AU706497B2 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- AU706497B2 AU706497B2 AU27307/97A AU2730797A AU706497B2 AU 706497 B2 AU706497 B2 AU 706497B2 AU 27307/97 A AU27307/97 A AU 27307/97A AU 2730797 A AU2730797 A AU 2730797A AU 706497 B2 AU706497 B2 AU 706497B2
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- 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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Description
WO 97/36585 PCT/US97/06259 -1- TITLE OF THE INVENTION INHIBITORS OF FARNESYL-PROTEIN
TRANSFERASE
BACKGROUND OF THE INVENTION The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP.
Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTPbound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes faresyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 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 WO 97/36585 PCT/US97/06259 -2farnesylation. Other famesylated proteins include the Ras-related GTPbinding 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 farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of famesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of famesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice Kohl et al., Proc. Natl. Acad.
Sci 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesylprotein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor WO 97/36585 PCTIUS97/06259 -3of isoprene biosynthesis.
Inhibitors of faresyl-protein transferase (FPTase) have been described in four general classes Graham, Expert Opinion Ther. Patents, (1995) 5:1269-1285). The first are analogs of faresyl diphosphate (FPP), while a second class of inhibitors is related to the protein substrates Ras) for the enzyme. Bisubstrate inhibitors and inhibitors of farnesyl-protein transferase that are non-competitive with the substrates have also been described. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the faresyl-protein transferase enzyme, or may be purely competitive inhibitors Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934- 1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
It has recently been 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 faresyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).
It has recently been reported that faresyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth S 30 muscle cells and are therefore useful in the prevention and therapy of S arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930).
It is, therefore, an object of this invention to develop WO 97/36585 PCT/US97/06259 -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 biheteroaryl-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: R6a-d
C'
R
3 e' I( RI a) Ri V A(CR 1 2 )nA 2
(CR
1 2 W (CR2)p- X -(CR22 R WO 97/36585 PCT/US97/06259 DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the famesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula A:
R
6 a-d
(R
8 )r
I
V -A'(CR'2)nA 2(CR' (CH 2 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; a'is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, O or
S;
RI and R 2 are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl. C2-C6 alkenyl, WO 97/36585 WO 9736585PCTIUS97/06259 -6- C2-C6 alkynyl, R 10 R I IS(0)m-, R I IC(0)0-,
R
1 I C(O)NR (Ri 0 R 10 2N-C(NR CN, N02, R IOC(0)-, N3, -N(R 10)2, or R I IOC(O)NR c) unsubstituted or substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R
10 2N-C(NRIO)-, CN, RIOC(0)-, N3, -N(R'0)2, and R I I0C(0)-NR 10- 1
R
3
R
4 at a) b)
C)
d) id R5 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 I 02NC(O)-, R I 0 2N-C(NR 1 CN, N02, R I OC(0)-, N3, -N(R 10)2, or R I I0C(0)NR 1 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 heterocycl ic, C3-C 1O cycloalkyl, C2-C6 aikenyl, C2-C6 alkynyl, R 1 20-, R I R I OC(O)NRI 10, (R 1 0 R 1 02N-C(NR CN, R IOC(0)-, N3, -N(R 1 0 and R I I0C(0)-NR
R
6 c and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl. C2-C6 alkynyl, halogen, CI-C6 perfluoroalkyl,
R
12 RI IS(0)m-, RIOC(0)NRIO-, RI IC(O)0-, R6a, R6b, WO 97/36585 PCTIUS97/06259 -7- (R 1 R 1 0 2N-C(NR 1 CN, N02, Ri I N3, -N(R 1 0 or R I I0C(O)NR c) unsubstituted C I -C6 alkyl, d) substituted ClI-C6 alkyl wherein the substituent on the substituted C I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted hetero cyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20-, R' IIS(O)m-, R 1 I C(O)NR (R I 0 )2NC(O)-, R 10 2N-C(NR CN, R IOC(O)-, N3, -N(R'1 0 and R I I0C(O)-NR
R
7 is selected from: H; CI-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)
-YR
0 f) S 2 1 g) N(R 10 )2 or h) CIA perfluoroalkyl;
R
8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 R I I R I C(O)NR 1 (R 10 )2NC(O)-, R 1 0 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10)2, or- R' IIOC(O)NR 10-, and WO 97/36585 PCT/US97/06259 8- R9 is c) C I-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfiuoroalkyl, F, Cl, Br, R 10 R I IS(O)m-, R IOC(O)NH-, (R'1 0 )2NC(O)-, RIO02N-C(NR CN, R I 0 N3, -N(R 10)2, or
R
1
I
0 0C(O)NH-; provided that when R8 is heterocycle, attachment of RS to V is through a substitutable ring carbon; independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Ci, Br, R I R I IS(O)m-, R'IOC(O)NR (R I 0 R I 0 2N..C(NR CN, N02, Ri I 0 N3, -N(R 10)2, or R I I0C(O)NR 10-, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, CI, Br, R 1 0 RI ~S R I 0 (R I 0 Ri 0 2N..C(NR CN, R 1
I
0 N3, -N(RiO0)2, or R I I0C(O)NRl10-; R 10 is independently selected from hydrogen, C I -C6 alkyl, 2,2,2trifluoroethyl, benzyl and aryl; Ri I is independently selected from C1I-C6 alkyl and aryl; Ri1 2 is independently selected from hydrogen, C I -C6 alkyl, C I -C6 aralkyl, C I -C6 substituted araikyl, CjI -C6 heteroaralkyl, C I-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Ci -C6 perfluoroalkyl, 2-aminoethyl and 2 2 ,2-trifluoroethyl;
A
1 I and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRi10-, -NR I 0 0, -N(R -S(O)2N(R -N(R IO)S(O) 2 or S(O)m; WO 97/36585 PCT/US97/06259 -9- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; and 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(O)NR
7
-NR
7 -C(0)NR 7
-NR
7 -S(O)2N(R 1
O),
-N(R
10 or provided that if a is N, then X is not O, -C(O)NR 7 -C(0)NR 7 -S(0)2N(R 1 0 or -NR7-; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1, 2 or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and tis 0 or 1; or the pharmaceutically acceptable salts thereof.
SA preferred embodiment of the compounds of this invention is illustrated by the following formula A: WO 97/36585 PCTIUS97/06259
R
6 a-d
(R
8 (R)q I IR R V A'(CR 1 2 )nA 2
(CR
1 2 )n W (CR 2
X
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH; O or S; a'is N or C; from 0-4 of d' and e' are independently N, NH, 0 and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, 0 or
S;
RI is independently selected from: hydrogen, C3-C10 cycloalkyl,
R
10 -N(R10)2, F or Cl-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl. heterocycle, C3-C10 cycloalkyl,
R
10 -N(R10)2, F or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Ci-C6 alkyl is selected from WO 97/36585 PCTIUS979js259 unsubstituted or substituted aryl, heterocycle, C3-C cycloalkyl, C2-C6 alkenyl,
R
1 0 0- and -N(RIO)2;
R
3
R
4 and R 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfluoroalkyl, RlO02N-C(NR CN, N02, R IOC(O)-, N3. -N(R 10)2, or R I c) unsubstituted C I-C6 alkyl; d) substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(O)m-, R I C(O)NR 10-, (R 1 %2NC(O)-, RlO02N-C(NR CN, R I N3, -N(R 10)2, and
R
6 a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2,-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 20-, R' IIS(O)m... R' I C(O)NR 10-, (RI 1%2NC(O)-, RlO02N-C(NR 10O> CN, N02, R IOC(O)-, N3, -N(R 10)2, or R c) unsubstituted C I -C6 alkyl; d) substituted C I -C6 alkyl wherein the substituent on the substituted Ci -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R I IS(O)m-, WO 97/36585 PCT/UJS97/06259 -12 R I 0 C(O)NR 10-, (RI 0 R 1 0 2N -C(NR 1 CN, RI 0 N3, -N(RI 0)2, and R 11 OC(O)-NR
IO
R
7 is selected from: H; Ci -4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Ci1 -4 aikoxy, b) aryl or heterocycle, c) halogen, d) HO.
e) 'YR 11 0 f) -0R g) N(R 10)2 or h) Ci1.4 perfluoroalkyl; RS is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, CI -C6 alkyl, C2-C6 alkenyl, C2-C6 aikynyl, C I -C6 perfluoroalkyl, F, Cl, R 100.., Ri I C(O)NR 1 0, CN, N02, (R I 0 )2N-C(NR R IOC(O)-, -N(R 10)2, or R I I0C(O)NR 10-, and C) C I -C6 alkyl substituted by C I -C6 perfluoroaikyl, R 1 00., RlIOC(O)NR 10., (R IO)2N-C(NR 10)- R IOC(O)-, -N(R 10)2, 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;
R
9 is selected from: hydrogen, b) C2-C6 alkenyl, C2-C6 aikynyl, ClI-C 6 perfluoroalkyl,
F,
Cl, Ri I R I IS(O)m-, R IOC(O)NR 10-, (RiO0)2NC(O)-, WO 97/36585 PCTJUS97/06259 -13 CN, N02, (RlIO)2N-C(NRI10), R IOC(O)-, -N(R 1O) 2 or R I I0C(O)NR 10-, and c) C I -C6 alkyl unsubsiiituted or substituted by C I -C6 perfiuoroalkyl, F, Cl, RIO0-, RI IS(O)m-, RIOC(O)NR1O-, (R I 0Q2NC(O)-, CN, (R 1 0Q2N-C(NR R I OC(O)-, 102,or R I IOC(O)NR R 1 0 is independently selected from hydrogen, C I-C6 alkyl, 2,2,2trifluoroethyl, benzyl and aryl; R I I s independently selected from C I-C6 alkyl and aryl; R 1 2 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 trifi uoro ethyl; A 1 and A 2 are independently selected from: a bond, -CH=CH-,
-CX=C-,
-C(O)NR 10-, 0, -N(R or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and C2-C20 alkenyl, and provided that V is not hydrogen if Alis S(O)m and V is not hydrogen if AlI is abond, n is 0and
A
2 is S()m; WO 97/36585 PCTUS97/06S259 -14 provided that when V is heterocycle, attachment of V to R8 and to A 1 is through a substitutable ring carbon; W is a heterocycle selected from pyrrolidinyl, irnidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl; X is a bond, 0, -CH=CH-, -C(0)NR 7
-NR
7
-NR
7 -N(RI 0 or provided that if a is N, then X is not 0, -C(0)NR 7 -,-S(O)2N(RI10).
