CA2249607A1 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- CA2249607A1 CA2249607A1 CA002249607A CA2249607A CA2249607A1 CA 2249607 A1 CA2249607 A1 CA 2249607A1 CA 002249607 A CA002249607 A CA 002249607A CA 2249607 A CA2249607 A CA 2249607A CA 2249607 A1 CA2249607 A1 CA 2249607A1
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Abstract
The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
Description
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 conforrnational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is termin~ted by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound folm (D.R. 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 leukemia~s. The protein product,s 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-terminu,s 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 310:583-5~6 (1984)). Depend-ing on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a Cls or C20 isoprenoid, respectively. (S. Clarke., - Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of .several proteins that are known to undergo post-translational farnesyl-ation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesyl-ated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it ha,s been .shown that an inhibitor of farnesyl-protein tran,sferase blocks the growth of ras-dependent tumor,s in nude mice (N.E. Kohl et al., Proc. Natl.
Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transfera,se in vilJo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ihid; Schafer et al., Science 245:379 (19~9)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farne,syl-protein transferase utilizes farnesy]
pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990);
Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1 133-1139 (1990); Manne et al., P)~oc. Natl. Acad. Sc~i USA, 87:7541-7545 (1990)). Inhibition of farne~syl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor WO 97/36901 PCT/US97/0~304 of isoprene ~iosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in four general classes (S. Graham, Expert Opinion Ther. Patents, (1995) 5:1269-1285). The first are analogs of farnesyl 5 diphosphate (FPP), while a second class of inhibitors is related to the protein substrates (e.g., 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 10 molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss etal., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive 15 inhibitors (U.S. Patent 5,141,g51, University of Texas; N.E. Kohl et al ., Sc~ience, 260: 1934- 1937 (1993); Graham, et al., J. Med . Chem., 37, 725 (1994)). In ~eneral, 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 20 places limitation,s on the therapeutic application of FPTase inhibitors with respect to pharmacokinetic~s, pharmacodynamics and toxicity.
Therefore, a functional replacement for the thiol is de.sirable.
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety 25 are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Lmidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 A1).
It has recently been reported that farnesyl-protein 30 transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930).
It is, therefore, an object of this invention to develop W O 97/36901 PCTrUS97/05304 low 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 5 for producing the compounds of this invention.
SUMMARY OF THE INVENT~ON
The present invention comprises arylheteroaryl-containing compounds which inhibit the farnesyl-protein tran.sferase.
10 Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A:
6a-e /_~/R
</
R3 )~
(I 8)r /~9~ f~
V - A1 (CR12)nA2(CR 12)n ~;~W~ - (CR22)p - X -(CR 2)p 4 R5 lS A
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene 20 protein Ras. In a first embodiment of this invention, the inhibitors of farnesyl-protein tran~sferase are illustrated by the formula A:
W O 97/36901 PCTrUS97/05304 R6a-e R3 >~
(R8) / 9~ /f~
V - A1(CR12)nA2(CR12)n ;~W~ (CR22)p - X -(CR22)p R5 wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f'~
5 are independently CH;
Rl and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0O-, R I I S(O)m-, R 1 0C(O)NR 10, R 1 1 C(O)O-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 , c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or sub.stituted aryl, heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100- Rl lS(o)m, RIOC(O)NRlO-, (R10)2NC(o)-, K102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;
R3, R4 and R5 are independently selected from:
a) hydrogen, - b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R12O-, W O 97/36901 PCT~US97/05304 R 1 1 S(O)m ~ R 1 0C(o)NR 10, (R 1 0)2NC(o)-, R 1 1 C(O)O-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or Rl lOC(O)NR10 c) unsubstituted Cl-C6 alkyl, S d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2O, R 1 1 S(O)m-~ R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o), Rl lC(o)o-R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2 or R 1 1 OC(O)NR 10 c) unsubstituted C 1 -C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is .selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, RllS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or ~0 any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
W O 97/36901 rcTrusg7~0s304 provided that when R3, R4, RS, R6a, R6b~ R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4 R5 R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a S substitutable heterocycle ring carbon;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~ R
f) --SO2R1 1 l S g) N(R 1 0)2 or h) C 1-4 perfluoroalkyl;
R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, Rl lS(O)m, RlOC(O)NR10-~ (R10)2NC(o)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0o-, R I 1 S(O)m ~ R 1 0C(O)NH-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, or R10OC(O)NH-;
provided that when R~ is heterocycle, attachrnent of R~ to V i~;
through a substitutable ring carbon;
R9 is independently selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl lo-, Rl lS(O)m-, Rloc(o)NRlo- (R10)2NC(o) R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O~-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, RllS(O)m-, R10C(O)NR10-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10;
~5 R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl I is independently selected from Cl-C6 alkyl and aryl;
~0 R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;~5 Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10, -NR I ~C(O)-, O, -N(R 10 -S(O)2N(R 10), -N(R I ~)S(O)2-, or S(O)m;
~0 V is selected from:
a) hydrogen, - b) heterocycle, c) aryl, d) Cl-C20 alkyl wherein from O to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and ~ e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen S if Al is a bond, n is O and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
W is a heterocycle;
X is a bond, -CH=CH-, O, -C(=O)-, -C(o)NR7-, -NR7C(o)-, -C(O)O-, -OC(O)-, -C(o)NR7C(o)-, -NR7-, -S(0)2N(R 1 0) , -N(R10)S(0)2- or-S(=O)m-;
1 5 m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is O to 5, provided that r is O when V is hydrogen; and 20 tis Oorl;
or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of thi.s invention is illustrated by the following fo~nula A:
R6a-e (R8)r /(1l19~ f~
- V - A1(CR12)nA2(CR12)n~;~W~ - (CR22)p - X -(CR22)p R5 A
wherein:
from 1-2 of f(,s) are independently N or N->O, and the rem~ining rs are independently CH;
s Rl is independently selected from: hydrogen, C3-CIo cycloalkyl, R 1 00-, -N(R 1 0)2, F or C l -C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C I o cycloalkyl, R 1 00-, -N(R 1 0)2, F or C2-C6 alkenyl, c) unsubstituted or ~ubstituted Cl-C6 alkyl wherein the substituent on the sub.stituted C 1 -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3, R4 and R5 are independently selected from:
a) hydrogen, b) un.substituted or substituted aryl, unsubstituted or substituted heterocycle, C3-c 1 o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 10), CN, N02, R I ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 , c) u~substituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R120 RllS(O)m, KlOC(O)NR10-, (R10)2NC(o)-, - R102N-C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and Rl lOC(o) NR10;
CA 02249607 l998-09-23 R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, - b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120, Rl lS(O)m, KlOC(O)NR10-, (Rl0)2Nc(o)-~
R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, Rl lS(O)m-, R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R5, R6a~ R6b, R6C, R6d or R6e ;~; ;
unsubstituted or substituted heterocycle, attachment of R3, R4 R5, R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, - c) halogen, d) HO, o f) --So2R 1 ~
g) N(R l ~)2 or h) C l -4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R10O-, R 1 0C(O)NR 10, CN, NO2, (R 10)2N-C(NR 10), R I ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R 1 0O-, R l 0C(O)NR 10, (R 1 0)2N-C(NR 10) R10C(O)-, -N(R10)2, or Rl lOC(O)NRI0-;
provided that when R~ is heterocycle, attachment of R~s to V is through a ,substitutable ring carbon;
R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, Rl lo-, Rl lS(O)m-, Rl0C(o)NRl0-, (Rl0)2NC(o) CN, NO2, (R l 0)2N-C(NR 10), R I ~C(O)-, -N(R l ~)2, or R I I OC(O)NR 10, and c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, Rl0O-, RllS(O)m-, Rl0C(O)NRl0-, (R l 0)2NC(O)-, CN, (R l 0)2N-C(NR l 0), R l ~C(O)-, -N(Rl0)2, or Rl lOC(O)NRl0-;
R10 is independently .selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
W O 97/36901 PCTrUS97/05304 R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R 10), or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and 20 provided that V is not hydrogen if Al is S(O)m and V i.s not hydrogen if Al is a bond, n is 0 and A2 i~s S(O)m;
provided that when V is heterocycle, attachment of V to RX and to Al is through a ~substitutable ring carbon;
25 W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
X is a bond, O, -C(=O)-, -CH=CH-, -C(o)N~7-, -NR7C(o)-, -NR7-, -S(O)2N(R 1 0)-, -N(R 1 0)S(0)2- or -S(=O)m-;
-mis 0, 1 or2;n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
W O97/36901 PCT~US97/05304 q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;
5 or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B:
R6a-e (R8)r R9a R3 f~
Rgb~ 4 wherem:
from 1-2 of f(s) are independently N or N->O, and the rem~ining f's are independently CH;
R l is selected from: hydrogen, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2, F
or Cl-C6 alkyl;
R2 is independently .selected from:
a) hydrogen, b) aryl, heterocycle, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3 and R4 are independently selected from:
a) hydrogen, - b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 - alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R 1 02N-C(NR 1 0)-, CN, N02, R 1 OC(O)-, N3, -N(R 1 0)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R I ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;
1~
R6a R6b R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsub.stituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R1o2N-c(NRlo)-~ CN, N02, RlOC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and - R1 1OC(O)-NR10; or CA 02249607 l998-09-23 any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a~ R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4 R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(O)NK 10, CN, NO2, (R 1 0)2N-C(NR 10) , R 10c(O)-, -N(R 1 ~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(o)NR 10, (R 1 0)2N-C(NR 10) , R I ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R~ i.s heterocycle, attachment of RX to V is through a ~substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, C1-C6 - aralkyl, C1-C6 .substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, WO 97/36901 PCT~US97/05304 2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently ,selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, 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) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and 15 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n ilS 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
20 X is a bond, -CH=CH-, -C(O)NR10-, -NRlOC(O)-, -NR10-, O or -C(=O)-;
mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
25 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 30 invention are illustrated by the formula C:
-R6a-e ~8~ 9 R3 V- A1(CR12)nA2(CR12) ~ f~
C R9b (CR22)p X R4 wherein:
from 1-2 of f(s) are independently N or N->0, and the remaining f 5 are independently CH;
R l is selected from: hydrogen, C3-CIo cycloalkyl, R100-, -N(R10)2, F
or Cl-C6 alkyl;
10 R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3 -C I o cycloalkyl, R 1 00-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) un~ubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i.s selected from unsubstituted or substituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, CN(R 1 0)2NC(0)-, R102N-C(NR10)-, CN, N02, R1OC(0)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m ~ R I OC(O)NR 10 (R 1 0)2NC(o)-R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R11OC(O) NR10;
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R 1 I S(O)m-~ R 1 OC(O)NR 10, CN(R 1 0)2NC(O)-, R 1 02N-C(NR 1 0) , CN, N02, R I ~C(O)-, N3, -N(R 1 ~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120, Rl lS(o)m, RlOc(o)NRlo-~ (R10)2NC(o)-, R 1 02N-C(NR 1 0) , CN, R 1 ~C(O)-, N3, -N(R 1 ~)2, and R 1 1 OC(O)-NR 10; or any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a~ R6b, R6C, R6d or R6e is ~ unsubstituted or substituted heterocycle, attachment of R3, R4 R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, i.s through a substitutable heterocycle ring carbon;
W O97136901 PCT~USg7/05304 R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(o)NR 10, CN, NO2, (R 1 0)2N-C(NR 1 0)-, R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(O)NR 10, (R 1 0)2N-C(NR 10) R 1 ~C(O)--N(R10)2, or Rl lOC(O)NR10-;
provided that when R~ is heterocycle, attachment of R~ to V i~
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, W O 97/36901 PCTrUS97/05304 b) heterocycle ~selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazol311 and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 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 A2 is S(O)m;
10 provided that when V is heterocycle, attachment of V to Rg and to Al is through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR 10 , -NR 1 ~C(O)-, -NR 10, O or -C(=O)-;
mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
and 20 r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illu~strated by the formula 25 D:
1 \ 2 ~ f\~, wherein:
W O 97136901 PCTrUS97/05304 from 1-2 of f(s) are independently N or N->0, and the remaining f's are independently CH;
5 R l is selected from: hydrogen, C3-Clo cycloalkyl or Cl -C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, R100-, -N(R10)2, F
or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R I ~)2;
lS R3 i.s selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, N02, R 1 ~C(0)-, N3, -N(R 1~)2 or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(0)NR 10 , (R 1 0)2NC(0)-, R 1 02N-C(NR 10), CN, R 1 ~C(0)-, N3, -N(R 1~)2, and R 1 1 0C(0)-NR 10;
- R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a, R6b, R6C, R6d and R6e are independently selected from:
W O97/36901 PCTrUS97/05304 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R I 1 S(O)m-~ R 1 0C(o)NR 10 , (R 1 0)2NC(O)-, R 102N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 I S(O)m-~ R 1 0C(o)NR 10 , (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R11OC(O)-NR10; or any two of R6a R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b, R6c, R6d or R6e j~;
unsubstituted or sub.stituted heterocycle, attachment of R3, R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-c6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(o)NR 10, CN, NO2, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and W O 97/36901 PCT~US97/05304 c) Cl-C6 alkyl sub.stituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(o)NR 10, (R 1 0)2N-C(NR 10), R 1 ~C(O)--N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R~s is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-c6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R 1 1 i,s independently selected from Cl -C6 alkyl and aryl;
R12 i.s independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 ~5 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
20 Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR~0-, O or -C(=O) -, n is 0 or 1; provided that n is not 0 if Al is a bond, O, -N(R10)- or S(O)m;
m is 0, 1 or 2; and pi.s 0, 1, 2, 3 or4;
30 or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
W O97/36901 PCT~US97/05304 ~N~R9a ~ ~ R6a-e Al (CR1 2)n~j ~N~ ~ ~
9b (CR22)p X' R4 ~¦~ E
r,8 n wherein:
from 1-2 of f(s) are independently N or N-~0, and the remaining f's 5 are independently CH;
Rl is selected from: hydrogen, C3-Clo cycloalkyl, R100-, -N(R10)2, F
or C I -C6 alkyl;
10 R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-CIo cycloalkyl, R100-, -N(R10)2, F
or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R 1 ~)2;
R3 i,s selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsub.stituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R I 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(0)-, R 1 02N-C(NR 10), CN, N02, R 1 ~C(0)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, W O 97/36901 PCTrUS97/05304 d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and K 1 1 OC(O)-NR 10;
R4 is selected from H, halogen, Cl-C6 alkyl and CF3;
R6a R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen, b) un.substituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R 1 1 S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2, or Rl lOC(o)NR10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-c6 alkyl is selected from un.substituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120, RllS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b, R6C, R6d or R6e i~
unsubstituted or substituted heterocycle, attachment of R3, R6~ R6b, R6C, R6d or R6e to the 6-membered hetero~ryl W O 97/36901 PCT~US97/05304 ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
Rf~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R l Oo, R 1 OC(o)NR 10, CN, N02, (R 1 0)2N-C(NR 10)-, R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R100-, R 10C(O)NR 10, (R 1 0)2N-C(NR10)- R 10c(O) -N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R8 is heterocycle, attachment of R~ to V is through a ~substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR 10 , -NR 1 ~C(O)-, -NR 10, 0 or 30 -C(=O)-;
n is O or l ;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not O if X is a bond or O;
W O 97/36901 PCTrUS97/05304 or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitor~s of farnesyl-protein transferase are illustrated by the formula F:
,~ R6a-e R9a\~= N \ ~
(~ (CR ~)p--NC F
wherein:
from 1-2 of f(s) are independently N or N->0, and the remaining fs are independently CH;
Rl is selected from: hydrogen, C3-CIo cycloalkyl or Cl-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3 -C l o cycloalkyl, R 1 00-, -N(R 1 0)2 or F, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1o cycloalkyl, R100-, or-N(Rl0)2;
20 R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 1 l S(O)m-~ R l OC(O)NR 10, (R l 0)2NC(0)-, R 1 02N-C(NR 1 0), CN, N02, R I ~C(0)-, N3, -N(R 1 ~)2, or R 1 1 OC(O)NR 10 - c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(o)m, RlOc(o)NRlo-~ (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10-;
10 R4 is selected from H, halogen, CH3 and CF3;
R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R I I S(O)m-, R 1 OC(O)NR 10-, (R 1 0)2NC(o)-, R 1 02N-C(NR 10)-, CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsub~stituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O~m-~ R 1 OC(O)NR 1 0-, (R 1 0)2NC(O)-, R102N-c(NRlo)-~ CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10; or any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b~ R6C, R6d or R6e is unsubstituted or sub.stituted heterocycle, attachrnent of R3, W O 97/36901 PCT~US97/05304 R6a R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 i.s independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, C1-C6 ,substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR 1 0-, -NR l OC(O)-, -NR 10-, O or -C(=O) -;
m is 0, 1 or 2; and pi,s 0, 1, 2, 3 or4;
or the pharrnaceutically acceptable salt.s thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula G:
R3 ~ R6a-e NC 3 . .
wherein:
from 1-2 of f(s) are independently N or N-~O, and the rem~ining fs are independently CH;
Rl is selected from: hydrogen, C3-CIo cycloalkyl, RlOO-, -N(RI0)27 F or Cl-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-Clo cycloalkyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, RIOO-~ or -N(R 1 ~)2;
R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or ,substituted heterocycle, C3-CIo cycloalkyl, C2-C6 a Ikenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R I I S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted C l -C6 alkyl wherein the .substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, RllS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;
R4 is selected from H, halogen, CH3 and CF3, W O 97/36901 PCTrUS97/0~304 R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R102N-C(NR10)-, CN, NO2, RlOC(O)-, N3, -N(Rl0)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, lO d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R I l S(O)m ~
R l OC(O)NR l O, (R I 0)2NC(O)-, R 1 02N-C(NR 1 0) , CN, RlOC(O)-, N3, -N(Rl0)2, and Rl lOC(O)-NRlO-; or any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -C~=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b~ R6C, R6d or R6e is unsub.stituted or sub,stituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R l l is independently selected from Cl -C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 ,substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and 10 n is 0 or 1;
or the pharmaceutically acceptable salts thereof.
Preferred compounds of the invention are:
1 -(2-Phenylpyrid-5 -ylmethyl)-5 -(4-cyanobenzyl)imidazole 1 -(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 20 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole I -(3-Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole I -(2-(3 -Trifluoromethoxyphenyl)-pyrid-S-ylmethyl)-5-(4-25 cyanobenzyl)imidazole I -(2-(2-Trifluoromethylphenyl)-pyrid-S-ylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(3 -Phenyl-2-Chloropyrid-6-ylmethyl)-5 -(4-cyanobenzyl)imidazole CA 02249607 l998-09-23 W O 97/36901 PCT~US97/05304 1 -(3 -Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole and I -(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
Specific examples of the compounds of the instant invention are:
I -(2-Phenylpyrid-5 -ylmethyl)-5 -(4-cyanobenzyl)imidazole NC
N-~
1 -(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole NC~
~ N~
or the pharmaceutically acceptable salts thereof.
