CA2250936A1 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- CA2250936A1 CA2250936A1 CA002250936A CA2250936A CA2250936A1 CA 2250936 A1 CA2250936 A1 CA 2250936A1 CA 002250936 A CA002250936 A CA 002250936A CA 2250936 A CA2250936 A CA 2250936A CA 2250936 A1 CA2250936 A1 CA 2250936A1
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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
CA 022~0936 1998-09-28 W 0 97/36898 PCTAUSg7/05512 TITLE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
BACKGROUND OF THE ~VENTION
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. ln the inactive state, Ras is bound to GDP.
Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is termin~ted by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (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 leukemias. The protein products of these genes are defective in their GTPase activity and con.stitutively 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 modification,s occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xa~"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depend-ing on the specific ~sequence, this motif .serves as a signal se4uence 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 farne.~yl-CA 022~0936 1998-09-28 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., Scienc~, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad.
Sci U.S.A ., 91 :9141 -9145 (1994) and induces regression of mammary and salivary carcinoma.s in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1 :792-797 (199~).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ihid; Ca~sey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-XX (1990);
Schaber et al., J. Bio~. Chem., 265: 14701 -14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sc~i USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane - localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor CA 022~0936 1998-09-28 of isoprene biosynthesis.
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., if~id; Reiss et. al., ihid; Reis~s 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,~S51, University of Texas; N.E. Kohl et al., Science, 2l50:1934-1937 (1993); Graham, et al., J. Mecl. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations 20 on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol i.s desirable.
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are 25 inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 A1).
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitor~; of proliferation of vascular 30 smooth muscle cells and are therefore u.seful in the prevention and therapy of arterio.sclerosis and diabetic disturbance of blood ves.sels - (JP H7- 112930).
It is, therefore, an object of this invention to develop .
CA 022~0936 1998-09-28 low molecular weight compounds that will inhibit farnesyl-protein transferase and thus, the post-translational farnesylation o~ 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 INVENTION
The present invention comprises biheteroaryl-cont~ining compounds which inhibit the farnesyl-protein transferase. Further 10 contained in this invention are chemotherapeutic compositions containing these farnesyl tran.sferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A:
R6a-d R3 a~ e 8) / ~ /f V - A1(CR12)nA2(CR12)n~W~ (CR22)p - X -(CR22)p R5 R
.. .. . . . .
~ DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of 5 farne,syl-protein transferase are illustrated by the formula A:
~6a-d R3 a~ e V - A (CR12)nA2(CR12)n\W - (CR2 ) X (CR
wherem:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at lea.st one of b, c, d or e is independently N, NH, O or S;
15 from 1-2 of f(,s) are independently N, and the remaining f's are independently CH;
Rl and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, Rl lS(O)m-, R10C(O)NR10-, 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 , CA 022~0936 1998-09-28 WO 97136898 PCT/US97/û5512 c) unsubstituted or substituted Cl -C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 OO-~ R 1 1 S(O)m-~ RlOC(O)NRlO-~(Rlo)2Nc(o)-~
R102N-c(NRlo)-~cN~Rloc(o)-~ N3,-N(R10)2, and Rlloc(o)-NRlo-;
R3,R4 and R5 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-R102N-c(NRlo)-~cN~No2~ RlOC(O)-, N3,-N(R10)2, or RllOC(O)NR1O-, 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, unsub,stituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120,RllS(o)m,RlOC(o)NRlo-~(Rlo)2Nc(o)-~
R102N-c(NRlo)-~cN~Rloc(o)-~ N3,-N(R10)2, and Rlloc(o) NRlO;
provided that when R3,R4 or RSis unsubstituted or substituted heterocycle, attachment of R3,R4 or R5 to the six-membered heteroaryl ring is through a sub,stitutable heterocycle ring carbon;
R6a R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R12O-, CA 022~0936 1998-09-28 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 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-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(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;
R7 i.s selected from: H; C1 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, aryl.sulfonyl, heteroaryl.sulfonyl, unsubstituted or~5 substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --SO2R
g) N(R 1~)2 or h) C l 4 perfluoroalkyl;
R~ is independently ~elected from:
a) hydrogen, b) aryl, sub~tituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0O , R 1 1 S(O)m-~ R 1 0C(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, and CA 022~0936 1998-09-28 c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0O, R 1 1 S(O)m-~ R 1 0C(O)NH-~ (R 1 0)2NC(O)-, R 1 02N-C(NR 1 0)-, CN, R 1 ~C(O)-, N3, -N(R 1 0)2, or R 1 0OC(O)NH-;
provided that when R8 is heterocycle, attachment of R8 to V i,s through a substitutable ring carbon;
10 R9 is independently ~selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, Br, Rl lo-, Rl lS(O)m-, R10C(o)NR10-, (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, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(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;
R10 i.s 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, C1-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 sub,stituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-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)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) , -S(0)2N(R 10), -N(R 1 ~)S(O)2-, or S(O)m;
CA 022~0936 1998-09-28 V is selected from:
a) hydrogen, b) heterocycle, S c) aryl, d) Cl -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen 10 if A I is a bond, n i.s 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;
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(R 1 0), -N(R 1 ~)S(O)2- or -S(=O)m-;
20 mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
is 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and 25 ti,s 0 or 1;
or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention is illustrated by the following formula A:
(R8)r ~9~ ~f/\( ~dea'd V - A1(CR12)nA2(CR12)n~;~W~ - (CR22)p - X -(CR22)p ¦ R5 wherein:
ais N orC;
s from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
10 from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
Rl is independently selected from: hydrogen, C3-Clo cycloalkyl, R l ~O, -N(R 1 ~)2, F or C 1 -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, R l OO- and -N(R 1 0)2;
2;~ R3, R4 and RS are independently selected from:
CA 022~0936 1998-09-28 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-c10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 2O, R 1 1 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 Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 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 Rl 10C(O)-NR10;
provided that when R3, R4 or RS is unsubstituted or substituted heterocycle, attachment of R3, R4 or RS to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120, RllS(O)m, KlOC(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 c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-c6 alkyl is selected from unsubstituted or - sub,stituted aryl, unsubstituted or substituted heterocyclic, C3-C l o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R l l S(O)m-, .
CA 022~0936 1998-09-28 W O 97/3689B PCT~US97/05512 R 1 0C(O)NR 10, (R l 0)2NC(o)-, R l02N-C(NR 10), CN, R l ~C(O)-, N3, -N(R 1~)2, and R 1 l OC(O)-NR l 0;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, 5 aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) "R1' f) --So2R ~ ~
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, Rl0O-, Rl0C(O)NRl0, CN, NO2, (Rl0)2N-C(NR10)-, R 1 ~C(O)-, -N(R 1~)2, or R l 1 OC(O)NR l 0, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, R l 0C(O)NR l 0, (R l 0)2N-C(NR l 0), R l ~C(O)-, -N(R l ~)2, or R 1 l OC(O)NR l 0;
provided that when R8 i,s heterocycle, attachment of Rg 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-~ (R10)2Nc(o) CA 022~0936 1998-09-28 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 c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 1 S(O)m ~ R 1 0C(O)NR 10 (R 1 0)2NC(O)-, CN, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10 , 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 .sub,stituted 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 l and A2 are independently .selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 1 0-, O, -N(R 1 0)-, 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 provided that V is not hydrogen if Al i.s S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(O)m;
provided that when V i.s heterocycle, attachment of V to R~ and to A 1 is through a ~substitutable ring carbon;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
X is a bond, 0, -C(=0)-, -CH=CH-, -C(o)NR7-, -NR7C(o)-, -NR7-, -S(0)2N(R 1 0), -N(R 1 ~)S(0)2- or -S(=O)m-;
mis 0, 1 or2;
10 n is independently 0, 1, 2, 3 or 4;
p i~s independently 0, 1, 2, 3 or 4;
qis 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and ti,s 0 or 1 ;
or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B:
R6a-d (R8) R9a B (CR 2)p X R
20 wherein:
a is N or C;
- *om 0-4 of b, c, d and e are independently N, NH, 0 and S, and the 25 rem~ining b, c, d and e atoms are independently CH, provided that if a i~i C, then at least one of b, c, d or e is independently N, NH, 0 or S;
CA 022~0936 1998-09-28 from 1-2 of f(s) are independently N, and the rem~ining ~s are independently CH;
5 Rl is independently selected from: hydrogen, C3-clo cycloalkyl, R l OO, -N(R 1 ~)2, F or C 1 -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-CIo cycloalkyl, C2-C6 alkenyl, RlOO- 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 1 2O, R 1 1 S(O)m-~ R I 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 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, R12O, 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 ;
provided that when R3 or R4 i,s unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered CA 022~0936 1998-09-28 W O 97/36898 PCT~US97/05512 heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R102N-C(NR10)-, CN, N02, RlOC(O)-, N3, -N(R10)2, or RIlOC(O)NRl0-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, unsub,stituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R102N-c(NRlo)-~ CN, R10C(O)-, N3, -N(R10)2, and RllOc(o)-NRlo-;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C~-C6 perfluoroalkyl, F, Cl, R10O-,R10C(O)NRl0-~ CN, N02,(R10)2N-C(NR10)-, Rl0c(o)-~-N(Rlo)2~ or RllOC(O)NR10-, and c) Cl -C6 alkyl substituted by Cl -C6 perfluoroalkyl, R 1 0o-, Rl0c(o)NRlo-~(Rlo)2N-c(NRlo)- R10C(o)--N(R10)2, or RllOC(O)NR10-;
provided that when R~ is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
CA 022~0936 1998-09-28 WO 97/368g8 PCI/US97/05512 R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R 1 1 is independently selected from Cl -C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, Cl-c6 sub.stituted 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 and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 1 0-, O, -N(R 10)-, or S(O)m;
V i~ selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, i.soquinolinyl, 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 25 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al i.s a bond, n i,s 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R~ and to Al is through a substitutable ring carbon;
30 X is a bond, -CH=CH-, -C(O)NR10-~ NR10C(o), NR10, O or -C(=O)-;
-mi,s 0, 1 or2;n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salt.s thereof.
5Another preferred embodiment of the compounds of this invention are illustrated by the forrnula C:
R6a-d (R8)r ~$1 V- A1(cR12)nA2(cR12)n~
C R9b (CR22)FX R4 wherein:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining r.s are independently CH;
Rl i.s independently selected from: hydrogen, C3-Clo cycloalkyl, RlOo-~-N(Rlo)2~For Cl-C6alkyl;
R2 is independently selected from:
a) hydrogen, - b) aryl, heterocycle, C3-C I o cycloalkyl, R l OO-, -N(R 1 0)2, F or C2-C6 alkenyl, CA 022~0936 l998-09-28 WO 97/36898 PCTrUS97/05512 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, R10O- and -N(R10)2;
s R3 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, un,substituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R 1 1 S(O)m-~ R 1 0C(o)NR 10, CN(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 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)NR10-, (R10)2NC(o)-, R 1 02N-C(NR 1 0)-, CN, R 1 0C(o)-, N3, -N(R 1 0)2, and RllOC(O) NR10;
provided that when R3 or R4 is unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-c6 perfluoroalkyl, - R120, Rl lS(o)m, RlOc(o)NRlo-~ CN(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, CA 022~0936 1998-09-28 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-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m ~
R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 10C(o)-, N3, -N(R10)2, and R1 1OC(O)-NR10-;
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 10), R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) C I -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, R 1 0O-, 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 R8 is heterocycle, attachment of R~ 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, 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, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
.. . . ..
CA 022~0936 1998-09-28 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, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, 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, and provided that V is not hydrogen if A l is S(O)m and V is not hydrogen if Al isabond,n i,sOandA2i,sS(O)m;
15 provided that when V is heterocycle, attachrnent of V to R8 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)-;
mils 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
pis 0, 1,2,30r4,providedthatpisnotOifXisabondorO;
and 25 r is O to 5, provided that r is O when V is hydrogen;
or the pharmaceutically acceptable salt~s thereof.
In a more preferred embodiment of this invention, the inhibitors of farne,syl-protein transferase are illustrated by the formula 30 D:
. .
