triturated with EtOAc and collected on a frit. The product was dried in vacuo at 50 0 C for 24 hours. mp: 245-246°C 1 H NMR (DMSO-d6, 400MHz, free base) 8 4.57(s, 2H), 5.68(s, 2H), 7.36(d, j=8Hz, 2H), 7.52(m, 2H), 7.68(d, j=8Hz, 2H), 7.74(br s, 1H), 7.96 3H), 8.1 l(s, 1H), 8.35(s, 1H) and 9.22(s, 1H) ppm.
EXAMPLE 1-((4-(2-methylphenyl)-5-methylthiazole-2-ylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt Step A: 1-o-Tolyl-propan- -one To an oven dried 100 ml 3 neck flask equipped with septa, thermo probe and stirred bar was stirring a solution of o-tolunitrile (1 ml, 8.5 mmol) in 40 ml dry THF at 0°C. To this cold, well stirred solution was added a solution of ethylmagnesium bromide (17 ml, 17 mmol) in THF via syringe while keeping the temperature below 5°C Removed ice bath and allowed the yellow solution to stir at ambient WO 97/36881 PCT/US97/05514 -99temperature for 24 h. The reaction was cooled to 0°C and quenched with a solution of saturated NH4C1 (50 ml), extracted with 2X EtOAc and washed with H20, brine, drying (MgSO4), filtration and removal of solvent in vacuo to give a crude oil. This material was chromatographed (Silica gel, 3% EtOAc/Hexane) to affort the title product.
1 H NMR (CDC13, 300MHz) 8 1.17(t, 3H), 2.31(s, 3H), 2.6(q, 2H), 7.15-7.26(m, 4H) Step B: 2-Bromo- 1-o-tolyl-propan-1-one To a 50 ml round bottomed flask with stirring bar and an argon inlet was added CH3Cl (10 ml), THF (5 ml), 1-o-tolyl-propan-1one (318 mg, 2.14 mmol, and pyridium bromide perbromide (735 mg, 2.36 mmol). This solution was stirred at ambient temperature for 2 h.
The reaction mixture was washed with 5% aqueous HCI, H20, and brine. Drying (MgSO4), filtration and removal of sovent in vacuo gave an oil. This material was chromatographed (Silica gel, EtOAc/Hexane) to affort the title product.
1 H NMR (CDC13, 400MHz) 5 1.88(d, J=6.7Hz, 3H), 2.5(s, 3H), 5.20(q, 1H), 7.25-7.29(m, 2H), 7.38(m, 1H), 7.61(d, J=7.14Hz, 1H).
Step C: 1-((4-(2-methylphenyl)-5-methylthiazole-2-ylmethyl)-5- (4-cyanobenzyl)imidazole hydrochloride salt To a 100 mL round bottomed flask with a stirring bar, refluxed condenser and an argon inlet was added 1-(4-cyanobenzyl)- 1H-imidazol-5-yl]aminothiocarbonylmethyl (0.68, 2.65 mmol), THF mL), and 2-Bromo-l-o-tolyl-propan-l-one (1.2g, 5.3 mmol).
The well stirred mixture was heated at 60 0 C for 96 hours. The cooled mixture was concentrated in vacuo and the residue was partitioned between EtOAc and aq. NaHCO3 solution. The layers were separated and the organic phase was washed with H20 and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed (Silica gel, 2% 2-propanol in ammonia saturated CHCl3). The main chromatographic product was repurified by liquid chromatogrphy (0.1%TFA in H20:CH3CN gradient 95:5 to 5:95) to provide two WO 97/36881 PCT/US97/05514 -100compounds as TFA salts. The TFA salt material thus obtained was converted into the HCI salts with 4M HCI in 1,4-dioxane. The title compound, isolated as the major component, was triturated with ether and collected on a frit. The product was dried in vacuo at 50'C. mp:108-110°C 1H NMR (DMSO-d6, 400MHz) 8 2.07(s, 3H), 2.19(s, 3H), 4.44(s, 2H), 7.1 l(d, J=7.3Hz, 1H), 7.23-7.30(m, 3H), 7.38(d,J=8.2Hz, 2H), 7.70 1H), 7.78(d, J=8.0Hz, 2H), 9.28(br s, 1H).
EXAMPLE 11 1-((4-(2-methylphenyl)thiazole-2-ylethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt The title compound was prepared using the protocol described in examplel steps A-C, where step A was a standard reduction of urocanic acid and then Fisher esterification to provide the methylester in step C. The title compound was prepared using the procedures described in example 8 steps A and B.
IH NMR (CDC13, 400MHz) 6 2.37(s,lH), 3.18(br s, 2H), 3.46(br s, 2H), 5.71(br s,2H), 7.20(s,lH), 7.27-7.34(m, 4H), 7.38(d, J=6.95Hz, 2H), 7.49(d, J=7.14, 1H), 7.60(d, J=7.32, 2H) 9.69(br s, 1H).