The compounds of the present invention may have a.symmetric centers and occur as racemates, racemic mixtures, and a.s individual diastereomers, with all possible isomers, including optical W O 97/36901 PCTrUS97105304 isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, Rl, R2 etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables are 5 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 10 of carbon atoms attached through an oxygen bridge.
As used herein, "cycloalkyl" is intended to include non-aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds.
Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, I-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
"Alkynyl" groups include tho.se groups having the .specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl," and the aryl portion of aroyl and aralkyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or - acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable ~- to WO 97/36901 PCTrUS97/05304 1 I-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, O, and S, and including any bicyclic group in which any of the above-defined 5 heterocyclic rings is fused to a benzene ring. ~he 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, 10 benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, 1~ naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, 20 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 25 consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzi.soxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, 30 dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, - oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, WO 97/36901 PCT/US971û5304 - tetrahydroisoquinolinyl, tetrahydro4uinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
As used herein in the definition of R3, R4, R5 and R6a-e, the term "the substituted group" is intended to mean a substituted C1 8 S alkyl, substituted C2 8 allcenyl, sub.stituted C2 ~ alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R3, R4, R5 and R6a-e are selected.
As used herein in the definition of R7, the substituted Cl alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, 10 substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl-sulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
As used herein, when no specific substituents are set forth, 15 the terrns "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl)2~ NO2, CN, (cl-c6 alkyl)O-, -OH, (Cl-C6 20 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl-C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(CI-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and Cl-C2o alkyl.
Lines drawn into the ring systems from substituents (such 25 as from R3, R4, Q etc.) means that the indicated bond may be attached to any of the substitutable ring carbon atoms.
The substituent illustrated by the structure ,~
R6a-e is a simplifled representation of a phenyl ring having five (5) 30 substituents (hydrogens and/or non-hydrogens) and may also be represented by the structure W O97/36901 PCTrUS97/05304 - 3~ -R6b R6a~ R6c ~R6d R6e The moiety described as ~5, R6a-e where any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon S atoms are combined to form a diradical selected from -CH=CH-CH=CH, -CH=CH-CH-, -(CH2)4- and -(CH2)4- includes the following structures:
It is understood that such fused ring moieties may be further substituted 10 by the rem~ining R6a, R6b, R6C~ R6d and/or R6e as defined hereinabove.
The moiety designated by the following structure f"f~
~,f represents an aromatic 6-membered heterocyclic ring and includes the 15 following ring systems:
W O 97/36901 PCTrUS97/05304 N~ N ~- N ~, O~
N~ N~
,~N ~, N~N ~N ,~.,~N~
The moiety designated by the following structure , f ' ~.,~f' represents an aromatic 6-membered heterocyclic ring and includes the S following ring systems:
N
~J,\~N~,J N~"N ,~N
O O
N~N N~N HN NH N
~0 ~
wherein it is understood that one of the ring carbon atom.s is substituted with ~, R6~-e CA 02249607 l998-09-23 W O97/36901 PCT~US97/05304 Preferably, the aromatic 6-membered heterocyclic ring is a pyridyl ring.
Preferably, Rl and R2 are independently selected from:
hydrogen, R 1 1 C(0)0-, -N(R 1 ~)2, R 1 OC(O)NR 10 R l Oo or 5 unsubstituted or substituted Cl-c6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i.s selected from unsubstituted or substituted phenyl, -N(R 1 ~)2, R l ~O and R 1 OC(O)NR 10 Preferably, R3 is selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, CN, N02, R 1 ~C(0)- or -N(R 1~)2, c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(0)-, R102N-C(NR10)-, CN, RlOC(0)-, N3, -N(R10)2~ and R 1 1 0C(O)-NR 10 Preferably, R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and Cl-C6 alkyl.
Preferably, R5 is hydrogen.
Preferably R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, CN, N02, RlOC(0)- or -N(R10)2, c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, C3-C1o cycloalkyl, R120-, Rl lS(O)m-, - R 1 ~C(0)- or -N(R 1~)2; or any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3--Preferably, R8 is independently .selected from:
S a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C6 perfluoroalkyl or CN.
Preferably, R9 is hydrogen, halogen, CF3 or methyl.
Preferably, R10 is selected from H, Cl-C6 alkyl and 1 0 benzyl.
Preferably, A 1 and A2 are independently selected from:
a bond, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10), -S(O)2N(R 10) and-N(R I ~)S(O)2-.
Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
Preferably, n and r are independently 0, 1, or 2.
Preferably .s is 0.
Preferably t is 1.
Preferably, the moiety / \
(18)' Ç~9~\
V - A1(CR12)nA2(CR12)n tW~ - (CR22)p - X -(CR22)p -~-is selected from:
W O 97/36gO1 PCTrUS97/05304 R9a R9b >= N \) N
~ R~b and ~ ~ R~'a NC NC
It is intended that the definition of any substituent or variable (e.g., Rl, R2, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule.
5 Thus, -N(R 1 0)2 represents -NHH, -NHCH3, -NHC2Hs, etc. It is understood that sublstituent,s 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 tho.se methods 10 set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of thi.s invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those 15 derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitrlc 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, 20 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 25 methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired ~salt-forming inorganic or organic acid in a .suitable ,solvent or variou.s combinations of solvent~s.
CA 02249607 l998-09-23 W O 97/36901 PCTrUS97/05304 Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-21, in addition to other standard manipulations such a,s ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature 5 or exemplified in the experimental procedures. Substituents R3, R6 and R~, as shown in the Schemes, represent the substituents R3, R4, R5, R6a, R6b, R6C, R6d, R6e and R~; although only one such R3, R6 or R8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such 10 aryl or heteroaryl moieties contain multiple substituents.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. The reactions described in the 15 Scheme.s are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein.
Aryl-aryl coupling is generally described in "Comprehensive Organic 20 Functional Group Transformations," Katritsky et al. eds., pp 472-473, Pergamon Press (1995).
SynopsisofSchemes 1-21:
The re~uisite intermediates are in some cases commercially 25 available, or can be prepared according to literature procedures, for the most part. Schemes 1-12 illustrate synthesis of the instant aryl-heteroaryl compound which incorporate a preferred benzylimidazolyl sidechain. Thus, in Scheme 1, for example, a arylheteroaryl inter-mediate that is not commercially available may be synthesized by 30 methods known in the art. Thus, a suitably substituted phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl.
Chem., 63:419 (1991)) with a suitably substituted halogenated nicotinic acid, such as 4-bromonicotinic acid, to provide the arylheteroaryl carboxylic acid Il. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
Schemes 2-4 illustrate other methods of synthesizing the 5 key alcohol intermediates, which can then be processed as described in Scheme 1. Thus, Scheme 2 illustrates the analogous series of arylheteroaryl alcohol forming reactions starting with the methyl nicotinate boronic acid and the "terminal" phenyl moiety employed in the Suzuki coupling as the halogenated reactant. Such a coupling I0 reaction is also compatible when one of the reactant.s incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 3.
Negishi chemistry (Org. Synth., 66:67 (19~)) may also be employed to form the arylheteroaryl component of the instant compounds, as shown in Scheme 4. Thus, a suitably substituted zinc 15 bromide adduct may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the arylheteroaryl VIl.
The heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
Scheme 5 illu.strates the preparation of a suitably substituted 20 biphenylmethyl bromide which could also be utilized in the reaction with the protected imidazole as described in Scheme 1.
As illustrated in Scheme 6, the sequence of coupling reactions may be modified such that the aryl-heteroaryl bond i~s formed last. Thus, a suitably substituted imidazole may first be alkylated with 25 a suitably substituted benzyl halide to provide intermediate VIII.
Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid.
Scheme 7 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
30 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.
W O97136901 PCTrUS97105304 Scheme 8 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkyl-imidazole XII, wherein the primary amine is protected as the phthali-mide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR I 2)n linker i.s oxygen may be synthesized by methods known in the art, for example as shown in Scheme 9.
The suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as de.scribed for the benzylimidazoles hereinabove.
Scheme 10 illustrates an analogous series of reactions wherein the (CR22)pX(CR22)p linker of the instant compounds is oxygen. Thus, a suitably sub.stituted halopyridinol, such as 3-chloro-2-pyridinol, is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI. Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a aryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR 1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 11. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard condition~s 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.
W O 97/36901 PCT~US97/05304 Addition of various nucleophiles to an imidazolyl aldehyde may also be employed to form a substituted alkyl linker between the biheteroaryl and the preferred W (imidazolyl) as shown in Scheme 12.
Thus an aryllithium can be reacted with pyridine to form the 2-5 substituted N-lithio-1~2-dihydropyridine XXa. Intermediate XXa can then react with a aldehyde to provide a suitably substituted instant compound. Similar substituent manipulation as shown in Scheme 11 may be performed on the fully functionalized compound which incorporates an R2 hydroxyl moiety.
SCHEME I
~ R6 Nll,Br (HO)2B/~
R2 Pd(PPh3)4 ~N~,~ LiAlH4 HObJ~,\~ 2 ~ ~1 -W O 97/36901 PCTrUS97/05304 SCHEME I (continued) NiCI2(P~h~
~il R6 ~N~ (C F3SO2)20, -78~C ~
HO~'\R2 NEtiPr2 -78~C-20~C
~I N~ R6 R8 1~--R6 ~ N~\~
R8/~l V
CA 02249607 l998-09-23 ,B(OH)2 ~--R6 o R2 Pd(PPh ~)4 ~N~ LiAlH4 MeO~,\
o R2 ~f3 ,R6 HO~,\
~R6 N~ B(~H)2 ~l~
R3SiO~J~\
\R2 Pd(PPh3)4 ~ R6 N ~ ~ Bu4NF
R3SiO~\R2 N~_ - R6 HO~\R2 R SiO~J~,~ (HO)2B
R2 Pd(PPh3)4 ~, R6 N ~J Bu4NF
R3SiOJ~'~R2 ~J3 R6 HOJ~'\R2 W O 97/36901 PCT~US97/05304 ~/ BrZn/~
R3SiOJ~
R2 NiCl2(Pph3)2 N ~ R 6 R3SiO Vll R2 1~--R6 ~N
~J~ 2 Zn l "~--R 6 R2 NiCI2(PPh3)2 ~N~ Bu4NF
R3SiO,~,\R2 ~,N
J~ 2 WO 97/36901 PCr/US97/05304 SCHEME S
H3C~ 2 LiAlH4 ~J3--R6 ~ R6 J~ ~ (HO)2B KMnO4 H3C ~R2 Pd(PPh3)4 N~ R6 LiAlH4 HO2C ~\ 2 HoJ~,\
W O 97/36901 PCT~US97/05304 Tr R2 N~ Br~J~N
~N j;. MeOH
~J reflux R8/~l ~_~N~ ~ (HO)2B
R8 Vlll ~, R6 ~N ~,\,N
W O 97/36901 PCTrUS97/05304 S C~DE~DE 7 H H
R9b~ Nal, NaHCO3,!2 Rgb~ T , 3 IX X
Tr~ N
R9b~, ~INiCI2(PPh3)2, ~N
R8~\ZnBr v~J
~ 6 Tr~ ~N ~ R
~/ i. -78~C-20~C
~/~ ii. MeOH, reflux Xl 9b ~I R2 W 097/36901 rCT~US97/05304 SCHEME
0~
i. ~~Br <\ ~ ~ 55~C,CH3CN
N N~i. EtOH,80~C, NH2NH2 o Xll N
N~NH2 R 8 ~ /
Xlll acylation, sulfonylation </ ~ ~ R2 o;alkylation R8 ~ I HN~/~
N ~" "~ R2 R6 N N ~S~/
</ 3--N~/
R8 ~J N~
~ OH i, Na, MeOH
NC ~/ ii. 1 20~C
XIV H3C~o ~N--~N
H Tr~
N N
~N TrCI, NEt3 , ~N
NC~ NC~
XV XVI
~ R6 TrN~ 78~C-20~C
ii. MeOH reflux NC ~ OTf XVI
<~-- ~ R6 ~
NC ~\~
N
~N OH i, Na, MeOH ~ N
Cl~ ii. 120~C q_N\~o R2 H3C~o Ci~ \J
N~ R2 XVI
~/~
Tr~ ~
N
TrCI. NEt3 . ~ N
N 1~ i -78~C-20~C
~~ ii. MeOH reflux Cl \~\J
R2 R8 ~B(OH)2 N ~ J~ R6 ~
Cl~ \~O DMF, Pd(PPh3)4 ~ K3PO4, 80~C
N ~ ~
'~;~'~~
W O 97136901 PCTrUS97/05304 Tr~
Tr~ ~N~
~N~ EtMgBr ~ N
~_N ~ ~\OH
Tr~ ~ R6 Ac20, PY <~ N HO ~\ 2 ~OA (CF3S02)20,-780c NEtiPr2,CH2cl2 ~OAc R2 ~\ R .
~OH
CA 02249607 l998-09-23 W O97/36901 PCT~US97/05304 SCHEME 11 (continued) ~N~J~ ~NH3, MeOH
/J Cl ~J NH2 +
~- R6 ~_ N ,~
~/ OMe _ 59 _ Li N~
N
¢~ R' N
~/ OH
/~
W O 97136901 PCTrUS97/05304 Schemes 13-21 illustrate reactions wherein the moiety (R8) /~9~
V - A1 (CRl 2)nA2(CR 12)n ~W ,,~ - (CR12)p-X
incorporated in the compounds of the instant invention is represented by other than a substituted imidazole-cont~ining group.
Thus, the interrnediates whose synthesis are illustrated in Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid.
Lithioheteroaryl chemistry may be utilized, a,s shown in Scheme 13, to incorporate the arylheteroaryl moiety. Thus, a suitably substituted arylheteroaryl N-lithio reagent is reacted with an aldehyde to provide the C-alkylated instant compound XXI. Compound XXI can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII. The final product XXII
may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product di~mine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. I~emoval of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures.
If the arylheteroaryl subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI
in Scheme 14, the protecting groups can be subsequently removed to nm~k the hydroxyl group (Schemes 14, 1~). 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 W 0 97/36901 PCTrUS97/05304 alkyl lithium reagents, to obtain secondary alcohols such as XXX.
In addition, the fully deprotected amino alcohol XXXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such a,s XXXII
5 (Scheme lS), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as XXXIII
(Scheme 16). Treating XXVIII with l,l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the lO formation of aziridine XXXIII . The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIV .
In addition, the arylheteroaryl subunit reagent can be reacted with aldehydes derived from amino acids such as O-alkylated 15 tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 17. When R' is an aryl group, XL can first be hydrogenated to llnm~k the phenol, and the amine group deprotected with acid to produce XLI. Alternatively, the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII
20 produced.
Schemes 1P~-21 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for 25 variable W are also well known in the art.
Boc NH
6 Boc NH CHO
R6 1. catalytic ~/ hydrogenation HO ~ ~ 2. CF3CO2H
Boc NH~
NHBoc XXI
~ i CH2CI2 N~,~R6 CHO
BocN H ~/
\~ NaBH(OAc)3 NH2 Et3N, CICH2CH2CI
XXIII
SCHEME 13 (continued) BocNH~ CF3CO2H, CH2C12, ~=~ NH NaHCO3 ~~ XXIV
NH~ ~ NC
NH AgCN
,~, R6 N~N~
~ XXV
~3 PCTrUS97/05304 ~R6 E120 BocNH CHO
XXVI
BnO HO ~=N ~=~ R6 20% Pd(OH)2 H2 NHBoc CH3C02H
HO r¦ N /=\~ R CICOCOCI
\_~ DMSO CH2CI2 (c2H5)3N
NHBoc XXVII
W O 97/36901 PCTrUSg7/05304 SCHEME 14 (continued) /~1 ~ R
~~ R'MgX
H NHBoc XXIX
R'~ R6 NHBoc XXX
\ ~ CH2CI2 NHBoc XXVIII
~=¦N /=~R RCHO
HO~ NaBH(OAC)3 XXXI
~)~S R6 NH
R'CH2 XXXII
WO 97/36901 PCTtUS97/05304 H H
R2 N =\~= N
HO~f ~R6 ~N S \~
NHBoc XXVIII
,=¦ N ~=, R"SH
, I CH30H
NH
XXXIII
R"S~ R6 XXXIV
; ~3 1 ) Boc20, K2C03 )~
H2NCO2H2) CH2N2, EtOAc XXXV XXXVI
HO~,~
LiAlH4 ~,~ R"'CH2X
THF J~ Cs2CO3 0-20~C BocNH CH2OH DMF
XXXVII
R"'CH2~~, R"'CH20 (C
BocNH CH2OH 20~C BocNH CHO
XXXVIII IXL
SCHEME 17 (continued) R"'C H~3 ¢~
BocNH CHO R6 IXL / ~ R"' not aryl Et20 /
2. 20% Pd(OH)2, H2 CH30H, CH3CO2H
3. HCI, EtOAc ~ho~ ~=¦ N /=\~ R6 R"'C H20 \~
NHBoc 2. 20% Pd(OH)2, H2 CH30H, CH3C02H
/~\ R2 2) HCI, EtOAc / ~ ~=¦ N /=\~R
/ R"'CH20 HO~R6 XLII
XLI
-W O 97/36901 PCTrUS97/05304 ~CH3 1) HNO2,Br2 ~CO2CH3 ~ 2) KMnO4 r H2N N 3) MeOH, H+ Br N
~\ MgCI R~,CO2CH3 Zncl2~Nicl2(ph3p)2 NaBH4 (excess) ~ ;CH20H
DM50 ~,CHO
WO 97/36901 PCT/US97/0~304 1. EtO(CO)CI R6 2 ~ [~,,COzCH3 N 3. S, xylene, heat N
NaBH4 ~j~ SO3Py, Et3N ~
(excess) ~3,CH20H DMSO ~CHO
Br~,CO CH l~l/\MgCI ¢~
ZnCI2, NiC12(Ph3P)2 N
NaBH4 ~ SO3Py, Et3N ¢~~CH20H ~ ~,CHO
(excess) N DMSO N
W O 97/36901 PCTrUS97/05304 C~2C H3 Br~1. LDA, CO2 Br~
N2. MeOH, H+ N
~MgCI ~2CH3 ZnCI2, Nicl2(ph3p)2 N
NaBH4 (excess) ~3OH SO3 Py, Et3N
DMSO
N
CHO
N~
C~2C H3 [~3~ 1 LDA, CO2 ~Br 2. (CH3)3sicHN2 R6 ~\Br R6. 3~
Zn, NiC12(Ph3P)2 N~C02CH3 R6 ~
excess NaBH4 I~J~ SO3 Py, Et3N
N~CH20H DMSO
R6 1~
N ~,CHO
The instant compounds are useful as pharmaceutical agents for m~mm~ls, especially for humans. These compounds may be a~lmini~tered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this 5 invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-l), neu, scr, abl, Ick, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
The instant compound.s may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. 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 (i.e., the Ras gene itself is not activated by mutation to an oncogenic forrn) with said inhibition being accomplished by the a~lministration of an effective amount of the compounds of the invention to a m~mmal in need of such treatment. For example, a component of NF-I 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 (J.S. 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 (C. 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 (D.L. Schaffner et al.