CA 022~0936 1998-09-28 R6a-d R 9a ~
wherein:
a is N or C;
s from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
10 from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
Rl is independently selected from: hydrogen, C3-Clo cycloalkyl or Cl-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C I o cycloalkyl, R l OO-, -N(R l O)27 F or C2-C6 alkenyl, c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, RlOO-, or -N(R I ~)2;
- R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or sub,stituted heterocycle, C3-Clo cycloalkyl, C2-C6 CA 022~0936 1998-09-28 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, 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 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 2O, 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 RllOC(O)NR10;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is lS through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, Cl-C6 alkyl and CF3;
R6a R6b, R6c and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, un~ubstituted or substituted heterocycle, C3-CIo cycloalkyl, C2-c6 alkenyl, C2-c6 alkynyl. halogen, Cl-c6 perfluoroalkyl, R120, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R I 02~-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, - R120-, RI lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R102N-C(NRI0)-, CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;
CA 022~0936 1998-09-28 Rg 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 100-, R10C(o)NR 10, CN, N02, (R10)2N-C(NR10)-, 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 1 OC(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~ is heterocycle, attachment of R8 to V i.s through a sub.stitutable ring carbon;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10 i~s independently selected from hydrogen, C1-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;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR 10, -NR 1 ~C(O)-, -NR 10, o or 30 -C(=O)-;
- nis Oorl;
m is 0, 1 or 2; and pis 0, 1, 2, 3 or4;
. .
or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the 5 formula E:
R 6a-d ~ ~ R3 _~àC~e A1(CR12)n ,~_N\ ~ ~
R9b (CR22)p- X' f R4 wherein:
a i,s N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
15 from 1-2 of f(s) are independently N, and the remaining fs are independently CH;
Rl is independently selected from: hydrogen, C3-clo cycloalkyl, R l Oo, -N(R 1 ~)2, F or C 1 -C6 alkyl;
R2 is independently ~selected from:
a) hydrogen, - b) aryl, heterocycle, C3-Clo cycloalkyl, RlOO-, -N(R10)2, F or C2-C6 alkenyl, CA 022~0936 1998-09-28 W O 97/36898 PCTrUS97/05S12 c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R 1 ~)2;
S R3 is 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 1 S(O)m ~ R I OC(O)NR 10, (R 1 0)2NC(0)-, R 1 02N-C(NR 1 0), 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 1 20, R 1 1 S(O)m-~ R 1 OC(O)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;
provided that when R3 i.s unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, Cl-C6 alkyl and CF3;
R6a R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen~ 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 ~C(0)-, N3, -N(R 1 ~)2, or R 1 1 0C(0)NR 10 CA 022~0936 1998-09-28 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;
10 R~ i.s 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 1 OC(O)NR 10, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R10)2, or R1 1OC(O)NR10-;
provided that when R8 i.s heterocycle, attachment of Rg to V i.s throu~h a stitutable ring carbon;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 i.s independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, C1-C6 sub~stituted aralkyl, C1-C6 heteroaralkyl, C1-C6 .substituted heteroaralkyl, aryl, substituted aryl, - heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
CA 022~0936 1998-09-28 WO 97/36898 PCT/US97tO5512 X is a bond, -CH=CH-, -C(O)NR10-, -NR 10C(o)-, -NR 10-, O or -C(=O)-;
n is O or l; provided that n is not O if Al is a bond, O, S -N(R10)-, or S(O)m;
m is 0, 1 or 2; and pis 0, 1,2,30r4,providedthatpi,snotOifXisabondorO;
or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula F:
R 6a-d R9a~N R~f~à(--~e (CR 2)p NC F
wherein:
aisNorC;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the rem~ining f's are independently CH;
R 1 is independently selected from: hydrogen, C3-C 1 o cycloalkyl or 25 Cl-C6 alkyl;
CA 022~0936 l998-09-28 W O 97136898 PCTrUS97/05512 R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, R 1 0O-, -N(R 1 0)2 or F, c) Cl-c6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-c l o cycloalkyl, R 1 0O-, or -N(R 1 0)2;
R3 is 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-, (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, c) unsubstituted C1-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-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 0C(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;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, CH3 and CF3;
30 R6a, R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 CA 022~0936 1998-09-28 W 0 97/36898 rCTAUS97/05512 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120,RllS(o)m-~RlOC(o)NRlo-~(Rl 0)2NC(O)-R102N-C(NR10)-, CN, NO2, RlOC(0)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR10-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, I 0 R 120,Rll S(O)m-~ R 1 0c(o)NRlo-~(Rlo)2Nc(o)-~
R102N-C(NR10)-, CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R l l OC(O)-NR 10;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10i.s independently selected from hydrogen, Cl -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 i,s 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)NR10-,-NRlOC(O)-,-NRlO-,O or -C(=O)-;
30 m is 0, 1 or 2; and pis 0, 1,2, 3 or4;
-or the pharmaceutically acceptable salt,s thereof.
CA 022~0936 1998-09-28 W O 97136898 PCT~US97/05512 In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula G:
'A ~;
wherem:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a 10 is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
15 Rl is independently selected from: hydrogen, C3-Clo cycloalkyl, R l OO, -N(R 1 ~)2, F or C l -C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl or heterocycle, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, RlOO-, or -N(R I ~)2;
25 R3 is selected from:
a) hydrogen, CA 022~0936 1998-09-28 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 l l S(O)m , R l OC(O)NR 10-, (R 1 0)2NC(O)-, R102N-c(NRlo)-~cN~No2~ RlOC(O)-~ N3,-N(R10)2, or RllOC(O)NR10-c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is .selected from unsubstituted or sub~stituted 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) R102N-c(NRlo)-~cN~Rloc(o)-~ N3,-N(R10)2, and RllOC(O)-NR10-;
provided that when R3is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4is selected from H, halogen, CH~ and CF3;
R6a R6b R6c and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or sub.stituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-c6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120,RllS(o)m,RlOC(o)NRlo-~(Rlo)2Nc(o)-~
R102N-C(NRlO)-~CN,No2~ RlOC(O)-, N3,-N(R10)2, or RllOC(O)NR10-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, CA 022~0936 1998-09-28 W O 97/36898 PCTrUS97tO5512 R 1 20, R 1 I S(O)m-~ R 1 OC(O)NR 10 , (R I 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R11OC(O) NR10;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R 1 0 is independently selected from hydrogen, Cl -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
10 Rl 1 is independently selected from Cl-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;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
20 m is 0, 1 or 2; and nis Oor 1;
or the pharmaceutically acceptable salts thereof.
Specific examples of the compounds of the invention are:
I -(2-[Thien-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole.
NC~--l ~/ N
N
.. .. .~.
CA 022~0936 1998-09-28 N- { 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl)methyl } -5-(thien-2-yl)-2-. . .
amlno-pyrlml~lne NC ~ ,~
~ y N
or the phannaceutically acceptable salts thereof.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and a~s individual diastereomers, with all possible isomers, including optical 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 permissible only if such combinations result in stable compounds.
As used herein, "alkyl" and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
As used herein, "cycloalkyl" is intended to include 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, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
CA 022~0936 1998-09-28 "Alkynyl" groups include those groups having the ,specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
S "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl," and the aryl portion of aralkyl and aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydro-naphthyl, 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 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Example.s of such heterocyclic element~;
include, but are not limited to, azepinyl, benzimidazolyl, benzi.soxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, - tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
CA 022~0936 1998-09-28 W O 97/36898 PCTrUS97/05S12 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 S consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, 10 dihydrobenzothiopyranyl .sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, i,soquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, 15 thienothienyl, and thienyl.
As used herein in the definition of R3, R4, RS and R6a-d the term "the substituted group" intended to mean a sub.stituted Cl ~
alkyl, substituted C2 ~ alkenyl, substituted C2 ~ alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R3, R4, R5 and 20 R6a-e are selected.
As used herein in the definition of R7, the substituted C
alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl-sulfonyl and substituted heterocycle include moieties containing from 1 25 to 3 substituents in addition to the point of attachment to the rest of the compound.
As used herein, when no specific substituents are set forth, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted 30 on a substitutable ring carbon atom with 1 or 2 substitutents selected ~rom 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 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-c(NH)-~ (cl-c6 alkyl) C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and Cl-C20 alkyl.
Lines drawn into the ring systems from substituents (such 5 as from R3, R4 etc.) means that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms.
The moiety designated by the following structure f "f_~
~f' represents an aromatic 6-membered heterocyclic ring and includes the 10 following ring systems:
~,1,~ N ~ N ,~,~ N
The moiety designated by the following structure f ' ~f~
~,,~f/f represents an aromatic 6-membered heterocyclic ring and includes the 15 following ring systems:
. .
~q J~ oqN
N~N N~N HN NH
~0 wherein it is understood that one of the ring carbon atoms is .substituted with bà~)/d 5 Preferably, the aromatic 6-membered heterocyclic ring is a pyridyl ring.
The moiety designated by the following structure ba~/d represents an aromatic 5-membered heterocyclic ring and includes the 10 following ring sy.stems:
~ .. .... .. .
W O 97/36898 rcTrusg71o5512 ~> N--~N Nb~ N~,N N~N
N--~ N~\ N--~ N--~
N ' N ' N 11 N
N~/ N~/ N~N~ N--N~
N ~> ~> N~
~ N_ N> N~ S,~ N~
N~ ~ N_ N/> N--~>
Preferably the aromatic S-membered heterocyclic ring is selected from:
N--~N N~
~> N ~>
~ N ~> ~
S Preferably, Rl and R2 are independently selected from:
hydrogen, R 1 1 C(O)O-, -N(R 1 ~)2, R I OC(O)NR 10 , R l ~O or unsubstituted or substituted Cl-c6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 1 ~)2, R l Oo and R 1 OC(O)NR 10 .
Preferably, R3 is selected from:
a) hydrogen, CA 022~0936 1998-09-28 WO 97t36898 PCT/US97/05512 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 1 20, R 1 1 S(O)m-~ R 1 OC(O)NR10-, (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 OC(0)-NR 10 Preferably, R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and Cl-C6 alkyl.
Preferably, RS is hydrogen.
Preferably, R6a, R6b, R6C and R6d are independently l:S selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl 1S(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-Clo cycloalkyl, R120-, Rl lS(O)m-, R 1 ~C(0)- or -N(R 1~)2.
Preferably, R~ is independently ,selected from:
a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C6 perfluoroalkyl or CN.
Preferably, R9 is hydrogen, halogen or methyl.
Preferably, R10 is .selected from H, Cl-C6 alkyl and benzyl.
Preferably, Al and A2 are independently selected from:
a bond, -C(O)NR10-, -NRlOC(0)-, 0, -N(R10)-, -S(0)2N(R10)- and-N(R 1 ~)S(0)2-.
CA 022~0936 1998-09-28 WO 97/36898 PCT~US97/05512 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 5 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 from 1-2 of f(s) are independently N, and the 10 rem~ining f's are independently CH.
Preferably, the moiety (R8) 1~9)\
V-A1(CR12)nA2(CRl2)ntW~ (CR22)p-X-(CR22)p~-is selected from:
R9a R9b ~ \~ 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 el.sewhere in that molecule. Thus, -N(RlO)2 represent.s -NHH, -NHCH3, -NHc2H~ etc. It is understood that substituents and substitution patterns on the compounds of the 20 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 techni4ues known in the art, as well a,s those methods set forth below, from readily available starting materials.
CA 022~0936 1998-09-28 The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compound.s of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those S derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, 10 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 15 methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention 20 are prepared by employing reactions as shown in the Schemes 1-22, in addition to other standard manipulation~s such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R3, R6 and R~, as shown in the Scheme.s, represent the substituents R3, R4, 25 R5 R6a R6b, R6C, R6d and RX; although only one such R3, R6 or R~ is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents.
These reaction,s may be employed in a linear sequence 30 to provide the compounds of the invention or they may be used to synthe~size fragments which are subsequently joined by the alkylation - reactions described in the Scheme,s. The reactions described in the Schemes are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moieties are described CA 022~0936 1998-09-28 in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein.
Aryl-aryl coupling is generally described in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, 5 Pergamon Press (1995).
Synopsis of Schemes 1-22:
The requisite intermediates are in some case,s commercially available, or can be prepared according to literature procedures, for the 10 most part. Schemes 1- 13 illustrate synthesis of the instant biheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain.
Thus, in Scheme 1, for example, a biheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted thienyl boronic acid I may be reacted 15 under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted activated nicotinic acid, such as nicotinic acid 6-triflate, to provide the biheteroaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl 20 IV to provide, after deprotection, the instant compound V.
Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1. Thus, Scheme 2 illustrates the reaction wherein the "terminal" 5-membered heteroaryl moiety is employed in the Suzuki 25 coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 3.
Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biheteroaryl component of the instant 30 compounds, as shown in Scheme 4. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted heteroaryl - halide in the presence of nickel (II) to provide the biheteroaryl VII.
The heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
... . .. . . . .. .. . ...
CA 022~0936 1998-09-28 Scheme 5 illustrates the preparation of a suitably substituted biheteroaryl alcohol starting from the halogenated methylpyridine.
As illustrated in Scheme 6, the sequence of coupling reactions may be modified such that the biphenyl bond is formed S last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII.
Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid.
Scheme 7 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
Thus, a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
Scheme 8 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biheteroaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-amino-alkylimidazole XII, wherein the primary amine is protected as the phthalimide, i.s 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 biheteroaryl moieties to provide the instant compounds shown.
Use of another 6-member heteroaryl in the synthesi.s of the instant compounds i.s illustrated in Scheme 9. Thus, a halogenated 2-aminopyrimidine may be coupled with a heteroaryl boronic acid to provide the biheteroaryl amine XIIIa, which can then be reacted with the preferred imidazolylmethyl sidechain to provide the instant compound.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR 1 2)n linker is oxygen may be synthesized by - methods known in the art, for example as shown in Scheme 10.
The suitably sub~stituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
CA 022~0936 1998-09-28 After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
Scheme 11 illustrates an analogous series of reactions 5 wherein the (CR22)pX(CR22)p linker of the instant compounds is oxygen. Thus, a suitably substituted halopyridinol, such as, is reacted with methyl N-(cyano)meth~nimidate 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.
10 The intermediate XVII can then be coupled to a heteroaryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR 1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 12. Thus, the N-protected 15 imidazolyl iodide XVIII i~s reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 1 ) provides the instant compound XX. If other R I substituents are desired, the acetyl moiety can be manipulated as 20 illustrated in the Scheme.