or -NR 7 mnis 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, 2or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0Oor 1; or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B: R 6 a-d
(R
8 )r R aR 3
C
V A1(CR 2 )A 2 (CR 2 )7nN
I'.N
R 9b B (CR 2 2 )F-x wherein: a is N or C; WO 97/36585 PCT/US97/06259 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; a'is N orC: from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, 0 or
S;
R1 is independently selected from: hydrogen, C3-CI0 cycloalkyl,
R
10 -N(R10)2, F or CI-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl,
R
1 0 -N(R 0)2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-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, R1 0 0- and -N(R10)2;
R
3 and R 4 a) b) are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C -C6 perfluoroalkyl,
R
12
R
1 1
R
10 C(O)NR10-, (R R102N-C(NR1)-,_ CN, NO2, RIOC(O)-, N3, -N(R 10 )2, or R llOC(O)NR unsubstituted CI-C6 alkyl, substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or WO 97/36585 PCTIUS97/06259 16
R
6 a, R6b, a) b) substituted aryl, unsubstituted or substituted heterocyclic, C3-CI10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 R I
R
1 J C(0)NRI 10, I R 'O2N..C(NR 10), CN, R IOC(0)-, N3, -N(R 10)2, and R I IOC(0)-NR10-;
R
6 c and R6d are 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, RlO02N-C(NR 10), CN, N02, R IOC(0)-, N3, -N(R 10) 2 or R I'I0C(0)NR unsubstituted C-1 -C6 alkyl, substituted C I-C6 alkyl wherein the substituent on the substituted C I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R' IIS(0)m-, R IOC(0)NR 10-, (R I 0 R IO2N..C(NRI10O> CN, R IOC(0)-, N3, -N(R 10)2, and R I I0C(O)-NR
R
8 is independently selected from: a) hydrogen, h) aryl, substituted aryl, heterocycle, Ci -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 10 R'IOC(0)NR CN, N02, (R'O0)2N..C(NR R IOC(0)-, -N(R 10) 2 or R T I'0C()NR 10-, and c) C I-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 10 0-, R I OC(0)NR (R I O)2N-C(NR R I OC(0)-, -N(R 10)2, or R I I0C(0)NR provided that when R8 is heterocycle, attachment of R8 to v is through a substitutable ring carbon; WO 97/36585 PCT/US97/06259 -17-
R
9 a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R
10 is independently selected from hydrogen, C -C6 alkyl, 2,2,2trifluoroethyl, benzyl and aryl;
R
1 1 is independently selected from Cl-C6 alkyl and aryl;
R
12 is independently selected from hydrogen, C1-C6 alkyl, CI-C6 aralkyl, Cl-C6 substituted aralkyl, C -C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C I-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 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 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; WO 97/36585 PCT/US97/06259 18 X is a bond, -CH=CH-, -C(O)NRO -NRIOC(O)-, -NR 10, 0 or provided that if a is N, then X is not -C(0)NR10-, -NR 10-, or O; mis 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
Another preferred embodiment of the compounds of this invention are illustrated by the formula C: R6a-d
(P
8 }r b' (R
R
3 i N
R
9a b ca'" V- A(CR' 2 )nA2(CR 2 )n-/R9 b n
R
4 C R 9 b (CR2 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; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining b' d' and e' atoms are independently CH, provided that if a is C, then at least one of d' or e' is independently N, NH, O or
S;
WO 97/36585 PCTIUS97/06259 -19 RI is independently selected from: hydrogen, C3-CIO cycloalkyl, R 10 -N(R 1 0 F or C I-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl, RIO0-, -N(RJO)2, F or C2-C6 alkenyl, c) unsubstituted or substituted Cl -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3 -C cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(R 10)2;
R
3 and R 4 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 12 R I IS(O)m-, R IOC(O)NR 10-, CN(R 1O)2NC(O)-, RiO02N-C(NR 10), CN, N02, R I N3, -N(R 1 0)2, or R' 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 heterocycli c, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20., R I R' I C(O)NRI 10, 0 RiO02N-C(NRl10O> CN, R I N3, -N(R'10)2, and
-R
6 a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl. unsubstituted or substituted heterocycle, C3 -Cj0 cycloalky1, C2-C6 WO 97/36585 PCTIUS97/06259 20 alkenyl, C2-C6 alkynyl, halogen, CI -C6 perfluoroalkyl, R 1 2 R I I R IOC(O)NR10-, CN(R 1O)2NC(Oy-, RlO02N-C(NR 10), CN, N02, R IOC(O)-, N3, -N(R 10) 2 or R I I0C(O)NRJ10, c) unsubstituted C I-C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted Cj -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 aikynyl, R'1 0 2N-C(NR CN, R I N3, -N(R 10)2, and R I'IOC(O)..NR R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci -C6 perfluoroalkyl, F, Cl, R 10 R'IOC(O)NRI10, CN, N02, (R 1 0 )2N-C(NR10)-, R IOC(O)-, -N(R 10)2, or R I IOC(O)NRJ10, and c) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 00, Ri I C(O)NR 1 0, (R J 0 )2N-C(NR
R
1 I -N(R 10)2, or R provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; R 9a and R9b are independently hydrogen, C I -C6 alkyl, trifluoromethyl and halogen; is independently selected from hydrogen, C I -C6 alkyl, 2,2,2trifluoroethyl, benzyl and aryl; R II's independently selected from C I -C6 alkyl and aryl; WO 97/36585 PCT/US97/0625 9 21
R
12 is independently selected from hydrogen, C1-C6 alkyl, C -C6 aralkyl, Cl-C6 substituted aralkyl, C1-C6 heteroaralkyl, C -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, CI-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, -N(R or S(O)m; V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(O)NRIO-, -NRIOC(O)-, -NR10-, 0 or provided that if a is N, then X is not -C(0)NR10-, -NR 10- or O; m is 0, 1 or 2; nis 0, 1, 2 3 or 4; Sp 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; WO 97/36585 PCT/US97/06259 22 or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula
D:
R 6a-d
R
9 a R3 a R
A
I
CR 2)n j bA-> R S/ R 9 b (CR 2 2 )p-X R8
D
wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of 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(R10)2, WO 97/36585 PCT/US97/06259 -23 F or C2-C6 alkenyl, c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, RIO0-, or -N(R 10)2;
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 120-, R I R' I C(O)NR 10-, (R 1 0 )2NC(O)-, R'O02N-C(NRlO 10- N, N02, R IOC(O)-, N3, -N(R 10)2, or R I I0C(O)NR c) unsubstituted C I-C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3 -C 1 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20-, R I
R
1 I C(O)NR 10-, (R I RIO02N-C(NRI10O> CN, R I N3, -N(R 1 0 and
R
4 is selected from H, halogen, C I -C6 alkyl and CF3;
R
6 a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Ci 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, RlIO09N-C(NR 10Oy CN, N02, R IOC(O)-, N3 -N(R'1 0 )2, or R'I IOC(O)NR c) unsubstituted C I -C6 alkyl, WO 97/36585 PCTJUS97/06259 24 d) substituted Ci -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 120-, R I R' I 0 C(0)NR 10-, (R 1 0 R 102N-C(NR 10)- CN, R IOC(0)-, N3, -N(R 10 and R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 1 00-, R 1
I
0 C(0)NR 10>, CN, N02, (R I O)2N-C(NR
R
1
I
0 -N(R 10)2, or R I I0C(0)NR 10>, and c) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 00, RI 0 C(0)NRI10> (RI 0 )2N-C(NRIO0>, RI 0 -N(RI 0)2, or R I OC(0)NR 1 0-; 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, ClI-C6 alkyl, 2,2,2trifluoroethyl, benzyl and aryl;
R
1 is independently selected from C I -C6 alkyl and aryl; R 1 2 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-triflu oioethyl;
A
1 I is selected from: a bond, 0, -N(R or S(O)m; WO 97/36585 PCT/US97/06259 X is a bond, -CH=CH-, -C(O)NR10-, -NRIOC(O)-, -NRIO-, 0 or provided that if a is N, then X is not -C(0)NR1O-,
-NR
1
O-
or O; n is m is p is 0 or 1; provided that n is not 0 if Al is a bond, 0, -N(R or S(O)m; 0, 1 or 2; and 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula E: R 6a-d
A
R
8 H9a (CR2)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; a' is N or C; WO 97/36585 PCT/US97/06259 26 from 0-4 of bU, d' and e' are independently N, NH, 0 and S, and the remaining bU, d' and e' atoms are independently CHI, provided that if a' is C, then at least one of bU, d' or e' is independently N, NH, 0 or R I is independently selected from: hydrogen, R 100-, -N(R 10)2, F, cycloalkyl or CI -C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3 -C 10 cycloalkyl, R 10 -N(R 10)2, F or C2-C6 alkenyl, C) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CI10 cycloalkyl, C2-C6 alkenyl, R 1 0 or -N(R 1 0)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, C I -C6 perfluoroalkyl, R 1 20-, R I IS(O)m-
R
1 I C(O)NR 1 0, (R I 0 )2NC(O)-, R 10 2N.-C(NR CN, N02, R I N3, -N(R 1 0 )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 Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20-, R I IS(O)m-,
R
1 I C(0)NRI 10, (R 1 0 R'1 0 2N-C(NR CN, R I N3, -N(R 10)2, and
R
4 is selected from H, halogen, C I-C6 alkyl and CF3; WO 97/36585 PCT/US97/06259 27 R6a, R6b, a) b)
C)
d)
R
6 C and R6d are 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 2 R' IIS(O)m-, R IOC(O)NR 10-, (R IO)2NC(O)-, RIO02N-.C(NRJ10)-, CN, N02, R IOC(O)-, N3, -N(R 1 0)2, or R I IOC(O)NR unsubstituted C I -C6 alkyl, substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I R IOC(O)NR 10-, (R 1%2NC(O)-, R 1 O2N-C(NRl10)-, CN, R IOC(O)-, N3, -N(R 10)2, and R I I0C(O)-NR 1-;
R
8 is independently selected from: I'0a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 1
R
1 I C(O)NR 1 CN, N02, (R 1 0%2N-C(NRl R I -N(R 1 0)2, or R II OC(O)NR 1 and c) C I-C6 alkyl substituted by C I-C6 perfluoroaikyi, R 1 0 0-,
R