Ameri~an Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al .FASEB Journal, 2:A3 160 ( 19~8)).
The instant compounds may also be useful for the treatment of fungal infections.
The compounds of this invention may be administered to m~mmals, 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 ~f~ministered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound accord-ing to this invention, the selected compound may be ~lministered, for example, in the forrn 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 u.se, 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-~-lministered 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-l, restinosis, polycystic W O97/36901 PCTrUS97/05304 kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed do,se, such combination products employ the compounds of this invention within the dosage range 5 described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
The present invention also encompasses a pharmaceutical 10 composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compound.s of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include a(lueous solutions comprising compounds of this invention and pharmacolo-15 gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. Thesolutions 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 20 amounts, as well as any product which result.s, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is a~lministered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally 25 varying according to the age, weight, and response of the individual patient, as well a.s the severity of the patient's symptoms.
In one exemplary application, a suitable amount of compound is ~dministered to a m~mm~l undergoing treatment for cancer. A-lmini.stration occurs in an amount between about O.l mg/kg 30 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 farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine 5 terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known 10 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 15 assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quanti-20 tating the enzyme. Thus, potent inhibitor compounds of the instantinvention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase 25 (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 (i.e., one that has a Ki substantially smaller than the concentration of enzyme in 30 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.
W O97/36901 PCT~US97/05304 EXAMPLES
Examples provided are intended to assist in a further understanding of the illvention. Particular material~s employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.
1 -(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: l -Trityl-4-(4-cyanobenzyl)-imidazole To a ~suspension of activated zinc du.st (3.57g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon at 20~C. The suspension was cooled to 0~C and a-bromo-p-tolunitrile (9.33g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes.
The reaction was then allowed to stir at 20~C for 6 hours and bis(triphenylphosphine)Nickel II chloride (2.4g, 3.64 mmol) and 4-iodo-1-tritylimidazole (15.95g, 36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739 (1991)) were added in one portion.The resulting mixture was stirred 16 hours at 20~C and then quenched by addition of sat. a4. NH4CI solution (100 mL) and the mixture stirred for 2 hours. Saturated aq. NaHCO3 solution w;~ added to give a pH
of ~ and the solution was extracted with EtOAc (2 x 250 mL), dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc in CH2C12 to afford the title compound as a white solid.
lH NMR (CDC13, 400MHz) ~ 7.54 (2H, d, J=7.9Hz), 7.3~(1H, s), 7.36-7.29 (1 lH, m), 7.15-7.09(6H, m), 6.5~(1H, s), and 3.93(2H, s)ppm.
Step B: 2-Phenyl-5-methylpyridine A mixture of 2-bromo-5-methylpyridine (2.00 g, 11.63 mmol), phenylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50g, 17.4 mmol), DME (80 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenylphosphine)palladium(0) (672 mg, 0.5~ mmol) was added, and the resultant solution was stirred at 80~C for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1 M
a4. HCI. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5~o aq. Na2S203, dried (Na2S04), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, CH2C12) to afford the title compound.
IH NMR (CDC13, 400MHz) ~ ~.52 (lH, s), 7.96(2H, d, J=7.0Hz), 7.63(1H, d, J=8.0Hz), 7.55(1H, brd, J=~.OHz), 7.50-7.35(3H, m), and 2.37(3H, s) ppm.
Step C: 2-Phenyl-5-carboxypyridine A suspension of 2-phenyl-5-methyl pyridine (1.03g, 6.09 mmol) and potassium permanganate (2.~9g, 1 ~.3 mmol), in water (25 mL) was heated at reflux for 2 hours. The reaction was allowed to cool to ambient temperature and filtered throu~h celite to remove the solids. Acetic acid (I mL) was added to the colourles.s filtrate and the product was collected as a white solid by filtration.
1 H NMR (CD30D, 400MHz) ~ 9.1 ~(1 H, s), ~ .41 (1 H, dd, 2.2 and 8.2Hz), ~.0~-~.02(2H, m), 7.97(1H, dd,3=~.2 and 0.7Hz) and 7.56-7.46(3H, m) ppm.
Step D: 2-Phenyl-5-hydroxymethylpyridine To a solution of 2-phenyl-5-carboxypyridine (520 mg, 2.61 mmol) in tetrahydrofuran (10 mL) at 0~C was added 1.0 M
- lithium aluminum hydride in tetrahydrofuran (2.61 mL, 2.61 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours, cooled to 0~C, and quenched by dropwise W O97/36901 PCT~US97/053~4 addition of water (0.20 mL), 4 N aq. NaOH (0.20 mL), and water (0.60 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 0-5% MeOH in CH2C12) to afford the title compound.
1H NMR (CDC13, 400MHz) ~ 8.66(1H, s), 7.97(2H, d, J=7.9Hz), 7.82-7.70(2H, m), 7.52-7.38(3H, m), 4.77(2H, s) and 1.89(1H, brs) ppm.
Step E: 1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt To a solution of 2-phenyl-5-hydroxymethylpyridine (264 mg, 1.43 mmol) and diisopropylethylamine (0.522 mL, 3.00 mmol) in dichloromethane (10 mL) at -78~C was added trifluoro-methanesulfonic anhydride (0.252 mL, 1.50 mmol) and the mixture stirred at -78~C for 15 minutes. To this mixture wa,s added a solution of l-trityl-4-(4-cyanobenzyl)imidazole (608 mg, 1.43 mmol) in dichloromethane (9 mL). The mixture was allowed to warm to ambient temperature and stirred for 16 hour~. The solvent was evaporated in vacuo. The residue was dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-5% NH40H in CH2C12). The amine was converted to the HCI salt by treatment with 1.0M HCI
in aqueous acetonitri~e. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
FAB MS 351 (MH+) lH NMR (CD30D, 400MHz) ~ 8.38(1H, d, J=2.4Hz),7.97(2H, m), 7.64(1H, d, J=8.2Hz), 7.60(1H, s), 7.56-7.40(5H, m), 7.28-7.20(1H, m), 7.17(2H, d, J=8.0Hz), 6.97(1H, s), 4.96(2H, s) and 3.89(2H, Is) ppm.
1 -(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt l -(2-Phenylpyrid-5-ylmethyl)-5 -(4-cyanobenzyl) 5 imidazole hydochloride (66.7mg, 0.159 mmol) was partitioned between CH2CI2 (lmL) and sat. aq. Na2CO3 (1 mL). The organic layer was separated, dried, (MgSO4) and the solvent evaporated in vacuo. The residue was dissolved in CH2Cl2 (2 mL), 3-chloro-perbenzoic acid (109 mg, 0.506 mmol) was added and the solution 10 stirred at ambiant temperature for 16 hours. The reaction was partitioned between CH2Cl2 (5mL) and sat. aq. Na2CO3 (2mL) and the organic layer separated, dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel 4-10% MeOH in CH2CI2). The amine wa,s converted to the HCI salt 15 by treatment with 1.0M HCl in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
lH NMR (CD30D, 400MHz) ~ 9.18(1H, s), 8.13(1H,s), 7.80-7.20(12H,m), 5.53(2H,s) and 4.28(2H,s) ppm.
1 -(3 -Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt 25 Step A: 3-Phenyl-6-carboxypyridine A suspension of 3-phenyl-6-methyl pyridine (1.99g, 11.7~ mmol) and potassium permanganate (7.65, 48.6 mmol), in water (50 mL) was heated at reflux for 16 hours. The reaction was allowed to cool to ambient temperature and filtered through celite 30 to remove the solids. Acetic acid (2 mL) was added to the colourlesls filtrate and the product was collected as a white solid by filtration.
1H NMR (CD30D, 400MHz) ~ 8.86(1H, s), 8.15(2H,m), 7.70(2H,d, J=6.7Hz) and 7.60-7.30(3H,m) ppm.
35 Step B: 3-Phenyl-6-hydroxymethylpyridine W O 97/36901 PCT~US97/05304 To a solution of 3-phenyl-6-carboxypyridine (l.OSg, 5.27 mmol) in tetrahydrofuran (25 mL) at 0~C was added 1.0 M
lithium aluminum hydride in tetrahydrofuran (10.0 mL, 10.0 mmol) over 10 minutes. The reaction was allowed to stir at ambient 5 temperature for 6 hours, cooled to 0~C, and quenched by dropwise addition of water (0.50 mL), 4 N aq. NaOH (0.50 mL), and water (1.5 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue wa.s chromatographed (silica gel, 0-5% MeOH in CH2CI2) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ ~.79(1H, d, J=l.OHz), 7.~s~s(1H, dd, J=~.6 and l.SHz), 7.5~(2H,d, J=6.7Hz), 7.49(2H,t, J=7.0Hz), 7.41(1H,t, J=7.0Hz), 7.33(1H,d, J=7.6Hz), 4.83(2H,s) and 3.75(1 H,brs) ppm.
~5 Step C: 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride.salt To a solution of 3-phenyl-6-hydroxymethylpyridine (192 mg, 1.04 mmol) and diisopropylethylamine (0.360 mL, 2.07 mmol) in dichloromethane (8 mL) at -7~~C was added trifluoro-20 methanesulfonic anhydride (0.1 ~0 mL, 1.07 mmol) and the mixturestirred at -78~C for 1 hour. To this mixture wa~s added a solution of 1-trityl-4-(4-cyanobenzyl)imidazole (441 mg, 1.04 mmol) in dichloromethane (9 mL). The mixture was allowed to warm to ambient temperature and stirred for 4 hour.s. The solvent was 25 evaporated in vacuo. The residue was dissolved in methanol (10 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chroma-30 tographed (Silica gel, EtOAc and then 5% MeOH in CH2C12). Theamine was converted to the HCI salt by treatment with 1.0M HCI in - aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
WO 97/36901 PCItUS97/05304 FAB HRMS exact mass calcd for C23H19N4 351.160972 (MH+);
found 351.161206.
1 H NMR (CD30D, 400MHz) ~ 9.20(1 H, d, J= 1.4Hz), 8.75(1 H, d, J=2.2Hz), 8.16(1H, d, J=8.20), 7.66 (2H, d, J=8.4Hz), 7.60-7.40(7H, 5 m), 7.26(2H, d, J=8.0Hz), 5.73(2H, s) and 4.27(2H, s) ppm.
Anal. Calcd. for C23Hl~N4-2.00 HCI 0.80 H2O:
C, 63.11; H,4.97; N, 12.80.
Found: C, 63.10; H, 4.97; N, 12.95.
1 -(3 -Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt 1 -(3 -Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl) 15 imidazole hydochloride (100.Omg, 0.236mmol) was partitioned between CH2CI2 (2mL) and sat. aq. Na2CO3 (lmL). The organic layer was separated, dried, (MgSO4) and the solvent evaporated in vacuo.
The residue was dissolved in CH2CI2 (2 mL), 3-chloroperbenzoic acid (143mg, 0.472 mmol) was added and the solution .stirred at 20 ambient temperature for 16 hours. The reaction was partitioned between CH2Ck (SmL) and sat. a4. Na2CO3 (2mL) and the organic layer separated, dried, (MgSO4) and the solvent evaporated in vacuo.
The residue was chromatographed (Silica gel 4-10% MeOH in CH2CkThe amine wa,s converted to the HCl salt by treatment with 25 1.0M HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
lH NMR free base (CDC13, 400MHz) ~ 8.44(1H, d, J=l.SHz), 7.63(1H,s), 7.60-7.20(10H,m), 7.03(1H,s), 6.35(1H,d, J=~.2Hz), 5.29(2H,s) and 3.96(2~,s) ppm.
EXAMPLE S
1 -(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt W O97/36901 PCT~US97/05304 Step A: 2-(3-Trifluoromethoxyphenyl)-S-methylpyridine To a solution of 3-bromotrifluoromethoxybenzene (0.590mL, 4.00 mmol) in THF (12 mL) at -7~~C was added t-butyl 5 lithium (4.71mL, of a 1.7M solution in pentane, ~.00 mmol. After 10 minutes zinc chloride(4.0mL, of a IM solution in diethylether, 4.00 mmol) wa,s added. The reaction was stirred for 10 minutes at -78~C and then allowed to warrn to 0~C and stirred for 30minutes.
This solution was added via cannula to a solution of 2-bromo-5-10 methyl pyridine and bis(triphenylphosphine) Nickel II chloride. The reaction stirred for I hour at 0~C and then at ambient temperature for a furthur 1 hour. Saturated ammonium hydroxide ,solution (3 mL) was added and the mixture stirred until homogenous, extracted with Et20 and the organic extracts washed with saturated brine, 15 dried (MgSO4) and evaporated in vacuo. The residue was chromato~raphed (Silica gel, 25-50% CH2CI2 in hexanes).
lH NMR (CD30D, 400MHz) a ~.4~S(1H~ s),7.93(1H, brd, J=8.0Hz), 7.~7(1H, s), 7.79(2H, d, J=8.0Hz), 7.74(2H, d, J=~.OHz), 7.56(1H, t, J=8.0Hz), 7.32(1H, brd, J=~.OHz) and 2.40(3H, s) ppm.
Step B: 2-(3 -Trifluoromethoxyphenyl )-5-carboxy pyridine A solution of 2-(3-Trifluoromethoxyphenyl)-5-methylpyridine (2.35g, 2.22 mmol) and tetrabutylammonium permanganate (1.904, 0.012mol), in pyridine (8 mL) was heated 25 at 75~C for 16 hours. The cooled reaction was filtered through celite to remove the solids. The solid was washed with EtOAc and MeOH
and the filtrate evaporated in vacuo to afford the title compound of sufficient purity to be used in the next step.
30 Step C: 2-(3-Trifluoromethoxyphenyl)-5-hydroxymethylpyridine - To a solution of 2-(3-trifluoromethoxyphenyl)-5-carboxy pyridine (2.0 g, 7.06 mmol) in tetrahydrofuran (15 mL) at 0~C was added 1.0 M lithium aluminum hydride in tetrahydrofuran W O 97/36901 PCTAUS97/0~304 (7.07 mL, 7.07 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 4 hours, cooled to 0~C, and quenched by dropwise addition of saturated Na2SO4 (1.0 mL). The reaction was diluted with diethylether, filtered through a pad of 5 Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 50% EtOAc in hexane,s) to afford the title compound.
1 H NMR (CD30D, 400MHz) ~ 8.62(1 H, d, J= I .OHz), 8.00-7.84(H,m), 7.57(1H, t, J=8.0Hz), 7.33(1H,brd, J=8.0Hz) and 10 4.~4(2H,s) ppm.
Step D: 1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt To a solution of 2-(3-trifluoromethoxyphenyl)-5-15 hydroxymethylpyridine (66 mg, 0.25 mmol), diisopropylethylamine (0.085 mL, 0.49 mmol), and 1-trityl-4-(4-cyanobenzyl)imidazole (105 mg, 0.25 mmol) in dichloromethane (1.4 mL) at -7~~C was added trifluoromethanesulfonic anhydride (0.041 mL, 0.25 mmol) and the mixture stirred at -7~~C for 1 hour. The reaction wa.s 20 allowed to warm to ambient temperature and stirred for 4 hours.
The solvent was evaporated in vacuo. The re,sidue wa~s dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloro-methane and sat. aq. Na2CO3 solution. The organic layer was dried, 2~S (Na2SO4) and the solvent evaporated in vacuo. The residue wa.s chromatographed (Silica gel, 3% MeOH in CH2Ck). The amine was converted to the HCI salt by treatment with 1.0M HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
IH NMR (CD30D, 400MHz) ~ 9.23(1H, s), 8.67(1H,s), ~.18-- 8.04(2H, m), 8.00-7.90(2H,m), 7.74(1H, t, J=7.9Hz), 7.62-7.50(4H, m), 7.31(2H, d, J=7.9Hz), 5.71(2H, s), 4.29(2H, .s) ppm.
W O 97/36901 PCT~US97/05304 FAB HRMS exact mass calcd for C24HlsN4 OF3 435.143271 (MH+);
found 435.144474.
Anal. Calcd. for C24HI7N4 OF3 -2.00 HCI:
C, 56.82; H, 3.77; N, 11.04.
Found: C, 56.50; H, 3.88; N, 10.86.
1 -(2-(2-Trifluoromethylphenyl)-pyrid-S-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 2-(2-Trifluoromethylphenyl)-5-methylpyridine To a solution of 2 bromo-5-methyl pyridine (1.81g, 10.53 mmol) and barium hydroxide (4.97 g, 15.7~ mmol) in water (15 mL) was added DME (80 mL). This mixture was treated sequentially with 2-(trifluoromethyl)phenylboronic acid (2.00g, 10.53 mmol) and palladium tetrakis(triphenylphosphine) (553 mg, 0.48 mmol) and the mixture warmed to 80~C for 4~ hours.
Water (lOOmL) was added and the pH of the solution was adjusted to 10 and extracted with EtOAc (3X200mL).
The organic extracts were combined, washed with brine, dried (MgSO4), and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel,50% -100% CH2Ck in hexanes) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.52(1H, s), 7.75(1H, d, J=7.9Hz), 7.64-7.44(4H, m), 7.32(1H, d, J=7.9Hz) and 2.40(3H,s) ppm.
Step B. 2-(2-Trifluoromethylphenvl)-;S-carboxypyridine A suspension of 2-(2-Trifluoromethylphenyl)-5-methylpyridine (0.40g, 1.6~ mmol) and potassium permanganate (1.60g, 10.1 mmol), in water (10 m~) was heated at reflux for 16 - hours. The reaction was filtered hot through celite to remove the solids. Acetic acid was added to the colourless filtrate to yield a pH
of S and the resulting suspension was extracted with CH2Ck.washed WO 97t36901 PCT/US97/05304 with water (10 mL), dried, (MgSO4), and the solvent evaporated in vacuo to afford the title compound.
1 H NMR (CD30D, 400MHz) ~ 9.34(1 H, s), 8.41 ( I H,d, J=8.2Hz), 7.80(1H,d, J=7.9Hz) and 7.70-7.50(4H,m) ppm.
s Step C: 2-(2-Trifluoromethylphenyl)-5-hydroxymethvlpyridine To a solution of 2-(2-Trifluoromethylphenyl)-5-carboxypyridine (220 mg, 1.23 mmol) in tetrahydrofuran (10 mL) at 0~C was added 1.0 M lithium aluminum hydride in tetrahydrofuran (1.23 mL, 1.23 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours, cooled to 0~C, and quenched by dropwise addition of water (0.05 mL), 2.5 N aq. NaOH (0.05 mL), and water (0.15 mL). Sodium sulfate wa.s added, the reaction filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, CH2CI2 then EtOAc) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.63(1H, s), 7.80-7.40(6H,m) and 4.77(2H, s) ppm.