Addition of various nucleophiles to an imidazolyl aldehyde may also be employed to form a substituted alkyl linker between the biheteroaryl and the preferred W (imidazolyl) as shown in Scheme 13. Thus a lithiothiophene can be reacted with pyridine to form the 25 2 substituted N-lithio-1,2-dihydropyridine XXa. lntermediate XXa can then react with a aldehyde to provide a suitably substituted instant compound. Similar substituent manipulation as shown in Scheme 12 may be performed on the fully functionalized compound which incorporates an R2 hydroxyl moiety.
N~oTf (H~)2B~R6 ~\R2 Pd(OAc)2 N~R6 ~iAlH4 HO~'\ 2 J~\R~
SCHEME 1 (continued) Tr Tr, Nicl2~ h~)z _~
J~,~R6 (CF3SO2)20,;78~C
H0 R2 CH2CI2 -78~C-20~C
~_~N~\~ 55~C CH30H
R8 <~ R6 /~ V
WO 97/36898 PCTtUS97/05512 - 4~ -SCHEl\/IE 2 S--f~N~,B(OH) MeO ~,\
o R2 pd(pph3)4 S~
~ ~ R6 LiAlH4 MeO~
o R2 N~R6 HO J~,\
CA 02250936 l998-09-28 W O 97/36898 PCTrUS97/05512 SC~DE~IE 3 N~B(oH)2 J_~ R6 R3SiO~,\
R2 Pd(Pph3)4 N~e R Bu4NF
R3SiO J~\R2 b - c~
HO\~ 2 N Br b,c;~
R3SiO~,~ (H~)2B
R2 Pd(PPh3)4 N~ll-~R6 R3SiO J~\R2 b~
HO~,~R2 ~ ,Br J~R6 R3SiO R2 NiCI2(PPh3)2 N~ R Bu4NF
R3SiO 2 Vll R S
N~y~R6 HO~,\
~ Znl ~ R6 R3SiO R2 NiCI2(PPh3)2 ~S~
~N~--R Bu4NF
R3SiO~\R2 J~\
,g~ (HO)2B R6 KMnO4 H3C R2 Pd(PPh3)4 ~ ' R6 S~
~N~\ R6 HO~,\
W O 97/36898 PCTrUS97/05512 - ~2 -Tr~ i r~
N~ Br ~N
<~ N j; MeOH
~_J reflux R
Pd(PPh~) R Vlll S~
N~ ~:v\ R6 <~ N ~,\, N
R~ R2 CA 022',0936 1998-09-28 H H
Rsb~ Nal, NaHCO3,!~ Rgb~ TrCI, NEt3 IX X
Tr, N
Rgb ~ NiCI2(PPh3)2 > ~N
~ ZnBr,~
S~
Tr~ ~N~\ R6 ~J i. -78~C-20~C, /~ ii. MeOH, reflux Xl R9b~ R6 ,~_/ R2 SCHEME ~
0~
~~ R8 ~, <N~ O 55~C,CH3CN "
N~ N~ii. EtOH.80~C, NH2NH2 o Xll N
</~
R 1~1 Xlll acylation, sulfonylation </ 3~'~ ~ R2 - - - - - - - --- N N ~ /~
or alkylation Rs ~_ <~ ~ N~
~ N ~
R8~/ H'\~S~R6 W O 97136898 PCTrUS97/05512 N~Br Pd(OAC)2 <N~
N--' CI
N~R6 Rs~
Xllla ~,~N+ Nl'~ 55~C,CH30H
S~
R8 N~ R6 .. . . .. . . ..
PCT~US97/05512 ~--OH i~ Na, MeOH
NC ~/ ii. 120~C
XIV H3C~o ~N/\~N
H Tr~
~ N TrCI, NEt3 <~_ NC ~ NC ~¢~
XV XVI
Tr~N~N + R~N~~ R j -78~C-20~C
ii. MeOH reflux NC ~ OTf XVI
~ N~J~
~0 NC ~
W O 97/36898 rCT~US97/05512 N OH i, Na, MeOH ~N
Cl~\~ ii. 120~C ,~N O
R2 H3C~ ,o Cl~\~
N~ R2XV
~q Tr~
TrCI, NEt3 <~N OTf -78~C-20~C
ii. MeOH reflux R2 R8 ~B(~H)2 N ~ ~ R<6\/~ S
Cl~O DMF, Pd(PPh3)4 K3PO4, 80~C
N
R ~ ~
W O 97/36898 PCTrUS97/05512 Tr N~
N~ EtMgBr ~N
~N ~ ~'OH
Tr~
AC20~ PY ~ ~ NH~J~\ 2 ~\OAc(CF3S02)20,-780c 8 /\~NEtiPr2,C H2Cl2 N N~ R6 LiOH
~OAc R2 ~_~N~\~ SOCI~
59 _ SCHEME 12 (continued) ~N~J~ ~ N H3, MeOH
/J Cl <~q J~ R6 ¢~ R2 /~/ N H2 +
~N~
OMe .. , . ... ... .. . , . . .. ~ . . .. . .. ...
W O 97/36898 PCTrUS97/05512 S
~, ' N
N
</~
N
S R~
XXa N~R6 ~J OH
. .
CA 022~0936 1998-09-28 W 0 97~6898 PCTnUS97/05512 Schemes 14-20 illustrate reaction~s wherein the moiety (l8)r (/R9~\
V ~ A1 (CR12)nA2(CR 12)n tW~ ~ (CR22)p-X
incorporated in the compounds of the instant invention is represented by 5 other than a .substituted imidazole-containing group.
Thus, the intermediates whose ,synthesis are illustrated in Schemes hereinabove and other biheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such 10 as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid.
Lithioheteroaryl chemistry may be utilized, as shown in Scheme 14, to incorporate the biheteroaryl moiety. Thus, a suitably substituted biheteroaryl N-lithio reagent is reacted with an aldehyde to provide 15 the C-alkylated instant compound XXI. Compound XXI can be deoxygenated by methods known in the art, such a.s 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, 20 hydrochloride or acetate salt, among others. The product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by 25 literature procedures.
If the biheteroaryl .subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI
in Scheme 15, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 15, 16). The alcohol can be 30 oxidized under standard conditions to e.(~. an aldehyde, which can , . , ~ .. , .. , . . . .. . , . .. ... _,, .
CA 022~0936 1998-09-28 W O 97136898 PCT~US97/05512 then be reacted with a variety of organometallic reagent.s such as 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 5 a variety of aldehydes to obtain secondary amines, such as XXXII
(Scheme 16), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylbiheteroaryl such as XXXIII
(Scheme 17). Treating XXVI~I with 1 ,1 '-sulfonyldiimidazole and 10 sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXIII . The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIV .
In addition, the biheteroaryl subunit reagent can be reacted 15 with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 1~. When R' is an aryl group, XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI. Alternatively, the amine protecting group 20 in XL can be removed, and O-alkylated phenolic amines such as XLII
produced.
Schemes 19-22 illustrate synthe,se.s 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 25 for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.
Boc NHl R6 Boc NH CHO
1. catalytic HO ~ ~ 6 hydrogenation Boc NH )~1 2. CF3CO2H
--~ CH2CI2 NHBoc XXI
NH2~R6 co~c2cOz, ~ N~ R6 ~C HO
BocN H
\~ NaBH(OAc)3 NH2 Et3N, CICH2CH2CI
XXIII
-CA 02250936 l998-09-28 W O 97/36898 PCTrUS97/05512 SCHEME 14 (continued) BocNH~"~ CF3CO2H, ~=~ NH NaHCO3 ~~ XXIV
NH~ R6 ~NC
~=~ NH AgCN
~=N S~ R6 ,~
N ~ N~
~ XXV
~3 3 Et20 R6 BnOl BocNH CHO
XXVI
BnO~;S 20% Pd(oH)2 H2 NHBoc CH3CO2H
XXVII
HO~I N~ ~S CICOCOCI
NHBoc R6 (C2Hs)3N
XXVIII
.. , . . . ~ .. .. . ...... . . .. .. ... . ..
SCHEME 15 (continued) H~ R'MgX
N HBoc XXIX
R'~R6 NHBoc XXX
,=¦ N ~S CF3CO2H
HO ~\J 6 CH2CI2 NHBoc XXVIII
H~~~Ri 6 NaBH(OAc)3 XXXI
HO~ J
rH
R'CH2 XXXII
.. .. ..
W O 97/36898 PCT~US97/05512 - 6~ -~ NaH, DM F O~C
NHBoc XXVIII
R"SH
~I R6 CH30H
N
H X
R"S ,~JS
XXXIV
WO 97/368g8 PCT/US97/05512 SCHEME Ig HO~ 1) Boc20, K2C~3 HO~
~/ TH F- H20 ~ 2) CH2N2, EtOAc ,1~
H2NCO2H BocNH CO2CH3 XXXV XXXVI
HO~
LiAlH4 ~1~ R"'CH2X
THF l Cs2CO3 0-20~C BocNH CH2OH DMF
XXXVII
R"'CH20 R"'CH20 ~ pyrldine SO3, 1 BocNH CH2OH (C2H5)3N BocNH CHO
XXXVIII IXL
W O 97/36898 PCTrUS97/05512 SCHEME I g (continued) ~3 + i~e~R6 BocNH CHO
IXL ~\R"' not aryl 1. Et20 1. Et20 2. 20% Pd(OH)2, H2 CH30H, CH3CO2H
~ R2 3. HCI, EtOAc R"'C H20~ ~ R 6 NHBoc 1) 20% Pd(OH)2, H2 CH30H, CH3CO2H
R cH20 / -- ~ r R6 /~\ ~ XLII
HO~ R6 NH2 ' R2 XLI
~CH3 1) HNo2~Br2 ~CO2cH3 1~ ~ 2) KMnO4 H2N N 3) MeOH, H+ Br N
~\~\MgCI R6 Zncl2lNicl2(ph3p)2 CO2CH3 NaBH4 (excess) ~ CH20H
DMSO ~ 3,CHo .......... ~ . ... . ~ . .. . . . , . . . ~
1. EtO(CO)CI R6 Zn Cl/CN ~CO~CH3 N 3. S, xylene, heat N
NaBH4 ~j~ SO3Py, Et3N ~
(excess) [~,CH20H DMSO ~CHO
Br~l,C02CH3 [~
N ~ CO2C H3 ZnCI2, NiC12(Ph3P)2 N~
NaBH4 T S03 Py Et3N 1' (excess) \~ DMSO ~3,CHO
Br~31. LDA, CO2 Br~
N2. MeOH, H+ N
R6 MgCI 1~ CO2CH3 ZnCI2, NiC12(Ph3P)2 N
~/1 NaBH4 (excess) ~20H SO3 Py, Et3N
~ ~I DMSO
N
1~~
..... . . .. . .... . . . . . . . .. . .
WO 97t36898 PCT/US97/05512 [~ 1 . LDA, CO2 [~ Br 2. (CH3)3sicHN2 R6 ~/\Br R6 ~
N ~C02CH3 Zn, NiCI2(Ph3P)2 R6 ~
excess NaBH4 ~1~ SO3-Py, Et3N
N~CH20H DMSO
R6 r~
N ~,CHO
~, CA 022~0936 1998-09-28 W O 97/36898 PCTnUS97105512 The instant compounds are useful as pharmaceutical agents for m~mm~ls, especially for humans. These compounds may be ~dministered to patients for use in the treatment of cancer. Example~s 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, lck, 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 compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-45P~0 (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 form) with said inhibition being accompli,shed by the a-lministration of an effective amount of the compounds of the invention to a m~mm;~l in need of such treatment. For example, a component of NF- 1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also u~seful 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.
.. . .... .. . . ....
CA 022~0936 1998-09-28 American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (19~
The instant compounds may also be useful for the treatment of fungal infections.
S The compounds of this invention may be administered to m~mm~ls, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral ~dministration in cap.sule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are re4uired for oral use, the active ingredient is combined with emulsifying and suspending agent.s.
If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use sterile solution~s 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-~dministered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be useful in - combination with known anti-cancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF- 1, restinosis, polycy~stic CA 022~0936 1998-09-28 kidney disease, infections of hepatiti.s 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 S 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 a-lmini~tration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and 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 bolu,s injection.
As used herein, the term "composition" is intended to encompas,s a product comprising the specified ingredients in the specific 20 amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention i,s admini~tered 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 as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg 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 CA 022~0936 1998-09-28 W O 97/36898 PCT~US97/OS512 quantity of farnesyl-protein transferase (FPTase) in a composition.
Thu,s 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 immuno-10 logical, radiochemical or chromatographic techniques. Becausethe compound.s of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay 15 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 farne~syl-protein transferase and quantitat-20 ing the enzyme. Thus, potent inhibitor compoundls of the instantinvention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A serie~s of samples composed of aliquots of a tissue extract cont~ining 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.
CA 022~0936 1998-09-28 EXAMPLES
Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species 5 and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.
10 1-(2-rThien-2-yllpyrid-~S-ylmethyl)-5-(4-cyanobenzyl)imidazole.
Step A: 2-Trifluoromethanesulfonvloxv-5-pyridinecarboxylic acid To a .solution of 2-hydroxy 5-pyridinecarboxylic acid (1~5 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 15 mmol) in dichloromethane (7 mL) at -7~~C is added trifluoromethane-sulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -7~~C for 1 hour and then at ambient temperature for 1 hour. The reaction is diluted with water and extracted with CH2C12, and the organic extract is dried, (MgSO4) and the solvent is evaporated in 20 vacuo. The residue is purified by chromatography to afford the title compound.