1 I C(O)NR 1 (R I O)2N-C(NR 1 Ri I -N(R102,or R I I provided that when R 8 is hetero cycle, attachment of R 8 to V is through a substitutable ring carbon; R9a and R9b are independently hydrogen, halogen, CF3 or methyl; RIO is independently selected from hydrogen, C I -C6 alkyl, 2,2,2trifluoroethyl, benzyl and aryl; WO 97/36585 PCT/UJS97/06259 28 Ri 1 is independently selected from C I -C6 alkyl and aryl; R 1 2 is independently selected from hydrogen, C I-C6 alkyl, C I -C6 aralkyl, Cl -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; X is a bond, -CH=CH-, -C(O)NR 10-, -NR I -NR 1 0 or provided that if a is N, then X is not -C(O)NR 10-, -NR 1 0- or 0; n is m is p is 0 or 1; 0, 1 or 2; and 0, 1, 2,3 or 4, provided that p is not 0 if X is a bond, -NR 10- or 0; or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of famesyl-protein transferase are illustrated by the formula
F:
R\6a-e NC
F
wherein: a is NorC; WO 97/36585 PCT/US97/062 5 9 -29from 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; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, O or
S;
RI is independently selected from: hydrogen, C3-C10 cycloalkyl or C -C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CI0 cycloalkyl,
R
10 -N(RlO)2 or
F,
c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl,
R
10 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, C1-C6 perfluoroalkyl, R 120-, R 11S(O)m-, R IOC(O)NR10-, (R I0)2NC(O)- R102N-C(NR 10), CN, N02, R1OC(O)-, N3, -N(R10)2, or R11OC(0)NRIO-, c) unsubstituted C1-C6 alkyl, d) substituted CI-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 97/36585 PCTIUS97/06259 30 R 1 R1 1 S
R
1 I C(0)NR 10, (R 1 R lO2N-.C(NRI10), CN, R IOC(O)-, N3, -N(R 10)2, and
R
4 is selected from H, halogen, CH3 and CF3;
R
6 a, R6b, a) b) c) d)
R
6 C and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or suibstituted heterocycle, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 RII S(0)m 1 R I OC(0)NR
(R
1 0 )2NC(O), R'1 0 2N-C(NR 10)- CN, N02, R IOC(0)-, N3, -N(R 10)2, or R I'I0C(0)NRl10-, unsubstituted CJ-C6 alkyl, substituted ClI -C6 alkyl wherein the substituent on the substituted C I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120-, R I I R I OC(0)NR (Rl 0 )2NC(O)-, RlO02N-C(NRI10)- CN, R IOC(O)-, N3, -N(R 10)2, and RI I OC(0)-NR
R
9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, C I -C6 alkyl, 2,2,2trifluoroethyl, beuzyl and aryl; R is independently selected from C I -C6 alkyl and aryl: R1 2 is independently selected from hydrogen, Ci -C6 alkyl. Ci -C6 aralkyl, C I -C6 substituted aralkyl, C I -C6 heteroaralkyl, ClI-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C I-C6 perfluoroalkyl, WO 97/36585 PCTIUiS97/06259 -31 2-aminoethyl and 2 2 ,2-trifluoroethyl; X is a bond, -CH=CH-, -C(O)NR10-, -NR -NR10-, O or provided that if a is N, then X is not -C(O)NR10-, -NR10- or O; m is p is 0, 1 or 2; and 0, 1, 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula
G:
R
6 a-d NC
C
G
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 if a is C, then at least one of b, c, d or e is independently N, NH, O or S; a' is N or
C;
from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if WO 97/36585 PCTIUS97/06259 32 a' is C, then at least one of bU, d' or e' is independently N, Ni-I, 0 or R I is independently selected from: hydrogen, R 10 -N(R 1O) 2
F,
C3-CIO cycloalkyl or CI-C6 alkyl;
R
2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-CIO cycloalkyl, c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, R 10 or -N(R 10)2;
R
3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 12 R I I R IOC(0)NR 1 (R 102NC(O)-, RIO02N-C(NR 10y, CN, N02, R I N3, -N(R 10)2, or R II0C(O)NRl10-, c) unsubstituted C1I-C6 alkyl, d) substituted C I -C6 alkyI wherein the substituent on the substituted C1-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 IS(0)m-, R I C(0)NR 1 (R 0 RlO02N-C(NR10)-, CN, R IOC(0)-, N3, -N(R 10)2, and R I I0C(0)-NR
R
4 is selected from H, halogen, CH3 and CF73;
R
6 a, R6b. R 6 c and R6d are independently selected from: a) hydrogen, WO 97/36585 PCT/US97/06259 33 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 R I
R
1 I C(0)NR 10-, (R 1 0 RIO02N-.C(NRI10OY CN, N02, R IOC(0)-, N3, -N(R 10)2, or R I I0C(0)NR c) unsubstituted ClI -C6 alkyl, d) substituted ClI-C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituied or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20., R' IIS(O)m-, R' I C(0)NR 10-, (R 1 0
R'
0 2N-C(NRlO).. CN, RIOC(0>-, N3, -N(R 1 0 and
R
9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, ClI -C6 alkyl, 2,2,2trifluoroethyl, benzyl and aryl; Rl I I s independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen, C I -C6 alkyl, ClI -C6 aralkyl, Ci -C6 substituted aralkyl, CI -C6 heteroaralkyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, ClI -C6 perfluoroalkyl, 2-aminoetliyl and 2 2 ,2-trifluoroethyl; A I is selected from: a bond, 0, or S(O)m; M is 0,lor 2; and n is 0Oor 1; WO 97/36585 PCT/US97/06259 -34or the pharmaceutically acceptable salts thereof.
Specific examples of the compounds of the invention are: 2 '-yl)thien-2-ylmethyl)-5-(4-cyanobenzyl)imidazole
NC
Nf S
S
N-/
1 -(4-Cyanobenzyl)-5-(5-( 1 -methylpyrrol-2-yl)-thiazol-2ylmethyl)imidazole NC
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.
As used herein, "cycloalkyl" is intended to include nonaromatic cyclic hydrocarbon groups having the specified number of WO 97/36585 PCT/US97/06259 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds.
Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, famesyl, geranyl, geranylgeranyl and the like.
"Alkynyl" groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2 -butynyl, 2 -pentynyl, 3 -pentynyl and the like.
"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl," and the aryl portion of aralkyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, WO 97/36585 PCT/US97/06259 36 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. triazolyl and thienyl.
As used herein in the definition of R 3
R
4
R
5 and R6a-d the term "the substituted group" is intended to mean a substituted C1-8 alkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl, substituted aryl or substituted heterocycle from which the substituent(s)
R
3
R
4
R
5 and R6a-e are selected.
As used herein in the definition of R 7 the substituted Cj -8 alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, S substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from I to 3 substituents in addition to the point of attachment to the rest of the compound.
WO 97/36585 PCT/US97/06259 37 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 I or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(C I-C6 alkyl)2, N02, CN, (ClI-C6 alkyl)O-, (C I-C6 alkyl)S(0)m-, (ClI -C6 alkyl)C(0)NH-, H2N-C(NH)-, (C I -C6 alkyl)C(0)-, (ClI -C6 alkyl)OC(O)-, N3,(C I -C6 alkyl)OC(O)NH-., phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and ClI-C20 alkyl.
The moieties designated by the following structures b ljDd
I
arepresent aromatic 5-rnembered following ring systems: heterocyclic rings and includes the
N
IN
0 N r 0
NN
N
N'N
0
N!:N
N
NN'
S
N-S
W~S
K:>
IN-0 r,0 N,1> Preferably Preeralythe aromatic 5-membered heterocyclic ring is selected from: WO 97/36585 PCTIUS97/062 5 9
N
0/
S
0 0/ -38
N
S
r 0 1/
NU
I
It is understood that and that such ring systems may be independently selected bC 1 1d and q'd'
C\
I Dl a-.1 may be the same or different in the instant compounds.
Lines drawn into the ring systems from substituents (such as from R 3
R
4 etc.) means that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms.
Preferably, RI and R 2 are independently selected from: hydrogen, R 11C(O)O-, -N(R 10) 2 R10C(O)NR10-,
R
10 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(R10)2,
R
10 0- and R10C(O)NR10 Preferably,
R
3 is selected from: a) hydrogen, b) C3-C10 cycloalkyl, halogen, C -C 6 perfluoroalkyl,
R
1 2 0-, CN, N02, R10C(O)- or -N(R10) 2 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substitutent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C 6 alkenyl, C2-C6 alkynyl, WO 97/36585 PCT/US97/062 5 9 39 R 1 20-, R
R
1 I C(O)NR 10O., (RI 0 )2NC(O)-, RlO2N-C(NRIO)>, CN, RIOC(O)-, N3, -N(RlO) 2 and R I I OC(O)-NR Preferably, R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and Cj -C6 alkyl.
Preferably,
R
5 is hydrogen.
Preferably,
R
6 a, R6b, R 6 C and R6d are independently a) b) n: hydrogen, C3-C 10 cycloalkyl, halogen, Cl -C6 perfluoroalkyr, R 12 0-, R I IS(O)m-, CN, N02, R IOC(Oy- or -N(R 10)2, unsubstituted C I-C6 alkyl; substituted C I-C6 alkyl wherein the substitutent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, C3-CIO0 cycloalkyl, R 12 R I I S(O)m-, R IOC()-or -N(R 10)2.
Preferably, R8 is independently selected from: hydrogen, and aryl, substituted aryl, heterocycle, substituted heterocycle, C 1 -C6 perfluoroalkyl or CN.
Preferably,
R
9 is hydrogen, halogen, CF3 or methyl.
Preferably, R 10 is selected from H, ClI-C6 alkyl and benzyl.
Preferably, A I and A 2 are independently selected from: a bond, -C(O)NR 10-, -NR IOC(O)-, 0, -S(0)2N(RI10) and -N(RI 0 Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
Preferably, W is selected from irnidazolinyl, 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.
WO 97/36585 PCT/US97/06259 It is intended that the definition of any substituent or variable R R 2
R
9 n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds 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.
1 0 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 chroma-tography 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 1-24, in addition to other standard manipulations such as ester hydrolysis, S 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 and R 8 although only one such R 6 or R 8 is present WO 97/36585 PCT/US97/06259 -41 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 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 1-24: The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures, for the most part. Schemes 1- 14 illustrate synthesis of the instant diheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain.
Thus, in Scheme 1, for example, the commercially available dithienylcarboxylic acid I may be reduced. The triflate of the intermediate alcohol II may be formed in situ and coupled to a suitably substituted benzylimidazolyl III to provide, after deprotection, the instant compound IV.