Step D: 1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt The title compound was prepared using the procedure described for Example 5, step D using 2-(2-trifluoromethylphenyl) -5-hydroxymethylpyridine from Step C in place of 2-(3-trifluoro-methoxyphenyl)-5-hydroxymethylpyridine.
1 H NMR (CD30D, 400MHz) â 9.17(1 H, s), 8.42(1 H,s), 8.00-7.40(1 lH, m), 5.60(2H, s), 4.26(2H, s) ppm.
FAB MS 419 (MH+) Anal. Calcd. for C24HI7N4 F3 -2.95 HCI. 0.6 EtOAc:
C, 54.78; H, 4.31; N, 9.68.
Found: C, 54.79; H, 4.18; N, 9.68.
W O 97/36901 PCT~US97/05304 1 -(3 -Phenyl-2-Chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 3-Phenyl-6-methylpyridine N-oxide A solution of 3-phenyl-6-methyl pyridine (2.36g, 13.95 mmol), in CH2Cl2 (40 mL) at 0~C was treated with MCPBA (3.58g, 13.95 mmol) for 1 hour. Saturated aq. Na2CO3 (50 mL) was added and the reaction was extracted with CH2CI2 (20 mL). The organic extracts were dried (MgSO4), and the solvent evaporated in vacuo to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.53(1H, s), 7.60-7.20(7H, m) and 2.57(3H, s) ppm.
Step B: 3-Phenyl-2-chloro-6-methylpyridine and 3-phenyl-4-1 5 chloro-6-methvlpyridine A solution of 3-phenyl-6-methyl pyridine-N-Oxide (1.42g, 7.66 mmol), in P2Os (50 mL) at 0~C was at 80~C for 3 hours. The reaction was allowed to cool to room temperature and then poured over ice (400g). Saturated aq. Na2CO~ wa.s added until the pH of the solution wa,~ 8 and the reaction was extracted with CH2Ck (3X250 mL). The organic extracts were ~ried (MgSO4), and the solvent evaporated in vacuo. The re,sidue was chromatographed (silica gel, 10-20~o EtOAc in CH2CI2 to afford 3-Phenyl-2-chloro-6-methylpyridine (First eluted) lH NMR (CDC13, 400MHz) ~ 7.56(1H, d, J=7.6Hz), 7.60-7.30(5H,m), 7.15(1H,d, J=7.6Hz) and 2.59(3H, s) ppm.
3-Phenyl-4-chloro-6-methylpyridine (Second eluted).
IH NMR (CDC13, 400MHz) ~ 8.43(1H, ,s), 7.60-7.40(5H,m~, 7.29(1H,s) and 2.59(3H, s) ppm.
Step C: 3-Phenyl-2-chloro-6-bromomethylpyridine - A ~olution of 3-Phenyl-2-chloro-6-methylpyridine (0.094g, 0.462 mmol), NBS (0.086g, 0.485 mmol) and AIBN
(0.008g, 0.046mmol) in CCl4 (3 mL) were heated at reflux for 2 hours. The solvent was evaporated and the residue chroma-tographed(Silica gel, 100% CH2CI2 to afford the title compound.
1}~ NMR (CDC13, 400MHz) ~ 7.68(1H, d, J=7.6Hz), 7.60-7.40(6H,m), and 4.56(2H, s) ppm.
Step D: 1-(3-Phenyl-2-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt To l-trityl-4-(4-Cyanobenzyl)-imidazole (88.4mg, 0.208 mmol) in acetonitrile (1 mL) was added 3-phenyl-2-chloro-6-bromomethylpyridine (53.5mg, 0.189 mmol) and the mixture heated at 65~C for 16 hours. The re~idue was dissolved in methanol (3 ml) and heated at reflux for 2 hours, cooled and evaporated to dryness. The re.sidue was partitioned between sat. aq. Na2CO~
solution and CH2Cl2. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 2.5-3% MeOH in CH2CI2) to afford the free ba.se which was converted to the HCI salt by treatment with one equivalent of HCI in aqueous acetonitrile. Evaporation of solvent in vacuo afforded the title compound as a white powder.
1 H NMR (CD30D, 400MHz) ~ 9.1 1 ( 1 H, ~), 7.64(1 H.d, J=7.7Hz), 7.55(2H,d, ~=8.2Hz), 7.51(1H,s), 7.50-7.34(5H,m), 7.32-7.20(3H, m), 5.56(2H, s), 4.27(2H, s) ppm.
Anal. Calcd. for C23HI7CIN4 1.00 HCI. 0.6 EtOAc:
C, 54.78; H, 4.31; N, 9.68.
Found: C, 54.79; H, 4.18; N, 9.68.
1 -(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt - The title compound was prepared using the procedure described for Example 7, steps C and D using 3-phenyl-4-chloro-6-methylpyridine in place of 3-phenyl-6-methyl pyridine.
W O 97/36901 PCTrUS97/OS304 Anal. Calcd. for C24HI7N4 Cl l.OO HCI. 0.30 H20:
C,64.74; H,4.39; N, 13.13.
Found: C, 64.~2; H, 4.52; N, 12.93.
1 -(2-Amino-3 -phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 2-Amino-3-Phenyl-6-methylpyridine A solution of 3-phenyl-6-methyl pyridine (0.815 g, 4.82 mrnol), and sodium amide (752mg, 19.3mmol) in diethylaniline (lOmL) was heated at 1~0~C for 72 hours. The reaction was cooled and quenched with ice (lOOg), and the mixture extracted with EtOAc. The organic extract was washed with brine 15 (50 mL), dried (MgSO4), silica gel (lOOg) was added and the ,solvent evaporated in vacuo.
The material was loaded onto a column and chromatographed (Silica gel, eluting with 0-100% EtOAc in CH2Ck) to afford the title compound.
20 lH NMR (CDC13, 400MHz) o 7.50-7.20(6H, m) 6.61(1H,d, ~=7.0Hz), and 2.42(3H, s) ppm.
Step B: N-bis t-Butoxycarbonyl-2-Amino-3-Phenyl-6-methylpyridine A solution of 2-amino-3-phenyl-6-methyl pyridine (1.21 g, 6.57 mmol), di t-butylcarbonate(3.58g, 16.4 mmol), triethylamine 5 (2.29 mL, 16.4 mrnol) and DMAP (0.803g, 6.57 mmol) in CH2C12 (20mL) were heated at 65~C for 16 hours. The reactionwas diluted with sat. aq. Na2CO3 and extracted with CH2Cl2 The solvent was evaporated in vacuo. and the residue chromatographed (Silica gel, eluting with 20% EtOAc in CH2CI2) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 7.62(1H, d, J=7.7H~), 7.41-7.30(5H, m), 7.19(1H, d, J=7.7Hz), 2.59(3H, s) and 1.2X(18H, s) ppm.
Step C: 2-(bis t-butoxycarbonylamino)-3-phenyl-6-methylpvridine-N-oxide A solution of N-bis t-butoxycarbonyl-2-amino-3-phenyl-6-methylpyridine (0.215g, 0.56 mmol), in CH2CI2 (4 mL) at 0~C was treated with MCPBA (0.220g, 0.727 mmol) for 1 hour. Saturated aq. Na2CO3 (50 mL) was added and the reaction was extracted with CH2CI2 (2X50 mL). The organic extracts were dried (MgSO4), and 20 the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, eluting with 100% EtOAc to afford the title compound.
1H NMR (CDC13, 400MHz) ~ 7.44-7.36(6H,m), 7.13(1H, d, J=7.7Hz), 2.56(3H, s) and 1.31(1~H, s) ppm.
~5 StepD: N-bis t-Butoxycarbonyl-2-amino-3-phenyl-6-acetoxymethylpyridine A solution of 2-(bis t-butoxycarbonylamino)-3-phenyl-6-methylpyridine-N-oxide (0.223g, 0.557 mmol), in acetic anhydride (5 mL) was heated at 65~C for 24 hours. The solvent was evaporated 30 in vacuo and the residue chromatographed (30-50%EtOAc in hexanes) to afford the title compound.
- lH NMR (CDC13, 400MHz) ~ 7.74(1H, d, J=7.7Hz), 7.50-7.30(6H, m), 5.25(2H, s), 2.17(3H, s) and 1.28(18H, s) ppm.
W O97/36901 PCTrUS97/05304 Step E: N-bis t-Butoxycarbonyl-2-amino-3-phenyl-6-hydroxymethylpyridine A solution of 2-(bis t-butoxycarbonylamino)-3-phenyl-6-acetoxymethylpyridine (0.040g, 0.09 mmol), THF (1.3 mL) was S treated with Lithium hydroxide (lM solution in water 0.271 ml, 0.271 mmol) at room temperature for 16 hours. The reaction was diluted with water and extracted with CH2Cl2. The organic extracts were dried (MgSO4),and the solvent evaporated in vacuo to afford the title compound.
lH NMR (CDC13, 400MHz) â 7.74(1H, d, J=7.P~ Hz), 7.44-7.33(5H, m), 7.31(1H,brd, J=7.8Hz), 4.~1(2H, s), and 1.29(18H, s) ppm.
Step F: 1 -(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt The title compound was prepared using the procedure described for Example 3 ,step C using N-bis t-butoxycarbonyl-2-amino-3-phenyl-6-hydroxymethylpyridine in place of 3-phenyl-6-hydroxymethyl-pyridine. In this case the free base was treated with TFA and triethylsilane to effect cleavage of the t-butoxycarbonyl groups which was followed by its conversion to the hydrochloride salt.
lH NMR (CD30D, 400MHz) ~ 9.23(1H, s), 7.80-7.20(H, m), 6.96(1H,s), 6.65(1H,d, J=7.6Hz), 5.66(2H, s), 4.33(2H, s) ppm.
Anal. Calcd. for C2~HIsN~ 1.00 HCI. 0.95 H20 0.35 EtOAc:
C, 60.26; H, 5.33; N, 14.40.
Found: C, 60.04; H, 5.10; N, 14.45.
ln vitro inhibition of ras farnesyl transferase Assays offarnesyl-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 31:3~00 (1992) and Gibbs et al., PNAS U.S.A. ~6:6630-6634 (19~9), respectively. Bovine FPTase was assayed in a volume of 100 ~1 containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgC12, 5 mM dithiothreitol (Dl~), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mrnol, New England Nuclear), 650 nM Ras-CVLS and 10 ~g/ml FPTase at 5 31 ~C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach Il cell harvestor, washed with 100%
ethanol, dried and counted in an LKB ,~-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10 10% of the [3Hl-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 15 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 ~lM ZnC12 and 100 nM Ras-CVIM were 20 added to the reaction mixture. Reactions were perforrned for 30 min., stopped with 100 ~l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compound of the instant invention described in the above Examples 1-9 were tested for inhibitory activity against human 25 FPTase by the assay described above and were found to have IC50 of <50 ~M.
30 In viv~ ras farnesylation assay The cell line used in this assay is a v-ras line derived - from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is perforrned essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cell.s in 10 cm dishes at 50-75%
W O 97136901 PCT~US97/05304 confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, i.s 0.1%). After 4 hours at 37~C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 5 mCi[35SJmethionine (1000 Ci/mmol). After an additional 20 hour,s, the cells are Iysed in 1 ml Iysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptinl2 mg/ml antipain/0.5 mM PMSF) and the Iysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of Iysates containing equal numbers 10 of acid-precipitable counts are bought to 1 ml with IP buffer (Iysi.s buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et ah, J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
15 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-100Ø5% 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 20 autoradiographed. The intensities of the bands corresponding to farne,sylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
In l~ivo ~rowth 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 30 v-ras, v-raf, or v-mos oncogene i.s 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 tran.sformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in W O 97/36901 PCTrUS97/05304 a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in 5 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. Photo-micrographs are taken 16 days after the cultures are seeded and comparisons are made.
. , ,~ . .. . . .. . . .
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 conforrnational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is termin~ted by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound folm (D.R. 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 leukemia~s. The protein product,s 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-terminu,s 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 310:583-5~6 (1984)). Depend-ing on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a Cls or C20 isoprenoid, respectively. (S. Clarke., - Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of .several proteins that are known to undergo post-translational farnesyl-ation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesyl-ated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it ha,s been .shown that an inhibitor of farnesyl-protein tran,sferase blocks the growth of ras-dependent tumor,s in nude mice (N.E. Kohl et al., Proc. Natl.
Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transfera,se in vilJo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ihid; Schafer et al., Science 245:379 (19~9)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farne,syl-protein transferase utilizes farnesy]
pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990);
Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1 133-1139 (1990); Manne et al., P)~oc. Natl. Acad. Sc~i USA, 87:7541-7545 (1990)). Inhibition of farne~syl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor WO 97/36901 PCT/US97/0~304 of isoprene ~iosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in four general classes (S. Graham, Expert Opinion Ther. Patents, (1995) 5:1269-1285). The first are analogs of farnesyl 5 diphosphate (FPP), while a second class of inhibitors is related to the protein substrates (e.g., 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 10 molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss etal., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive 15 inhibitors (U.S. Patent 5,141,g51, University of Texas; N.E. Kohl et al ., Sc~ience, 260: 1934- 1937 (1993); Graham, et al., J. Med . Chem., 37, 725 (1994)). In ~eneral, 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 20 places limitation,s on the therapeutic application of FPTase inhibitors with respect to pharmacokinetic~s, pharmacodynamics and toxicity.
Therefore, a functional replacement for the thiol is de.sirable.
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety 25 are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Lmidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 A1).
It has recently been reported that farnesyl-protein 30 transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930).
It is, therefore, an object of this invention to develop W O 97/36901 PCTrUS97/05304 low 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 5 for producing the compounds of this invention.
SUMMARY OF THE INVENT~ON
The present invention comprises arylheteroaryl-containing compounds which inhibit the farnesyl-protein tran.sferase.