Step B: 2-(Thien-2-yl)-5-pyridinecarboxylic acid A mixture of 2-trifluoromethane.sulfonyloxy-5-pyridine-25 carboxylic acid (0.442 g, 1.72 mmol), 2-thienylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (0.~13 mg, 2.5~ mmol), DME (~ mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenyl-phosphine) palladium(0) (99.0 mg, 0.0~6 mmol) is added, and the resultant .solution i.s stirred at ~0 ~C for 4 hours. The solvents are 30 evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc.
- The organic extracts are combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) and the solvent is evaporated in . , , . ... . . , .. , . ., ~ ., .
CA 022~0936 1998-09-28 - ~0 -vacuo. The residue is purified by chromatography to afford the title compound.
Step C: 2-(Thien-2-yl)-5-hydroxymethylpyridine To a solution of 2-(thien-2-yl)-5-pyridinecarboxylic acid (0.333 g, 1.60 mmol) in THF (5 mL) at 0~C is added 1.0 M lithium aluminum hydride in diethyl ether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction is allowed to stir at ambient temperature for 3 hours, cooled to 0~C, and water (0.10 mL), 4 N aq. NaOH (0.10 mL), 10 and water (0.30 mL) are added sequentially. The reaction is filtered through a pad of Celite and the filtrate i,s evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Step D: 1 -(2-(Thien-2-yl) pyrid-5-ylmethyl)-5-(4-1 5 cyanobenzyl)imidazole To a solution of 2-(thien-2-yl)-5-hydroxymethylpyridine (255 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -7~~C is added trifluoromethane-sulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at 20 -7~~C for 1 hour. To this mixture is added a solution of l-trityl-4-(4-cyanobenzyl)-imidazole (566mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and the 25 solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.
CA 022~0936 1998-09-28 W O 97/36898 PCT~US97/05512 N- { 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl)methyl } -5-(thien-2-yl)-2-amin o -pyrimidine s Step A: 5-(Thien-2-yl)-2-aminopyrimidine A mixture of 2-amino-S-bromopyrimidine (0.299 g, 1.72 mmol), 2-thienylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME (P~ mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenyl-phosphine) palladium(0) (99.0 mg, 0.086 mmol) is added, and the resultant solution is stirred at 80~C
for 4 hours. The solvents are evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is .separated, and extracted with EtOAc. The organic extracts are combined, washed with sat. a4. NaHCO3 and 5% aq- Na2s2o3 dried, (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Step B: l-Triphenylmethyl-4-(hydroxymethyl)imidazol To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in dry DMF (250 mL) at room temperature was added triethylamine (90.6 mL, 650 mmol). A white .solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL) was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Step C: I-Triphenylmethyl-4-(acetoxymethyl)imidazole The alcohol from Step B (260 mmol, prepared above) was - suspended in pyridine (500 mL). Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into EtOAc, washed sequentially with water, 5% aq. HCI solution, sat. aq. NaHCO3, .. . ~. . . . ... . . . .. .. ... .. ~
CA 022~0936 1998-09-28 solution, and brine. The organic extracts were dried, (Na2so4)~ and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction.
5 Step D: 1-(4-Cyanobenzyl)-S-(acetoxymethyl)imidazole hydrobromide A solution of the product from Step C (85.8 g, 225 mmol) and 4-cyano benzyl bromide (50.1 g, 232 mmol) in EtOAc (500 mL) was stirred at 60~C for 20 hours, during which a pale yellow precipi-10 tate formed. The reaction was cooled to room temperature and filteredto provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume (200 mL), heated at 60~C for 2 hours, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to a volume (100 mL), heated at 60~C for 2 15 hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in methanol (500 mL), and warmed to 60~C. After 2 hours, the solution was concentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble by products. Removal of 20 residual solvents in vacuo provided the titled product as a white .solid which was used in the next step without further purification.
Step E: I -(4-Cyanobenzyl)-S-(hydroxymethyl)imidazole To a solution of the acetate from Step D (50.4 g, 150 25 mmol) in 3:1 THF/water (1.5 L) at 0 ~C was added lithium hydroxide monohydrate (18.9 g, 450 rnmol). After lhour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo t~ provide the crude 30 product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
CA 022~0936 1998-09-28 W O 97/36898 PCTrUS97/OSS12 - ~3 -Step F: 1 -(4-Cyanobenzyl)-5-(chloromethyl)imidazol A solution of 1-(4-cyanobenzyl)-5-(hydroxymethyl) imidazole (l.OOg, 4.70 mmol), in thionyl chloride (5 mL), was stirred at 70~C for 16 hours. The solvent was evaporated in vacuo and the resulting solid suspended in CH2cl2~ collected by filtration and dried in vacuo. The material was sufficiently pure for use in the next step without further purification.
lH NMR (CD30D 400MHz) ~ 9.06 (lH, s), 7.~3(2H, d, J=~.OHz), 7.77(1H, s), 7.55(2H, d, J=~.OHz), 5.67(2H, s) and 4.7P~(2H, s) ppm.
Step G: N-{ 1-(4-Cyanobenzyl)-lH-imidazol-5-yl)methyl}-5-(thien-2-yl)-2-aminopyrimidine To a solution of the chloride from step F (500mg, 1.65 mmol) in DMF (10 mL) at 0~C is added sequentially, the amine from step A (292mg, 1.65 mmol) and sodium hydride (145mg, 60%
dispersion in mineral oil, 3.62 mmol). Stirring is continued at 0~C for 1 hour and then at room temperature for 16 hours. The reaction is 4uenched with water (50 mL), and extracted with CH2C12. The organic extracts are dried, (MgS04), and the solvent is evaporated in vacuo.
The residue is purified by chromatography to afford the title compound In vitr~ inhibition of ras farnesyl transferase Assays offarnesyl-protein transfera~e. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et ah, J. Biol. Chem. 265:14701-14704 (1990), Pompliano, etah, Biochemistry 31:3~00 (1992) and Gibbs et ah, PNAS U.S.A. ~6:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 111 containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH
- 7.4, 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM ~3H]-farnesyl diphosphate ([3H]-FPP; 740 CB4/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ~g/ml FPTase at 31 ~C for 60 min. Reactions CA 022~0936 1998-09-28 were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ,13-plate counter. The assay was linear with respect to both S substrates, FPTase levels and time; less than 10% of the ~3H~-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 10 when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ,UM ZnCI2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ~1 of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention are tested for inhibitory activity against human FPTa.se by the assay described above.
EXAMPLE~ 4 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0. I %). 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 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are Iysed in 1 ml lysis buffer ( I % NP40/20 mM HEPES, pH 7.5/5 CA 022~0936 1998-09-28 ~5 _ mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 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 of acid-precipitable counts are bought to 1 ml with IP buffer (Iysis S buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et ah, J. Virol. 43:294-304, (19~S2)). 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
is added for 45 min. The immunoprecipitates are washed four times 10 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 autoradiographed. The intensities of the band,s corresponding to 15 farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
20 ln vivo growth inhibition assay To determine the biological conse4uences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-m~s oncogene is tested. Cells transformed by v-Raf 25 and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's 30 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 methanol at 1000 times the final concentration u.sed in the assay).
. , .. . . , . . . ~ . . . .
CA 02250936 l998-09-28 W O 97/36898 PCTrUS97/05512 The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound.
Photomicrographs are taken 16 days after the cultures are seeded a nd comparisons are made.
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
BACKGROUND OF THE ~VENTION
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. ln the inactive state, Ras is bound to GDP.
Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is termin~ted by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (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 leukemias. The protein products of these genes are defective in their GTPase activity and con.stitutively 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 modification,s occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xa~"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depend-ing on the specific ~sequence, this motif .serves as a signal se4uence 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 farne.~yl-CA 022~0936 1998-09-28 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., Scienc~, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N.E. Kohl et al., Proc. Natl. Acad.
Sci U.S.A ., 91 :9141 -9145 (1994) and induces regression of mammary and salivary carcinoma.s in ras transgenic mice (N.E. Kohl et al., Nature Medicine, 1 :792-797 (199~).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and compactin (Hancock et al., ihid; Ca~sey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-XX (1990);
Schaber et al., J. Bio~. Chem., 265: 14701 -14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sc~i USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane - localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor CA 022~0936 1998-09-28 of isoprene biosynthesis.
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., if~id; Reiss et. al., ihid; Reis~s 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,~S51, University of Texas; N.E. Kohl et al., Science, 2l50:1934-1937 (1993); Graham, et al., J. Mecl. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations 20 on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol i.s desirable.
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are 25 inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 A1).
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitor~; of proliferation of vascular 30 smooth muscle cells and are therefore u.seful in the prevention and therapy of arterio.sclerosis and diabetic disturbance of blood ves.sels - (JP H7- 112930).
It is, therefore, an object of this invention to develop .
CA 022~0936 1998-09-28 low molecular weight compounds that will inhibit farnesyl-protein transferase and thus, the post-translational farnesylation o~ 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 INVENTION
The present invention comprises biheteroaryl-cont~ining compounds which inhibit the farnesyl-protein transferase. Further 10 contained in this invention are chemotherapeutic compositions containing these farnesyl tran.sferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A:
R6a-d R3 a~ e 8) / ~ /f V - A1(CR12)nA2(CR12)n~W~ (CR22)p - X -(CR22)p R5 R
.. .. . . . .
~ DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of 5 farne,syl-protein transferase are illustrated by the formula A:
~6a-d R3 a~ e V - A (CR12)nA2(CR12)n\W - (CR2 ) X (CR
wherem:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at lea.st one of b, c, d or e is independently N, NH, O or S;
15 from 1-2 of f(,s) are independently N, and the remaining f's are independently CH;
Rl and R2 are independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-, Rl lS(O)m-, R10C(O)NR10-, 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 , CA 022~0936 1998-09-28 WO 97136898 PCT/US97/û5512 c) unsubstituted or substituted Cl -C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 OO-~ R 1 1 S(O)m-~ RlOC(O)NRlO-~(Rlo)2Nc(o)-~
R102N-c(NRlo)-~cN~Rloc(o)-~ N3,-N(R10)2, and Rlloc(o)-NRlo-;
R3,R4 and R5 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-R102N-c(NRlo)-~cN~No2~ RlOC(O)-, N3,-N(R10)2, or RllOC(O)NR1O-, 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, unsub,stituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120,RllS(o)m,RlOC(o)NRlo-~(Rlo)2Nc(o)-~
R102N-c(NRlo)-~cN~Rloc(o)-~ N3,-N(R10)2, and Rlloc(o) NRlO;
provided that when R3,R4 or RSis unsubstituted or substituted heterocycle, attachment of R3,R4 or R5 to the six-membered heteroaryl ring is through a sub,stitutable heterocycle ring carbon;
R6a R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R12O-, CA 022~0936 1998-09-28 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 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-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(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;
R7 i.s selected from: H; C1 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, aryl.sulfonyl, heteroaryl.sulfonyl, unsubstituted or~5 substituted with:
a) C 1-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o f) --SO2R
g) N(R 1~)2 or h) C l 4 perfluoroalkyl;
R~ is independently ~elected from:
a) hydrogen, b) aryl, sub~tituted aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0O , R 1 1 S(O)m-~ R 1 0C(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, and CA 022~0936 1998-09-28 c) Cl-C6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 1 0O, R 1 1 S(O)m-~ R 1 0C(O)NH-~ (R 1 0)2NC(O)-, R 1 02N-C(NR 1 0)-, CN, R 1 ~C(O)-, N3, -N(R 1 0)2, or R 1 0OC(O)NH-;
provided that when R8 is heterocycle, attachment of R8 to V i,s through a substitutable ring carbon;
10 R9 is independently ~selected from:
a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, Br, Rl lo-, Rl lS(O)m-, R10C(o)NR10-, (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, and c) C I -C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R10O-, Rl lS(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;
R10 i.s 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, C1-C6 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl, Cl-C6 sub,stituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteraryl, Cl-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)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) , -S(0)2N(R 10), -N(R 1 ~)S(O)2-, or S(O)m;
CA 022~0936 1998-09-28 V is selected from:
a) hydrogen, b) heterocycle, S c) aryl, d) Cl -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen 10 if A I is a bond, n i.s 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;
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(R 1 0), -N(R 1 ~)S(O)2- or -S(=O)m-;
20 mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
is 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and 25 ti,s 0 or 1;
or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention is illustrated by the following formula A:
(R8)r ~9~ ~f/\( ~dea'd V - A1(CR12)nA2(CR12)n~;~W~ - (CR22)p - X -(CR22)p ¦ R5 wherein:
ais N orC;
s from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
10 from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
Rl is independently selected from: hydrogen, C3-Clo cycloalkyl, R l ~O, -N(R 1 ~)2, F or C 1 -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, R l OO- and -N(R 1 0)2;
2;~ R3, R4 and RS are independently selected from:
CA 022~0936 1998-09-28 a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-c10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 2O, R 1 1 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 Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 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 Rl 10C(O)-NR10;
provided that when R3, R4 or RS is unsubstituted or substituted heterocycle, attachment of R3, R4 or RS to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120, RllS(O)m, KlOC(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 c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-c6 alkyl is selected from unsubstituted or - sub,stituted aryl, unsubstituted or substituted heterocyclic, C3-C l o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R l l S(O)m-, .