Anal. Calcd. for C23H20N4S-2.0HCl-1.50H20- C, 57.03; H, 5.20; N, 11.57.
Found: C, 56.86; H, 4.99; N, 11.95.
EXAMPLE 12 In vitro inhibition of ras famesyl transferase Assays of farnesyl-protein transferase. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et al., J. Biol. Chem. 265:14701- 14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A. 86:6630-6634 (1989), respectively. Bovine WO 97/36881 PCT/US97/05514 101 FPTase was assayed in a volume of 100 jl containing 100 mM N-(2hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM 3 H]-farnesyl diphosphate 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 gg/ml FPTase at 31 oC 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 (-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 gM ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 l. of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention described in the above Examples 1-11 were tested for inhibitory activity against human FPTase by the assay described above and were found to have of <50 gM.
WO 97/36881 PCT/US97/05514 102- EXAMPLE 13 In vivo ras famesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supplemeted with 10% regular DMEM, 2% fetal bovine serum and 400 (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 MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4 0 C, 200 ml of a suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M 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 famesyl transfer to protein.
WO 97/36881 PCT/US97/05514 103- EXAMPLE 14 In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay). The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.
Claims (10)
- 20-, R I R I C(O)NR 10-, (R 10 )2NC(O>-, R 10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R I I OC(O)-NR 10-; or WO 97/36881 WO 9736881PCTIUS97/05514 106 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 6 a, R6b, R6c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R 6 c, R6d or R 6 e to Q is through a substitutable ring carbon; R 7 is selected from: H; CJ.-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) 'YR 0 f) -S0 2 R 11 g) N(R 10 )2 or h) CI-4 perfinoroalkyl; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RIO0-, RI IS(O)m-, RIOC(O)NRIO-, (RIO)2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R' I IC(O)NR 10-, and c) C I-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, CI, Br, RIO0-, RI RIOC(O)NI--, (R 1 0 )2NC(O)-. WO 97/36881 WO 9736881PCTIUS97/05514 107 R 10 2N-C(NR CN, R IOC(O)-, N3, -N(R 1 0 or R' 0 0C(O)NH-; provided that when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon; R 9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 perfluoroalkyl, F, Cl, Br, R I R I IS(0)m-, R IOC(0)NR 10 (RIO)2NC(0)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(R 10 or R I IOC(0)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by C I -C6 peffluoroalkyl, F, Cl, Br, RIO0-, RI IS(0)m-, R 1 0 C(0)NRl (R 1 0 R 1 0 2N-C(NR CN, R IOC(O)-, N3, -N(R 10 or R I IOC(O)NR 10 R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R I is independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen, C I -C6 alkyl, ClI -C6 aralkyl, ClI -C6 substituted aralkyl, C I -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Ci -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10-, -NR IOC(0)-, 0, -N(R -S(O)2N(R -N(R I or S(O)m; V is selected from: a) hydrogen, b) heterocycle, 108 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, 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; X is a bond, -CH=CH-, O, -C(0)NR 7 -NR 7 -C(0)NR 7 -NR 7 -S(0)2N(R 10 -N(R 10 or provided that if a is N, then 15 X is not 0, -C(0)NR 7 -C(0)NR 7 S: -S(0)2N(R 10 or -NR7-; m is 0, 1 or 2; n is independently 2, 3 or 4; 20 p is independently 0, 1, 2, 3 or 4; 20 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 tis 1; is 25 or a pharmaceutically acceptable salt thereof. 2. The compound according to Claim I of the formula A: WO 97/36881 PCT/US97/05514
- 109- R 6 a-e (R")r V A'(CR 1 2)nA2(CR (CR22)p X -(C wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; RI is independently selected from: hydrogen, C3-C10 cycloalkyl, R 10 -N(R 10 F or Cl-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 C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R1OO- and -N(RO1)2; R 3 R 4 and a) b) R5 are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 12 R 1 lS(0)m-, R 10 C(O)NR10-, (R 10 WO 97/36881 WO 97/688 1PCTJUS97/05514 -110- R6a, R6b, a) b) R 1 O2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 1 0 )2, or R I IOC(O)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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 RI 1 R 1 0 C(O)NR 1 0 (RIO)2NC(O)-, R'1 0 2N-C(NR'1 0 