10 Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A:
6a-e /_~/R
</
R3 )~
(I 8)r /~9~ f~
V - A1 (CR12)nA2(CR 12)n ~;~W~ - (CR22)p - X -(CR 2)p 4 R5 lS A
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene 20 protein Ras. In a first embodiment of this invention, the inhibitors of farnesyl-protein tran~sferase are illustrated by the formula A:
W O 97/36901 PCTrUS97/05304 R6a-e R3 >~
(R8) / 9~ /f~
V - A1(CR12)nA2(CR12)n ;~W~ (CR22)p - X -(CR22)p R5 wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f'~
5 are independently CH;
Rl and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 0O-, R I I S(O)m-, R 1 0C(O)NR 10, R 1 1 C(O)O-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 , c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or sub.stituted aryl, heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R100- Rl lS(o)m, RIOC(O)NRlO-, (R10)2NC(o)-, K102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;
R3, R4 and R5 are independently selected from:
a) hydrogen, - b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R12O-, W O 97/36901 PCT~US97/05304 R 1 1 S(O)m ~ R 1 0C(o)NR 10, (R 1 0)2NC(o)-, R 1 1 C(O)O-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or Rl lOC(O)NR10 c) unsubstituted Cl-C6 alkyl, S d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 2O, R 1 1 S(O)m-~ R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o), Rl lC(o)o-R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2 or R 1 1 OC(O)NR 10 c) unsubstituted C 1 -C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is .selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, RllS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or ~0 any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
W O 97/36901 rcTrusg7~0s304 provided that when R3, R4, RS, R6a, R6b~ R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4 R5 R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a S substitutable heterocycle ring carbon;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) ~ R
f) --SO2R1 1 l S g) N(R 1 0)2 or h) C 1-4 perfluoroalkyl;
R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R100-, Rl lS(O)m, RlOC(O)NR10-~ (R10)2NC(o)-, R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0o-, R I 1 S(O)m ~ R 1 0C(O)NH-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, or R10OC(O)NH-;
provided that when R~ is heterocycle, attachrnent of R~ to V i~;
through a substitutable ring carbon;
R9 is independently selected from:
a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, Rl lo-, Rl lS(O)m-, Rloc(o)NRlo- (R10)2NC(o) R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O~-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10-, and c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, RllS(O)m-, R10C(O)NR10-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10;
~5 R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl I is independently selected from Cl-C6 alkyl and aryl;
~0 R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;~5 Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 10, -NR I ~C(O)-, O, -N(R 10 -S(O)2N(R 10), -N(R I ~)S(O)2-, or S(O)m;
~0 V is selected from:
a) hydrogen, - b) heterocycle, c) aryl, d) Cl-C20 alkyl wherein from O to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and ~ e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen S if Al is a bond, n is O and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
W is a heterocycle;
X is a bond, -CH=CH-, O, -C(=O)-, -C(o)NR7-, -NR7C(o)-, -C(O)O-, -OC(O)-, -C(o)NR7C(o)-, -NR7-, -S(0)2N(R 1 0) , -N(R10)S(0)2- or-S(=O)m-;
1 5 m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is O to 5, provided that r is O when V is hydrogen; and 20 tis Oorl;
or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of thi.s invention is illustrated by the following fo~nula A:
R6a-e (R8)r /(1l19~ f~
- V - A1(CR12)nA2(CR12)n~;~W~ - (CR22)p - X -(CR22)p R5 A
wherein:
from 1-2 of f(,s) are independently N or N->O, and the rem~ining rs are independently CH;
s Rl is independently selected from: hydrogen, C3-CIo cycloalkyl, R 1 00-, -N(R 1 0)2, F or C l -C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C I o cycloalkyl, R 1 00-, -N(R 1 0)2, F or C2-C6 alkenyl, c) unsubstituted or ~ubstituted Cl-C6 alkyl wherein the substituent on the sub.stituted C 1 -C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3, R4 and R5 are independently selected from:
a) hydrogen, b) un.substituted or substituted aryl, unsubstituted or substituted heterocycle, C3-c 1 o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 10), CN, N02, R I ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 , c) u~substituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R120 RllS(O)m, KlOC(O)NR10-, (R10)2NC(o)-, - R102N-C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and Rl lOC(o) NR10;
CA 02249607 l998-09-23 R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, - b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120, Rl lS(O)m, KlOC(O)NR10-, (Rl0)2Nc(o)-~
R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, Rl lS(O)m-, R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R5, R6a~ R6b, R6C, R6d or R6e ;~; ;
unsubstituted or substituted heterocycle, attachment of R3, R4 R5, R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl 4 alkoxy, b) aryl or heterocycle, - c) halogen, d) HO, o f) --So2R 1 ~
g) N(R l ~)2 or h) C l -4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R10O-, R 1 0C(O)NR 10, CN, NO2, (R 10)2N-C(NR 10), R I ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R 1 0O-, R l 0C(O)NR 10, (R 1 0)2N-C(NR 10) R10C(O)-, -N(R10)2, or Rl lOC(O)NRI0-;
provided that when R~ is heterocycle, attachment of R~s to V is through a ,substitutable ring carbon;
R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, Rl lo-, Rl lS(O)m-, Rl0C(o)NRl0-, (Rl0)2NC(o) CN, NO2, (R l 0)2N-C(NR 10), R I ~C(O)-, -N(R l ~)2, or R I I OC(O)NR 10, and c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, Rl0O-, RllS(O)m-, Rl0C(O)NRl0-, (R l 0)2NC(O)-, CN, (R l 0)2N-C(NR l 0), R l ~C(O)-, -N(Rl0)2, or Rl lOC(O)NRl0-;
R10 is independently .selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
W O 97/36901 PCTrUS97/05304 R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R 10), or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and 20 provided that V is not hydrogen if Al is S(O)m and V i.s not hydrogen if Al is a bond, n is 0 and A2 i~s S(O)m;
provided that when V is heterocycle, attachment of V to RX and to Al is through a ~substitutable ring carbon;
25 W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
X is a bond, O, -C(=O)-, -CH=CH-, -C(o)N~7-, -NR7C(o)-, -NR7-, -S(O)2N(R 1 0)-, -N(R 1 0)S(0)2- or -S(=O)m-;
-mis 0, 1 or2;n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
W O97/36901 PCT~US97/05304 q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;
5 or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B:
R6a-e (R8)r R9a R3 f~
Rgb~ 4 wherem:
from 1-2 of f(s) are independently N or N->O, and the rem~ining f's are independently CH;
R l is selected from: hydrogen, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2, F
or Cl-C6 alkyl;
R2 is independently .selected from:
a) hydrogen, b) aryl, heterocycle, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3 and R4 are independently selected from:
a) hydrogen, - b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 - alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R 1 02N-C(NR 1 0)-, CN, N02, R 1 OC(O)-, N3, -N(R 1 0)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R I ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;
1~
R6a R6b R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsub.stituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R1o2N-c(NRlo)-~ CN, N02, RlOC(O)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and - R1 1OC(O)-NR10; or CA 02249607 l998-09-23 any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a~ R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4 R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(O)NK 10, CN, NO2, (R 1 0)2N-C(NR 10) , R 10c(O)-, -N(R 1 ~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(o)NR 10, (R 1 0)2N-C(NR 10) , R I ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R~ i.s heterocycle, attachment of RX to V is through a ~substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, C1-C6 - aralkyl, C1-C6 .substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, WO 97/36901 PCT~US97/05304 2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently ,selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, 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) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and 15 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al is a bond, n ilS 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon;
20 X is a bond, -CH=CH-, -C(O)NR10-, -NRlOC(O)-, -NR10-, O or -C(=O)-;
mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
25 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 30 invention are illustrated by the formula C:
-R6a-e ~8~ 9 R3 V- A1(CR12)nA2(CR12) ~ f~
C R9b (CR22)p X R4 wherein:
from 1-2 of f(s) are independently N or N->0, and the remaining f 5 are independently CH;
R l is selected from: hydrogen, C3-CIo cycloalkyl, R100-, -N(R10)2, F
or Cl-C6 alkyl;
10 R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3 -C I o cycloalkyl, R 1 00-, -N(R 1 0)2, F
or C2-C6 alkenyl, c) un~ubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i.s selected from unsubstituted or substituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, CN(R 1 0)2NC(0)-, R102N-C(NR10)-, CN, N02, R1OC(0)-, N3, -N(R10)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m ~ R I OC(O)NR 10 (R 1 0)2NC(o)-R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R11OC(O) NR10;
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R 1 I S(O)m-~ R 1 OC(O)NR 10, CN(R 1 0)2NC(O)-, R 1 02N-C(NR 1 0) , CN, N02, R I ~C(O)-, N3, -N(R 1 ~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120, Rl lS(o)m, RlOc(o)NRlo-~ (R10)2NC(o)-, R 1 02N-C(NR 1 0) , CN, R 1 ~C(O)-, N3, -N(R 1 ~)2, and R 1 1 OC(O)-NR 10; or any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a~ R6b, R6C, R6d or R6e is ~ unsubstituted or substituted heterocycle, attachment of R3, R4 R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, i.s through a substitutable heterocycle ring carbon;
W O97136901 PCT~USg7/05304 R~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(o)NR 10, CN, NO2, (R 1 0)2N-C(NR 1 0)-, R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(O)NR 10, (R 1 0)2N-C(NR 10) R 1 ~C(O)--N(R10)2, or Rl lOC(O)NR10-;
provided that when R~ is heterocycle, attachment of R~ to V i~
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C-C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, W O 97/36901 PCTrUS97/05304 b) heterocycle ~selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazol311 and thienyl, c) aryl, d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, 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 A2 is S(O)m;
10 provided that when V is heterocycle, attachment of V to Rg and to Al is through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR 10 , -NR 1 ~C(O)-, -NR 10, O or -C(=O)-;
mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
and 20 r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illu~strated by the formula 25 D:
1 \ 2 ~ f\~, wherein:
W O 97136901 PCTrUS97/05304 from 1-2 of f(s) are independently N or N->0, and the remaining f's are independently CH;
5 R l is selected from: hydrogen, C3-Clo cycloalkyl or Cl -C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-Clo cycloalkyl, R100-, -N(R10)2, F
or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R I ~)2;
lS R3 i.s selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, N02, R 1 ~C(0)-, N3, -N(R 1~)2 or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(0)NR 10 , (R 1 0)2NC(0)-, R 1 02N-C(NR 10), CN, R 1 ~C(0)-, N3, -N(R 1~)2, and R 1 1 0C(0)-NR 10;
- R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a, R6b, R6C, R6d and R6e are independently selected from:
W O97/36901 PCTrUS97/05304 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R I 1 S(O)m-~ R 1 0C(o)NR 10 , (R 1 0)2NC(O)-, R 102N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 I S(O)m-~ R 1 0C(o)NR 10 , (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R11OC(O)-NR10; or any two of R6a R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b, R6c, R6d or R6e j~;
unsubstituted or sub.stituted heterocycle, attachment of R3, R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-c6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(o)NR 10, CN, NO2, (R 1 0)2N-C(NR 10), R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and W O 97/36901 PCT~US97/05304 c) Cl-C6 alkyl sub.stituted by Cl-C6 perfluoroalkyl, R10O-, R 1 0C(o)NR 10, (R 1 0)2N-C(NR 10), R 1 ~C(O)--N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R~s is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-c6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R 1 1 i,s independently selected from Cl -C6 alkyl and aryl;
R12 i.s independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 ~5 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
20 Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR~0-, O or -C(=O) -, n is 0 or 1; provided that n is not 0 if Al is a bond, O, -N(R10)- or S(O)m;
m is 0, 1 or 2; and pi.s 0, 1, 2, 3 or4;
30 or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
W O97/36901 PCT~US97/05304 ~N~R9a ~ ~ R6a-e Al (CR1 2)n~j ~N~ ~ ~
9b (CR22)p X' R4 ~¦~ E
r,8 n wherein:
from 1-2 of f(s) are independently N or N-~0, and the remaining f's 5 are independently CH;
Rl is selected from: hydrogen, C3-Clo cycloalkyl, R100-, -N(R10)2, F
or C I -C6 alkyl;
10 R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-CIo cycloalkyl, R100-, -N(R10)2, F
or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R 1 ~)2;
R3 i,s selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsub.stituted or substituted heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R I 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(0)-, R 1 02N-C(NR 10), CN, N02, R 1 ~C(0)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, W O 97/36901 PCTrUS97/05304 d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and K 1 1 OC(O)-NR 10;
R4 is selected from H, halogen, Cl-C6 alkyl and CF3;
R6a R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen, b) un.substituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R 1 1 S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2, or Rl lOC(o)NR10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-c6 alkyl is selected from un.substituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120, RllS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b, R6C, R6d or R6e i~
unsubstituted or substituted heterocycle, attachment of R3, R6~ R6b, R6C, R6d or R6e to the 6-membered hetero~ryl W O 97/36901 PCT~US97/05304 ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
Rf~ is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R l Oo, R 1 OC(o)NR 10, CN, N02, (R 1 0)2N-C(NR 10)-, R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R100-, R 10C(O)NR 10, (R 1 0)2N-C(NR10)- R 10c(O) -N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R8 is heterocycle, attachment of R~ to V is through a ~substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR 10 , -NR 1 ~C(O)-, -NR 10, 0 or 30 -C(=O)-;
n is O or l ;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not O if X is a bond or O;
W O 97/36901 PCTrUS97/05304 or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitor~s of farnesyl-protein transferase are illustrated by the formula F:
,~ R6a-e R9a\~= N \ ~
(~ (CR ~)p--NC F
wherein:
from 1-2 of f(s) are independently N or N->0, and the remaining fs are independently CH;
Rl is selected from: hydrogen, C3-CIo cycloalkyl or Cl-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3 -C l o cycloalkyl, R 1 00-, -N(R 1 0)2 or F, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C1o cycloalkyl, R100-, or-N(Rl0)2;
20 R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R 1 l S(O)m-~ R l OC(O)NR 10, (R l 0)2NC(0)-, R 1 02N-C(NR 1 0), CN, N02, R I ~C(0)-, N3, -N(R 1 ~)2, or R 1 1 OC(O)NR 10 - c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(o)m, RlOc(o)NRlo-~ (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10-;
10 R4 is selected from H, halogen, CH3 and CF3;
R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R I I S(O)m-, R 1 OC(O)NR 10-, (R 1 0)2NC(o)-, R 1 02N-C(NR 10)-, CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsub~stituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O~m-~ R 1 OC(O)NR 1 0-, (R 1 0)2NC(O)-, R102N-c(NRlo)-~ CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10; or any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b~ R6C, R6d or R6e is unsubstituted or sub.stituted heterocycle, attachrnent of R3, W O 97/36901 PCT~US97/05304 R6a R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 i.s independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, C1-C6 ,substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR 1 0-, -NR l OC(O)-, -NR 10-, O or -C(=O) -;
m is 0, 1 or 2; and pi,s 0, 1, 2, 3 or4;
or the pharrnaceutically acceptable salt.s thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula G:
R3 ~ R6a-e NC 3 . .
wherein:
from 1-2 of f(s) are independently N or N-~O, and the rem~ining fs are independently CH;
Rl is selected from: hydrogen, C3-CIo cycloalkyl, RlOO-, -N(RI0)27 F or Cl-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-Clo cycloalkyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, RIOO-~ or -N(R 1 ~)2;
R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or ,substituted heterocycle, C3-CIo cycloalkyl, C2-C6 a Ikenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 120, R I I S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(o)-, R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, d) substituted C l -C6 alkyl wherein the .substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, RllS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10;
R4 is selected from H, halogen, CH3 and CF3, W O 97/36901 PCTrUS97/0~304 R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R102N-C(NR10)-, CN, NO2, RlOC(O)-, N3, -N(Rl0)2, or R 1 1 OC(O)NR 10 c) unsubstituted Cl-C6 alkyl, lO d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R I l S(O)m ~
R l OC(O)NR l O, (R I 0)2NC(O)-, R 1 02N-C(NR 1 0) , CN, RlOC(O)-, N3, -N(Rl0)2, and Rl lOC(O)-NRlO-; or any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -C~=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b~ R6C, R6d or R6e is unsub.stituted or sub,stituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R l l is independently selected from Cl -C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 ,substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and 10 n is 0 or 1;
or the pharmaceutically acceptable salts thereof.
Preferred compounds of the invention are:
1 -(2-Phenylpyrid-5 -ylmethyl)-5 -(4-cyanobenzyl)imidazole 1 -(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 20 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole I -(3-Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole I -(2-(3 -Trifluoromethoxyphenyl)-pyrid-S-ylmethyl)-5-(4-25 cyanobenzyl)imidazole I -(2-(2-Trifluoromethylphenyl)-pyrid-S-ylmethyl)-5-(4-cyanobenzyl)imidazole 1 -(3 -Phenyl-2-Chloropyrid-6-ylmethyl)-5 -(4-cyanobenzyl)imidazole CA 02249607 l998-09-23 W O 97/36901 PCT~US97/05304 1 -(3 -Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole and I -(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
Specific examples of the compounds of the instant invention are:
I -(2-Phenylpyrid-5 -ylmethyl)-5 -(4-cyanobenzyl)imidazole NC
N-~
1 -(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole NC~
~ N~
or the pharmaceutically acceptable salts thereof.
The compounds of the present invention may have a.symmetric centers and occur as racemates, racemic mixtures, and a.s individual diastereomers, with all possible isomers, including optical W O 97/36901 PCTrUS97105304 isomers, being included in the present invention. When any variable (e.g. aryl, heterocycle, Rl, R2 etc.) occurs more than one time in any constituent, its definition on each occurence is independent at every other occurence. Also, combinations of substituents/or variables are 5 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 10 of carbon atoms attached through an oxygen bridge.
As used herein, "cycloalkyl" is intended to include non-aromatic cyclic hydrocarbon groups having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" groups include those groups having the specified number of carbon atoms and having one or several double bonds.
Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, I-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
"Alkynyl" groups include tho.se groups having the .specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl," and the aryl portion of aroyl and aralkyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or - acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable ~- to WO 97/36901 PCTrUS97/05304 1 I-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, O, and S, and including any bicyclic group in which any of the above-defined 5 heterocyclic rings is fused to a benzene ring. ~he 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, 10 benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, 1~ naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, 20 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 25 consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzi.soxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, 30 dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, - oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, WO 97/36901 PCT/US971û5304 - tetrahydroisoquinolinyl, tetrahydro4uinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl.
As used herein in the definition of R3, R4, R5 and R6a-e, the term "the substituted group" is intended to mean a substituted C1 8 S alkyl, substituted C2 8 allcenyl, sub.stituted C2 ~ alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R3, R4, R5 and R6a-e are selected.
As used herein in the definition of R7, the substituted Cl alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, 10 substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl-sulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
As used herein, when no specific substituents are set forth, 15 the terrns "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl)2~ NO2, CN, (cl-c6 alkyl)O-, -OH, (Cl-C6 20 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl-C6 alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(CI-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and Cl-C2o alkyl.
Lines drawn into the ring systems from substituents (such 25 as from R3, R4, Q etc.) means that the indicated bond may be attached to any of the substitutable ring carbon atoms.
The substituent illustrated by the structure ,~
R6a-e is a simplifled representation of a phenyl ring having five (5) 30 substituents (hydrogens and/or non-hydrogens) and may also be represented by the structure W O97/36901 PCTrUS97/05304 - 3~ -R6b R6a~ R6c ~R6d R6e The moiety described as ~5, R6a-e where any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon S atoms are combined to form a diradical selected from -CH=CH-CH=CH, -CH=CH-CH-, -(CH2)4- and -(CH2)4- includes the following structures:
It is understood that such fused ring moieties may be further substituted 10 by the rem~ining R6a, R6b, R6C~ R6d and/or R6e as defined hereinabove.
The moiety designated by the following structure f"f~
~,f represents an aromatic 6-membered heterocyclic ring and includes the 15 following ring systems:
W O 97/36901 PCTrUS97/05304 N~ N ~- N ~, O~
N~ N~
,~N ~, N~N ~N ,~.,~N~
The moiety designated by the following structure , f ' ~.,~f' represents an aromatic 6-membered heterocyclic ring and includes the S following ring systems:
N
~J,\~N~,J N~"N ,~N
O O
N~N N~N HN NH N
~0 ~
wherein it is understood that one of the ring carbon atom.s is substituted with ~, R6~-e CA 02249607 l998-09-23 W O97/36901 PCT~US97/05304 Preferably, the aromatic 6-membered heterocyclic ring is a pyridyl ring.
Preferably, Rl and R2 are independently selected from:
hydrogen, R 1 1 C(0)0-, -N(R 1 ~)2, R 1 OC(O)NR 10 R l Oo or 5 unsubstituted or substituted Cl-c6 alkyl wherein the substituent on the substituted Cl-C6 alkyl i.s selected from unsubstituted or substituted phenyl, -N(R 1 ~)2, R l ~O and R 1 OC(O)NR 10 Preferably, R3 is selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, CN, N02, R 1 ~C(0)- or -N(R 1~)2, c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(0)-, R102N-C(NR10)-, CN, RlOC(0)-, N3, -N(R10)2~ and R 1 1 0C(O)-NR 10 Preferably, R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and Cl-C6 alkyl.
Preferably, R5 is hydrogen.
Preferably R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, CN, N02, RlOC(0)- or -N(R10)2, c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, C3-C1o cycloalkyl, R120-, Rl lS(O)m-, - R 1 ~C(0)- or -N(R 1~)2; or any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3--Preferably, R8 is independently .selected from:
S a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C6 perfluoroalkyl or CN.
Preferably, R9 is hydrogen, halogen, CF3 or methyl.
Preferably, R10 is selected from H, Cl-C6 alkyl and 1 0 benzyl.
Preferably, A 1 and A2 are independently selected from:
a bond, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10), -S(O)2N(R 10) and-N(R I ~)S(O)2-.
Preferably, V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
Preferably, n and r are independently 0, 1, or 2.
Preferably .s is 0.
Preferably t is 1.
Preferably, the moiety / \
(18)' Ç~9~\
V - A1(CR12)nA2(CR12)n tW~ - (CR22)p - X -(CR22)p -~-is selected from:
W O 97/36gO1 PCTrUS97/05304 R9a R9b >= N \) N
~ R~b and ~ ~ R~'a NC NC
It is intended that the definition of any substituent or variable (e.g., Rl, R2, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule.
5 Thus, -N(R 1 0)2 represents -NHH, -NHCH3, -NHC2Hs, etc. It is understood that sublstituent,s 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 tho.se methods 10 set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of thi.s invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those 15 derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitrlc 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, 20 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 25 methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired ~salt-forming inorganic or organic acid in a .suitable ,solvent or variou.s combinations of solvent~s.
CA 02249607 l998-09-23 W O 97/36901 PCTrUS97/05304 Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-21, in addition to other standard manipulations such a,s ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature 5 or exemplified in the experimental procedures. Substituents R3, R6 and R~, as shown in the Schemes, represent the substituents R3, R4, R5, R6a, R6b, R6C, R6d, R6e and R~; although only one such R3, R6 or R8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such 10 aryl or heteroaryl moieties contain multiple substituents.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes. The reactions described in the 15 Scheme.s are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moieties are described in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein.
Aryl-aryl coupling is generally described in "Comprehensive Organic 20 Functional Group Transformations," Katritsky et al. eds., pp 472-473, Pergamon Press (1995).
SynopsisofSchemes 1-21:
The re~uisite intermediates are in some cases commercially 25 available, or can be prepared according to literature procedures, for the most part. Schemes 1-12 illustrate synthesis of the instant aryl-heteroaryl compound which incorporate a preferred benzylimidazolyl sidechain. Thus, in Scheme 1, for example, a arylheteroaryl inter-mediate that is not commercially available may be synthesized by 30 methods known in the art. Thus, a suitably substituted phenyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl.