CA 022~0936 1998-09-28 W O 97/3689B PCT~US97/05512 R 1 0C(O)NR 10, (R l 0)2NC(o)-, R l02N-C(NR 10), CN, R l ~C(O)-, N3, -N(R 1~)2, and R 1 l OC(O)-NR l 0;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, 5 aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) Cl -4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e) "R1' f) --So2R ~ ~
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, Rl0O-, Rl0C(O)NRl0, CN, NO2, (Rl0)2N-C(NR10)-, R 1 ~C(O)-, -N(R 1~)2, or R l 1 OC(O)NR l 0, and c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-, R l 0C(O)NR l 0, (R l 0)2N-C(NR l 0), R l ~C(O)-, -N(R l ~)2, or R 1 l OC(O)NR l 0;
provided that when R8 i,s heterocycle, attachment of Rg 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-~ (R10)2Nc(o) CA 022~0936 1998-09-28 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 c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6 perfluoroalkyl, F, Cl, R 1 0O-, R 1 1 S(O)m ~ R 1 0C(O)NR 10 (R 1 0)2NC(O)-, CN, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10 , 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 .sub,stituted 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 l and A2 are independently .selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 1 0-, O, -N(R 1 0)-, 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 provided that V is not hydrogen if Al i.s S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(O)m;
provided that when V i.s heterocycle, attachment of V to R~ and to A 1 is through a ~substitutable ring carbon;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or isoquinolinyl;
X is a bond, 0, -C(=0)-, -CH=CH-, -C(o)NR7-, -NR7C(o)-, -NR7-, -S(0)2N(R 1 0), -N(R 1 ~)S(0)2- or -S(=O)m-;
mis 0, 1 or2;
10 n is independently 0, 1, 2, 3 or 4;
p i~s independently 0, 1, 2, 3 or 4;
qis 0, 1, 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and ti,s 0 or 1 ;
or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this invention are illustrated by the formula B:
R6a-d (R8) R9a B (CR 2)p X R
20 wherein:
a is N or C;
- *om 0-4 of b, c, d and e are independently N, NH, 0 and S, and the 25 rem~ining b, c, d and e atoms are independently CH, provided that if a i~i C, then at least one of b, c, d or e is independently N, NH, 0 or S;
CA 022~0936 1998-09-28 from 1-2 of f(s) are independently N, and the rem~ining ~s are independently CH;
5 Rl is independently selected from: hydrogen, C3-clo cycloalkyl, R l OO, -N(R 1 ~)2, F or C 1 -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-CIo cycloalkyl, C2-C6 alkenyl, RlOO- 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 1 2O, R 1 1 S(O)m-~ R I 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 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, R12O, 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 ;
provided that when R3 or R4 i,s unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered CA 022~0936 1998-09-28 W O 97/36898 PCT~US97/05512 heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R102N-C(NR10)-, CN, N02, RlOC(O)-, N3, -N(R10)2, or RIlOC(O)NRl0-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, unsub,stituted or substituted heterocyclic, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R102N-c(NRlo)-~ CN, R10C(O)-, N3, -N(R10)2, and RllOc(o)-NRlo-;
R8 is independently selected from:
a) hydrogen, b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C~-C6 perfluoroalkyl, F, Cl, R10O-,R10C(O)NRl0-~ CN, N02,(R10)2N-C(NR10)-, Rl0c(o)-~-N(Rlo)2~ or RllOC(O)NR10-, and c) Cl -C6 alkyl substituted by Cl -C6 perfluoroalkyl, R 1 0o-, Rl0c(o)NRlo-~(Rlo)2N-c(NRlo)- R10C(o)--N(R10)2, or RllOC(O)NR10-;
provided that when R~ is heterocycle, attachment of R8 to V is through a substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl and halogen;
CA 022~0936 1998-09-28 WO 97/368g8 PCI/US97/05512 R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
R 1 1 is independently selected from Cl -C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, Cl-C6 aralkyl, Cl-c6 sub.stituted 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 and A2 are independently selected from: a bond, -CH=CH-, -C_C-, -C(O)-, -C(O)NR 1 0-, O, -N(R 10)-, or S(O)m;
V i~ selected from:
a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, i.soquinolinyl, 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 25 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if Al i.s a bond, n i,s 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R~ and to Al is through a substitutable ring carbon;
30 X is a bond, -CH=CH-, -C(O)NR10-~ NR10C(o), NR10, O or -C(=O)-;
-mi,s 0, 1 or2;n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salt.s thereof.
5Another preferred embodiment of the compounds of this invention are illustrated by the forrnula C:
R6a-d (R8)r ~$1 V- A1(cR12)nA2(cR12)n~
C R9b (CR22)FX R4 wherein:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining r.s are independently CH;
Rl i.s independently selected from: hydrogen, C3-Clo cycloalkyl, RlOo-~-N(Rlo)2~For Cl-C6alkyl;
R2 is independently selected from:
a) hydrogen, - b) aryl, heterocycle, C3-C I o cycloalkyl, R l OO-, -N(R 1 0)2, F or C2-C6 alkenyl, CA 022~0936 l998-09-28 WO 97/36898 PCTrUS97/05512 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, R10O- and -N(R10)2;
s R3 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, un,substituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R 1 20, R 1 1 S(O)m-~ R 1 0C(o)NR 10, CN(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 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)NR10-, (R10)2NC(o)-, R 1 02N-C(NR 1 0)-, CN, R 1 0C(o)-, N3, -N(R 1 0)2, and RllOC(O) NR10;
provided that when R3 or R4 is unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Cl-c6 perfluoroalkyl, - R120, Rl lS(o)m, RlOc(o)NRlo-~ CN(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, CA 022~0936 1998-09-28 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-C1o cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R 1 1 S(O)m ~
R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 10C(o)-, N3, -N(R10)2, and R1 1OC(O)-NR10-;
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 10), R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and c) C I -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, R 1 0O-, 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 R8 is heterocycle, attachment of R~ 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, 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, Cl-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
.. . . ..
CA 022~0936 1998-09-28 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, b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, 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, and provided that V is not hydrogen if A l is S(O)m and V is not hydrogen if Al isabond,n i,sOandA2i,sS(O)m;
15 provided that when V is heterocycle, attachrnent of V to R8 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)-;
mils 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
pis 0, 1,2,30r4,providedthatpisnotOifXisabondorO;
and 25 r is O to 5, provided that r is O when V is hydrogen;
or the pharmaceutically acceptable salt~s thereof.
In a more preferred embodiment of this invention, the inhibitors of farne,syl-protein transferase are illustrated by the formula 30 D:
. .
CA 022~0936 1998-09-28 R6a-d R 9a ~
wherein:
a is N or C;
s from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
10 from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
Rl is independently selected from: hydrogen, C3-Clo cycloalkyl or Cl-C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C I o cycloalkyl, R l OO-, -N(R l O)27 F or C2-C6 alkenyl, c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, RlOO-, or -N(R I ~)2;
- R3 is selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or sub,stituted heterocycle, C3-Clo cycloalkyl, C2-C6 CA 022~0936 1998-09-28 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-, 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 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 2O, 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 RllOC(O)NR10;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is lS through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, Cl-C6 alkyl and CF3;
R6a R6b, R6c and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, un~ubstituted or substituted heterocycle, C3-CIo cycloalkyl, C2-c6 alkenyl, C2-c6 alkynyl. halogen, Cl-c6 perfluoroalkyl, R120, Rl lS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-, R I 02~-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, - R120-, RI lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o) R102N-C(NRI0)-, CN, RlOC(O)-, N3, -N(R10)2, and R 1 1 OC(O)-NR 10;
CA 022~0936 1998-09-28 Rg 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 100-, R10C(o)NR 10, CN, N02, (R10)2N-C(NR10)-, 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 1 OC(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~ is heterocycle, attachment of R8 to V i.s through a sub.stitutable ring carbon;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10 i~s independently selected from hydrogen, C1-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;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR 10, -NR 1 ~C(O)-, -NR 10, o or 30 -C(=O)-;
- nis Oorl;
m is 0, 1 or 2; and pis 0, 1, 2, 3 or4;
. .
or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the 5 formula E:
R 6a-d ~ ~ R3 _~àC~e A1(CR12)n ,~_N\ ~ ~
R9b (CR22)p- X' f R4 wherein:
a i,s N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the rem~ining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
15 from 1-2 of f(s) are independently N, and the remaining fs are independently CH;
Rl is independently selected from: hydrogen, C3-clo cycloalkyl, R l Oo, -N(R 1 ~)2, F or C 1 -C6 alkyl;
R2 is independently ~selected from:
a) hydrogen, - b) aryl, heterocycle, C3-Clo cycloalkyl, RlOO-, -N(R10)2, F or C2-C6 alkenyl, CA 022~0936 1998-09-28 W O 97/36898 PCTrUS97/05S12 c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or -N(R 1 ~)2;
S R3 is 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 1 S(O)m ~ R I OC(O)NR 10, (R 1 0)2NC(0)-, R 1 02N-C(NR 1 0), 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 1 20, R 1 1 S(O)m-~ R 1 OC(O)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;
provided that when R3 i.s unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, Cl-C6 alkyl and CF3;
R6a R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen~ 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 ~C(0)-, N3, -N(R 1 ~)2, or R 1 1 0C(0)NR 10 CA 022~0936 1998-09-28 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;
10 R~ i.s 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 1 OC(O)NR 10, (R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R10)2, or R1 1OC(O)NR10-;
provided that when R8 i.s heterocycle, attachment of Rg to V i.s throu~h a stitutable ring carbon;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 i.s independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6 aralkyl, C1-C6 sub~stituted aralkyl, C1-C6 heteroaralkyl, C1-C6 .substituted heteroaralkyl, aryl, substituted aryl, - heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
CA 022~0936 1998-09-28 WO 97/36898 PCT/US97tO5512 X is a bond, -CH=CH-, -C(O)NR10-, -NR 10C(o)-, -NR 10-, O or -C(=O)-;
n is O or l; provided that n is not O if Al is a bond, O, S -N(R10)-, or S(O)m;
m is 0, 1 or 2; and pis 0, 1,2,30r4,providedthatpi,snotOifXisabondorO;
or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula F:
R 6a-d R9a~N R~f~à(--~e (CR 2)p NC F
wherein:
aisNorC;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the rem~ining f's are independently CH;
R 1 is independently selected from: hydrogen, C3-C 1 o cycloalkyl or 25 Cl-C6 alkyl;
CA 022~0936 l998-09-28 W O 97136898 PCTrUS97/05512 R2 is independently selected from:
a) hydrogen, b) aryl, heterocycle, C3-C 10 cycloalkyl, R 1 0O-, -N(R 1 0)2 or F, c) Cl-c6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-c l o cycloalkyl, R 1 0O-, or -N(R 1 0)2;
R3 is 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-, (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, c) unsubstituted C1-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-CIo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 120, R 1 1 S(O)m-~ R 1 0C(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;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, CH3 and CF3;
30 R6a, R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 CA 022~0936 1998-09-28 W 0 97/36898 rCTAUS97/05512 alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120,RllS(o)m-~RlOC(o)NRlo-~(Rl 0)2NC(O)-R102N-C(NR10)-, CN, NO2, RlOC(0)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR10-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, I 0 R 120,Rll S(O)m-~ R 1 0c(o)NRlo-~(Rlo)2Nc(o)-~
R102N-C(NR10)-, CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R l l OC(O)-NR 10;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R10i.s independently selected from hydrogen, Cl -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
Rl 1 i,s 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)NR10-,-NRlOC(O)-,-NRlO-,O or -C(=O)-;
30 m is 0, 1 or 2; and pis 0, 1,2, 3 or4;
-or the pharmaceutically acceptable salt,s thereof.
CA 022~0936 1998-09-28 W O 97136898 PCT~US97/05512 In a further embodiment of this invention, the inhibitors of farnesyl-protein transferase are illustrated by the formula G:
'A ~;
wherem:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a 10 is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
15 Rl is independently selected from: hydrogen, C3-Clo cycloalkyl, R l OO, -N(R 1 ~)2, F or C l -C6 alkyl;
R2 is independently selected from:
a) hydrogen, b) aryl or heterocycle, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, RlOO-, or -N(R I ~)2;
25 R3 is selected from:
a) hydrogen, CA 022~0936 1998-09-28 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 l l S(O)m , R l OC(O)NR 10-, (R 1 0)2NC(O)-, R102N-c(NRlo)-~cN~No2~ RlOC(O)-~ N3,-N(R10)2, or RllOC(O)NR10-c) unsubstituted Cl-C6 alkyl, d) substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is .selected from unsubstituted or sub~stituted 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) R102N-c(NRlo)-~cN~Rloc(o)-~ N3,-N(R10)2, and RllOC(O)-NR10-;
provided that when R3is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4is selected from H, halogen, CH~ and CF3;
R6a R6b R6c and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or sub.stituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, C2-c6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120,RllS(o)m,RlOC(o)NRlo-~(Rlo)2Nc(o)-~
R102N-C(NRlO)-~CN,No2~ RlOC(O)-, N3,-N(R10)2, or RllOC(O)NR10-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, CA 022~0936 1998-09-28 W O 97/36898 PCTrUS97tO5512 R 1 20, R 1 I S(O)m-~ R 1 OC(O)NR 10 , (R I 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and R11OC(O) NR10;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl or methyl;
R 1 0 is independently selected from hydrogen, Cl -C6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
10 Rl 1 is independently selected from Cl-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;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
20 m is 0, 1 or 2; and nis Oor 1;
or the pharmaceutically acceptable salts thereof.