Those biheteroaryl intermediates that are not commercially available may be synthesized by methods known in the art as well as those reactions illustrated in Schemes 2-6. Thus, as illustrated in Scheme 2 a thienyl boronic acid V may be reacted under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted halogenated heteroaryl moiety, such as 2-bromo, to provide the biheteroaryl carboxylic acid VI, which can then be processed as described in Scheme 1. Scheme 3 illustrates the analogous series of reactions starting with the halogenated heteroarylaldehyde.
WO 97/36585 PCT/US97/06259 -42- Scheme 4 illustrates the reaction wherein the "terminal" heteroaryl moiety is employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biheteroaryl component of the instant compounds, as shown in Scheme 6. Thus, a zinc bromide adduct, such as 3-thienyl zinc bromide, may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the biheteroaryl VII. The heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
As illustrated in Scheme 7, the sequence of coupling reactions may be modified such that the heteroaryl-heteroaryl bond is formed last. Thus, a suitably substituted imidazole may first be alkylated with a heteroarylmethyl halide to provide intermediate
VIII.
Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted heteroaryl boronic acid.
Scheme 8 illustrates the synthesis of a thiazole containing instant compound from the acyclic precursors. Similar strategies may be utilized to prepare other bisheteroatom moieties.
Scheme 9 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 10 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biheteroaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4 -aminoalkylimidazole XII, wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well WO 97/36585 PCT/US97/0625 9 -43 known in the art with various activated biheteroaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the A (CR12)nA 2 (CR 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 11.
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 12 illustrates an analogous series of reactions wherein the (CR 2 2)pX(CR2 2 )p linker of the instant compounds is oxygen. Thus, a suitably substituted haloheteroaryl alcohol, such as, 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 second heteroaryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the A (CR 2)nA 2 (CR 12)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 13. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 1) provides the instant compound XX. If other
R
1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.
Addition of various nucleophiles to an imidazolyl aldehyde may also be employed to form a substituted alkyl linker between the S biheteroaryl moiety and the preferred W (imidazolyl) as shown in Scheme 14. Thus a bishalogenated five membered heteroaryl, such as 2, 4 -dibromothiophene, may undergo metal halogen exchange followed by reaction with a suitably substituted imidazolyl aldehyde and WO 97/36585 PCTIUS97/06259 -44acteylation 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 5-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 13 may be performed on a fully functionalized compound which incorporates an R 2 hydroxyl moiety.
WO 97/36585 PCTIUS97/06259 45 SCHEME 1 0
OH
S LiAIH4
OH
S
II
NiCI 2 (PPh 3 2 R/ 8CJ ZnBr Tr R 8
OF
s S (C F 3
SO
2 2 0, -78 "C NEtiPr 2
CH
2
CI
2 -78 0 C-20 0
C
0 C, CH 3 0H WO 97/36585 PCTIUS97106259 46 SCHEME 2 Is
(HO)
2 B T A
V
HO /7 Br r Pd(PPh 3 4 0 A LiAIH 4 H 0 O v I
A
HO,, SCHEME 3
S
A 1 Br (HO) 2
B
Pd(PPh 3 4 0
A
/7NaBH 4 0
A
I/ 7 WO 9736585PCT/US97/06259 47 SCHEME 4 A Is MeO7 B(OH) 2 Br P d(PP h 3 4 0
A
MeO I LiAIH 4 0 HO 1 s SCHEME A Is
R
3 SiO 7 B(OH) 2
BO
Pd(PPh 3 4 s jA
,BU
4
NF
R
3 SiO I
A
HO0,_ WO 97/36585 PCTIUS97/062 5 9 48 SCHEME 5 (continued)
A
R
3 SiO Br
R
3 SiO 1
(HO)
2 Bo Pd(P Ph 3 4
BU
4
NF
A
HO I/ WO 97/36585 PCT/US9'7/06259 49 SCHEME 6
A
R
3 SiO Br
A
R
3 SiO 1
VI'
A HO 7 7 BrZnlf) Ni C'2 (PPh 3 2
BU
4
NF
R
3 SiO 7 ZnBr Br"DI NiC'2 (P Ph 3 2 S BU 4
NF
R
3 Si0
A
HO7 WO 97/36585 PCT/US97/06259 50 SCHEME 7 Tr
'IN
,-I
i. IBr Br ii. MeOH ref lux N~B r
R
8 Vill
S
Pd(PPh3 4 WO 97/36585 PCTIUS97/06259 51 SCHEME 8 R 8
NH
3 /EtOH /RT (N
COOCH
3 (N
-CONH
2 Lawesson' s Reagent 1 ,4-dioxane 800C N /r CSNH 2 WO 97/36585 PCTIUS97/06259 52 SCHEME_8 cotined 'Me
N
0 Py. HBr.Br 2 Me Br
H
6 0
N
NNH
H
8
H
R
8 WO 97/36585 PCTIUS97/06259 53 SCHEME 9
H
N 9 R~b -IN Nal, NaHCO 3 ,j 2
N
R
9 b -T -TrO!, NEt.
Tr1
N
Rp9b
N
NiCI 2 (PPh 3 2 ZnBr Tr R 9 b ~i
N
R
8 b-c 'a e OTf i. -78 0 C-20 0
C
ii. MeOH, refiux WO 97/36585 PCTJ[JS97/06259 54 SCHEME 0zz Br ii. EtOH,8000,
NH
2
NH
2 xii
N
Nl
NH
2
R
8 xiI' acylation, sulfonylation or alkylation
N
N N J H hV-L~
N
R/
N
R
8 WO 97/36585 PCTIUS97/06259 55 SCHEME I11 i, Na, MeOH ii. 1200C NC rH xIv K3, Tr TrCl, NEt 3 N
NC
Tr
NC
OTf i. -7800-2000 ii. MeOH ref lux xvi b-c a e NC WO 97/36585 PCT/US97/06259 56
R
2 Pr
OH
SCHEME 12 i, Na, MeOH
R
2
N
S
XV
Pr
H
3
C,
N
N
TrC 1, N Et 3 Br R K2 0 Br R 2
N
0
R
8 1vi OTf i-78-C-20-C ii. MeOH refiux
B(OH)
2 R 6 DMF, Pd(PPh 3 4
K
3 P0 4 8000 WO 97/36585 PCTIUS97/06259 57 SCHEME 13 Tr
AVI
EtMgBr
R
8
OH
R8 b-c e HO,_,a2e.
R
(CF
3
SO
2 2 0, -780C NEtiPr 2
,CH
2
CI
2
,,R
Tr Q 0Ac
R
8 OAc R8 XX LiOH I8R6 b-c
OH
WO 97/36585 PCTIUS97/06259 58 SCHEME 13 (continued) I
NH.
3 MeOH
NH
2
R
8 bbs b-c *al el, e H 2 OMe WO 97/36585 PCTIUS97/06259 59 BuLi Br Li Br S Li R 8 OAc 2. AcCI LiOH Pd(PPh 3 4 N
S\
</I
Na OH e Q l d' R 6 R 8 WO 97/36585 PCT/US97/06259 60 Schemes 15-24 illustrate reactions wherein the moiety (R V A(CR 2
)A
2 (CR1 2 W
(CR
2 2 )p-X incorporated in the compounds of the instant invention is represented by other than a substituted imidazole-containing group.
Thus, the intermediates whose synthesis are illustrated in Schemes hereinabove and other biheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Scheme 15). Metal halogen exchange chemistry (Scheme 14) may be employed when manipulating the aldehydes. Alternatively, Grignard chemistry may be utilized, as shown in Scheme 15. 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 S be accomplished by literature procedures.
Scheme 16 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 97/36585 PCT/US97/06259 -61 If the biheteroaryl subunit is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXVI in Reaction Scheme 17, the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes 17, 18). 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 (Reaction Scheme 18), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2 -aziridinylmethylbiheteroaryl such as XXXIII (Reaction Scheme 19). 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 biheteroaryl 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 Reaction Scheme 20. 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 0-alkylated phenolic amines such as XLII produced.
Schemes 21-24 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 97/36585 PCTIUS97/06259 62 SCHEME Br
H
Pd(PPh 3 4 EtM gBr xxi
RA
6
N
Br~g XXIa WO 97/36585 PCT/US97/06259 63 SCHEME 15 (continued) Boc
NHI
Boo NH
CHO
Et 2
O
R
6 1.catalytic hydrogenation 2. 0F 3 C0 2
H
CH
2
CI
2 Boc 2 0
CH
2 C1 2 Boo NH NHBoc xxi
I
NH
2 XXIia BocNH
~CHO
NaB H(OAc) 3 Et 3 N, CICH 2
CH
2
CI
NH
2 xx"'l WO 97136585 PCT/US97/06259 64 SCHEME 15 (cntinued) BocNH
NH
XXIV
0F 3 00 2 H, 0H 2 C1 2 NaHCO,
NC
AgCN L xxv WO 97/36585 PCTIUJS97/0625 9 65 SCHEME 16 Br
N
alkyl I R 6 (HO) 2 B _,,ael Pd(PPh 3 4 R 6 e
N
alkyl
HO
Boc NH \1~ Bu~i Boc NHI Bu~iBoc NH
CHO
TMEDA Et 2
O
NHBoc WO 97/36585 PCTIUS97/06259 66 SCHEME 17 BrMg ai, a 0 Et 2
O
BnOI BocNH
CHO
XXVi HO Bno NHBoc 20% Pd(OH) 2
H
2
CH
3 0H C H 3 00 2
H
HO b-.
e'a
R
NHBoc b-c R A 6 a" C!COCOci DM80 0H 2 C1 2 (C2
H
6 3
N
XXV ii WO 97136585 PCTIUS97/06259 67 SCHEME 17 (CONTINUED) R'MgX NHBoc
XXIX
bU-C' R 6 a"( ey NHBoc
XXX
WO 97/36585 PCTIUS97/0625 9 68 SCHEME 18 NHBoc
CF
3 00 2
H
CH
2 Ci 2
XXVI!'