Chem., 63:419 (1991)) with a suitably substituted halogenated nicotinic acid, such as 4-bromonicotinic acid, to provide the arylheteroaryl carboxylic acid Il. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl IV to provide, after deprotection, the instant compound V.
Schemes 2-4 illustrate other methods of synthesizing the 5 key alcohol intermediates, which can then be processed as described in Scheme 1. Thus, Scheme 2 illustrates the analogous series of arylheteroaryl alcohol forming reactions starting with the methyl nicotinate boronic acid and the "terminal" phenyl moiety employed in the Suzuki coupling as the halogenated reactant. Such a coupling I0 reaction is also compatible when one of the reactant.s incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 3.
Negishi chemistry (Org. Synth., 66:67 (19~)) may also be employed to form the arylheteroaryl component of the instant compounds, as shown in Scheme 4. Thus, a suitably substituted zinc 15 bromide adduct may be coupled to a suitably substituted heteroaryl halide in the presence of nickel (II) to provide the arylheteroaryl VIl.
The heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
Scheme 5 illu.strates the preparation of a suitably substituted 20 biphenylmethyl bromide which could also be utilized in the reaction with the protected imidazole as described in Scheme 1.
As illustrated in Scheme 6, the sequence of coupling reactions may be modified such that the aryl-heteroaryl bond i~s formed last. Thus, a suitably substituted imidazole may first be alkylated with 25 a suitably substituted benzyl halide to provide intermediate VIII.
Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid.
Scheme 7 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
30 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.
W O97136901 PCTrUS97105304 Scheme 8 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkyl-imidazole XII, wherein the primary amine is protected as the phthali-mide, is selectively alkylated then deprotected to provide the amine XIII. The amine XIII may then react under conditions well known in the art with various activated arylheteroaryl moieties to provide the instant compounds shown.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR I 2)n linker i.s oxygen may be synthesized by methods known in the art, for example as shown in Scheme 9.
The suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as de.scribed for the benzylimidazoles hereinabove.
Scheme 10 illustrates an analogous series of reactions wherein the (CR22)pX(CR22)p linker of the instant compounds is oxygen. Thus, a suitably sub.stituted halopyridinol, such as 3-chloro-2-pyridinol, is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI. Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl. The intermediate XVII can then be coupled to a aryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR 1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 11. Thus, the N-protected imidazolyl iodide XVIII is reacted, under Grignard condition~s 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.
W O 97/36901 PCT~US97/05304 Addition of various nucleophiles to an imidazolyl aldehyde may also be employed to form a substituted alkyl linker between the biheteroaryl and the preferred W (imidazolyl) as shown in Scheme 12.
Thus an aryllithium can be reacted with pyridine to form the 2-5 substituted N-lithio-1~2-dihydropyridine XXa. Intermediate XXa can then react with a aldehyde to provide a suitably substituted instant compound. Similar substituent manipulation as shown in Scheme 11 may be performed on the fully functionalized compound which incorporates an R2 hydroxyl moiety.
SCHEME I
~ R6 Nll,Br (HO)2B/~
R2 Pd(PPh3)4 ~N~,~ LiAlH4 HObJ~,\~ 2 ~ ~1 -W O 97/36901 PCTrUS97/05304 SCHEME I (continued) NiCI2(P~h~
~il R6 ~N~ (C F3SO2)20, -78~C ~
HO~'\R2 NEtiPr2 -78~C-20~C
~I N~ R6 R8 1~--R6 ~ N~\~
R8/~l V
CA 02249607 l998-09-23 ,B(OH)2 ~--R6 o R2 Pd(PPh ~)4 ~N~ LiAlH4 MeO~,\
o R2 ~f3 ,R6 HO~,\
~R6 N~ B(~H)2 ~l~
R3SiO~J~\
\R2 Pd(PPh3)4 ~ R6 N ~ ~ Bu4NF
R3SiO~\R2 N~_ - R6 HO~\R2 R SiO~J~,~ (HO)2B
R2 Pd(PPh3)4 ~, R6 N ~J Bu4NF
R3SiOJ~'~R2 ~J3 R6 HOJ~'\R2 W O 97/36901 PCT~US97/05304 ~/ BrZn/~
R3SiOJ~
R2 NiCl2(Pph3)2 N ~ R 6 R3SiO Vll R2 1~--R6 ~N
~J~ 2 Zn l "~--R 6 R2 NiCI2(PPh3)2 ~N~ Bu4NF
R3SiO,~,\R2 ~,N
J~ 2 WO 97/36901 PCr/US97/05304 SCHEME S
H3C~ 2 LiAlH4 ~J3--R6 ~ R6 J~ ~ (HO)2B KMnO4 H3C ~R2 Pd(PPh3)4 N~ R6 LiAlH4 HO2C ~\ 2 HoJ~,\
W O 97/36901 PCT~US97/05304 Tr R2 N~ Br~J~N
~N j;. MeOH
~J reflux R8/~l ~_~N~ ~ (HO)2B
R8 Vlll ~, R6 ~N ~,\,N
W O 97/36901 PCTrUS97/05304 S C~DE~DE 7 H H
R9b~ Nal, NaHCO3,!2 Rgb~ T , 3 IX X
Tr~ N
R9b~, ~INiCI2(PPh3)2, ~N
R8~\ZnBr v~J
~ 6 Tr~ ~N ~ R
~/ i. -78~C-20~C
~/~ ii. MeOH, reflux Xl 9b ~I R2 W 097/36901 rCT~US97/05304 SCHEME
0~
i. ~~Br <\ ~ ~ 55~C,CH3CN
N N~i. EtOH,80~C, NH2NH2 o Xll N
N~NH2 R 8 ~ /
Xlll acylation, sulfonylation </ ~ ~ R2 o;alkylation R8 ~ I HN~/~
N ~" "~ R2 R6 N N ~S~/
</ 3--N~/
R8 ~J N~
~ OH i, Na, MeOH
NC ~/ ii. 1 20~C
XIV H3C~o ~N--~N
H Tr~
N N
~N TrCI, NEt3 , ~N
NC~ NC~
XV XVI
~ R6 TrN~ 78~C-20~C
ii. MeOH reflux NC ~ OTf XVI
<~-- ~ R6 ~
NC ~\~
N
~N OH i, Na, MeOH ~ N
Cl~ ii. 120~C q_N\~o R2 H3C~o Ci~ \J
N~ R2 XVI
~/~
Tr~ ~
N
TrCI. NEt3 . ~ N
N 1~ i -78~C-20~C
~~ ii. MeOH reflux Cl \~\J
R2 R8 ~B(OH)2 N ~ J~ R6 ~
Cl~ \~O DMF, Pd(PPh3)4 ~ K3PO4, 80~C
N ~ ~
'~;~'~~
W O 97136901 PCTrUS97/05304 Tr~
Tr~ ~N~
~N~ EtMgBr ~ N
~_N ~ ~\OH
Tr~ ~ R6 Ac20, PY <~ N HO ~\ 2 ~OA (CF3S02)20,-780c NEtiPr2,CH2cl2 ~OAc R2 ~\ R .
~OH
CA 02249607 l998-09-23 W O97/36901 PCT~US97/05304 SCHEME 11 (continued) ~N~J~ ~NH3, MeOH
/J Cl ~J NH2 +
~- R6 ~_ N ,~
~/ OMe _ 59 _ Li N~
N
¢~ R' N
~/ OH
/~
W O 97136901 PCTrUS97/05304 Schemes 13-21 illustrate reactions wherein the moiety (R8) /~9~
V - A1 (CRl 2)nA2(CR 12)n ~W ,,~ - (CR12)p-X
incorporated in the compounds of the instant invention is represented by other than a substituted imidazole-cont~ining group.
Thus, the interrnediates whose synthesis are illustrated in Schemes hereinabove and other arylheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid.
Lithioheteroaryl chemistry may be utilized, a,s shown in Scheme 13, to incorporate the arylheteroaryl moiety. Thus, a suitably substituted arylheteroaryl N-lithio reagent is reacted with an aldehyde to provide the C-alkylated instant compound XXI. Compound XXI can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXII. The final product XXII
may be isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others. The product di~mine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. I~emoval of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures.
If the arylheteroaryl subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI
in Scheme 14, the protecting groups can be subsequently removed to nm~k the hydroxyl group (Schemes 14, 1~). 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 W 0 97/36901 PCTrUS97/05304 alkyl lithium reagents, to obtain secondary alcohols such as XXX.
In addition, the fully deprotected amino alcohol XXXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such a,s XXXII
5 (Scheme lS), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylarylheteroaryl such as XXXIII
(Scheme 16). Treating XXVIII with l,l'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the lO formation of aziridine XXXIII . The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIV .
In addition, the arylheteroaryl subunit reagent can be reacted with aldehydes derived from amino acids such as O-alkylated 15 tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 17. When R' is an aryl group, XL can first be hydrogenated to llnm~k the phenol, and the amine group deprotected with acid to produce XLI. Alternatively, the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII
20 produced.
Schemes 1P~-21 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for 25 variable W are also well known in the art.
Boc NH
6 Boc NH CHO
R6 1. catalytic ~/ hydrogenation HO ~ ~ 2. CF3CO2H
Boc NH~
NHBoc XXI
~ i CH2CI2 N~,~R6 CHO
BocN H ~/
\~ NaBH(OAc)3 NH2 Et3N, CICH2CH2CI
XXIII
SCHEME 13 (continued) BocNH~ CF3CO2H, CH2C12, ~=~ NH NaHCO3 ~~ XXIV
NH~ ~ NC
NH AgCN
,~, R6 N~N~
~ XXV
~3 PCTrUS97/05304 ~R6 E120 BocNH CHO
XXVI
BnO HO ~=N ~=~ R6 20% Pd(OH)2 H2 NHBoc CH3C02H
HO r¦ N /=\~ R CICOCOCI
\_~ DMSO CH2CI2 (c2H5)3N
NHBoc XXVII
W O 97/36901 PCTrUSg7/05304 SCHEME 14 (continued) /~1 ~ R
~~ R'MgX
H NHBoc XXIX
R'~ R6 NHBoc XXX
\ ~ CH2CI2 NHBoc XXVIII
~=¦N /=~R RCHO
HO~ NaBH(OAC)3 XXXI
~)~S R6 NH
R'CH2 XXXII
WO 97/36901 PCTtUS97/05304 H H
R2 N =\~= N
HO~f ~R6 ~N S \~
NHBoc XXVIII
,=¦ N ~=, R"SH
, I CH30H
NH
XXXIII
R"S~ R6 XXXIV
; ~3 1 ) Boc20, K2C03 )~
H2NCO2H2) CH2N2, EtOAc XXXV XXXVI
HO~,~
LiAlH4 ~,~ R"'CH2X
THF J~ Cs2CO3 0-20~C BocNH CH2OH DMF
XXXVII
R"'CH2~~, R"'CH20 (C
BocNH CH2OH 20~C BocNH CHO
XXXVIII IXL
SCHEME 17 (continued) R"'C H~3 ¢~
BocNH CHO R6 IXL / ~ R"' not aryl Et20 /
2. 20% Pd(OH)2, H2 CH30H, CH3CO2H
3. HCI, EtOAc ~ho~ ~=¦ N /=\~ R6 R"'C H20 \~
NHBoc 2. 20% Pd(OH)2, H2 CH30H, CH3C02H
/~\ R2 2) HCI, EtOAc / ~ ~=¦ N /=\~R
/ R"'CH20 HO~R6 XLII
XLI
-W O 97/36901 PCTrUS97/05304 ~CH3 1) HNO2,Br2 ~CO2CH3 ~ 2) KMnO4 r H2N N 3) MeOH, H+ Br N
~\ MgCI R~,CO2CH3 Zncl2~Nicl2(ph3p)2 NaBH4 (excess) ~ ;CH20H
DM50 ~,CHO
WO 97/36901 PCT/US97/0~304 1. EtO(CO)CI R6 2 ~ [~,,COzCH3 N 3. S, xylene, heat N
NaBH4 ~j~ SO3Py, Et3N ~
(excess) ~3,CH20H DMSO ~CHO
Br~,CO CH l~l/\MgCI ¢~
ZnCI2, NiC12(Ph3P)2 N
NaBH4 ~ SO3Py, Et3N ¢~~CH20H ~ ~,CHO
(excess) N DMSO N
W O 97/36901 PCTrUS97/05304 C~2C H3 Br~1. LDA, CO2 Br~
N2. MeOH, H+ N
~MgCI ~2CH3 ZnCI2, Nicl2(ph3p)2 N
NaBH4 (excess) ~3OH SO3 Py, Et3N
DMSO
N
CHO
N~
C~2C H3 [~3~ 1 LDA, CO2 ~Br 2. (CH3)3sicHN2 R6 ~\Br R6. 3~
Zn, NiC12(Ph3P)2 N~C02CH3 R6 ~
excess NaBH4 I~J~ SO3 Py, Et3N
N~CH20H DMSO
R6 1~
N ~,CHO
The instant compounds are useful as pharmaceutical agents for m~mm~ls, especially for humans. These compounds may be a~lmini~tered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this 5 invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-l), neu, scr, abl, Ick, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
The instant compound.s may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. 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 (i.e., the Ras gene itself is not activated by mutation to an oncogenic forrn) with said inhibition being accomplished by the a~lministration of an effective amount of the compounds of the invention to a m~mmal in need of such treatment. For example, a component of NF-I 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 (J.S. 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 (C. 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 (D.L. Schaffner et al.
Ameri~an Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al .FASEB Journal, 2:A3 160 ( 19~8)).
The instant compounds may also be useful for the treatment of fungal infections.
The compounds of this invention may be administered to m~mmals, 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 ~f~ministered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound accord-ing to this invention, the selected compound may be ~lministered, for example, in the forrn 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 u.se, 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-~-lministered 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-l, restinosis, polycystic W O97/36901 PCTrUS97/05304 kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed do,se, such combination products employ the compounds of this invention within the dosage range 5 described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
The present invention also encompasses a pharmaceutical 10 composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compound.s of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include a(lueous solutions comprising compounds of this invention and pharmacolo-15 gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. Thesolutions 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 20 amounts, as well as any product which result.s, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is a~lministered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally 25 varying according to the age, weight, and response of the individual patient, as well a.s the severity of the patient's symptoms.
In one exemplary application, a suitable amount of compound is ~dministered to a m~mm~l undergoing treatment for cancer. A-lmini.stration occurs in an amount between about O.l mg/kg 30 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 farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine 5 terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known 10 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 15 assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain farnesyl-protein transferase and quanti-20 tating the enzyme. Thus, potent inhibitor compounds of the instantinvention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase 25 (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 (i.e., one that has a Ki substantially smaller than the concentration of enzyme in 30 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.
W O97/36901 PCT~US97/05304 EXAMPLES
Examples provided are intended to assist in a further understanding of the illvention. Particular material~s employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.
1 -(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: l -Trityl-4-(4-cyanobenzyl)-imidazole To a ~suspension of activated zinc du.st (3.57g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon at 20~C. The suspension was cooled to 0~C and a-bromo-p-tolunitrile (9.33g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes.
The reaction was then allowed to stir at 20~C for 6 hours and bis(triphenylphosphine)Nickel II chloride (2.4g, 3.64 mmol) and 4-iodo-1-tritylimidazole (15.95g, 36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739 (1991)) were added in one portion.The resulting mixture was stirred 16 hours at 20~C and then quenched by addition of sat. a4. NH4CI solution (100 mL) and the mixture stirred for 2 hours. Saturated aq. NaHCO3 solution w;~ added to give a pH
of ~ and the solution was extracted with EtOAc (2 x 250 mL), dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc in CH2C12 to afford the title compound as a white solid.
lH NMR (CDC13, 400MHz) ~ 7.54 (2H, d, J=7.9Hz), 7.3~(1H, s), 7.36-7.29 (1 lH, m), 7.15-7.09(6H, m), 6.5~(1H, s), and 3.93(2H, s)ppm.
Step B: 2-Phenyl-5-methylpyridine A mixture of 2-bromo-5-methylpyridine (2.00 g, 11.63 mmol), phenylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (5.50g, 17.4 mmol), DME (80 mL) and water (15 mL) was purged with dry argon. Tetrakis(triphenylphosphine)palladium(0) (672 mg, 0.5~ mmol) was added, and the resultant solution was stirred at 80~C for 4 hours. The solvents were evaporated in vacuo, and the residue partitioned between EtOAc and water and acidified with 1 M
a4. HCI. The aqueous extract was separated, and extracted with EtOAc. The organic extracts were combined, washed with NaHCO3 and 5~o aq. Na2S203, dried (Na2S04), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, CH2C12) to afford the title compound.
IH NMR (CDC13, 400MHz) ~ ~.52 (lH, s), 7.96(2H, d, J=7.0Hz), 7.63(1H, d, J=8.0Hz), 7.55(1H, brd, J=~.OHz), 7.50-7.35(3H, m), and 2.37(3H, s) ppm.
Step C: 2-Phenyl-5-carboxypyridine A suspension of 2-phenyl-5-methyl pyridine (1.03g, 6.09 mmol) and potassium permanganate (2.~9g, 1 ~.3 mmol), in water (25 mL) was heated at reflux for 2 hours. The reaction was allowed to cool to ambient temperature and filtered throu~h celite to remove the solids. Acetic acid (I mL) was added to the colourles.s filtrate and the product was collected as a white solid by filtration.
1 H NMR (CD30D, 400MHz) ~ 9.1 ~(1 H, s), ~ .41 (1 H, dd, 2.2 and 8.2Hz), ~.0~-~.02(2H, m), 7.97(1H, dd,3=~.2 and 0.7Hz) and 7.56-7.46(3H, m) ppm.
Step D: 2-Phenyl-5-hydroxymethylpyridine To a solution of 2-phenyl-5-carboxypyridine (520 mg, 2.61 mmol) in tetrahydrofuran (10 mL) at 0~C was added 1.0 M
- lithium aluminum hydride in tetrahydrofuran (2.61 mL, 2.61 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours, cooled to 0~C, and quenched by dropwise W O97/36901 PCT~US97/053~4 addition of water (0.20 mL), 4 N aq. NaOH (0.20 mL), and water (0.60 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 0-5% MeOH in CH2C12) to afford the title compound.
1H NMR (CDC13, 400MHz) ~ 8.66(1H, s), 7.97(2H, d, J=7.9Hz), 7.82-7.70(2H, m), 7.52-7.38(3H, m), 4.77(2H, s) and 1.89(1H, brs) ppm.