Specific examples of the compounds of the invention are:
I -(2-[Thien-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole.
NC~--l ~/ N
N
.. .. .~.
CA 022~0936 1998-09-28 N- { 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl)methyl } -5-(thien-2-yl)-2-. . .
amlno-pyrlml~lne NC ~ ,~
~ y N
or the phannaceutically acceptable salts thereof.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and a~s individual diastereomers, with all possible isomers, including optical 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 permissible only if such combinations result in stable compounds.
As used herein, "alkyl" and the alkyl portion of aralkyl and similar terms, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
As used herein, "cycloalkyl" is intended to include 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, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
CA 022~0936 1998-09-28 "Alkynyl" groups include those groups having the ,specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
S "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl," and the aryl portion of aralkyl and aroyl, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
Examples of such aryl elements include phenyl, naphthyl, tetrahydro-naphthyl, 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 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Example.s of such heterocyclic element~;
include, but are not limited to, azepinyl, benzimidazolyl, benzi.soxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, - tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
CA 022~0936 1998-09-28 W O 97/36898 PCTrUS97/05S12 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 S consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, 10 dihydrobenzothiopyranyl .sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, i,soquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, 15 thienothienyl, and thienyl.
As used herein in the definition of R3, R4, RS and R6a-d the term "the substituted group" intended to mean a sub.stituted Cl ~
alkyl, substituted C2 ~ alkenyl, substituted C2 ~ alkynyl, substituted aryl or substituted heterocycle from which the substituent(s) R3, R4, R5 and 20 R6a-e are selected.
As used herein in the definition of R7, the substituted C
alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl-sulfonyl and substituted heterocycle include moieties containing from 1 25 to 3 substituents in addition to the point of attachment to the rest of the compound.
As used herein, when no specific substituents are set forth, the terms "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl" are intended to include the cyclic group which is substituted 30 on a substitutable ring carbon atom with 1 or 2 substitutents selected ~rom 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 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-c(NH)-~ (cl-c6 alkyl) C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(O)NH-, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and Cl-C20 alkyl.
Lines drawn into the ring systems from substituents (such 5 as from R3, R4 etc.) means that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms.
The moiety designated by the following structure f "f_~
~f' represents an aromatic 6-membered heterocyclic ring and includes the 10 following ring systems:
~,1,~ N ~ N ,~,~ N
The moiety designated by the following structure f ' ~f~
~,,~f/f represents an aromatic 6-membered heterocyclic ring and includes the 15 following ring systems:
. .
~q J~ oqN
N~N N~N HN NH
~0 wherein it is understood that one of the ring carbon atoms is .substituted with bà~)/d 5 Preferably, the aromatic 6-membered heterocyclic ring is a pyridyl ring.
The moiety designated by the following structure ba~/d represents an aromatic 5-membered heterocyclic ring and includes the 10 following ring sy.stems:
~ .. .... .. .
W O 97/36898 rcTrusg71o5512 ~> N--~N Nb~ N~,N N~N
N--~ N~\ N--~ N--~
N ' N ' N 11 N
N~/ N~/ N~N~ N--N~
N ~> ~> N~
~ N_ N> N~ S,~ N~
N~ ~ N_ N/> N--~>
Preferably the aromatic S-membered heterocyclic ring is selected from:
N--~N N~
~> N ~>
~ N ~> ~
S Preferably, Rl and R2 are independently selected from:
hydrogen, R 1 1 C(O)O-, -N(R 1 ~)2, R I OC(O)NR 10 , R l ~O or unsubstituted or substituted Cl-c6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 1 ~)2, R l Oo and R 1 OC(O)NR 10 .
Preferably, R3 is selected from:
a) hydrogen, CA 022~0936 1998-09-28 WO 97t36898 PCT/US97/05512 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 1 20, R 1 1 S(O)m-~ R 1 OC(O)NR10-, (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 OC(0)-NR 10 Preferably, R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and Cl-C6 alkyl.
Preferably, RS is hydrogen.
Preferably, R6a, R6b, R6C and R6d are independently l:S selected from:
a) hydrogen, b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-, Rl 1S(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-Clo cycloalkyl, R120-, Rl lS(O)m-, R 1 ~C(0)- or -N(R 1~)2.
Preferably, R~ is independently ,selected from:
a) hydrogen, and b) aryl, substituted aryl, heterocycle, substituted heterocycle, Cl-C6 perfluoroalkyl or CN.
Preferably, R9 is hydrogen, halogen or methyl.
Preferably, R10 is .selected from H, Cl-C6 alkyl and benzyl.
Preferably, Al and A2 are independently selected from:
a bond, -C(O)NR10-, -NRlOC(0)-, 0, -N(R10)-, -S(0)2N(R10)- and-N(R 1 ~)S(0)2-.
CA 022~0936 1998-09-28 WO 97/36898 PCT~US97/05512 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 5 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 from 1-2 of f(s) are independently N, and the 10 rem~ining f's are independently CH.
Preferably, the moiety (R8) 1~9)\
V-A1(CR12)nA2(CRl2)ntW~ (CR22)p-X-(CR22)p~-is selected from:
R9a R9b ~ \~ 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 el.sewhere in that molecule. Thus, -N(RlO)2 represent.s -NHH, -NHCH3, -NHc2H~ etc. It is understood that substituents and substitution patterns on the compounds of the 20 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 techni4ues known in the art, as well a,s those methods set forth below, from readily available starting materials.
CA 022~0936 1998-09-28 The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compound.s of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those S derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, 10 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 15 methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention 20 are prepared by employing reactions as shown in the Schemes 1-22, in addition to other standard manipulation~s such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R3, R6 and R~, as shown in the Scheme.s, represent the substituents R3, R4, 25 R5 R6a R6b, R6C, R6d and RX; although only one such R3, R6 or R~ is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents.
These reaction,s may be employed in a linear sequence 30 to provide the compounds of the invention or they may be used to synthe~size fragments which are subsequently joined by the alkylation - reactions described in the Scheme,s. The reactions described in the Schemes are illustrative only and are not meant to be limiting. Other reactions useful in the preparation of heteroaryl moieties are described CA 022~0936 1998-09-28 in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic Compounds" ed. P.G. Sammes, Oxford (1979) and references therein.
Aryl-aryl coupling is generally described in "Comprehensive Organic Functional Group Transformations," Katritsky et al. eds., pp 472-473, 5 Pergamon Press (1995).
Synopsis of Schemes 1-22:
The requisite intermediates are in some case,s commercially available, or can be prepared according to literature procedures, for the 10 most part. Schemes 1- 13 illustrate synthesis of the instant biheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain.
Thus, in Scheme 1, for example, a biheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art. Thus, a suitably substituted thienyl boronic acid I may be reacted 15 under Suzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substituted activated nicotinic acid, such as nicotinic acid 6-triflate, to provide the biheteroaryl carboxylic acid II. The acid may be reduced and the triflate of the intermediate alcohol III may be formed in situ and coupled to a suitably substituted benzylimidazolyl 20 IV to provide, after deprotection, the instant compound V.
Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1. Thus, Scheme 2 illustrates the reaction wherein the "terminal" 5-membered heteroaryl moiety is employed in the Suzuki 25 coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 3.
Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biheteroaryl component of the instant 30 compounds, as shown in Scheme 4. Thus, a suitably substituted zinc bromide adduct may be coupled to a suitably substituted heteroaryl - halide in the presence of nickel (II) to provide the biheteroaryl VII.
The heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
... . .. . . . .. .. . ...
CA 022~0936 1998-09-28 Scheme 5 illustrates the preparation of a suitably substituted biheteroaryl alcohol starting from the halogenated methylpyridine.
As illustrated in Scheme 6, the sequence of coupling reactions may be modified such that the biphenyl bond is formed S last. Thus, a suitably substituted imidazole may first be alkylated with a suitably substituted benzyl halide to provide intermediate VIII.
Intermediate VIII can then undergo Suzuki type coupling to a suitably substituted phenyl boronic acid.
Scheme 7 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
Thus, a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
Scheme 8 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biheteroaryl via an alkyl amino, sulfonamide or amide linker. Thus, the 4-amino-alkylimidazole XII, wherein the primary amine is protected as the phthalimide, i.s 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 biheteroaryl moieties to provide the instant compounds shown.
Use of another 6-member heteroaryl in the synthesi.s of the instant compounds i.s illustrated in Scheme 9. Thus, a halogenated 2-aminopyrimidine may be coupled with a heteroaryl boronic acid to provide the biheteroaryl amine XIIIa, which can then be reacted with the preferred imidazolylmethyl sidechain to provide the instant compound.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR 1 2)n linker is oxygen may be synthesized by - methods known in the art, for example as shown in Scheme 10.
The suitably sub~stituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
CA 022~0936 1998-09-28 After selective protection of one of the imidazolyl nitrogens, the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
Scheme 11 illustrates an analogous series of reactions 5 wherein the (CR22)pX(CR22)p linker of the instant compounds is oxygen. Thus, a suitably substituted halopyridinol, such as, is reacted with methyl N-(cyano)meth~nimidate 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.
10 The intermediate XVII can then be coupled to a heteroaryl moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the A 1 (CR 1 2)nA2(CR 1 2)n linker is a substituted methylene may be synthesized by the methods shown in Scheme 12. Thus, the N-protected 15 imidazolyl iodide XVIII i~s reacted, under Grignard conditions with a suitably protected benzaldehyde to provide the alcohol XIX. Acylation, followed by the alkylation procedure illustrated in the Schemes above (in particular, Scheme 1 ) provides the instant compound XX. If other R I substituents are desired, the acetyl moiety can be manipulated as 20 illustrated in the Scheme.
Addition of various nucleophiles to an imidazolyl aldehyde may also be employed to form a substituted alkyl linker between the biheteroaryl and the preferred W (imidazolyl) as shown in Scheme 13. Thus a lithiothiophene can be reacted with pyridine to form the 25 2 substituted N-lithio-1,2-dihydropyridine XXa. lntermediate XXa can then react with a aldehyde to provide a suitably substituted instant compound. Similar substituent manipulation as shown in Scheme 12 may be performed on the fully functionalized compound which incorporates an R2 hydroxyl moiety.
N~oTf (H~)2B~R6 ~\R2 Pd(OAc)2 N~R6 ~iAlH4 HO~'\ 2 J~\R~
SCHEME 1 (continued) Tr Tr, Nicl2~ h~)z _~
J~,~R6 (CF3SO2)20,;78~C
H0 R2 CH2CI2 -78~C-20~C
~_~N~\~ 55~C CH30H
R8 <~ R6 /~ V
WO 97/36898 PCTtUS97/05512 - 4~ -SCHEl\/IE 2 S--f~N~,B(OH) MeO ~,\
o R2 pd(pph3)4 S~
~ ~ R6 LiAlH4 MeO~
o R2 N~R6 HO J~,\
CA 02250936 l998-09-28 W O 97/36898 PCTrUS97/05512 SC~DE~IE 3 N~B(oH)2 J_~ R6 R3SiO~,\
R2 Pd(Pph3)4 N~e R Bu4NF
R3SiO J~\R2 b - c~
HO\~ 2 N Br b,c;~
R3SiO~,~ (H~)2B
R2 Pd(PPh3)4 N~ll-~R6 R3SiO J~\R2 b~
HO~,~R2 ~ ,Br J~R6 R3SiO R2 NiCI2(PPh3)2 N~ R Bu4NF
R3SiO 2 Vll R S
N~y~R6 HO~,\
~ Znl ~ R6 R3SiO R2 NiCI2(PPh3)2 ~S~
~N~--R Bu4NF
R3SiO~\R2 J~\
,g~ (HO)2B R6 KMnO4 H3C R2 Pd(PPh3)4 ~ ' R6 S~
~N~\ R6 HO~,\
W O 97/36898 PCTrUS97/05512 - ~2 -Tr~ i r~
N~ Br ~N
<~ N j; MeOH
~_J reflux R
Pd(PPh~) R Vlll S~
N~ ~:v\ R6 <~ N ~,\, N
R~ R2 CA 022',0936 1998-09-28 H H
Rsb~ Nal, NaHCO3,!~ Rgb~ TrCI, NEt3 IX X
Tr, N
Rgb ~ NiCI2(PPh3)2 > ~N
~ ZnBr,~
S~
Tr~ ~N~\ R6 ~J i. -78~C-20~C, /~ ii. MeOH, reflux Xl R9b~ R6 ,~_/ R2 SCHEME ~
0~
~~ R8 ~, <N~ O 55~C,CH3CN "
N~ N~ii. EtOH.80~C, NH2NH2 o Xll N
</~
R 1~1 Xlll acylation, sulfonylation </ 3~'~ ~ R2 - - - - - - - --- N N ~ /~
or alkylation Rs ~_ <~ ~ N~
~ N ~
R8~/ H'\~S~R6 W O 97136898 PCTrUS97/05512 N~Br Pd(OAC)2 <N~
N--' CI
N~R6 Rs~
Xllla ~,~N+ Nl'~ 55~C,CH30H
S~
R8 N~ R6 .. . . .. . . ..