CN, R IOC(O)-, N3, -N(R 10 and R I R 6 c, R6d and R6e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, ClI -C6 perfluoroalkyl, R 1 2 R I IS(O)m-, RI 10 C(O)NR 10 (R I 0 )2NC(O)-, R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)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-Cl10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 10 2N-C(NRIO)-, CN, RIOC(O)-, N3, -N(RIO)2, and R I IOC(O)-NR 1 0 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=CI--CH2-, -(CH2)4- and -(CH2)3-; provided that when R6a, R6b, R6c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 6 a, R6b, R6c, R6d or R 6 e to Q is through a substitutable ring carbon; WO 97/36881 WO 9736881PCTIUS97/05514 -1II1- R 7 is selected from: H; CI1-4 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, e) 'YR 0 f) -S0 2 R 11 g) N(R 1 0 )2 or h) C 1-4 perfluoroalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 peffluoroalkyl, F, Cl, RlO00, R 1 OC(O)NR CN, N02, (R IO2N-C(NRI10>, R lOC(O)-, -N(RIO)2, or R 1 1 0C(O)NRI10O., and c) C1I-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 1 0 0-, RIOC(O)NR 10., (RI 0 )2N-C(NRI10>, RIOC(O)-, 102,or R I I0C(O)NR 1 0-; provided that when R8 is heterocycle, attachment of RS to V is through a substitutable ring carbon; R 9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, CN, N02, (R 1 0 )2N-C(NRIO)-, RIOC(O)-, -N(RIO)2, or R I IOC(O)NR 10-, and WO 97/36881 PCT/US97/05514
- 112- c) C 1-C6 alkyl unsubstituted or substituted by C l-C6 perfluoroalkyl, F, Cl, R 0 R11 R 10 C(O)NRO (R 10)2NC(O)-, CN, (RI 0)2N-C(NR RI OC(O)-, -N(R 10)2, or R 11OC(O)NR10-; R 10 is independently selected from hydrogen, CI-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R 1 1 is independently selected from CI-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C -C6 alkyl, Cl-C6 aralkyl, CI-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 10 O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O; S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 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;
- 113- 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(RIO)-, -N(R' 0 or provided that if a is N, then X is not 0, -C(O)NR 7 -,-S(0)2N(RIO)- or -R- m is 0,l1or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0,1, 2 or3; r is 0 to 5, provided that r is 0 when V is hydrogen;and 0* or a pharmaceutically acceptable salt thereof. *0 0 00:06 00.. 3. The compound according to Claim 1 of the formula B: R 6 a-a N b0 0:00% Rb (CR 2 2 20 B 0 wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH-, 0 or S; WO 97/36881 WO 9736881PCTIUS97/05514
- 114- RI is independently selected from: hydrogen, C3-C1O cycloalkyl, R 1 0 -N(R 10 F or C I-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, RIO0-, -N(RIO)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-C1 0 cycloalkyl, C2-C6 alkenyl, RIO0- and -N(R 1 0 )2; R 3 and R~ a) b) c) d) R 6 a, R6b, a) b) lare independently selected from: hydrogen, 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 S R 1 I C(O)NR 1 0 (R I R 10 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 1 0 )2, or R 1 IOC(O)NRIO-, unsubstituted C I -C6 alkyl, 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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, R I R' I C(0)NR (R R 1 0 2N- C(NRIO)-, CN, RIOC(0)-, N3, -N(R 1 0 and RII0C(0)- R6c, R6d and R6e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Ci 0 cycloalkyl, C2-C6 WO 97/36881 WO 9736881PCTIUS97/05514 115 alkenyl, C2-C6 alkynyl, halogen, C1I-C6 perfluoroalkyl, R 12 R I IS(O)m-, R I C(O)NR 1 0 (R I 02NC(O)-, R102N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R' IIOC(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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I 1 R I C(O)NR 10 (R I 02NC(O)-, R 10 2N-C(NRIO)-, CN, RIOC(O)-, 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 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 6 a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 6 a, R6b, R 6 c, R6d or R 6 e to Q is through a substitutable ring carbon; R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Ci -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I-C6 perfluoroalkyl, F, Cl, RIO0-, RIOC(O)NRIO-, CN, N02, (R 1 0 )2N-C(NRIO)-, R IOC(O)-, -N(R 10 or R I I0C(O)NR 10-, and C) ClI-C6 alkyl substituted by C1I-C6 perfluoroalkyl, R 10 0-, R 1 OC(O)NR (R 10 )2N-C(NRI10>, R 0 102,or R I IOC(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, C 1 -C6 alkyl, trifluoromethyl and halogen; WO 97/36881 PCTIUS97/05514 116 R 10 is independently selected from hydrogen, C1-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, C1-C6 aralkyl, Cl-C6 substituted aralkyl, C1-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRlO-, O, or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(0)NRO1-, -NRIOC(O)-, -NR10-, O or provided that if a is N, then X is not -C(O)NR 10 -NR 10 or O; m is 0, 1 or 2; WO 97/36881 PCT/US97/05514