R'CHO
NaBH(OAc) 3 CIG H 2 C H 2
CI
NH
2
XXXI
b- C' R 6 R 2 N H
R'CH
2
XXXII
WO 97/36585 PCT/US97/06259 69 SCHEME 19 HO 4 ar NHBoc H H N, N NaH, DMF 0OT xxvii' a{9 H'S H
(C
2
H
5 3
N
CH
3 0H xxxiI' R 2 XXXI V WO 97/36585 PCTIUS97/06259 70 SCHEME 1) Boo 2 O, K 2 00 3
THF-H
2 0 2) CH 2
N
2 EtOAc
HO
BocNH C0 2 0H 3 xxxvi
H
2 N 0C0 2
H
xxxv LiAIH 4
THF
0-20 0
C
R CH 2
X
CS
2
CO
3
DMF
BocN
CH
2 0H xxxv"l BocNH CH 2 0H xxxv"'l pyridine -SO~ 'C 2
DMSO
(C
2
H
5 3 N BoN CH 2000 oN
H
WO 97/36585 PCTJUS97/06259 71 SCHEME 20 (continued) R 0H 2 0 BocNH CHO R 6 Et 2
O
2. 2
C
el 0% Pd(OH) 2
H
2
~H
3 OH, CH 3 00 2
H
3. HG!, EtOAc R 6 ot aryl 1) 20% Pd(OH) 2
H
2
CH
3 OH, CH 3
CO
2
H
2) HO!, EtOAc a~
NH
2
XL!II
XLI
NH
2 WO 97/36585 PCT/US97/06259 72 SCHEME 21
OH
3
H
2 N- N 1) HNO 2 ,Br 2 2) KMnO 4 3) MeOH,H+ Br' N IC0 2 0H 3 MgCI CO 2 CH 3 ZnC1 2 ,NiCI 2 (Ph 3 p) 2 NaB H 4 (excess) S0 3 -Py, Et 3
N
R 6
CHO
JN
DMSO
WO 97/36585 PCT/US97/06259 73 SCHEME22 EtO(CO)CI 2.
X
"Icc Nf Zn, CuON 3. S, xylene, heat
R
6
SO
3 -Py, Et 3
N
CH
2 0H DMSO
N'
C02 0H 3 NaBH 4 (excess) 13 MgCI ZnCI 2 NiC1 2 (Ph 3 p) 2 CO 2 CH 3 NaBH 4 (excess)
CH
2 0H S0 3 ?Py, Et 3
N
DMSO
WO 97/36585 PCT/US97/062 5 9 74 SCHEME 23 002 CH 3 LDA,
CO
2 2. MeOH, H+
RH
6 ZnCJ 2 NiCI 2 (PhP) 2 q 0 2 CH 3 NaB H 4 (excess)
R
6 S0 3 'Py, Et 3
N
DMSO
CHO
WO 97/36585 PCTIUS97/06259 SCHEME 24 N Br 1. LDA, C02 2. (CH 3 ),SiCHN 2
CO
2
CH
3 Br
N
R
6 1 Br Zn, NiCl 2 (Ph 3
P)
2 .C0 2
CH
3 excess NaBH 4 R6 N
CH
2
OH
S03-Py, Et 3
N
DMSO
.CHO
The instant compounds are useful as pharmaceutical a gents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this Invention include, but are not limited to, colorectal carcinoma, exocrine WO 97/36585 PCT/US97/06259 -76pancreatic 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 faresylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment. For example, a component of NF-1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease Schaffner et al.
American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
The instant compounds may also be useful for the treatment of fungal infections.
The compounds of this invention may be administered WO 97/36585 PCT/US97/06259 -77 to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.
If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.
The compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within WO 97/36585 PCT/US97/06259 78 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 famesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, WO 97/36585 PCTUS97/06259 -79a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to famesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-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.
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.
WO 97/36585 PCT/US97/062 5 9 EXAMPLE 1 1 -(5-(Thien-2'-yl)thien-2-ylmethyl)-5-(4-cyanobenzyl)imidazole trifluoroacetic acid salt Step A: -Tritvl-4-(4-cvanoenzhy)-imidazol To a suspension of activated zinc dust 3 5 7g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon for 45 minutes, at 0 C. The suspension was cooled to 0 0 C and a-bromo-p-tolunitrile 9 .33g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20 0
C
for 6 hours and bis(triphenylphosphine)Nickel II chloride 2 4 0g, 3.64 mmol) and 4 -iodotritylimidazole (15.
9 5g, 36.6 mmol) were added in one portion. The resulting mixture was stirred 16 hours at 200C and then quenched by addition of saturated NH4C solution (100 mL) and the mixture stirred for 2 hours. Saturated aq.
NaHCO3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2 x 250 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc inCH2C12) to afford the title compound as a white solid.
1 H NMR (CDC13, 400Mz) 8 (7.54 (2H, d, J=7.9Hz), 7.38(1H, s), 7.36-7.29 (11H, 7.15-7.09(6H, 6.58(1H, s) and 3.93(2H, s) ppm.
teB: 5-(Thien 2 -l-thiohene-2-carboxaldeh de To a solution of thien-2-ylboronic acid (0.939 g, 7.34 mmol) and Na2CO 3 (2.40 g, 22.6 mmol) in water (75 mL) is added p-dioxane (75 mL). This mixture is treated sequentially with 5-carboxy- 2 -thiophenecarboxaldehyde (1.
4 3g, 7.48 mmol) and palladium (II) acetate (151 mg, 0.673 mmol) and allowed to WO 97/36585 PCT/US97/06259 81 stir at ambient temperature for 16 hours. The solvent is evaporated in vacuo. To the residue is added EtOAc (400 mL) and water (300 mL). The aqueous layer is acidified to pH 1 with 1.0 N aq. HCI The aqueous layer is extracted with EtOAc (2 x 200 mL). The organic extracts are combined, washing with brine (200 mL), 5% aq.
Na2S203 (200 mL), sat. aq. NaCI (200 mL), drying (Na2SO4), and the solvent evaporation in vacuo affords the title compound.
Step C: 5-hien-2-l)-2-hvdrox methvlthio hene To a solution of 5-(thien-2'-yl)-thiophen-2ylcarboxaldehyde (1.11 g, 5.73 mmol) in THF (25 mL) at 0°C is added 1.0 M lithium aluminum hydride in tetrahydrofuran (12.0 mL, 12.0 mmol) over 10 minutes. The reaction is allowed to stir at ambient temperature for 3 hours. The reaction is cooled to 0°C, and water (0.5 mL), 4 N aq. NaOH (0.5 mL), and water (1.5 mL) are added sequentially. The reaction is filtered through a pad of Celite and the filtrate is evaporated in vacuo. The residue is chromatographed to afford the title compound.
Step D: 1-(5-(Thien-2-yl)thien-2-ylmethyl)-5-(4cvanobenzvl imidazole trifluoroacetic acid salt To a solution of 5-(thien-2'-yl)-2-hydroxymethyl thiophene (283 mg, 1.44 mmol) and diisopropylethylamine (0.260 mL, 1.49 mmol) in dichloromethane (6.0 mL) at -78°C is added trifluoromethanesulfonic anhydride (0.250 mL, 1.49 mmol) and the mixture stirred at -78 0 C for 1 hour. To this mixture is added a solution of 1-trityl-4-(4-cyanobenzyl)imidazole (613 mg 1.44 mmol) in dichloromethane (6.0 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent is evaporated in vacuo.
The residue is partitioned between CH2C12 and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by preparative
HPLC,
WO 97/36585 PCT/US97/06259 82- (gradient elution, 95 :5 to 5:95% water:acetonitrile containing 0.1% trifluoroacetic acid) to afford the title compound as a trifluoroacetic acid salt.
EXAMPLE 2 1 4 -Cyanobenzyl)-5-(5-(1 -methylpyrrol-2-yl)-thiazol-2ylmethyl)imidazole Step A: 1H-Imidazole-4-acetic acid methyl ester hydrochloride A solution of I H-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(IH, 3.89(2H, s) and 3.75(3H, s) ppm.
Step B: 1-(Triphenylmethyl)-1 H-imidazol-4-ylacetic acid methyl ester To a solution of the product from Step A (24.85 g, 0.141 mol) in DMF (115 mL) was added triethylamine (57.2 mL, 0.412 mol) and triphenylmethyl bromide (55.3 g, 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 97/36585 PCT/US97/06259 83 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 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 (CDCI3, 400MHz) 8 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(211, s) ppm.
Step D: 4 -[5-(Aminocarbonylmethyl)imidazol- ylmethyl]benzonitrile To a 100 mL glass pressure vessel with a stirring bar was addedl-( 4 -Cyanobenzyl)- lH-imidazol-5-yl] acetic acid methyl ester (6.00g, 23.5 mmol) and absolute ethanol (50 mL). This well stirred solution was cooled to -78 0 C and 50 mL of anhydrous ammonia was condensed in. The vessel was sealed and the mixture warmed to ambient temperature. This solution was stirred 24 hours at 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.
WO 97/36585 PCTIUS97/06259 84 IINMR (DMSO-d 6 ,400MHz) 8 3.25(s, 2H), 5.
3 2(s, 2H1), 6.88(s, 1 6 .96(s, 1 7.24(d, j=8H4z,2H), 7 .42(s, I 7.68(s, 1 7.83(d, j=8Hz, 2H).
Step E: l-( 4
H-
irnidazole To a 50 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4 -!iS-(aminocarbonylmethyl )imidazol -1 -ylmethyl Ibenzonitrile 36g, 1.49 mmol), Lawesson's reagent (0.
7 3g, 1.8 mmol) and l,4-dioxane (10 mL).
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.
I H1 NMR (DMSO-d 6 400MHz) 6 3 .66(s, 2H), 5.41(s, 2H1), 6 IH), 7.24(d, j=8Hz,2H), 7.70(s,lIH), 7 .82(d, j8Hz, 2H), 9.21
IJH),
9.56(s, 1H).
Step F: I 4 -Cyanobenzyl-5-[5-( -methylpyrrol.2yl )-thiazol-2vimethy~jLimi dazo le To a 25 mL round bottomed flask with a stirring bar refiux condenser and an argon inlet is added I 4 (aminothiocarbonyl )methyl -1H-imidazole (0.1 2g, 0.468 mmol), dry THF (10 mL), and N-methyl-a-bromoacetylpyrrole (0.098g, 0.491 mmol). This mixture is heated at 50'C for 7 hours. The cooled reaction mixture is diluted with EtOAc and washed sucessively with aq. NaHCO-; water, and brine. The organic extract is dried, -(MgSO4) and the solvent is evaporated in vacuo, The residue is purified by chromatography to afford the title compound.
WO 97/36585 PCT/US97/06259 85 EXAMPLE 3 In vitro inhibition of ras farnesyl 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 FPTase was assayed in a volume of 100 1p containing 100 mM N-(2hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM 3 H]-famesyl diphosphate 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 tg/ml FPTase at 31 0 C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB P-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the 3 H]-FPP was utilized during the reaction period. Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 (w/v) polyethylene glycol 20,000, 10 tM ZnC12 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 gl of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention are tested for inhibitory activity against human FPTase by the assay described above.