PCT~US97/05512 ~--OH i~ Na, MeOH
NC ~/ ii. 120~C
XIV H3C~o ~N/\~N
H Tr~
~ N TrCI, NEt3 <~_ NC ~ NC ~¢~
XV XVI
Tr~N~N + R~N~~ R j -78~C-20~C
ii. MeOH reflux NC ~ OTf XVI
~ N~J~
~0 NC ~
W O 97/36898 rCT~US97/05512 N OH i, Na, MeOH ~N
Cl~\~ ii. 120~C ,~N O
R2 H3C~ ,o Cl~\~
N~ R2XV
~q Tr~
TrCI, NEt3 <~N OTf -78~C-20~C
ii. MeOH reflux R2 R8 ~B(~H)2 N ~ ~ R<6\/~ S
Cl~O DMF, Pd(PPh3)4 K3PO4, 80~C
N
R ~ ~
W O 97/36898 PCTrUS97/05512 Tr N~
N~ EtMgBr ~N
~N ~ ~'OH
Tr~
AC20~ PY ~ ~ NH~J~\ 2 ~\OAc(CF3S02)20,-780c 8 /\~NEtiPr2,C H2Cl2 N N~ R6 LiOH
~OAc R2 ~_~N~\~ SOCI~
59 _ SCHEME 12 (continued) ~N~J~ ~ N H3, MeOH
/J Cl <~q J~ R6 ¢~ R2 /~/ N H2 +
~N~
OMe .. , . ... ... .. . , . . .. ~ . . .. . .. ...
W O 97/36898 PCTrUS97/05512 S
~, ' N
N
</~
N
S R~
XXa N~R6 ~J OH
. .
CA 022~0936 1998-09-28 W 0 97~6898 PCTnUS97/05512 Schemes 14-20 illustrate reaction~s wherein the moiety (l8)r (/R9~\
V ~ A1 (CR12)nA2(CR 12)n tW~ ~ (CR22)p-X
incorporated in the compounds of the instant invention is represented by 5 other than a .substituted imidazole-containing group.
Thus, the intermediates whose ,synthesis are illustrated in Schemes hereinabove and other biheteroaryl intermediates obtained commercially or readily synthesized, can be coupled with a variety of aldehydes. The aldehydes can be prepared by standard procedures, such 10 as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75, from the appropriate amino acid.
Lithioheteroaryl chemistry may be utilized, as shown in Scheme 14, to incorporate the biheteroaryl moiety. Thus, a suitably substituted biheteroaryl N-lithio reagent is reacted with an aldehyde to provide 15 the C-alkylated instant compound XXI. Compound XXI can be deoxygenated by methods known in the art, such a.s 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, 20 hydrochloride or acetate salt, among others. The product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by 25 literature procedures.
If the biheteroaryl .subunit reagent is reacted with an aldehyde which also has a protected hydroxyl group, such as XXVI
in Scheme 15, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 15, 16). The alcohol can be 30 oxidized under standard conditions to e.(~. an aldehyde, which can , . , ~ .. , .. , . . . .. . , . .. ... _,, .
CA 022~0936 1998-09-28 W O 97136898 PCT~US97/05512 then be reacted with a variety of organometallic reagent.s such as 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 5 a variety of aldehydes to obtain secondary amines, such as XXXII
(Scheme 16), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethylbiheteroaryl such as XXXIII
(Scheme 17). Treating XXVI~I with 1 ,1 '-sulfonyldiimidazole and 10 sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXIII . The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXXIV .
In addition, the biheteroaryl subunit reagent can be reacted 15 with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 1~. When R' is an aryl group, XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI. Alternatively, the amine protecting group 20 in XL can be removed, and O-alkylated phenolic amines such as XLII
produced.
Schemes 19-22 illustrate synthe,se.s 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 25 for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.
Boc NHl R6 Boc NH CHO
1. catalytic HO ~ ~ 6 hydrogenation Boc NH )~1 2. CF3CO2H
--~ CH2CI2 NHBoc XXI
NH2~R6 co~c2cOz, ~ N~ R6 ~C HO
BocN H
\~ NaBH(OAc)3 NH2 Et3N, CICH2CH2CI
XXIII
-CA 02250936 l998-09-28 W O 97/36898 PCTrUS97/05512 SCHEME 14 (continued) BocNH~"~ CF3CO2H, ~=~ NH NaHCO3 ~~ XXIV
NH~ R6 ~NC
~=~ NH AgCN
~=N S~ R6 ,~
N ~ N~
~ XXV
~3 3 Et20 R6 BnOl BocNH CHO
XXVI
BnO~;S 20% Pd(oH)2 H2 NHBoc CH3CO2H
XXVII
HO~I N~ ~S CICOCOCI
NHBoc R6 (C2Hs)3N
XXVIII
.. , . . . ~ .. .. . ...... . . .. .. ... . ..
SCHEME 15 (continued) H~ R'MgX
N HBoc XXIX
R'~R6 NHBoc XXX
,=¦ N ~S CF3CO2H
HO ~\J 6 CH2CI2 NHBoc XXVIII
H~~~Ri 6 NaBH(OAc)3 XXXI
HO~ J
rH
R'CH2 XXXII
.. .. ..
W O 97/36898 PCT~US97/05512 - 6~ -~ NaH, DM F O~C
NHBoc XXVIII
R"SH
~I R6 CH30H
N
H X
R"S ,~JS
XXXIV
WO 97/368g8 PCT/US97/05512 SCHEME Ig HO~ 1) Boc20, K2C~3 HO~
~/ TH F- H20 ~ 2) CH2N2, EtOAc ,1~
H2NCO2H BocNH CO2CH3 XXXV XXXVI
HO~
LiAlH4 ~1~ R"'CH2X
THF l Cs2CO3 0-20~C BocNH CH2OH DMF
XXXVII
R"'CH20 R"'CH20 ~ pyrldine SO3, 1 BocNH CH2OH (C2H5)3N BocNH CHO
XXXVIII IXL
W O 97/36898 PCTrUS97/05512 SCHEME I g (continued) ~3 + i~e~R6 BocNH CHO
IXL ~\R"' not aryl 1. Et20 1. Et20 2. 20% Pd(OH)2, H2 CH30H, CH3CO2H
~ R2 3. HCI, EtOAc R"'C H20~ ~ R 6 NHBoc 1) 20% Pd(OH)2, H2 CH30H, CH3CO2H
R cH20 / -- ~ r R6 /~\ ~ XLII
HO~ R6 NH2 ' R2 XLI
~CH3 1) HNo2~Br2 ~CO2cH3 1~ ~ 2) KMnO4 H2N N 3) MeOH, H+ Br N
~\~\MgCI R6 Zncl2lNicl2(ph3p)2 CO2CH3 NaBH4 (excess) ~ CH20H
DMSO ~ 3,CHo .......... ~ . ... . ~ . .. . . . , . . . ~
1. EtO(CO)CI R6 Zn Cl/CN ~CO~CH3 N 3. S, xylene, heat N
NaBH4 ~j~ SO3Py, Et3N ~
(excess) [~,CH20H DMSO ~CHO
Br~l,C02CH3 [~
N ~ CO2C H3 ZnCI2, NiC12(Ph3P)2 N~
NaBH4 T S03 Py Et3N 1' (excess) \~ DMSO ~3,CHO
Br~31. LDA, CO2 Br~
N2. MeOH, H+ N
R6 MgCI 1~ CO2CH3 ZnCI2, NiC12(Ph3P)2 N
~/1 NaBH4 (excess) ~20H SO3 Py, Et3N
~ ~I DMSO
N
1~~
..... . . .. . .... . . . . . . . .. . .
WO 97t36898 PCT/US97/05512 [~ 1 . LDA, CO2 [~ Br 2. (CH3)3sicHN2 R6 ~/\Br R6 ~
N ~C02CH3 Zn, NiCI2(Ph3P)2 R6 ~
excess NaBH4 ~1~ SO3-Py, Et3N
N~CH20H DMSO
R6 r~
N ~,CHO
~, CA 022~0936 1998-09-28 W O 97/36898 PCTnUS97105512 The instant compounds are useful as pharmaceutical agents for m~mm~ls, especially for humans. These compounds may be ~dministered to patients for use in the treatment of cancer. Example~s 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, lck, 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 compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-45P~0 (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 form) with said inhibition being accompli,shed by the a-lministration of an effective amount of the compounds of the invention to a m~mm;~l in need of such treatment. For example, a component of NF- 1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also u~seful 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.
.. . .... .. . . ....
CA 022~0936 1998-09-28 American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (19~
The instant compounds may also be useful for the treatment of fungal infections.
S The compounds of this invention may be administered to m~mm~ls, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For oral use of a chemotherapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral ~dministration in cap.sule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are re4uired for oral use, the active ingredient is combined with emulsifying and suspending agent.s.
If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use sterile solution~s 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-~dministered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be useful in - combination with known anti-cancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF- 1, restinosis, polycy~stic CA 022~0936 1998-09-28 kidney disease, infections of hepatiti.s 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 S 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 a-lmini~tration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and 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 bolu,s injection.
As used herein, the term "composition" is intended to encompas,s a product comprising the specified ingredients in the specific 20 amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention i,s admini~tered 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 as the severity of the patient's symptoms.
In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg 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 CA 022~0936 1998-09-28 W O 97/36898 PCT~US97/OS512 quantity of farnesyl-protein transferase (FPTase) in a composition.
Thu,s 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 immuno-10 logical, radiochemical or chromatographic techniques. Becausethe compound.s of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay 15 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 farne~syl-protein transferase and quantitat-20 ing the enzyme. Thus, potent inhibitor compoundls of the instantinvention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A serie~s of samples composed of aliquots of a tissue extract cont~ining 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.
CA 022~0936 1998-09-28 EXAMPLES
Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species 5 and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.
10 1-(2-rThien-2-yllpyrid-~S-ylmethyl)-5-(4-cyanobenzyl)imidazole.
Step A: 2-Trifluoromethanesulfonvloxv-5-pyridinecarboxylic acid To a .solution of 2-hydroxy 5-pyridinecarboxylic acid (1~5 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 15 mmol) in dichloromethane (7 mL) at -7~~C is added trifluoromethane-sulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -7~~C for 1 hour and then at ambient temperature for 1 hour. The reaction is diluted with water and extracted with CH2C12, and the organic extract is dried, (MgSO4) and the solvent is evaporated in 20 vacuo. The residue is purified by chromatography to afford the title compound.
Step B: 2-(Thien-2-yl)-5-pyridinecarboxylic acid A mixture of 2-trifluoromethane.sulfonyloxy-5-pyridine-25 carboxylic acid (0.442 g, 1.72 mmol), 2-thienylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (0.~13 mg, 2.5~ mmol), DME (~ mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenyl-phosphine) palladium(0) (99.0 mg, 0.0~6 mmol) is added, and the resultant .solution i.s stirred at ~0 ~C for 4 hours. The solvents are 30 evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc.
- The organic extracts are combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) and the solvent is evaporated in . , , . ... . . , .. , . ., ~ ., .
CA 022~0936 1998-09-28 - ~0 -vacuo. The residue is purified by chromatography to afford the title compound.
Step C: 2-(Thien-2-yl)-5-hydroxymethylpyridine To a solution of 2-(thien-2-yl)-5-pyridinecarboxylic acid (0.333 g, 1.60 mmol) in THF (5 mL) at 0~C is added 1.0 M lithium aluminum hydride in diethyl ether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction is allowed to stir at ambient temperature for 3 hours, cooled to 0~C, and water (0.10 mL), 4 N aq. NaOH (0.10 mL), 10 and water (0.30 mL) are added sequentially. The reaction is filtered through a pad of Celite and the filtrate i,s evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Step D: 1 -(2-(Thien-2-yl) pyrid-5-ylmethyl)-5-(4-1 5 cyanobenzyl)imidazole To a solution of 2-(thien-2-yl)-5-hydroxymethylpyridine (255 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -7~~C is added trifluoromethane-sulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at 20 -7~~C for 1 hour. To this mixture is added a solution of l-trityl-4-(4-cyanobenzyl)-imidazole (566mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and the 25 solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.
CA 022~0936 1998-09-28 W O 97/36898 PCT~US97/05512 N- { 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl)methyl } -5-(thien-2-yl)-2-amin o -pyrimidine s Step A: 5-(Thien-2-yl)-2-aminopyrimidine A mixture of 2-amino-S-bromopyrimidine (0.299 g, 1.72 mmol), 2-thienylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME (P~ mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenyl-phosphine) palladium(0) (99.0 mg, 0.086 mmol) is added, and the resultant solution is stirred at 80~C
for 4 hours. The solvents are evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is .separated, and extracted with EtOAc. The organic extracts are combined, washed with sat. a4. NaHCO3 and 5% aq- Na2s2o3 dried, (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Step B: l-Triphenylmethyl-4-(hydroxymethyl)imidazol To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in dry DMF (250 mL) at room temperature was added triethylamine (90.6 mL, 650 mmol). A white .solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in DMF (500 mL) was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Step C: I-Triphenylmethyl-4-(acetoxymethyl)imidazole The alcohol from Step B (260 mmol, prepared above) was - suspended in pyridine (500 mL). Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into EtOAc, washed sequentially with water, 5% aq. HCI solution, sat. aq. NaHCO3, .. . ~. . . . ... . . . .. .. ... .. ~
CA 022~0936 1998-09-28 solution, and brine. The organic extracts were dried, (Na2so4)~ and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction.