- 117- n is independently 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen; or a pharmaceutically acceptable salt thereof. 4. The compound according to Claim 1 of the formula C: R 6a-e (R 8 )r R 3 Q NI R 9 b.9a, V-A1(CR1 2 )nA2(CR 2 )n d R 4 C R9b (CR2 2 )-X wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; RI is independently selected from: hydrogen, C3-C10 cycloalkyl, R 10 -N(R 10 F or C1-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R1OO-, -N(R 10 )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, R100- and -N(R O)2; R 3 and R 4 are independently selected from: I- 118- C C C CC.. C. C CC 0 .C C C C *0 0 C.. C 0* CC C C C C C OC 0* C. C CC 0 0* OC R 6 a, R6b, a) b) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 2 R' RIOC(O)NRIO-, ,(RIO)2NC(O)-, R' 0 CN, N02, RlOC(O)-, N3, -N(RIO)2, or R I I OC(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 hetero cyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I 1 R 1OC(O)NR 1 0 (R 1 %2NC(O)-, R102N-C(NR'%)-, CN, RIOC(O)-, N3, -N(RIO)2, and R I IOC(O)-NR R 6 c, R6d and R6e are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 periluoroalkyl, R1 2 RI 1 RlOC(O)NRlO-,% (RIO)2NC(O)-, R' 0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R I IOC(O)NR 1 0 unsubstituted C1I-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-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R' IIS(O)m-, R I C(O)NR 1 0 (R 102NC(O)-, R' 0 2N-C(NR' 0 CN, RIOC(O)-, N3, -N(RIO)2, and WO 97/36881 PCT/US97/05514
- 119- provided that when R6a, R6b, R 6 c, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R 6 c, R6d or R6e to Q is through a substitutable ring carbon; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RIOO-, RIOC(O)NRIO-, CN, N02, (R 1 0 )2N-C(NR 10 RIOC(O)-, -N(R 10 or RI IOC(O)NR10-, and c) CI-C6 alkyl substituted by CI-C6 perfluoroalkyl, R1 0 0-, RI OC(O)NR 10-, (R1 0 )2N-C(NR R OC(O)-, -N(R10)2, or R provided that when R8 is heterocycle, attachment of RS to V is through a substitutable ring carbon; R 9 a and R9b are independently hydrogen, C 1 -C6 alkyl, trifluoromethyl and halogen; R 1 0 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, C -C6 alkyl, C -C6 aralkyl, C1-C6 substituted aralkyl, CI-C6 heteroaralkyl, C1 -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C -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, -N(RIO 0 or S(O)m; V is selected from: WO 97/36881 PCT/US97/05514 -120- 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(0)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)NRO 1 -NR1OC(O)-, -NR 10 O or provided that if a is N, then X is not -C(0)NR 10 -NR 10 or O; 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 0; 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: 9a- R6a-e R 9 a R 3 Q N bc A'(CR'2)n N d SR 9 b (CR2)p-X R 8 D WO 97/36881 PCT/US97/05514 121 wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1 is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; R 2 is R 3 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 -N(R 10 )2, F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 or -N(R10)2; selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CI-C6 perfluoroalkyl, R120-, R 11 R 10 C(0)NR10-, (R 10 R 10 2N-C(NR 1 CN, N02, R 10 N3, -N(R 10 )2, or RllOC(0)NR 1 O-, c) unsubstituted C1-C6 alkyl, d) substituted C -C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, WO 97/36881 WO 9736881PCTIUS97/05514 -122 R 10 2N-C(NR CN, R IOC(0)-, N3, -N(R 10 and R I IOC(0)-NR R 4 is selected from H, halogen, C1-C6 alkyl and CF3; 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-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 2 R I I8(0)m-, R I C(0)NR 1 0 (R 1 02NC(0)-, R 10 2N-C(NRIO)-, CN, N02, RlOC(0)-, N3, -N(RIO)2, or R I IOC(0)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-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 RI IS(0)m-, RIOC(0)NRIO-, R 1 0 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(RIO)2, and R 1 1 OC(0)-NR 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 -(CH2)3-; provided that when R 6 a, R6b, R 6 c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R6c, R6d or R6e to Q is through a substitutable ring carbon; R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, CI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1I-C6 perfinoroalkyl, F, Cl, WO 97/36881 WO 9736881PCTIUS97/05514 123 R 100-, R IOC(O)NR 10-, CN, N02, (R lO)2N-C(NR10)-, R IOC(O)-, -N(R 10)2, or R I IOC(O)NR 10-, and c) ClI-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 100-, R I OC(O)NR (R I 0 )2N-C(NR R I OC(O)-, -N(R 1 0 or R I I0C(O)NR provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; R 9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, C I -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; Ri 1 is independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen, C I-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 heteroaryl, C I -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; Al is selected from: a bond, 0, or S(O)m; X is a bond, -CH=CH-, -C(O)NRIO-, -NRIOC(O)-, -NRI 0 0 or provided that if a is N, then X is not -C(O)NR 10-, -NR 1 0 or 0; n is 0 or 1; provided n is not 0 if A 1 I is a bond, 0, -N(R or S(O)m; mnis 0, 1 or 2; and p is 0, 1,2, 3or 4; or a pharmaceutically acceptable salt thereof. WO 97/36881 PCTIUS97/05514
- 124- 6. The compound according to Claim 4 of the formula E: R 3 R6a-e R9a b d d A'(CR'2)n a R 4 R 9 b (CR 2 2 )p-X R 8 wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R is independently selected from: hydrogen, R 1 00-, -N(R10)2, F, C3-C10 cycloalkyl or C1-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 1 0 -N(R 10 )2, F or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 0 OO-, or -N(R10)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 WO 97/36881 WO 9736881PCT/US97/05514 125 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 R I R 1 0 C(0)NRIO-, (R' 0 R 10 2N-C(NR 10 CN, N02, R IOC(0)-, N3, -N(R 10 )2, or R I IOC(0)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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(0)m-, R I C(0)NR 10 (RI 0 R 10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(RIO)2, and R1 1 OC(0)-NR 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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfluoroalkyl, R 1 2 RIIS(0)m-, RIOC(0)NRIO-, R 10 2N-C(NRIO)-, CN, N02, RIOC(0)-, N3, -N(RIO)2, or R I IOC(0)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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120., R I R I OC(0)NR 10 (R 1 0%2NC(0)-, R 10 2N-C(NR 10 CN, R I N3, -N(R 10 and R I IOC(0)-NR provided that when R 6 a, R6b, R 6 c, R6d or R 6 e is unsubstiliuted or substituted heterocycle, attachment of R 6 a, R6b, R 6 c, R6d or Reto Q is through a substitutable ring carbon; WO 97/36881 WO 9736881PCTIUS97/05514 126 R9 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 peffluoroalkyl, F, Cl, R 1 R I OC(O)NR CN, N02, (R 10 )2N-C(NR 1 R I -N(R 10 or R I OC(O)NR and c) C1I-C6 alkyl substituted by C1I-C6 perfluoroalkyl, R 1 0 0-, R 1 0 C(O)NR (RIO)2N-C(NRIO)-, RIOC(O)-, -N(R 1 0 or R' IIOC(O)NR 1 0 provided that when R 8 is heterocycle, attachment of R9 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 I Iis independently selected from C I -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen, C I-C6 alkyl, ClI-C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, CI -C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NRIO-, -N-RlOC(O)-, -NRIO-, 0 or provided that if a is N, then X is not -C(O)NR 10 -NR 1 0- or 0; n is 0Oor 1; M is 0,l1or 2;and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, -NR IOC(O)-, -NR 10 or 0; WO 97/36881 PCT/US97/05514
- 127- or a pharmaceutically acceptable salt thereof. 7. The compound according to Claim 5 of the formula F: R R 3 Q R 6 ae =N ,C CR12N R9b b d 4 (CR 2 2 X NC F wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; R1 is independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycl6alkyl, R 1 0 -N(R 10 )2 or F, c) C -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, RIOO-, or -N(R10)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 WO 97/36881 WO 9736881PCTIUS97/05514 128 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 2 RI IS(O)m-, RIOC(O)NRIO 0 (R 1 R 1 O2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(R 10 )2, or R I IOC(O)NR 1 0 c) unsubstituted C I -C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted C 1 -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 RI IS(O)m-, RIOC(O)NRIO-, (R 1 0 )2NC(O)-, R 10 2N-C(NR 10 CN, R IOC(O)-, N3, -N(R 10 and R 4 is selected from H, halogen, CH3 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 1 2 RI IS(O)m-, RI 0 C(O)NRIO 0 (R 1 0 )2NC(O>-, R 1 0 2N-C(NRIO)-, CN, N02, RIOC(O)-, N3, -N(RIO)2, or R 1 lOC(O)NRIO-, c) unsubstituted Ci -C6 alkyl, d) substituted C Il-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 R I R 1 I C(0)NR 1 (R 1 0 R 1 0 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(R 10 and R I I0C(O)-NR 1 0 or WO 97/36881 PCT/US97/05514 129 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-; provided that when R6a, R6b, R 6 c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R6a, R6b, R 6 c, R6d or R6e to Q is through a substitutable ring carbon; R 9 a and R 9 b are independently hydrogen, halogen, CF3 or methyl; R 1 0 is independently selected from hydrogen, C1-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, C1-C6 aralkyl, C1-C6 substituted aralkyl, Ci-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NR10-, -NR1OC(O)-, O or provided that if a is N, then X is not -C(0)NR10- or O; m is 0, 1 or 2; and pis 0,1,2, 3 or4; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 6 of the formula G: WO 97/36881 PCT/US97/05514
- 130- R6a-e R 9b- wherein: a is C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that at least one of b, c, d or e is independently N, NH, O or S; R1 is independently selected from: hydrogen, R 1 0 -N(R 10 F, C3-C10 cycloalkyl or CI-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 O or-N(R10)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, Cl-C6 perfluoroalkyl, R 12 Rl lS(O)m-, R10C(O)NR 10 (R10)2NC(0)-, WO 97/36881 PCTIUS97/05514 131 R 1O2N-C(NR 1 0 CN, N02, R IOC(0)-, N3, -N(R 10)2, or R I I OC(0)NR 10 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 RI 1 R 1 OC(0)NR (R 1 0 R' 0 2N-C(NR' 0 CN, RIOC(0)-, N3, -N(RIO)2, and R I IOC(0)-NR R 4 is selected from H, halogen, CH3 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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1I-C6 perfluoroalkyl, R 12 RI I RIOC(0)NRIO-, R102N-C(NR 10 CN, N02, RIOC(0)-, N3, -N(RIO)2, or R I IOC(0)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-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 Rl 1 RIOC(0)NRIO-, R 1 02N-C(NR 1 CN, R 1OC(0)-, N3, -N(R 10 and R I IOC(0)-NR 10-; or any two of R 6 a, R6b, R6c, 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 97/36881 WO 9736881PCTIUS97/05514 132 provided that when R 6 a, R6b, R 6 C, R6d or R 6 e is unsubstituted or substituted heterocycle, attachment of R 6 a, R6b, R 6 c, R6d or R6e to Q is through a substitutable ring carbon; R 9 a? and R9b are independently hydrogen, halogen, CF3 or methyl; R 1 0 is independently selected from hydrogen, ClI-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl; R 1 1 is independently selected from C I-C6 alkyl and aryl; R 12 is independently selected from hydrogen, C I-C6 alkyl, C1I-C6 aralkyl, C I -C6 substituted aralkyl, C 1-C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C I -C6 peffluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl; A I is selected from: a bond, 0, -N(R 10 or S (O)m; m is 0, 1 or 2; and n is 0Oorl1; or the pharmaceutically acceptable salts thereof. 9. A compound which inhibits famnesyl-protein transferase which is: I I -(4-Cyanobenzyl)- 1 H-imidazol -5 -yI]ethyl I -4-phenyl-imidazole 1- {1 -(4-Cyanobenzyl)- I H-imidazol-5-yl)methyl I -4-(2-methyl)phenyl imidazole 1 -(3-Phenyl-5-isoxazolylmethyl)-5-(4-cyanobenzyl) imidazole WO 97/36881 WO 9736881PCTIUS97/05514 133 I -(3-Phenyl -isoxazol-5-ylacetyl)-5-(4-cyanobenzyl) imidazole 1 -(4-Cyanobenzyl)-5 -(4-Phenyl-thiazol-2-ylinethyl)imidazole 1 -(4-Cyanobenzyl)-5 -(4-(2-methylphenyl)-thiazol-2-ylmethyl)imidazo le 1 -(4-Cyanobenzyl)-5 -chlorophenyl)-thiazol -2-ylmethyl)imidazole or 1 -(4-Cyanobenzyl)-5 -(4-(naphth-2-yl) -thiazo 1-2-ylmethyl)imidazole 1 -((4-(2-methylphenyl)-5 -methylthiazole-2-ylmethyl)-5 -(4-cyanobenzyl) imidazole or 1 -(2-methylphenyl)thiazo le-2-ylethyl)-5-(4-cyanobenzyl) imidazole or a pharmaceutically acceptable salt thereof. The compound according to Claim 9 which is: 1 -Phenyl -5 -isoxazolylmethyl) -5 -(4-cyanobenzyl) imidazole hydrochloride salt or a pharmaceutically acceptable salt thereof. 11. The compound according to Claim 9 which is: 134 1-(4-cyanobenzyl)-5-(4-(2-methylphenyl)-thiazol-2-ylmethyl)imidazole hydrobromide salt H 3 0 N s N or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 9 which is: 1-((4-(2-methylphenyl)thiazole-2-ylethyl)-5- (4-cyanobenzyl)imidazole S /f CH 3 NC N N C N N or a pharmaceutically acceptable salt or optical isomer thereof. 13. A compound which inhibits famesyl-protein transferase, substantially as hereinbefore described with reference to any one of the examples. 1: 0o 14. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of any one of claims 1 to 13. 15. A pharmaceutical composition made by combining the compound of any one of claims 1 to 13 and a pharmaceutically acceptable carrier. 16. A process for making a pharmaceutical composition comprising combining a compound 15 of any one of claims 1 to 13 and a pharmaceutically acceptable carrier. 17. A method for inhibiting farnesyl-protein transferase, which method comprises :administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to .o 13 or of a composition of claim 14 or claim 18. A compound of any one of claims 1 to 13 or of a composition of claim 14 or claim 20 when used in inhibiting farnesyl-protein transferase. 19. The use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for inhibiting farnesyl-protein transferase. A method for treating cancer, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 13 or of a composition of claim 14 or claim 21. A compound of any one of claims 1 to 13 or of a composition of claim 14 or claim when used in treating cancer. 22. The use of a compound according to any one of claims 1 to 13 for the manufacture of a -sm 3 edicament for treating cancer. [R:\LIBAAj07795dOC :tab 135 23. A method for treating neurofibromin benign proliferative disorder, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 13 or of a composition of claim 14 o claim 24. A compound according to any one of claims 1 to 13 or a composition according to claim 14 or claim 15 when used in treating neurofibromin benign proliferative disorder. The use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for treating neurofibromin benign proliferative disorder. 26. A method for treating blindness related to retinal vascularisation, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 13 or of a composition of claim 14 or claim 27. A compound according to any one of claims 1 to 13 or a composition according to claim 14 or claim 15 when used in treating blindness related to retinal vascularisation. 28. The use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for treating blindness related to retinal vascularisation. 29. A method for treating infections from hepatitis delta and related viruses, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 13 or of a composition of claim 14 or claim .30. A compound according to any one of claims 1 to 13 or a composition according to claim 14 or claim 15 when used in treating infections from hepatitis delta and related viruses. 20 31. The use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for treating infections from hepatitis delta and related viruses. 32. A method for preventing restenosis, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 13 or of a composition of claim 14 or claim 25 33. A compound according to any one of claims 1 to 13 or a composition according to claim S14 or claim 15 when used in preventing restenosis. 34. The use of a compound according to any on eof claims 1 to 13 for the manufacture of a medicament for preventing restenosis. A method for treating polycystic kidney disease, which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 13 or of a composition of claim 14 or claim 36. A compound according to any one of claims 1 to 13 or a composition according to claim 14 or claim 15 when used in treating polycystic kidney disease. [R:\LIBAA07795.doc:tab 136 37. The use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for treating polycystic kidney disease. Dated 21 December, 1999 Merck Co., Inc. Patent Attorneys for the ApplicantlNominated Person SPRUSON FERGUSON 0 0e 00. 0 0 0 *00. 00 0 0 0 00 0 0* 0 00 0 0 0000 0* 00 00 0**0 0* 00 00 00 0 0* 00 0 000000 0 00 0 00 0a 0 00 0 00 0 00 0 0 [R:\L1BAA]07795.doc:tab
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| 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 | ||
| US2234096P | 1996-07-24 | 1996-07-24 | |
| US60/022340 | 1996-07-24 | ||
| GBGB9617278.8A GB9617278D0 (en) | 1996-08-16 | 1996-08-16 | Inhibitors of farnesyl-protein transferase |
| GB9617278 | 1996-08-16 | ||
| PCT/US1997/005514 WO1997036881A1 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
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| AU716381B2 true AU716381B2 (en) | 2000-02-24 |
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| EP (1) | EP0891339A1 (en) |
| JP (1) | JP2000509371A (en) |
| AU (1) | AU716381B2 (en) |
| CA (1) | CA2249639A1 (en) |
| WO (1) | WO1997036881A1 (en) |
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| ES2304996T3 (en) | 1999-11-15 | 2008-11-01 | Janssen Pharmaceutica Nv | TRIAZOLS AS INHIBITORS OF FARNESIL TRANSFERASA. |
| EP1296978A2 (en) | 2000-06-30 | 2003-04-02 | Bristol-Myers Squibb Company | N-ureidoheterocycloaklyl-piperidines as modulators of chemokine receptor activity |
| US7211595B2 (en) | 2000-11-30 | 2007-05-01 | Abbott Laboratories | Farnesyltransferase inhibitors |
| US6942836B2 (en) | 2001-10-16 | 2005-09-13 | Applera Corporation | System for filling substrate chambers with liquid |
| CA2532965C (en) | 2003-07-22 | 2013-05-14 | Astex Therapeutics Limited | 3, 4-disubstituted 1h-pyrazole compounds and their use as cyclin dependent kinases (cdk) and glycogen synthase kinase-3 (gsk-3) modulators |
| AP2007004047A0 (en) | 2005-01-20 | 2007-06-30 | Pfizer Ltd | Substituted triazole derivatives as oxtocin antagonists |
| AR054425A1 (en) | 2005-01-21 | 2007-06-27 | Astex Therapeutics Ltd | PIPERIDIN ADDITION SALTS 4-IL-ACID AMID 4- (2,6-DICLORO-BENZOILAMINO) 1H-PIRAZOL-3-CARBOXILICO. |
| US8404718B2 (en) | 2005-01-21 | 2013-03-26 | Astex Therapeutics Limited | Combinations of pyrazole kinase inhibitors |
| UY30892A1 (en) | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | AKT ACTIVITY INHIBITORS |
| UA103319C2 (en) | 2008-05-06 | 2013-10-10 | Глаксосмитклайн Ллк | Thiazole- and oxazole-benzene sulfonamide compounds |
| DE102009041242A1 (en) | 2009-09-11 | 2011-12-15 | Bayer Schering Pharma Aktiengesellschaft | New heterocyclically substituted aryl compounds are hypoxia-inducible factor inhibitors useful to treat and/or prevent e.g. cancer or tumor diseases, ischemic cardiovascular diseases, heart attack, arrhythmia, stroke, and psoriasis |
| DE102009041241A1 (en) | 2009-09-11 | 2011-08-04 | Bayer Schering Pharma Aktiengesellschaft, 13353 | New heteroaromatic compounds are hypoxia-inducible factor inhibitors useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis, diabetic retinopathy, rheumatoid arthritis and polycythemia |
| DE102008057364A1 (en) | 2008-11-14 | 2010-05-20 | Bayer Schering Pharma Aktiengesellschaft | New pyridyl or phenyl ring containing compounds are hypoxia-inducible factor regulation pathway modulators, useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis and diabetic retinopathy |
| DE102008057343A1 (en) | 2008-11-14 | 2010-05-20 | Bayer Schering Pharma Aktiengesellschaft | New phenyl or pyridyl ring containing compounds are hypoxia-inducible factor regulation pathway modulators, useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis and diabetic retinopathy |
| DE102008057344A1 (en) | 2008-11-14 | 2010-05-20 | Bayer Schering Pharma Aktiengesellschaft | Aminoalkyl-substituted aryl compounds and their use |
| RU2012136451A (en) | 2010-01-28 | 2014-03-10 | Президент Энд Феллоуз Оф Гарвард Колледж | COMPOSITIONS AND METHODS FOR IMPROVING PROTEASOMIC ACTIVITY |
| EP2560488B1 (en) | 2010-04-23 | 2015-10-28 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
| AR081626A1 (en) | 2010-04-23 | 2012-10-10 | Cytokinetics Inc | AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS |
| AR081331A1 (en) | 2010-04-23 | 2012-08-08 | Cytokinetics Inc | AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME |
| US8759380B2 (en) | 2011-04-22 | 2014-06-24 | Cytokinetics, Inc. | Certain heterocycles, compositions thereof, and methods for their use |
| DK2707101T3 (en) | 2011-05-12 | 2019-05-13 | Proteostasis Therapeutics Inc | PROTEOSTASE REGULATORS |
| US9849135B2 (en) | 2013-01-25 | 2017-12-26 | President And Fellows Of Harvard College | USP14 inhibitors for treating or preventing viral infections |
| EP2968275B1 (en) | 2013-03-15 | 2017-11-29 | Bristol-Myers Squibb Company | Lxr modulators |
| WO2015073528A1 (en) | 2013-11-12 | 2015-05-21 | Proteostasis Therapeutics, Inc. | Proteasome activity enhancing compounds |
| WO2016202935A1 (en) | 2015-06-19 | 2016-12-22 | Bayer Pharma Aktiengesellschaft | Glucose transport inhibitors |
| WO2020113094A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3764690A (en) * | 1972-03-03 | 1973-10-09 | Bayer Ag | Substituted n-benzylimidazoles as antimycotic agents |
| DE3736783A1 (en) * | 1987-10-30 | 1989-05-11 | Bayer Ag | USE OF NEW AZOLYL METHYL CARBINOLS FOR THE TREATMENT OF DISEASES |
| DE4112451A1 (en) * | 1991-04-12 | 1992-10-15 | Schering Ag | ISOXAZOLYLIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
| TW235963B (en) * | 1992-01-16 | 1994-12-11 | Shionogi & Co | |
| KR930017902A (en) * | 1992-02-14 | 1993-09-20 | 알베르투스 빌헬무스 요아네스 째스트라텐 | Insecticide Compounds and Methods for Making the Same |
| US5401851A (en) * | 1992-06-03 | 1995-03-28 | Eli Lilly And Company | Angiotensin II antagonists |
-
1997
- 1997-04-01 CA CA002249639A patent/CA2249639A1/en not_active Abandoned
- 1997-04-01 WO PCT/US1997/005514 patent/WO1997036881A1/en not_active Application Discontinuation
- 1997-04-01 AU AU26058/97A patent/AU716381B2/en not_active Ceased
- 1997-04-01 EP EP97917830A patent/EP0891339A1/en not_active Withdrawn
- 1997-04-01 JP JP9535590A patent/JP2000509371A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU2605897A (en) | 1997-10-22 |
| WO1997036881A1 (en) | 1997-10-09 |
| CA2249639A1 (en) | 1997-10-09 |
| JP2000509371A (en) | 2000-07-25 |
| EP0891339A1 (en) | 1999-01-20 |
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| FGA | Letters patent sealed or granted (standard patent) | ||
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