WO 97/36585 PCT/US97/06259 86 EXAMPLE 4 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 esearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37 0 C, the cells are labelled in 3 ml methionine-free DMEM 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 famesylated and nonfaresylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
WO 97/36585 PCT/US97/06259 87 EXAMPLE In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat I 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 (6)
1. A compound which inhibits farnesyl-protein transferase of the formula A: (R 8 )r I V A'CR'2)nA2(CR' R 6 a-d 'dt R 3 a X- R (CR 2 2)p X-(CR 2 2r R5e 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; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, O or S; R1 and R 2 a) b) are independently selected from: hydrogen, aryl, heterocycle, C3-C10 cycloalkyl, C2-C 6 alkenyl, WO 97/36585 PCT/US97106259 89 C2-C6 alkynyl, R 10 R I I R I IC(0)0-, R I OC(O)NR 1 0, (R 10 R 1 0 2N-C(NR CN, N02, R IOC(O)-, N3, -N(R 10)2, or R I I 0C(O)NR 0) unsubstituted or substituted C I-C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-Cj 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1O2N-C(NR10)-, CN, R IOC(O)-, N3, -N(R 1 0)2, and R I'IOC(O)-NR R 3 R 4 and R- 5 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfiuoroalkyi, R 12 R I IS(O)m-, R IOC(O)NR
10-, RI I C(0)0-, (R 1 RlO02N-C(NR10)-, CN, N02, R IOC(O)-, N3, -N(R 10)2, or R I IOC(O)NR 0) 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 0-, R 1 1 R 1 I C(O)NR 10>, (Ri 1%2NC(O)-, R 10 2N- C(NR CN, R IOC(O)-, N3, -N(R 10)2, and R 1 0C(O)- NRIO-: R6a, R6b, a) b) R 6 c and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Ci 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I-C6 perfluoroalkyl, R 1 2 R II 1 S(O)m R IOC(O)NR 10-, R I IC(0)0-, WO 97/36585 PCT/US97/06259 90 (R I RI 0 2N..C(NRI 10>, CN, N02, R I OC(O)-, N3, -N(R 10)2, or R I IOC(O)NR c) unsubstituted C1I-C6 alkyl, d) substituted Cj -C6 alkyl wherein the substituent on the substituted C I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 IS(O)m-, R 1 0 C(O)NRI10., (RI 0 )2NC(O)-, R 102N..C(NRIO 10,N, R IOC(O)-, N3, -N(R 10)2, and R R 7 is selected from: H; C 1 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 1 0 f) -S0 2 R 1 g) N(R 10)2 or h) CI-4 perfluoroalkyl; R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 00., R I R 1 I 0 C(O)NR 1 0. (R 1 0 )2NC(O)-, ~R 10 2N-C(NR 10>- CN, N02, R IOC(O)-, N3, -N(R 1 0 or R I'IOC(0)NR and WO 97/36585 PCTIUS97/06259 91 c) CI-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0 R I I R I C(O)NH-, (R 1 )2NC(O)-, R 102N-C(NR CN, R IOC(O)-, N3, -N(R 10)2, or R 1 0 0C(O)NH-; provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; R9 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfiuoroalkyl, F, Cl, Br, R 1 IO0, R I I8(O)m-, R IOC(O)NR (R I 0 R 1 0 2N-C(NR CN, N02, R I OC(O)-, N3, -N(R 10) 2 or R IIOC(O)NRI10Q and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 1 0 R I IS(O)m 1 R IOC(O)NR (R I )2NC(O>- RIO02N-C(NR 10>, CN, R IOC(O)-, N3, -N(R 10) 2 or R I I OC(O)NR is independently selected from hydrogen, C I -C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl; R 'is independently selected from C I -C6 alkyl and aryl; R 12 is independently selected from hydrogen, C I-C6 alkyl, ClI-C 6 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 -trifluoi-oethyl; A 1 I and A 2 are independently selected from: a bond, -CH=CH-, -CEC-, -C(O)NR 10O -NR IOC(oy- 0, -N(R -S(O)2N(R 10O)-, -N(RI 1 or S(O)m; WO 97/36585 PCT/US97/06259 -92- V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if 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; W is a heterocycle; X is a bond, -CH=CH-, 0, -C(0)NR 7 -NR 7 -C(O)NR 7 -NR 7 -S(0)2N(R -N(RIO)S(O) 2 or provided that if a is N, then X is not 0, -C(0)NR 7 -C(O)NR 7 C(O)- -S(0)2N(R 10)_ or -NR 7 m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; qis 0, 1. 2 or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and tis 0 or 1; or a pharmaceutically acceptable salt thereof. 2. The compound according to Claim I of the formula A: WO 97/36585 PCT/US97/06259 -93 R 6 a-d R 3 b (R b, a 'e 8 )r (R 9 b4'.d a R V A'(CR 2 )nA 2 (CR 2 )n (CR2)p -X -(CR 2 R 4 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; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of 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-C10 cycloalkyl, R 10 -N(R10)2, F or C2-C6 alkenyl, c) unsubstituted or substituted CI-C6 alkyl wherein the substituent on the substituted C -C6 alkyl is selected from WO 97/36585 R 3 R 4 and a) b) PCT/UJS97/06259 94 unsubstituted or substituted aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, R 1 0 0- and -N(R 10) 2 IR 5 are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CJI-C6 perfluoroalkyl, R 1 2 0-, R I 1 S(O)m R 1 I C(O)NR 10-, (Ri 102NC(O)-, R 1 0 2N- C(NR 1 CN, N02, R IOC(O)-, N3, -N(R 10)2, or R I IOC(O)NR 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-Cl10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1
20., R I R 1 I C(0)NR 1 (R 1 0 RlIO2N-C(NR 10Oy CN, R I N3, -N(R 10)2, and R I I OC(0)-NR R6a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyi, RlO02N-C(NR 10), CN, N02, R I N3, -N(R'1O)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, WO 97/36585 PCT/US97/06259 95 C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 0-, RI IS(O)m-, R' 0 C(O)NR 1 0, (RI 0 Ri 0 CN, R IOC(O)-, N3, -N(R 10)2, and R I R 7 is selected from: H; C1-4 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) "Y R 0 f) -S0 2 R" g) N(R'10)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, Ci -C6 perfluoroalkyl, F, Cl, R 100-, R' I 0 C(O)NR 1 0, CN, N02, (Ri O)2N-C(NR R I -N(R 10)2, or R II OC(O)NRi 10., atid c) CI-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 10 0-, RI 0 C(O)NRl (RI 0 )2N-C(NRI10>, RI OC(O)-, -N(R 1O) 2 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 aikenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R I R I IS(O)m-, R 1 I C(O)NRI 10, (R 1 0 )2NC(O)-, WO 97/36585 PCT/US97/06259 96 CN, N02, (RlO)2N-C(NR10>, RIOC(O)-, -N(R 10)2, or R I IOC(O)NRl10, and c) C I -C6 alkyl. unsubstituted or substituted by C I -C6 perfluoroalkyl, F, Cl, R 10 R I IS(O)m-, R I C(O)NR (R I 0 CN, (R IQ02N-C(NR R I OC(O)-, -N(R 10)2, or R I I0C(O)NR R 10 is independently selected from hydrogen, C I -C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl; R 1 I s 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, CI-C6 substituted heteroaraikyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C I -C6 perfluoroalkyl, 2-aminoethyl and 2 2 ,2-trifluoroethyl; A I and A 2 are independently selected from: a bond, -CH=CH-, -CFC-, -C(O)NR 10-, 0, -N(Ri10)-, 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 I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and C2-C20 alkenyl, and provided that V is not hydrogen if AIis S(O)m and V is not hydrogen if A I is a bond, n isO0 and A 2 is S(O)m; WO 97/36585 PCT/TJS97/06259 97 provided that when V is heterocycle, attachment of V to R8 and to A 1 is through a substitutable ring carbon; W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyi, pyridinyh. 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(RIO0>, -N(R 1 0 or provided that if a is N, then X is not 0, -C(0)NR 7 S(0)2N(R or -NR 7 M is 0, 1or 2; n is independently 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; q is 0,l1, 2or 3; r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0Gori1; or a pharmnaceutically acceptable salt thereof. 3. The compound according to Claim I of the formula B: (R 8 )R b 6 a-d (R")rR~a R 3 1 (1</dt H 4 B (CR 2 -x wherein: a is N or C; WO 97/36585 PCT/US97/06259 -98- 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; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, O or S; RI is independently selected from: hydrogen, C3-C10 cycloalkyl, R 10 -N(R10)2, F or CI-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 10 -N(R10)2, F or C2-C6 alkenyl, c) unsubstituted or substituted C -C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(R10) 2 R 3 and R 4 are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 12 RllS(O)m-, R IOC()NR 10, (R 10 )2NC(O)-, R102N-C(NR 10), CN, NO2, R 10 N3, -N(R 10 )2 or R11OC(O)NR c) unsubstituted Cl-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or WO 97/36585 PCTIUS97/06259 99 R 6 a, R6b, a) b) substituted aryl, unsubstituted or substituted heterocyclic, C3-CJO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R'1 0 2N-C(NRI10)-, CN. R IOC(O)-, N3, -N(R 1 0 and R 6 C and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cj -C6 perfluoroalkyl, R 12 R I IS(O)m-, R I C(O)NR 10-, (R I 0 )2NC(O)-, R 1 0 2N-C(NRl10O> CN, N02, R IOC(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 CI -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20-, R I 1 R 1 I C(O)NR 10-, (R I 0 )2NC(O)-, RlO02N-C(NRl10), CN, R IOC(O)-, N3, -N(R 10)2, and R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Cj -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C I -C6 perfluoroalkyl, F, Cl, R 1 00-, R 1 I C(O)NR 1 CN, N02, (R l%)2N-C(NR R 1 I -N(R 10)2, or R I OC(O)NR 1 0, and c) C I -C6 alkyl substituted by C I -C6 perfluoroalkyl, R 1 0 0-, R 1 I C(O)NR 10-, (R I %2N-C(NR R' I 102,or R provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon; WO 97/36585 PCT/US97/06259 -100- R 9 a and R9b are independently hydrogen, Ci-C6 alkyl, trifluoromethyl and halogen; R 1 0 is independently selected from hydrogen, CI-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl; R 1 1 is independently selected from C1-C6 alkyl and aryl; R1 2 is independently selected from hydrogen, C -C6 alkyl, C -C6 aralkyl, CI-C6 substituted aralkyl, Cj-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2 2 ,2-trifluoroethyl; A 1 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) C I-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; WO 97/36585 PCT/US97/06259 -101 X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NRlO-, O