Step E: 1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride salt To a solution of 2-phenyl-5-hydroxymethylpyridine (264 mg, 1.43 mmol) and diisopropylethylamine (0.522 mL, 3.00 mmol) in dichloromethane (10 mL) at -78~C was added trifluoro-methanesulfonic anhydride (0.252 mL, 1.50 mmol) and the mixture stirred at -78~C for 15 minutes. To this mixture wa,s added a solution of l-trityl-4-(4-cyanobenzyl)imidazole (608 mg, 1.43 mmol) in dichloromethane (9 mL). The mixture was allowed to warm to ambient temperature and stirred for 16 hour~. The solvent was evaporated in vacuo. The residue was dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-5% NH40H in CH2C12). The amine was converted to the HCI salt by treatment with 1.0M HCI
in aqueous acetonitri~e. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
FAB MS 351 (MH+) lH NMR (CD30D, 400MHz) ~ 8.38(1H, d, J=2.4Hz),7.97(2H, m), 7.64(1H, d, J=8.2Hz), 7.60(1H, s), 7.56-7.40(5H, m), 7.28-7.20(1H, m), 7.17(2H, d, J=8.0Hz), 6.97(1H, s), 4.96(2H, s) and 3.89(2H, Is) ppm.
1 -(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt l -(2-Phenylpyrid-5-ylmethyl)-5 -(4-cyanobenzyl) 5 imidazole hydochloride (66.7mg, 0.159 mmol) was partitioned between CH2CI2 (lmL) and sat. aq. Na2CO3 (1 mL). The organic layer was separated, dried, (MgSO4) and the solvent evaporated in vacuo. The residue was dissolved in CH2Cl2 (2 mL), 3-chloro-perbenzoic acid (109 mg, 0.506 mmol) was added and the solution 10 stirred at ambiant temperature for 16 hours. The reaction was partitioned between CH2Cl2 (5mL) and sat. aq. Na2CO3 (2mL) and the organic layer separated, dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel 4-10% MeOH in CH2CI2). The amine wa,s converted to the HCI salt 15 by treatment with 1.0M HCl in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
lH NMR (CD30D, 400MHz) ~ 9.18(1H, s), 8.13(1H,s), 7.80-7.20(12H,m), 5.53(2H,s) and 4.28(2H,s) ppm.
1 -(3 -Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt 25 Step A: 3-Phenyl-6-carboxypyridine A suspension of 3-phenyl-6-methyl pyridine (1.99g, 11.7~ mmol) and potassium permanganate (7.65, 48.6 mmol), in water (50 mL) was heated at reflux for 16 hours. The reaction was allowed to cool to ambient temperature and filtered through celite 30 to remove the solids. Acetic acid (2 mL) was added to the colourlesls filtrate and the product was collected as a white solid by filtration.
1H NMR (CD30D, 400MHz) ~ 8.86(1H, s), 8.15(2H,m), 7.70(2H,d, J=6.7Hz) and 7.60-7.30(3H,m) ppm.
35 Step B: 3-Phenyl-6-hydroxymethylpyridine W O 97/36901 PCT~US97/05304 To a solution of 3-phenyl-6-carboxypyridine (l.OSg, 5.27 mmol) in tetrahydrofuran (25 mL) at 0~C was added 1.0 M
lithium aluminum hydride in tetrahydrofuran (10.0 mL, 10.0 mmol) over 10 minutes. The reaction was allowed to stir at ambient 5 temperature for 6 hours, cooled to 0~C, and quenched by dropwise addition of water (0.50 mL), 4 N aq. NaOH (0.50 mL), and water (1.5 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue wa.s chromatographed (silica gel, 0-5% MeOH in CH2CI2) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ ~.79(1H, d, J=l.OHz), 7.~s~s(1H, dd, J=~.6 and l.SHz), 7.5~(2H,d, J=6.7Hz), 7.49(2H,t, J=7.0Hz), 7.41(1H,t, J=7.0Hz), 7.33(1H,d, J=7.6Hz), 4.83(2H,s) and 3.75(1 H,brs) ppm.
~5 Step C: 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl) imidazole hydrochloride.salt To a solution of 3-phenyl-6-hydroxymethylpyridine (192 mg, 1.04 mmol) and diisopropylethylamine (0.360 mL, 2.07 mmol) in dichloromethane (8 mL) at -7~~C was added trifluoro-20 methanesulfonic anhydride (0.1 ~0 mL, 1.07 mmol) and the mixturestirred at -78~C for 1 hour. To this mixture wa~s added a solution of 1-trityl-4-(4-cyanobenzyl)imidazole (441 mg, 1.04 mmol) in dichloromethane (9 mL). The mixture was allowed to warm to ambient temperature and stirred for 4 hour.s. The solvent was 25 evaporated in vacuo. The residue was dissolved in methanol (10 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chroma-30 tographed (Silica gel, EtOAc and then 5% MeOH in CH2C12). Theamine was converted to the HCI salt by treatment with 1.0M HCI in - aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
WO 97/36901 PCItUS97/05304 FAB HRMS exact mass calcd for C23H19N4 351.160972 (MH+);
found 351.161206.
1 H NMR (CD30D, 400MHz) ~ 9.20(1 H, d, J= 1.4Hz), 8.75(1 H, d, J=2.2Hz), 8.16(1H, d, J=8.20), 7.66 (2H, d, J=8.4Hz), 7.60-7.40(7H, 5 m), 7.26(2H, d, J=8.0Hz), 5.73(2H, s) and 4.27(2H, s) ppm.
Anal. Calcd. for C23Hl~N4-2.00 HCI 0.80 H2O:
C, 63.11; H,4.97; N, 12.80.
Found: C, 63.10; H, 4.97; N, 12.95.
1 -(3 -Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt 1 -(3 -Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl) 15 imidazole hydochloride (100.Omg, 0.236mmol) was partitioned between CH2CI2 (2mL) and sat. aq. Na2CO3 (lmL). The organic layer was separated, dried, (MgSO4) and the solvent evaporated in vacuo.
The residue was dissolved in CH2CI2 (2 mL), 3-chloroperbenzoic acid (143mg, 0.472 mmol) was added and the solution .stirred at 20 ambient temperature for 16 hours. The reaction was partitioned between CH2Ck (SmL) and sat. a4. Na2CO3 (2mL) and the organic layer separated, dried, (MgSO4) and the solvent evaporated in vacuo.
The residue was chromatographed (Silica gel 4-10% MeOH in CH2CkThe amine wa,s converted to the HCl salt by treatment with 25 1.0M HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
lH NMR free base (CDC13, 400MHz) ~ 8.44(1H, d, J=l.SHz), 7.63(1H,s), 7.60-7.20(10H,m), 7.03(1H,s), 6.35(1H,d, J=~.2Hz), 5.29(2H,s) and 3.96(2~,s) ppm.
EXAMPLE S
1 -(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt W O97/36901 PCT~US97/05304 Step A: 2-(3-Trifluoromethoxyphenyl)-S-methylpyridine To a solution of 3-bromotrifluoromethoxybenzene (0.590mL, 4.00 mmol) in THF (12 mL) at -7~~C was added t-butyl 5 lithium (4.71mL, of a 1.7M solution in pentane, ~.00 mmol. After 10 minutes zinc chloride(4.0mL, of a IM solution in diethylether, 4.00 mmol) wa,s added. The reaction was stirred for 10 minutes at -78~C and then allowed to warrn to 0~C and stirred for 30minutes.
This solution was added via cannula to a solution of 2-bromo-5-10 methyl pyridine and bis(triphenylphosphine) Nickel II chloride. The reaction stirred for I hour at 0~C and then at ambient temperature for a furthur 1 hour. Saturated ammonium hydroxide ,solution (3 mL) was added and the mixture stirred until homogenous, extracted with Et20 and the organic extracts washed with saturated brine, 15 dried (MgSO4) and evaporated in vacuo. The residue was chromato~raphed (Silica gel, 25-50% CH2CI2 in hexanes).
lH NMR (CD30D, 400MHz) a ~.4~S(1H~ s),7.93(1H, brd, J=8.0Hz), 7.~7(1H, s), 7.79(2H, d, J=8.0Hz), 7.74(2H, d, J=~.OHz), 7.56(1H, t, J=8.0Hz), 7.32(1H, brd, J=~.OHz) and 2.40(3H, s) ppm.
Step B: 2-(3 -Trifluoromethoxyphenyl )-5-carboxy pyridine A solution of 2-(3-Trifluoromethoxyphenyl)-5-methylpyridine (2.35g, 2.22 mmol) and tetrabutylammonium permanganate (1.904, 0.012mol), in pyridine (8 mL) was heated 25 at 75~C for 16 hours. The cooled reaction was filtered through celite to remove the solids. The solid was washed with EtOAc and MeOH
and the filtrate evaporated in vacuo to afford the title compound of sufficient purity to be used in the next step.
30 Step C: 2-(3-Trifluoromethoxyphenyl)-5-hydroxymethylpyridine - To a solution of 2-(3-trifluoromethoxyphenyl)-5-carboxy pyridine (2.0 g, 7.06 mmol) in tetrahydrofuran (15 mL) at 0~C was added 1.0 M lithium aluminum hydride in tetrahydrofuran W O 97/36901 PCTAUS97/0~304 (7.07 mL, 7.07 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 4 hours, cooled to 0~C, and quenched by dropwise addition of saturated Na2SO4 (1.0 mL). The reaction was diluted with diethylether, filtered through a pad of 5 Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 50% EtOAc in hexane,s) to afford the title compound.
1 H NMR (CD30D, 400MHz) ~ 8.62(1 H, d, J= I .OHz), 8.00-7.84(H,m), 7.57(1H, t, J=8.0Hz), 7.33(1H,brd, J=8.0Hz) and 10 4.~4(2H,s) ppm.
Step D: 1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt To a solution of 2-(3-trifluoromethoxyphenyl)-5-15 hydroxymethylpyridine (66 mg, 0.25 mmol), diisopropylethylamine (0.085 mL, 0.49 mmol), and 1-trityl-4-(4-cyanobenzyl)imidazole (105 mg, 0.25 mmol) in dichloromethane (1.4 mL) at -7~~C was added trifluoromethanesulfonic anhydride (0.041 mL, 0.25 mmol) and the mixture stirred at -7~~C for 1 hour. The reaction wa.s 20 allowed to warm to ambient temperature and stirred for 4 hours.
The solvent was evaporated in vacuo. The re,sidue wa~s dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloro-methane and sat. aq. Na2CO3 solution. The organic layer was dried, 2~S (Na2SO4) and the solvent evaporated in vacuo. The residue wa.s chromatographed (Silica gel, 3% MeOH in CH2Ck). The amine was converted to the HCI salt by treatment with 1.0M HCI in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
IH NMR (CD30D, 400MHz) ~ 9.23(1H, s), 8.67(1H,s), ~.18-- 8.04(2H, m), 8.00-7.90(2H,m), 7.74(1H, t, J=7.9Hz), 7.62-7.50(4H, m), 7.31(2H, d, J=7.9Hz), 5.71(2H, s), 4.29(2H, .s) ppm.
W O 97/36901 PCT~US97/05304 FAB HRMS exact mass calcd for C24HlsN4 OF3 435.143271 (MH+);
found 435.144474.
Anal. Calcd. for C24HI7N4 OF3 -2.00 HCI:
C, 56.82; H, 3.77; N, 11.04.
Found: C, 56.50; H, 3.88; N, 10.86.
1 -(2-(2-Trifluoromethylphenyl)-pyrid-S-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 2-(2-Trifluoromethylphenyl)-5-methylpyridine To a solution of 2 bromo-5-methyl pyridine (1.81g, 10.53 mmol) and barium hydroxide (4.97 g, 15.7~ mmol) in water (15 mL) was added DME (80 mL). This mixture was treated sequentially with 2-(trifluoromethyl)phenylboronic acid (2.00g, 10.53 mmol) and palladium tetrakis(triphenylphosphine) (553 mg, 0.48 mmol) and the mixture warmed to 80~C for 4~ hours.
Water (lOOmL) was added and the pH of the solution was adjusted to 10 and extracted with EtOAc (3X200mL).
The organic extracts were combined, washed with brine, dried (MgSO4), and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel,50% -100% CH2Ck in hexanes) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.52(1H, s), 7.75(1H, d, J=7.9Hz), 7.64-7.44(4H, m), 7.32(1H, d, J=7.9Hz) and 2.40(3H,s) ppm.
Step B. 2-(2-Trifluoromethylphenvl)-;S-carboxypyridine A suspension of 2-(2-Trifluoromethylphenyl)-5-methylpyridine (0.40g, 1.6~ mmol) and potassium permanganate (1.60g, 10.1 mmol), in water (10 m~) was heated at reflux for 16 - hours. The reaction was filtered hot through celite to remove the solids. Acetic acid was added to the colourless filtrate to yield a pH
of S and the resulting suspension was extracted with CH2Ck.washed WO 97t36901 PCT/US97/05304 with water (10 mL), dried, (MgSO4), and the solvent evaporated in vacuo to afford the title compound.
1 H NMR (CD30D, 400MHz) ~ 9.34(1 H, s), 8.41 ( I H,d, J=8.2Hz), 7.80(1H,d, J=7.9Hz) and 7.70-7.50(4H,m) ppm.
s Step C: 2-(2-Trifluoromethylphenyl)-5-hydroxymethvlpyridine To a solution of 2-(2-Trifluoromethylphenyl)-5-carboxypyridine (220 mg, 1.23 mmol) in tetrahydrofuran (10 mL) at 0~C was added 1.0 M lithium aluminum hydride in tetrahydrofuran (1.23 mL, 1.23 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours, cooled to 0~C, and quenched by dropwise addition of water (0.05 mL), 2.5 N aq. NaOH (0.05 mL), and water (0.15 mL). Sodium sulfate wa.s added, the reaction filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, CH2CI2 then EtOAc) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.63(1H, s), 7.80-7.40(6H,m) and 4.77(2H, s) ppm.
Step D: 1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt The title compound was prepared using the procedure described for Example 5, step D using 2-(2-trifluoromethylphenyl) -5-hydroxymethylpyridine from Step C in place of 2-(3-trifluoro-methoxyphenyl)-5-hydroxymethylpyridine.
1 H NMR (CD30D, 400MHz) â 9.17(1 H, s), 8.42(1 H,s), 8.00-7.40(1 lH, m), 5.60(2H, s), 4.26(2H, s) ppm.
FAB MS 419 (MH+) Anal. Calcd. for C24HI7N4 F3 -2.95 HCI. 0.6 EtOAc:
C, 54.78; H, 4.31; N, 9.68.
Found: C, 54.79; H, 4.18; N, 9.68.
W O 97/36901 PCT~US97/05304 1 -(3 -Phenyl-2-Chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 3-Phenyl-6-methylpyridine N-oxide A solution of 3-phenyl-6-methyl pyridine (2.36g, 13.95 mmol), in CH2Cl2 (40 mL) at 0~C was treated with MCPBA (3.58g, 13.95 mmol) for 1 hour. Saturated aq. Na2CO3 (50 mL) was added and the reaction was extracted with CH2CI2 (20 mL). The organic extracts were dried (MgSO4), and the solvent evaporated in vacuo to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.53(1H, s), 7.60-7.20(7H, m) and 2.57(3H, s) ppm.
Step B: 3-Phenyl-2-chloro-6-methylpyridine and 3-phenyl-4-1 5 chloro-6-methvlpyridine A solution of 3-phenyl-6-methyl pyridine-N-Oxide (1.42g, 7.66 mmol), in P2Os (50 mL) at 0~C was at 80~C for 3 hours. The reaction was allowed to cool to room temperature and then poured over ice (400g). Saturated aq. Na2CO~ wa.s added until the pH of the solution wa,~ 8 and the reaction was extracted with CH2Ck (3X250 mL). The organic extracts were ~ried (MgSO4), and the solvent evaporated in vacuo. The re,sidue was chromatographed (silica gel, 10-20~o EtOAc in CH2CI2 to afford 3-Phenyl-2-chloro-6-methylpyridine (First eluted) lH NMR (CDC13, 400MHz) ~ 7.56(1H, d, J=7.6Hz), 7.60-7.30(5H,m), 7.15(1H,d, J=7.6Hz) and 2.59(3H, s) ppm.
3-Phenyl-4-chloro-6-methylpyridine (Second eluted).
IH NMR (CDC13, 400MHz) ~ 8.43(1H, ,s), 7.60-7.40(5H,m~, 7.29(1H,s) and 2.59(3H, s) ppm.
Step C: 3-Phenyl-2-chloro-6-bromomethylpyridine - A ~olution of 3-Phenyl-2-chloro-6-methylpyridine (0.094g, 0.462 mmol), NBS (0.086g, 0.485 mmol) and AIBN
(0.008g, 0.046mmol) in CCl4 (3 mL) were heated at reflux for 2 hours. The solvent was evaporated and the residue chroma-tographed(Silica gel, 100% CH2CI2 to afford the title compound.
1}~ NMR (CDC13, 400MHz) ~ 7.68(1H, d, J=7.6Hz), 7.60-7.40(6H,m), and 4.56(2H, s) ppm.
Step D: 1-(3-Phenyl-2-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt To l-trityl-4-(4-Cyanobenzyl)-imidazole (88.4mg, 0.208 mmol) in acetonitrile (1 mL) was added 3-phenyl-2-chloro-6-bromomethylpyridine (53.5mg, 0.189 mmol) and the mixture heated at 65~C for 16 hours. The re~idue was dissolved in methanol (3 ml) and heated at reflux for 2 hours, cooled and evaporated to dryness. The re.sidue was partitioned between sat. aq. Na2CO~
solution and CH2Cl2. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 2.5-3% MeOH in CH2CI2) to afford the free ba.se which was converted to the HCI salt by treatment with one equivalent of HCI in aqueous acetonitrile. Evaporation of solvent in vacuo afforded the title compound as a white powder.
1 H NMR (CD30D, 400MHz) ~ 9.1 1 ( 1 H, ~), 7.64(1 H.d, J=7.7Hz), 7.55(2H,d, ~=8.2Hz), 7.51(1H,s), 7.50-7.34(5H,m), 7.32-7.20(3H, m), 5.56(2H, s), 4.27(2H, s) ppm.
Anal. Calcd. for C23HI7CIN4 1.00 HCI. 0.6 EtOAc:
C, 54.78; H, 4.31; N, 9.68.
Found: C, 54.79; H, 4.18; N, 9.68.
1 -(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt - The title compound was prepared using the procedure described for Example 7, steps C and D using 3-phenyl-4-chloro-6-methylpyridine in place of 3-phenyl-6-methyl pyridine.
W O 97/36901 PCTrUS97/OS304 Anal. Calcd. for C24HI7N4 Cl l.OO HCI. 0.30 H20:
C,64.74; H,4.39; N, 13.13.
Found: C, 64.~2; H, 4.52; N, 12.93.
1 -(2-Amino-3 -phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt Step A: 2-Amino-3-Phenyl-6-methylpyridine A solution of 3-phenyl-6-methyl pyridine (0.815 g, 4.82 mrnol), and sodium amide (752mg, 19.3mmol) in diethylaniline (lOmL) was heated at 1~0~C for 72 hours. The reaction was cooled and quenched with ice (lOOg), and the mixture extracted with EtOAc. The organic extract was washed with brine 15 (50 mL), dried (MgSO4), silica gel (lOOg) was added and the ,solvent evaporated in vacuo.
The material was loaded onto a column and chromatographed (Silica gel, eluting with 0-100% EtOAc in CH2Ck) to afford the title compound.
20 lH NMR (CDC13, 400MHz) o 7.50-7.20(6H, m) 6.61(1H,d, ~=7.0Hz), and 2.42(3H, s) ppm.
Step B: N-bis t-Butoxycarbonyl-2-Amino-3-Phenyl-6-methylpyridine A solution of 2-amino-3-phenyl-6-methyl pyridine (1.21 g, 6.57 mmol), di t-butylcarbonate(3.58g, 16.4 mmol), triethylamine 5 (2.29 mL, 16.4 mrnol) and DMAP (0.803g, 6.57 mmol) in CH2C12 (20mL) were heated at 65~C for 16 hours. The reactionwas diluted with sat. aq. Na2CO3 and extracted with CH2Cl2 The solvent was evaporated in vacuo. and the residue chromatographed (Silica gel, eluting with 20% EtOAc in CH2CI2) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 7.62(1H, d, J=7.7H~), 7.41-7.30(5H, m), 7.19(1H, d, J=7.7Hz), 2.59(3H, s) and 1.2X(18H, s) ppm.
Step C: 2-(bis t-butoxycarbonylamino)-3-phenyl-6-methylpvridine-N-oxide A solution of N-bis t-butoxycarbonyl-2-amino-3-phenyl-6-methylpyridine (0.215g, 0.56 mmol), in CH2CI2 (4 mL) at 0~C was treated with MCPBA (0.220g, 0.727 mmol) for 1 hour. Saturated aq. Na2CO3 (50 mL) was added and the reaction was extracted with CH2CI2 (2X50 mL). The organic extracts were dried (MgSO4), and 20 the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, eluting with 100% EtOAc to afford the title compound.
1H NMR (CDC13, 400MHz) ~ 7.44-7.36(6H,m), 7.13(1H, d, J=7.7Hz), 2.56(3H, s) and 1.31(1~H, s) ppm.
~5 StepD: N-bis t-Butoxycarbonyl-2-amino-3-phenyl-6-acetoxymethylpyridine A solution of 2-(bis t-butoxycarbonylamino)-3-phenyl-6-methylpyridine-N-oxide (0.223g, 0.557 mmol), in acetic anhydride (5 mL) was heated at 65~C for 24 hours. The solvent was evaporated 30 in vacuo and the residue chromatographed (30-50%EtOAc in hexanes) to afford the title compound.
- lH NMR (CDC13, 400MHz) ~ 7.74(1H, d, J=7.7Hz), 7.50-7.30(6H, m), 5.25(2H, s), 2.17(3H, s) and 1.28(18H, s) ppm.
W O97/36901 PCTrUS97/05304 Step E: N-bis t-Butoxycarbonyl-2-amino-3-phenyl-6-hydroxymethylpyridine A solution of 2-(bis t-butoxycarbonylamino)-3-phenyl-6-acetoxymethylpyridine (0.040g, 0.09 mmol), THF (1.3 mL) was S treated with Lithium hydroxide (lM solution in water 0.271 ml, 0.271 mmol) at room temperature for 16 hours. The reaction was diluted with water and extracted with CH2Cl2. The organic extracts were dried (MgSO4),and the solvent evaporated in vacuo to afford the title compound.
lH NMR (CDC13, 400MHz) â 7.74(1H, d, J=7.P~ Hz), 7.44-7.33(5H, m), 7.31(1H,brd, J=7.8Hz), 4.~1(2H, s), and 1.29(18H, s) ppm.
Step F: 1 -(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole hydrochloride salt The title compound was prepared using the procedure described for Example 3 ,step C using N-bis t-butoxycarbonyl-2-amino-3-phenyl-6-hydroxymethylpyridine in place of 3-phenyl-6-hydroxymethyl-pyridine. In this case the free base was treated with TFA and triethylsilane to effect cleavage of the t-butoxycarbonyl groups which was followed by its conversion to the hydrochloride salt.
lH NMR (CD30D, 400MHz) ~ 9.23(1H, s), 7.80-7.20(H, m), 6.96(1H,s), 6.65(1H,d, J=7.6Hz), 5.66(2H, s), 4.33(2H, s) ppm.
Anal. Calcd. for C2~HIsN~ 1.00 HCI. 0.95 H20 0.35 EtOAc:
C, 60.26; H, 5.33; N, 14.40.
Found: C, 60.04; H, 5.10; N, 14.45.
ln vitro inhibition of ras farnesyl transferase Assays offarnesyl-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 31:3~00 (1992) and Gibbs et al., PNAS U.S.A. ~6:6630-6634 (19~9), respectively. Bovine FPTase was assayed in a volume of 100 ~1 containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgC12, 5 mM dithiothreitol (Dl~), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mrnol, New England Nuclear), 650 nM Ras-CVLS and 10 ~g/ml FPTase at 5 31 ~C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach Il cell harvestor, washed with 100%
ethanol, dried and counted in an LKB ,~-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10 10% of the [3Hl-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 15 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 ~lM ZnC12 and 100 nM Ras-CVIM were 20 added to the reaction mixture. Reactions were perforrned for 30 min., stopped with 100 ~l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compound of the instant invention described in the above Examples 1-9 were tested for inhibitory activity against human 25 FPTase by the assay described above and were found to have IC50 of <50 ~M.
30 In viv~ ras farnesylation assay The cell line used in this assay is a v-ras line derived - from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is perforrned essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cell.s in 10 cm dishes at 50-75%
W O 97136901 PCT~US97/05304 confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, i.s 0.1%). After 4 hours at 37~C, the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400 5 mCi[35SJmethionine (1000 Ci/mmol). After an additional 20 hour,s, the cells are Iysed in 1 ml Iysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptinl2 mg/ml antipain/0.5 mM PMSF) and the Iysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of Iysates containing equal numbers 10 of acid-precipitable counts are bought to 1 ml with IP buffer (Iysi.s buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et ah, J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a 25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
15 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-100Ø5% 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 20 autoradiographed. The intensities of the bands corresponding to farne,sylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
In l~ivo ~rowth 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 30 v-ras, v-raf, or v-mos oncogene i.s 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 tran.sformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in W O 97/36901 PCTrUS97/05304 a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in 5 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. Photo-micrographs are taken 16 days after the cultures are seeded and comparisons are made.
. , ,~ . .. . . .. . . .
Claims (30)
1. A compound which inhibits farnesyl-protein transferase of the formula A:
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;
R1 and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, K11S(O)m-, R10C(O)NR10-, R11C(O)O-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R3, R4 and R5 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10;
R6a, R6b, R6C, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-, provided that when R3, R4, R5, R6a, R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4, R5, R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) -SO2R11, g) N(R10)2 or h) C1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, sublstituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O, R11S(O)m-, R10C(O)NR10 , (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, or R10OC(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) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R11O, R11S(O)m-, R10C(o)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, Cl-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
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 heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;
W is a heterocycle;
X is a bond, -CH=CH-, O, -C(=O)-, -C(O)NR7-, -NR7C(O)-, -C(O)O-, -OC(O)-, -C(O)NR7C(O)-, -NR7-, -S(O)2N(R10)-, -N(R10)S(O)2- or -S(=O)m-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;
or a pharmaceutically acceptable salt thereof.
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;
R1 and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, K11S(O)m-, R10C(O)NR10-, R11C(O)O-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R3, R4 and R5 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10;
R6a, R6b, R6C, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-, provided that when R3, R4, R5, R6a, R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4, R5, R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) , f) -SO2R11, g) N(R10)2 or h) C1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, sublstituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O, R11S(O)m-, R10C(O)NR10 , (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, or R10OC(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) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R11O, R11S(O)m-, R10C(o)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, Cl-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10, -NR10C(O)-, O, -N(R10)-, -S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
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 heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;
W is a heterocycle;
X is a bond, -CH=CH-, O, -C(=O)-, -C(O)NR7-, -NR7C(O)-, -C(O)O-, -OC(O)-, -C(O)NR7C(O)-, -NR7-, -S(O)2N(R10)-, -N(R10)S(O)2- or -S(=O)m-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1;
or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 of the formula A:
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;
R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3, R4 and R5 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2NC(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R6a, R6b, R6C, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12O-, R11S(O)m-, R 10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, RS, R6a, R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4, R5, R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO.
, f) ~SO2R11, g) N(R10)2 or h) C1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R11O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, CN, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-. -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
X is a bond, O, -C(=O)-, -CH=CH-, -C(O)NR7-, -NR7C(O)-, -NR7-, -S(O)2N(R10), -N(R10)S(O)2- or -S(=O)m-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ;
or a pharmaceutically acceptable salt thereof.
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;
R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3, R4 and R5 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2NC(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R6a, R6b, R6C, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12O-, R11S(O)m-, R 10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, RS, R6a, R6b, R6C, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4, R5, R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO.
, f) ~SO2R11, g) N(R10)2 or h) C1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9 is selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R11O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, CN, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-. -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
X is a bond, O, -C(=O)-, -CH=CH-, -C(O)NR7-, -NR7C(O)-, -NR7-, -S(O)2N(R10), -N(R10)S(O)2- or -S(=O)m-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ;
or a pharmaceutically acceptable salt thereof.
3. The compound according to Claim 1 of the formula B:
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3 and R4 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R6a, R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is;
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3 and R4 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R6a, R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is;
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 1 of the formula C:
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3 and R4 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10,-c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R6a R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
and r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3 and R4 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10,-c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R6a R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R4, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl and halogen;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-, -C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
and r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.
5. The compound according to Claim 3 of the formula D:
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;
R3 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, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a, R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-, n is 0 or 1; provided that n is not 0 if A1 is a bond, O, -N(R10)- or S(O)m;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;
R3 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, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a, R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-, n is 0 or 1; provided that n is not 0 if A1 is a bond, O, -N(R10)- or S(O)m;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
6. The compound according to Claim 4 of the formula E:
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;
R3 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, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)NR10-;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;
n is 0 or 1;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
or a pharmaceutically acceptable salt thereof.
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;
R3 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, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)NR10-;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-, R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;
n is 0 or 1;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
or a pharmaceutically acceptable salt thereof.
7. The compound according to Claim 5 of the formula F:
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R10O-, or -N(R10)2;
R3 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, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2 or F, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, R10O-, or -N(R10)2;
R3 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, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or -C(=O)-;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
8. The compound according to Claim 6 of the formula G:
>
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;
R3 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, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)NR10-;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and n is 0 or 1;
or a pharmaceutically acceptable salt thereof.
>
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or -N(R10)2;
R3 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, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)NR10-;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6c, R6d and R6e 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, C1-C6 perfluoroalkyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are combined to form a diradical selected from -CH=CH-CH=CH-, -CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is unsubstituted or substituted heterocycle, attachment of R3, R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl ring, or phenyl ring respectively, is through a substitutable heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl, C1-C6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and n is 0 or 1;
or a pharmaceutically acceptable salt thereof.
9. A compound which inhibits farnesyl-protein transferase which is:
1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Phenyl-2-Chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole or 1-(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Phenyl-2-Chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole 1-(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole or 1-(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
10. The compound according to Claim 9 which is:
1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
11. The compound according to Claim 9 which is:
1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1.
13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 3.
14. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4.
15. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 9.
16. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.
17. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 13.
18. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 14.
19. A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 15.
20. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.
21. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 13.
22. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 14.
23. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 15.
24. A method for treating neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.
25. A method for treating blindness related to retinal vascularization which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.
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 composition of Claim 12.
27. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.
28. A method for treating polycystic kidney disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 12.
29. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier.
30. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1459296P | 1996-04-03 | 1996-04-03 | |
| US60/014,592 | 1996-04-03 | ||
| GB9613462.2 | 1996-06-27 | ||
| GBGB9613462.2A GB9613462D0 (en) | 1996-06-27 | 1996-06-27 | Inhibitors of farnesyl-protein transferase |
| US2264796P | 1996-07-24 | 1996-07-24 | |
| US60/022,647 | 1996-07-24 | ||
| GBGB9617277.0A GB9617277D0 (en) | 1996-08-16 | 1996-08-16 | Inhibitors of farnesyl-protein transferase |
| GB9617277.0 | 1996-08-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2249607A1 true CA2249607A1 (en) | 1997-10-09 |
Family
ID=27451473
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002249607A Abandoned CA2249607A1 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0891361A1 (en) |
| JP (1) | JP2000507590A (en) |
| AU (1) | AU706150B2 (en) |
| CA (1) | CA2249607A1 (en) |
| WO (1) | WO1997036901A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6015817A (en) * | 1996-12-05 | 2000-01-18 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US5939439A (en) * | 1996-12-30 | 1999-08-17 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US6093737A (en) * | 1996-12-30 | 2000-07-25 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US6127390A (en) * | 1997-10-02 | 2000-10-03 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
| EP1045846B1 (en) | 1997-11-28 | 2003-05-02 | Lg Chemical Limited | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
| CA2312366A1 (en) * | 1997-12-04 | 1999-06-10 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US6420555B1 (en) | 1998-06-16 | 2002-07-16 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Imidazolyl derivatives |
| WO1999065898A1 (en) * | 1998-06-16 | 1999-12-23 | Societe De Conseils De Recherches Et D'applications Scientifiques Sas | Imidazolyl derivatives |
| WO2000064891A1 (en) * | 1999-04-13 | 2000-11-02 | Lg Chem Investment Ltd. | Farnesyl transferase inhibitors having a pyrrole structure and process for preparation thereof |
| EP1420015A1 (en) * | 1999-06-11 | 2004-05-19 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Imidazolyl derivatives |
| AR034257A1 (en) | 2000-06-30 | 2004-02-18 | Du Pont Pharm Co | UREIDO COMPOUND, PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS IT AND METHOD TO MODULATE THE ACTIVITY OF THE CHEMIOKIN RECEPTOR |
| US7211595B2 (en) | 2000-11-30 | 2007-05-01 | Abbott Laboratories | Farnesyltransferase inhibitors |
| US20020115640A1 (en) * | 2000-11-30 | 2002-08-22 | Claiborne Akiyo K. | Farnesyltransferase inhibitors |
| CN1665506A (en) | 2002-07-02 | 2005-09-07 | 霍夫曼-拉罗奇有限公司 | 2, 5-substituted pyrimidine derivatives as CCR-3 receptor antagonists IX |
| CA2574600C (en) | 2004-07-23 | 2010-08-31 | Pfizer Inc. | Pyridine derivatives |
| CA2672373C (en) | 2006-12-19 | 2011-08-30 | Pfizer Products Inc. | Nicotinamide derivatives as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases |
| UY30892A1 (en) | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | AKT ACTIVITY INHIBITORS |
| JP2010519328A (en) | 2007-02-26 | 2010-06-03 | ファイザー・プロダクツ・インク | Nicotinamide derivatives as inhibitors of H-PGDS and their use for the treatment of diseases mediated by prostaglandin D2 |
| CN101743242A (en) | 2007-06-29 | 2010-06-16 | 苏尼西斯制药有限公司 | Heterocyclic compounds useful as RAF kinase inhibitors |
| TWI444379B (en) | 2007-06-29 | 2014-07-11 | Sunesis Pharmaceuticals Inc | Compounds useful as raf kinase inhibitors |
| PE20110843A1 (en) | 2008-09-22 | 2011-12-08 | Cayman Chem Co | DERIVATIVES OF 5- (1H-IMIDAZOL-5-IL) -2-PHENYLPYRIMIDINE, AS INHIBITORS OF PROSTAGLANDIN D HEMATOPOYETIC SYNTHASE |
| WO2010114896A1 (en) | 2009-03-31 | 2010-10-07 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
| JP5499160B2 (en) | 2010-04-06 | 2014-05-21 | 日本曹達株式会社 | Nitrogen-containing heterocyclic compound and method for producing the same |
| AU2014201037B9 (en) * | 2010-04-06 | 2015-11-19 | Nippon Soda Co., Ltd. | Nitrogen-containing heterocyclic compound and method for producing same |
| US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| ES2900806T3 (en) | 2013-10-04 | 2022-03-18 | Infinity Pharmaceuticals Inc | Heterocyclic compounds and uses thereof |
| WO2015051241A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| JP6701088B2 (en) | 2014-03-19 | 2020-05-27 | インフィニティー ファーマシューティカルズ， インコーポレイテッド | Heterocyclic compounds for use in the treatment of PI3K-gamma mediated disorders |
| US9975874B2 (en) | 2014-07-28 | 2018-05-22 | Merck Sharp & Dohme Corp. | Factor XIa inhibitors |
| US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
| EP3319968A1 (en) | 2015-07-06 | 2018-05-16 | Rodin Therapeutics, Inc. | Heterobicyclic n-aminophenyl-amides as inhibitors of histone deacetylase |
| RS62639B1 (en) | 2015-07-06 | 2021-12-31 | Alkermes Inc | Hetero-halo inhibitors of histone deacetylase |
| US10160761B2 (en) | 2015-09-14 | 2018-12-25 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same |
| WO2017161116A1 (en) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors |
| US10919914B2 (en) | 2016-06-08 | 2021-02-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| RS62959B1 (en) | 2017-01-11 | 2022-03-31 | Alkermes Inc | Bicyclic inhibitors of histone deacetylase |
| MD3664802T2 (en) | 2017-08-07 | 2022-07-31 | Alkermes Inc | Bicyclic inhibitors of histone deacetylase |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2162513B (en) * | 1984-06-25 | 1988-01-20 | Toyama Chemical Co Ltd | Dihydropyridine derivatives |
| US5159083A (en) * | 1990-12-28 | 1992-10-27 | Neurogen Corporation | Certain aminomethyl phenylimidazole derivatives; a class of dopamine receptor subtype specific ligands |
| US5633376A (en) * | 1990-12-28 | 1997-05-27 | Neurogen Corporation | Certain aminomethyl phenylimidazole derivatives; and 4-aryl substituted piperazinyl and piperidinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype ligands |
| IT1255802B (en) * | 1992-08-07 | 1995-11-16 | Luso Farmaco Inst | IMIDAZOLIC DERIVATIVES FOR ACTIVITY A II ANTAGONIST |
-
1997
- 1997-04-01 WO PCT/US1997/005304 patent/WO1997036901A1/en not_active Application Discontinuation
- 1997-04-01 EP EP97920000A patent/EP0891361A1/en not_active Withdrawn
- 1997-04-01 CA CA002249607A patent/CA2249607A1/en not_active Abandoned
- 1997-04-01 JP JP9535534A patent/JP2000507590A/en active Pending
- 1997-04-01 AU AU24301/97A patent/AU706150B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997036901A1 (en) | 1997-10-09 |
| EP0891361A1 (en) | 1999-01-20 |
| AU706150B2 (en) | 1999-06-10 |
| JP2000507590A (en) | 2000-06-20 |
| AU2430197A (en) | 1997-10-22 |
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