5 Step D: 1-(4-Cyanobenzyl)-S-(acetoxymethyl)imidazole hydrobromide A solution of the product from Step C (85.8 g, 225 mmol) and 4-cyano benzyl bromide (50.1 g, 232 mmol) in EtOAc (500 mL) was stirred at 60~C for 20 hours, during which a pale yellow precipi-10 tate formed. The reaction was cooled to room temperature and filteredto provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume (200 mL), heated at 60~C for 2 hours, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to a volume (100 mL), heated at 60~C for 2 15 hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in methanol (500 mL), and warmed to 60~C. After 2 hours, the solution was concentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble by products. Removal of 20 residual solvents in vacuo provided the titled product as a white .solid which was used in the next step without further purification.
Step E: I -(4-Cyanobenzyl)-S-(hydroxymethyl)imidazole To a solution of the acetate from Step D (50.4 g, 150 25 mmol) in 3:1 THF/water (1.5 L) at 0 ~C was added lithium hydroxide monohydrate (18.9 g, 450 rnmol). After lhour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo t~ provide the crude 30 product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
CA 022~0936 1998-09-28 W O 97/36898 PCTrUS97/OSS12 - ~3 -Step F: 1 -(4-Cyanobenzyl)-5-(chloromethyl)imidazol A solution of 1-(4-cyanobenzyl)-5-(hydroxymethyl) imidazole (l.OOg, 4.70 mmol), in thionyl chloride (5 mL), was stirred at 70~C for 16 hours. The solvent was evaporated in vacuo and the resulting solid suspended in CH2cl2~ collected by filtration and dried in vacuo. The material was sufficiently pure for use in the next step without further purification.
lH NMR (CD30D 400MHz) ~ 9.06 (lH, s), 7.~3(2H, d, J=~.OHz), 7.77(1H, s), 7.55(2H, d, J=~.OHz), 5.67(2H, s) and 4.7P~(2H, s) ppm.
Step G: N-{ 1-(4-Cyanobenzyl)-lH-imidazol-5-yl)methyl}-5-(thien-2-yl)-2-aminopyrimidine To a solution of the chloride from step F (500mg, 1.65 mmol) in DMF (10 mL) at 0~C is added sequentially, the amine from step A (292mg, 1.65 mmol) and sodium hydride (145mg, 60%
dispersion in mineral oil, 3.62 mmol). Stirring is continued at 0~C for 1 hour and then at room temperature for 16 hours. The reaction is 4uenched with water (50 mL), and extracted with CH2C12. The organic extracts are dried, (MgS04), and the solvent is evaporated in vacuo.
The residue is purified by chromatography to afford the title compound In vitr~ inhibition of ras farnesyl transferase Assays offarnesyl-protein transfera~e. Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et ah, J. Biol. Chem. 265:14701-14704 (1990), Pompliano, etah, Biochemistry 31:3~00 (1992) and Gibbs et ah, PNAS U.S.A. ~6:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 111 containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH
- 7.4, 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM ~3H]-farnesyl diphosphate ([3H]-FPP; 740 CB4/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ~g/ml FPTase at 31 ~C for 60 min. Reactions CA 022~0936 1998-09-28 were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ,13-plate counter. The assay was linear with respect to both S substrates, FPTase levels and time; less than 10% of the ~3H~-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 10 when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ,UM ZnCI2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ~1 of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention are tested for inhibitory activity against human FPTa.se by the assay described above.
EXAMPLE~ 4 In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75%
confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0. I %). 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 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are Iysed in 1 ml lysis buffer ( I % NP40/20 mM HEPES, pH 7.5/5 CA 022~0936 1998-09-28 ~5 _ mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 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 of acid-precipitable counts are bought to 1 ml with IP buffer (Iysis S buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et ah, J. Virol. 43:294-304, (19~S2)). 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
is added for 45 min. The immunoprecipitates are washed four times 10 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 autoradiographed. The intensities of the band,s corresponding to 15 farnesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
20 ln vivo growth inhibition assay To determine the biological conse4uences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-m~s oncogene is tested. Cells transformed by v-Raf 25 and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's 30 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 methanol at 1000 times the final concentration u.sed in the assay).
. , .. . . , . . . ~ . . . .
CA 02250936 l998-09-28 W O 97/36898 PCTrUS97/05512 The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound.
Photomicrographs are taken 16 days after the cultures are seeded a nd comparisons are made.
Claims (28)
1. A compound which inhibits farnesyl-protein transferase of the folmula A:
wherein:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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-, R11S(O)m-, R10C(O)NR 10, R11C(O)O-, (R10)2NC(O)-, R102N-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)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 R10OC(O)-NR10-;
provided that when R3,R4 or R5is unsubstituted or substituted heterocycle, attachment of R3,R4 or R5 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6c and R6d 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)O-, R102 N-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-;
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, substituted 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)-, R102 N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-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)-, R10 2N-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) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, 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-, -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, attachrnent 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-;
mis 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and tis 0 or 1;
or a pharmaceutically acceptable salt thereof.
wherein:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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-, R11S(O)m-, R10C(O)NR 10, R11C(O)O-, (R10)2NC(O)-, R102N-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)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 R10OC(O)-NR10-;
provided that when R3,R4 or R5is unsubstituted or substituted heterocycle, attachment of R3,R4 or R5 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6c and R6d 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)O-, R102 N-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-;
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, substituted 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)-, R102 N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and c) C1-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)-, R10 2N-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) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 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, 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-, -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, attachrnent 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-;
mis 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and tis 0 or 1;
or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 of the formula A:
wherein:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
provided that when R3, R4 or R5 is unsubstituted or substituted heterocycle, attachment of R3, R4 or R5 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6c and R6d 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)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
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, 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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
provided that when R3, R4 or R5 is unsubstituted or substituted heterocycle, attachment of R3, R4 or R5 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6c and R6d 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)-, R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-;
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, 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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or sub,stituted 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-;
provided that when R3 or R4 is unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6C and R6d 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-;
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 or2;
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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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 and R4 are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or sub,stituted 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-;
provided that when R3 or R4 is unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6C and R6d 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-;
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 or2;
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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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 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)-, 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-;
provided that when R3 or R4 is unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6c and R6d 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)-, 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-;
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)NR 10-, -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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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 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)-, 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-;
provided that when R3 or R4 is unsubstituted or substituted heterocycle, attachment of R3 or R4 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R6a, R6b, R6c and R6d 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)-, 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-;
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)NR 10-, -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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
R1 is independently 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)-, 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-;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a R6b, R6c and R6d 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-C1 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-;
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, ethyl, cyclopropyl 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;
m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
wherein:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
R1 is independently 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)-, 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-;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a R6b, R6c and R6d 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-C1 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-;
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, ethyl, cyclopropyl 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;
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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R 10O-, -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)-, 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-;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a, R6b, R6c and R6d 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-, R1OC(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)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR 10-;
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)NR 10-, 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, ethyl, cyclopropyl 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; 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, provided that p is not 0 if X is a bond or O;
or a pharmaceutically acceptable salt thereof.
wherein:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
R1 is independently selected from: hydrogen, C3-C10 cycloalkyl, R 10O-, -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)-, 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-;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a, R6b, R6c and R6d 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-, R1OC(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)-, R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR 10-;
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)NR 10-, 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, ethyl, cyclopropyl 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; 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, 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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
R1 is independently 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)-NR 10-;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-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 sub,stituted 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)-NR 10-;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl 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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, and the remaining f's are independently CH;
R1 is independently 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)-NR 10-;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6C and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-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 sub,stituted 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)-NR 10-;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl 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:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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 or heterocycle, 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-;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6c and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-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-;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl 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 the pharmaceutically acceptable salts thereof.
wherein:
a is N or C;
from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S;
from 1-2 of f(s) are independently N, 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 or heterocycle, 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-;
provided that when R3 is unsubstituted or substituted heterocycle, attachment of R3 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6c and R6d are independently selected from:
a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-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-;
R9a and R9b are independently hydrogen, ethyl, cyclopropyl 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 the pharmaceutically acceptable salts thereof.
9. A compound which inhibits farnesyl-protein transferase which is:
1-(2-[Thien-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole.
or N-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-5-(thien-2-yl)-2-amino-pyrimidine or a pharmaceutically acceptable salt or optical isomer thereof.
1-(2-[Thien-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole.
or N-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-5-(thien-2-yl)-2-amino-pyrimidine or a pharmaceutically acceptable salt or optical isomer thereof.
10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 1.
11. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 3.
12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 4.
13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of Claim 9.
14. 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 10.
15. 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 11.
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 treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10.
19. A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 11.
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 neurofibromin benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10.
23. 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 10.
24. 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 10.
25. A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of Claim 10.
26. 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 10.
27. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier.
28. 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 | ||
| GBGB9613462.2A GB9613462D0 (en) | 1996-06-27 | 1996-06-27 | Inhibitors of farnesyl-protein transferase |
| GB9613462.2 | 1996-06-27 | ||
| US2234296P | 1996-07-24 | 1996-07-24 | |
| US60/022,342 | 1996-07-24 | ||
| GBGB9617280.4A GB9617280D0 (en) | 1996-08-16 | 1996-08-16 | Inhibitors of farnesyl-protein transferase |
| GB9617280.4 | 1996-08-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2250936A1 true CA2250936A1 (en) | 1997-10-09 |
Family
ID=27451476
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002250936A Abandoned CA2250936A1 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0891357A1 (en) |
| JP (1) | JP2000507595A (en) |
| AU (1) | AU715606B2 (en) |
| CA (1) | CA2250936A1 (en) |
| WO (1) | WO1997036898A1 (en) |
Families Citing this family (22)
| 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 |
| AU1612099A (en) * | 1997-12-04 | 1999-06-16 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US6627629B2 (en) | 2000-06-30 | 2003-09-30 | Bristol-Myers Squibb Pharma | N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity |
| FR2819509B1 (en) | 2001-01-18 | 2004-04-16 | Servier Lab | NOVEL CYCLOHEPTENE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2819511A1 (en) * | 2001-01-18 | 2002-07-19 | Servier Lab | New N-substituted azepane or azepanone derivatives, are selective farnesyl transferase inhibitors useful for treating cancer diseases, restenosis or type I neurofibromatosis |
| US6992087B2 (en) | 2001-11-21 | 2006-01-31 | Pfizer Inc | Substituted aryl 1,4-pyrazine derivatives |
| EP1499599A1 (en) | 2002-04-26 | 2005-01-26 | Pharmacia & Upjohn Company LLC | Substituted pyrazine derivatives |
| JP2006525993A (en) | 2003-05-09 | 2006-11-16 | ファルマシア・アンド・アップジョン・カンパニー・エルエルシー | Compounds that are CRF1 receptor antagonists |
| EP1628666B1 (en) | 2003-05-14 | 2015-09-23 | NeuroGenetic Pharmaceuticals, Inc. | Compouds and uses thereof in modulating amyloid beta |
| DK2007752T3 (en) | 2006-03-31 | 2010-11-15 | Janssen Pharmaceutica Nv | Benzimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor |
| UY30892A1 (en) | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | AKT ACTIVITY INHIBITORS |
| UA103319C2 (en) | 2008-05-06 | 2013-10-10 | Глаксосмитклайн Ллк | Thiazole- and oxazole-benzene sulfonamide compounds |
| US9371311B2 (en) | 2008-06-30 | 2016-06-21 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine derivatives |
| TW201100398A (en) | 2009-03-31 | 2011-01-01 | Arqule Inc | Substituted indolo-pyridinone compounds |
| EP2560488B1 (en) | 2010-04-23 | 2015-10-28 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
| AR081331A1 (en) | 2010-04-23 | 2012-08-08 | Cytokinetics Inc | AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME |
| AR081626A1 (en) | 2010-04-23 | 2012-10-10 | Cytokinetics Inc | AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS |
| CN105025898B (en) | 2013-03-06 | 2018-01-23 | 詹森药业有限公司 | Histamine H4The yl pyrimidines conditioning agent of benzimidazole 2 of acceptor |
| CA3077383A1 (en) | 2017-09-29 | 2019-04-04 | Sunshine Lake Pharma Co., Ltd. | Substituted pyrimidine piperazine compound and use thereof |
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 CA CA002250936A patent/CA2250936A1/en not_active Abandoned
- 1997-04-01 AU AU26057/97A patent/AU715606B2/en not_active Ceased
- 1997-04-01 WO PCT/US1997/005512 patent/WO1997036898A1/en not_active Application Discontinuation
- 1997-04-01 JP JP9535589A patent/JP2000507595A/en active Pending
- 1997-04-01 EP EP97917829A patent/EP0891357A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU2605797A (en) | 1997-10-22 |
| JP2000507595A (en) | 2000-06-20 |
| AU715606B2 (en) | 2000-02-03 |
| EP0891357A1 (en) | 1999-01-20 |
| WO1997036898A1 (en) | 1997-10-09 |
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