or provided that if a is N, then X is not -C(0)NR1O-, -NR10-, or O; m is 0, 1 or 2; n is 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 I of the formula C: R 6a-d (R)r R 3 N R 9a e' 9 N a-- e R4 V A1CR 2 )nA2(CR 2 4 C R9b (CR22)J x wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, 0 and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; a' is N or C: S from 0-4 of d' and e' are independently N, NH, O and S, and the remaining b d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, O or 'Qd e WO 97/36585 PCTIUS97/06259 -102 R I is independently selected from: hydrogen, C3 -C 10 cycloalkyl, R 10 -N(R 10)2, F or C I-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-CIO cycloalkyl., R 1 0 -N(RiO) 2 F or C2-C 6 alkenyl, c) unsubstituted or substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, R 10 0- and -N(RlO)2; R 3 and F~ a) b) 4 are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfinoroalkyl, R 12 R I IS(O)m-, R'IOC(O)NR 10-, CN(RIO0)2NC(O>-, RIO02N..C(NRI10), CN, N02, R IOC(O)-, N3, -N(R 10)2, or R I I0C(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-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 R I R 1 I C(0)NR (R 1 RlO2N..C(NR1O)>, CN, RIOC(O)-, N3, and R I'IOC(O).NR R 6 c and R6d are independently selected from: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -Cj 0 cycloalkyl, C2-C 6 R6a, R6b, a) b) WO 97/36585 PCTfUS97/06259 -103 alkenyl, C2-C6 alkynyl, halogen, Cj -C6 perfluoroalkyl, R 12 R I IS(O)m-, R IOC(O)NRI10- CN(R iO)2NC(Oy-, R 102N-C(NR 10), CN, N02, R IOC(O>, N3, -N(R 1 0 2 or R I c) unsubstituted C I-C 6 alkyl, d) substituted Cl -C6 alkyl wherein the substituent on the substituted CI-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(O)m-, R I C(O)NR 10- (R 1 0 )2NC(Oy- R 1O2N-C(NR CN, R IOC(o)., N3, -N(R 10) 2 and R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci -C6 perfinoroalkyl, F, Cl, R 100.., R 1 I C(O)NR 10-t, CN, N02, (RI 0 )2N-C(NR R IOC(Oj., -N(R 10) 2 or R I I OC(O)NRI10O and C) C I-C6 alkyl substituted by C I -C6 perfluoroalkyl, R R I OC(O)NRJ 10, (R 1 0Q2N-C(NR R I OC(O)-, -N(R 10)2, 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, Cj -C6 alkyl, trifluoromethyl and halogen; R 10 is independently selected from hydrogen, C I -C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl; R 1 is independently selected from C I-C6 alkyl and aryl; I WO 97/36585 PCT/US97/06259 -104- R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, CI-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; 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) C -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon; X is a bond, -CH=CH-, -C(0)NRIO-, -NRIOC(O)-, -NR10-, O or provided that if a is N, then X is not -C(0)NRIO-, -NR10- or O; m is 0, 1 or 2; n is 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; WO 97/36585 WO 97/36585 PCT/US97/06259 105 or a pharmaceutically acceptable salt thereof. The compound according to Claim 3 of the formula D: R 6a-d R9a R 3 R 9 b (CR2 2 )p-X R8 D wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b. c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; a' is N or C: from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, O or S; Ri 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 1 0 -N(R 10 )2, F or C2-C6 alkenyl, WO 97136585 PCTIUS97/06259 -106 c) C I -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3 -CI10 cycloalkyl, C2-C6 alkenyl, R 10 or -N(RI 0)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, RlO02N-C(NR 10)- CNM N02, R IOC(O)-, N3, -N(R 10)2, or R I IOC(O)NR 10- c) unsubstituted C I -C6 alkyl, d) substituted ClI -C6 alkyl wherein the substituent on the substituted C I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(O)m-, R I C(O)NR 10-, (R I 0 )2NC(O)-, RlO02N-C(NR CN, R IOC(O)-, N3, -N(R 10)2, and R IIOC(O)-NR R 4 is selected from H, halogen, ClI-C6 alkyl and CF3; R6a, R6b, R 6 C and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -CI 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl. halogen, C I -C6 peffluoroalkyl, R 1 2 R I IS(O)m-, R I C(O)NR 1 (R 1 0 )2NC(O)-, R 1O2N-C(NR 10), CN, N02, R I N3, -N(R 1 0 )2, or R I I OC(O)NR c) unsubstituted C I -C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or WO 97/36585 PCTUS97/0j6259 -107 substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2 R I IS(O)m-, R I C(O)NR 10, (R I Q2NC(O)-, RIO02N-C(NR 10)- CN, N3, -N(R 10)2, and R'I IOC(O)-NR R8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ClI -C6 perfluoroalkyi, F, CI, R 1 00-, R 1 I C(O)NR 1 CN, N02, (RI Q02N-C(NR R 1 I -N(Rl 0)2, or R I I0C(O)NR and C) C I -C6 alkyl substituted by ClI -C6 perfluoroalkyl, R 10 0-, R 1 0 C(O)NRIO0, (R 1 Q2N-C(NRIO0>, R 1 0 -N(R 1 0)2, or R' IIOC(O)NR provided that when R8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon; R 9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 1 0 is independently selected from hydrogen, ClI -C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl; R I Iis independently selected from C 1 -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, ClI -C6 perfiuoroalkyl, 2-aminoethyl and 2 2 2 -trifluoroethyl; A 1 I is selected from: a bond, 0, -N(R or SOM WO 97/36585 PCT/US97/06259
108- X is a bond, -CH=CH-, -C(O)NR10-, -NRIOC(O)-, -NR 10-, O or provided that if a is N, then X is not -C(0)NR 10, -NR or O; n is 0 or 1; provided that n is not 0 if A is a bond, 0, or S(O)m; m is 0, 1 or 2; and pis 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 6. The compound according to Claim 4 of the formula E: R 6 a-d R 3 K SR 9a a- e /"I A'(CR12)n a- N a R R 4 SR 9 b (CR 2 2 )p-x R 8 E wherein: a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining b, d' and e' atoms are independently CH, provided that if WO 97/36585 PCT/tUS97/06259
109- a' is C, then at least one of bU, d' or e' is independently N, NH, 0 or 8; R I is independently selected from: hydrogen, R 10 -N(R 10) 2 F, C3 -C 10 cycloalkyl or C I -C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C 1 0 cycloalkyl, RIO0-, -N(RlO)2, F or C2-C6 alkenyl, c) CI-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, R 10 0-, or -N(R 10)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 2 R I IS(0)m-, R IOC(0)NR 10-, (R I 0 RlO02N-C(NR CN, N02, R IOC(0)-, N3, -N(R 1 0 )2, or R I c) unsubstituted C I -C6 alkyl, d) substituted Ci -C6 alkyl wherein the substituent on the substituted C I -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RiO02N-C(NR 10)- CN, R IOC(0)-, N3, -N(R 10)2, and R I I C(O)-NR R 4 is selected from H, halogen, CjI -C6 alkyl and CF3; R 6 a, R6b, R 6 c and R6d are independently selected from: WO 97/36585 PCTUS97/06259 -110- a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 2 R I R IOC(0)NR 10-, (R 1 0 RlO02N-C(NRl10)- CN, N02, R IOC(0)-, N3, -N(R'10)2, or R I I0C(0)NRi10-, 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 20-, R I R 1 I C(0)NR 10>, (Ri 1)2NC(0)-, RiO02N-C(NR10)-, CN, R I N3, -N(R 10)2, and R I IOC(0)-NR10-; R 8 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, Ci -C6 alkyl, C2-C6 alkenyl, C2-C6 aikynyl, Cl -C6 perfluoroalkyl, F, Cl, R 1 00., R 1 I 0 C(0)NR 1 0, CN, N02, (RI 0 )2N-C(NR R I 0 -N(R 10)2, or R I I0C(0)NRl10-, and c) C I-C6 alkyl substituted by C I-C6 perfluoroalkyl, R 10 0-, Ri I 0 C(0)NR 10>, (R 1 )2N-C(NR Rl I -N(R 10)2, or R I I0C(O)NR provided that when R8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon; R 9 a and R9b are independently hydrogen, halogen, CP3 or methyl; R 1 0 is independently selected from hydrogen, ClI-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl; Rl is independently selected from C I -C6 alkyl and aryl; WO 97/36585 PCTIUS97/06259 R-12 is R 12 s idepndetlyselected from hydrogen, ClI -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 perfiuoroalkyl, 2-aminoethyl and 2 2 ,2-trifluoroethyl; X is a bond, -C(O)NRIO-, -NRIOC(O)-, -NRIO-, 0 or provided that if a is N, then X is not -C(O)NR 10- -NR 10 or 0; n is 0 orl1; mnis 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, -NR 10 or 0; or a pharmaceutically acceptable salt thereof. 7. The compound according to Claim 5 of the formula F: R 6 a-d N R a el b RC, d C2 -N R b I-dc ae NC F wherein: a is N or C; WO 97/36585 PCT/US97/06259 -112- 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; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if a' is C, then at least one of d' or e' is independently N, NH, O or S; RI 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(R10) 2 or F, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R 1 0 or -N(R0)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 1 20-, R 1S(O)m-, RI OC(0)NR 10_, (R 10)2NC(0)- RI02N-C(NR1O)-, CN, N02, RIOC(O)-, N3, -N(R1 0 )2, or R 10C(0)NRIO_, c) unsubstituted Cl-C6 alkyl, d) substituted CI-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 97/36585 PCTJIJS97/06259 -113- R 1 20-, R 1 R 1 I C(O)NR 10- (R 1 0 )2NC(O)-, R 1 0 2N-C(NRI10)-, CN, R IOC(O)-, N3, -N(RIO0) 2 and RI 'OC(O)-NRIO;. R 4 is selected from H, halogen, CH3 and CF3; R 6 a, R6b, R 6 C and R6d are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3 -C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 120-, R I R' I C(O)NR 1 0, (RI 0 )2NC(O)-, R 102N-C(NR CN, N02, R IOC(O)-, N3, -N(Rl1O)2, or R I c) unsubstituted C I -C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted Ci -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12 R I I R IOC(O)NR 10-, (R I )2NC(O)-, R I 2N-C(NRI10)- CN, R IOC(O)-, N3, -N(R 10) 2 and R I'IOC(O)-NR R9a and R9b are independently hydrogen, halogen, CF3 or methyl; R 1 0 is independently selected from hydrogen, C I -C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl; Ri I1 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, ClI -C6 substituted aralkyl, C I -C6 heteroaraikyl, C I -C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C I -C6 perfluoroalkyl, WO 97/36585 PCT/US97/062 5 9
114- 2-aminoethyl and 2 ,2, 2 -trifluoroethyl; X is a bond, -CH=CH-, -C(O)NRIO-, -NR 10 -NR10-, O or provided that if a is N, then X is not -C(O)NR 10-, -NR10- or O; m is p is 0, 1 or 2; and 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 8. The compound according to Claim 6 of the formula G: :6a-d NC A\ ,R 2 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 if a is C, then at least one of b, c, d or e is independently N, NH, O or S; a' is N or C; from 0-4 of d' and e' are independently N, NH, O and S, and the remaining d' and e' atoms are independently CH, provided that if WO 97/36585 PCT/US97oei259 -115- a' is C, then at least one of bU, d' or e' is independently N, NH, 0 or R I is independently selected from: hydrogen, R 1 00-, -N(R 1 0)2, F, C3-C 10 cycloalkyl or C I-C6 alkyl; R 2 is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-Cj 0 cycloalkyl, c) C I-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-CIO cycloalkyl, C2-C6 alkenyl. RIO0-, or -N(R 1 0)2; R 3 is selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-CI0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, ClI -C6 perfluoroalkyl, R 1 R I R 1 I C(0)NR 10-, (R 1 0 RlO02N-C(NR10)-, CN, N02, R I N3, -N(R 10 )2, or R I I0C(0)NR c) unsubstituted C I-C6 alkyl, d) substituted ClI-C6 alkyl wherein the substituent on the substituted C I-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20-, R I IS(O)m-, R 1 I 0 C(0)NR 10-, (R I 0 RlO02N-C(NR 10), CN, R IOC(0)-, N3, -N(R 10 and R 4 is selected from H, halogen, CH3 and CF3; R 6 a, R6b, R 6 c and R6d are independently selected from: a) hydrogen, WO 97/36585 PCTUS97/06259 -116- b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C I -C6 perfluoroalkyl, R 1 20-, R I R 1 I C(O)NR (R 1 0 )2NC(O)-, R 102N-C(NR 10), CN, N02, R I N3, -N(R 10) 2 or R I 1 0 C(O)NR c) unsubstituted C I -C6 alkyl, d) substituted C I -C6 alkyl wherein the substituent on the substituted Cl -C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RIO02N-C(NR1)-., CN, R IOC(O)-, N3, -N(R 10)2, and R I I0C(O)-NR R 9 a and R9b are independently hydrogen, halogen, CF3 or methyl; R 10 is independently selected from hydrogen, C I -C6 alkyl, 2,2,2- trifluoroethyl, benzyl 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, 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 -trifiuoroethyl; A 1 is selected from: a bond, 0, -N(R or S(O)m; mnis 0, 1or 2;and n is 0 orl1; or the pharmaceutically acceptable salts thereof. 9. A compound which inhibits farnesyl-protein transferase which is: 1-(5-(thien-2'-yl)thien-2- ylmethyl)-5-(4-cyanobenzyl)imidazole ,or 1-(4-cyanobenzyl)-5-(5-(1-methylpyrrol-2-yl)-thiazol-2-ylmethyl)imidazole H 3 C N c S or a pharmaceutically acceptable salt thereof. 10. A compound which inhibits farnesyl-protein transferase, substantially as hereinbefore described with reference to any one of the examples. 10 11. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of any one of claims 1 to 12. A pharmaceutical composition made by combining the compound of any one of claims 1 to 10 and a pharmaceutically acceptable carrier. 13. A process for making a pharmaceutical composition comprising combining a compound s15 of any one of claims 1 to 10 and a pharmaceutically acceptable carrier. 14. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 10 or of a composition of claim 11 or claim 12. 15. A compound of any one of claims 1 to 10 or of a composition of claim 11 or claim 12 when used in inhibiting farnesyl-protein transferase. 16. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for inhibiting farnesyl-protein transferase. 17. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 10 or of a composition of claim 11 or claim 12. 18. A compound of any one of claims 1 to 10 or of a composition of claim 11 or claim 12 when used in treating cancer. 19. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for treating cancer. 20. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 10 or of a composition of claim 11 or claim 12. C04220 21. A compound according to any one of claims 1 to 10 or a composition according to claim 11 or claim 11 when used in treating neurofibromin benign proliferative disorder. 22. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for treating neurofibromin benign proliferative disorder. 23. A method for treating blindness related to retinal vascularisation which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 10 or of a composition of claim 11 or claim 12. 24. A compound according to any one of claims 1 to 10 or a composition according to claim 11 or claim 12 when used in treating blindness related to retinal vascularisation. 25. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for treating blindness related to retinal vascularisation. 26. A method for treating infections from hepatitis delta and related viruses which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 10 or of a composition of claim 11 or claim 12. 15 27. A compound according to any one of claims 1 to 10 or a composition according to claim 11 or claim 12 when used in treating infections from hepatitis delta and related viruses. 28. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for treating infections from hepatitis delta and related viruses. 29. A method for preventing restenosis which comprises administering to a mammal in need thereof a, therapeutically effective amount of a compound of any one of claims 1 to 10 or of a composition of claim 11 or claim 12. A compound according to any one of claims 1 to 10 or a composition according to claim 11 or claim 12 when used in preventing restenosis. *w e* 31. The use of a compound according to any one of claims 1 to 10 for the manufacture of a 25 medicament for preventing restenosis. 32. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to or of a composition of claim 11 or claim 12. 33. A compound according to any one of claims 1 to 10 or a composition according to claim 11 or claim 12 when used in treating polycystic kidney disease, 34. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for treating polycystic kidney disease. Dated 28 October 1998 MERCK CO., INC. Patent Attorneys for the Applicant/Nominated Person SPRUSON&FERGUSON C04220
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1459296P | 1996-04-03 | 1996-04-03 | |
| US60/014592 | 1996-04-03 | ||
| GBGB9613462.2A GB9613462D0 (en) | 1996-06-27 | 1996-06-27 | Inhibitors of farnesyl-protein transferase |
| GB9613462 | 1996-06-27 | ||
| US2258696P | 1996-07-24 | 1996-07-24 | |
| US60/022586 | 1996-07-24 | ||
| GB9617279 | 1996-08-16 | ||
| GBGB9617279.6A GB9617279D0 (en) | 1996-08-16 | 1996-08-16 | Inhibitors of farnesyl-protein transferase |
| PCT/US1997/006259 WO1997036585A1 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2730797A AU2730797A (en) | 1997-10-22 |
| AU706497B2 true AU706497B2 (en) | 1999-06-17 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU27307/97A Ceased AU706497B2 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0904076A1 (en) |
| JP (1) | JP2000507956A (en) |
| AU (1) | AU706497B2 (en) |
| CA (1) | CA2250204A1 (en) |
| WO (1) | WO1997036585A1 (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1188407C (en) * | 1997-11-28 | 2005-02-09 | Lg化学株式会社 | Imidazole derivatives with inhabiting activity to transterasa and preparing method thereof |
| AU779426B2 (en) | 1999-11-15 | 2005-01-27 | Janssen Pharmaceutica N.V. | Triazoles as farnesyl transferase inhibitors |
| US7049324B1 (en) | 1999-11-15 | 2006-05-23 | Ashis Kumar Saha | Triazoles as farnesyl transferase inhibitors |
| EP1296978A2 (en) | 2000-06-30 | 2003-04-02 | Bristol-Myers Squibb Company | N-ureidoheterocycloaklyl-piperidines as modulators of chemokine receptor activity |
| TWI372050B (en) | 2003-07-03 | 2012-09-11 | Astex Therapeutics Ltd | (morpholin-4-ylmethyl-1h-benzimidazol-2-yl)-1h-pyrazoles |
| PL2256106T3 (en) | 2003-07-22 | 2015-08-31 | Astex Therapeutics Ltd | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3) modulators |
| US8110573B2 (en) | 2004-12-30 | 2012-02-07 | Astex Therapeutics Limited | Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases |
| AP2007004047A0 (en) | 2005-01-20 | 2007-06-30 | Pfizer Ltd | Substituted triazole derivatives as oxtocin antagonists |
| US8404718B2 (en) | 2005-01-21 | 2013-03-26 | Astex Therapeutics Limited | Combinations of pyrazole kinase inhibitors |
| 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. |
| EP1968579A1 (en) | 2005-12-30 | 2008-09-17 | Astex Therapeutics Limited | Pharmaceutical compounds |
| WO2008001115A2 (en) | 2006-06-29 | 2008-01-03 | Astex Therapeutics Limited | Pharmaceutical combinations of 1-cyclopropyl-3- [3- (5-m0rphoolin-4-ylmethyl-1h-benzoimidazol-2-yl) -lh-1-pyrazol- 4-yl] -urea |
| 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 |
| AU2010232729A1 (en) | 2009-03-31 | 2011-10-20 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
| AR081331A1 (en) | 2010-04-23 | 2012-08-08 | Cytokinetics Inc | AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME |
| US9133123B2 (en) | 2010-04-23 | 2015-09-15 | 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 |
| US8759380B2 (en) | 2011-04-22 | 2014-06-24 | Cytokinetics, Inc. | Certain heterocycles, compositions thereof, and methods for their use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2468168A (en) * | 1945-06-11 | 1949-04-26 | Parke Davis & Co | 5, 5-di-(alpha-thienyl)hydantoin and method for obtaining same |
-
1997
- 1997-04-01 JP JP9535636A patent/JP2000507956A/en active Pending
- 1997-04-01 AU AU27307/97A patent/AU706497B2/en not_active Ceased
- 1997-04-01 WO PCT/US1997/006259 patent/WO1997036585A1/en not_active Application Discontinuation
- 1997-04-01 EP EP97921200A patent/EP0904076A1/en not_active Withdrawn
- 1997-04-01 CA CA002250204A patent/CA2250204A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU2730797A (en) | 1997-10-22 |
| EP0904076A1 (en) | 1999-03-31 |
| JP2000507956A (en) | 2000-06-27 |
| CA2250204A1 (en) | 1997-10-09 |
| WO1997036585A1 (en) | 1997-10-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |