Title of Invention

FARNESYL PROTEIN TRANSFERASE INHIBITORS AS ANTITUMOR AGENTS

Abstract Disclosed are novel tricyclic compounds represented by the formula (1.0) and a pharmaceutically acceptable salt or solvate thereof. The compounds are useful for inhibiting farnesyl protein transferase. Also disclosed are pharmaceutical compositions comprising compounds of formula 1.0. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
Full Text BACKGROUND
WO 95/10516, published April 20,1995 and WO 97/23478, published July 3, 1997 disclose tricyclic compounds useful for inhibiting farnosyl protein transferase.
WO 98/54966 published December 10,1998 discloses methods of treating cancer by administering at least Iwo therapeutic agents selected from a group consisting of a compound which is an antineoplastic agent and a compound which is an inhibitor of prenyl-protein transferase (e.g., a famesyl protein transferase inhibitor).
Farnesyi Protein Transferase (FPT) Inhibitors are i Shih et al., "The famesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo", Cancer Chemother Pharmacol (2000) 46; 387-393 discloses a study of the combination of SCH 66336 with paclitaxel, and SCH 66336 with docetaxel on certain cancer cell lines.
WO 01/45740 published June 28,2001 discloses a method of treating cancer (breast cancer) comprising administering a selective estrogen receptor modulator (SERM) and at least one famesyl transferase inhibitor (FTl). FTI-277:]s the exemplified FTL
The WEB site http://wvw..osip.com/press/p,r/Q7-25:01 discloses a press release of OSI Pharmaceuticals. The press release announces the initiation of a Phase HI clinical trial evaluating the use of the epidermal growth factor inhibitor Tarceva (TW) (OSI-774) In combination with Caitoplatin (Paraplatinf®) and Paclitaxel (Taxol®) for the treatment of Non Small Cell Lung Cancer
The WEB site httD://cancertrials-nci-nih.oov/tvpe3/lunQfiressa12100.Jltrril in a disclosure posted 12/14/00 discloses the following list of open clinical trials for

advanced (stage IIIB and IV} non-smalt ceil lung cancer, from NCI"s clinical trials database;
(1) phase ill Randomized Study of 2D 1839 (IRESSA, an epidermal growth factor inhibitor) combined with gemcitabine and cisplatin in chemotherapy-naive patients with Stage IIIB or IV non-small cell lung cancer; and
(2) phase IK Randomized Study of ZD 1839 (IRESSA, an epidermal growth factor inhibitor) combined with paclitaxel and carbop)atin in chemotherapy-naive patients with Stage IIIB or IV non-small cell lung cancer.
WO 01/56552 published August 9,2001 discloses the use of an FPT inhibitor for the preparation of a pharmaceutical composition for treating advanced breast cancer. The FPT inhibitor may be used in combination with one or more other treatments for advanced breast cancer especially endocrine therapy such as an antiestrogen agent such as an estrogen receptor antagonist {e.g., tamoxifen) or a selective estrogen receptor modulator or an aromatase inhibitor. Other anti-cancer agents which may be employed include, amongst others, platinum coordination compounds (such as cisplatin orcarboplatin), taxanes (such as paclitaxel or docetaxel), anti-tumor nucleoside derivatives (such as gemcitabine), and HER2 antibodies (such as trastzumab).
WO 01/62234 published August 30, 2001 discloses a method of treatment and dosing regimen for treating mammalian tumors by the discontinuous administration of a famesyl transferase inhibitor over an abbreviated one to five day dosing schedule. Disclosed is a regimen wherein the famesyl protein transferase inhibitor is administered over a one to five day period followed by at least two weeks without treatment. It is disclosed that in previous studies famesyl protein transferase inhibitors have been shown to inhibit the growth of mammalian-tueoors when administered as a twice daily dosing schedule. It is further disclosed that ttie administration of a famesyl protein transferase inhibitor in a single dose daily for one to five days produced a marked suppression of tumor growth tasting one to at least 21 days. It is also disclosed that the FTl may be used in combination with one or more other anti-cancer agents such as, platinum coordination compounds (e.g.. cisplatin or "^ carboplatin), taxane compounds (e.g., paclitaxel or docetaxel). anti-tumor nucleoside derivatives (e.g., gemcitabine), HER2 antibodies (e.g., trastzumab). and estrogen receptor antagonists or selective estrogen receptor modulators (e.g., tamoxifen).

wo 01/64199 published September?, 2001 discloses a combination of particular FPT inhtbitors with taxane compounds (e.g., paclitaxel or docetaxel) useful in the treatment of cancer.
!n view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
SUMMARY OF THE INVENTION
This invention provides compounds usefiji for the inhibition of farnesyl protein transferase (FPT). The FPT inhibitor compounds of this invention are represented by the formula:

or a pharmaceuticaily acceptable salt or solvate thereof, wherein:
one of a, b. c and d represents N or N*0", and the remaining a, b, c, and d
groups represent cartson, wherein each cartxin has an R" or R^ group bound to said
carbon; or " "-
each of a, b, c, and d is carbon, wherein each carbon has an R" or R^ group bound to said carbon;
the dotted line (—) represents optional bonds;
X represents N or CH when the optional bond (to Cl 1) is absent, and represents C when the optional bond (to C11) is present;
when the optional bond is present between carbon atom 5 (i.e., 05) and catbon atom 6 (i.e., C-6) (i.e., there is a double bond between C-5 and C-6) then there

is only one A substituent bound to C-5 and there is only one B substituent bound to C-6. and A or B is other than H;
when the optional bond is not present between carbon atom 5 and carbon atom 6 (i.e., there is a single bond between C-5 and C-6) then there are two A substituents bound to C-5, wherein each A substituent is independently selected, and two B substituents bound to C-6, wherein each B substituent is independently selected, and wherein at least one of the two A substituents or one of the two B substituents is H, and wherein at least one of the two A substituents or one of the two B substituents is other than H, (i.e., when there is a single bond between C-5 and C-6 one of the four substituents (A, A, 8, and B) is H and one is other than H);
A and B are independently selected from the group consisting of:
(1) -H;
(2) -R";
(3) -R^-C(0)-R^;
(4) - R^-COz- R^;
(5) -(CH2)pR^;
(6) -C(0)N(R^)2. wherein each R^ is the same or different;
(7) -C{0)NHR^;
(8) -C(0)NH-CH2-C(0)"NH2;
(9) -C(0)NHR^^
(10) -(CH2)pC(R^>0-R^;
(11) -(CH2)p.iCH(R^)2. provided that p is not 0, and wherein each R^ is the same or different;
(12) -(CH2)pC(0)R^-
(13) -(CH2)pC(0)R"^
(14) -(CH2)pC{0)N(R^)2. wherein each R^ is the same or different;
(15) -(CH2)pC(0)NH(R");
(16) "(CH2)pC(0)N(R2^)2. wherein each R^^ is the same or different;
(17) "(CH2)pN(R^)-R^, (e.g. -CH2-N(CH2-pyrid(ne)-CH2-imidazoIe);

(18) -(CH2)pN(R^^)2, wherein R^^ is the same or different (e.g., ~ (19) -(CH2)pNHC(0)R^°;
(20) -{CH2)pNHC(0)2R^;

(21) -{CH2VN(C(0)R^"^)2 Wherein each R^"^ is the same or different;
(22) -(CH2}pNR^"C(0)R^^
(23) -{CH2)DNR^^C(0)R^^ wherein R^" is not H. and R^" and R^^ taken
together with the atoms to which they are bound form a 5 or 6 membered
heterocycioalkyi ring consisting;
(24) -(CH2)pNR^"C(0)NR^";
different;
(25) -(CH2)pNR^"C(0)NR^^ wherein R^^ is not H, and R^" and R^^ taken together with the atoms to which they are bound form a 5 or 6 membered heterocycioalkyi ring;
(26) -(CH3)pNR^"C(0)N(R"")2, wherein each R"^ is the same or
(27) -(CH2)pNHS02N(R^")2, wherein each R^" is the same or different;
(28) -(CH2)pNHC0;R^,
(29) -(CH2)pNC(0)NHR^^:
(30) "(CH2)pC02R=":
(31) -NHR^:
{32)

-{CH,)p4-c-
Wherein R- ^nd R3" are the same or different, and each p is independently selected-provided that for each



group When one of R- cr R- is selected from the gro.p consisting "of: -OH =0 -OR . -NH. -NHR- -.(R.,, .,3, .,HR. ,„, _,,,.,,. ,,^„ ,^^ ^^^^^^^^ ^3„
R .3 selected from the group consisting of: H, al.yi, a^i (e.g., phenyl,, and a^a.^ (e.g., benzyl);
(33)
-(CH2)p-C C-R^
R31 ,,33

wherein R^°. R^\ R^^ and R^^ are the same or different; provided that when one of R^° or R^" is selected from the group consisting of: -OH, =0, -0R^^ -NH2, -NHR3^ -N(R^^)2, -N3, -NHR^^ and -N(R^)R^^ then the remaining R^" or R^" is selected from the group consisting of; H, aikyl, aryl (e.g., phenyl), and aryialkyl (e.g., benzyl); and provided that when one of R"^^ or R^ Is selected from the group consisting of: -OH, =0, -OR^, -NH2, -NHR^, -N(R^)2. -N3. -NHR^. and -N(R^^)R°^ then the remaining R""^ or R"^"" is selected from the group consisting of: H, aikyl. aryl (e.g., phenyl), and arylalkyi (e.g., benzyl);
(34) -alkeny1^C02R^;
(35) -aikenyl-C(0)R^^
(36) -aikenyl-COzR^";
(37) -alkenyi-C(0>-R"^
(38) (CH2)p-alkenyl-C02-R^"; (37) -(CH2)pC=N0R^^ and
(39) -(CH2)p-phthalimld;
pisO, 1,2,3 or 4;
each R^ and R^ is Independently selected from the group consisting of: (1) H;

(2) Halo;
(3) -CF3.
(4) -OR"°:
(5) -COR^°.
(e) -SR":
(7) -S(0)tR^^ whe
(3) -N(R\;
(9) -NO2;
(10) -oc(0)R^°:
(11) 10
"COjR ;
(12) "0C02R^^
(13) -CN;
(14) .NR^°C00R^=

(15) -SR"^C(0)OR"^
(16) -SR^^N{R"\ provided that R^^in -SR"^N(R"\ is not -CH^ and wherein each R" is independently selected from the group consisting of: H and
-C(0)OR"^:
(17) benzotriazol-1-yloxy;
(18) tetrazoI-5-ylthio;
(19) substituted tetrazol-5-ylthio;
(20) alkynyl;
(21) alkenyl;and
(22) alkyl,
said alkyl or alkenyl group optionally being substituted with halogen, -OR or
)0
-CO^R ;
R and R are the same or different and each independently represent H, and any of the substituents of R and R ;
R , R . R and R ^ each independently represent: H, -CF3, -COR . alkyl or aryl.
15 10 15 10
;aid alkyl or aryl optionally being substituted with-S(0),R .-NR COOR .-C(0)R ,
jr-COjR ,orR is combined with R to represent =0 or =S; R^ is selected from the group consisting of:


,R" O=S=O ,JS, ^R"^
R" I
H, O^^O"" " I., > 0^ N" O^^^C-R^

R12 and
(2.0) (3.0) (4.0) (5.0)
R^ is selected from the group consisting of:
(1) unsubs^tuted heteroaryl;
(2) substituted heteroaryl;
(3) aryialkoxy;
(4) substituted arylalkoxy;
(5) heterocycloalkyi;
(6) substituted heterocycloalkyi;
(7) heterocycloalkylalkyi;
(8) substituted heterocycloalkylalkyi;

(9) unsubstituted heteroarylalkyl;
(10) substituted heteroarylalkyl;
(11) unsubstituted heteraarytalkeny!;
(12) substituted hetecoatvlaikenyl;
(13) unsubstituted heteroaryialkynyl; and
(14) substituted heteroaryialkynyl;
wherein said substituted R^ groups are substituted with one or more (e.g.. 1, 2 or 3) substituents selected from the group consisting of;
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carlDon atom (i.e., only one -OH group can be bound to a carbon atom);
(2) -COjR^":
(3) -CH20R"^
(4) halogen (e.g., Br, CI or F),
(5) alkyl (e.g. methyl, ethyl, propyl, butyl or t-butyl);
(6) amino;
(7) trityl;
(8) heterocycloalkyi;
(9) cycloaikyi, (e.g., cyclopropyl or cydohexyl);
(10) arytalkyi;
(11) heteroaryl;
(12) heteroar^alkyl and

(13)
wherein R" is independently selected from: H; alkyl; aryl, aryfalk^i heteroaryl and heteroarylalkyi;
R^ is selected from the group consisting of: alky and arylalkyi;
R^"" is selected from the group consisting of:
(1) -C(0)R"^
(2) -SOzR^;
(3) -C(0)NHR^;
(4) -C(0)dk^^ and
(5) -C(0)t^(R^)2;

Each R^ is independently selected from the group consisting of: H, alkyl and arylalkyi;
R^° is selected from the group consisting of: H; alkyl; aryl and arylalkyi; R^^ is selected from the group consisting of:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyl;
(6) substituted cycloalkyl;
(7) unsubstituted heteroaryl;
(8) substituted heteroaryl;
(9) heterocydoaikyl;
(10) substituted heterocydoaikyl;
(11) unsubstftuted alkenyl {e.g., -CH2CH=CH2);
(12) -N(alkyl}2 wherein each alkyl is independently selected (e.g.,
-N(CH3}2);
(13) unsubstituted arylalkyi; and
(14) substituted arylalkyi;
wherein said substituted alky) R"*"* groups are substituted with one or more (e.g. 1. 2 or 3) substituents selected from the group consisting of:
(1) -OH, provided that when there is more than one-OH group then each -OH group is bound to a different carbon atom (i.e., only one -OH group can be bound lo a carbon atom);
(2) halogen (e.g.. Br. CI or F); and
(3) -CN; and
wherein said substituted cycloalkyl, and substituted heterocydoaikyl R" groups are substituted with one or more (e.g. 1, 2 or 3) substituents selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carfxin atom (i.e., only one -OH group can be bound to a carbon atom);
(2) halogen (e.g., Br. CI or F); and

(3) alkyi; and wherein said substituted aryl, substituted heteroaryl and the aryi moiety of said substituted arylalkyl R" groups are substituted with one or more (e.g. 1, 2 or 3) substituenls independently selected from the group consisting of;
(1) -OH, provided that when ttiere is more than one -OH group then each "OH group is bound to a different carbon atom (i.e., only one -OH group can be bound to a carbon atom);
(2) halogen(e.g,. Br, ClorF);
(3) alkyi;
(4) -CF3;
(5) -ON; and
(6) alkoxy (e.g., -OCHa);
R"^ is selected from the group consisting of;
(1) H;
(2) OH;
(3) alkyi;
(4) substituted alky!;
(5) aryl;
(6) substituted aryl;
(7) unsubstituted cycloalkyi;
(8) substituted cycloalkyi;
(9) unsubstituted heteroar^^;
(10) substituted heteroaiyl;
(11) heterocycloalkyi;
(12) substituted heterocycloalkyi;
(13) -OR^;
(14) unsubstituted arylalkyl;
(15) substituted arylalkyl; (16} unsubstituted alkenyl;

(17) unsubstituted arylacyl (e.g., -C(0)phenyl);and
(18) unsubstituted heteroarylalkyi (e.g., -CHrpyridyl);
wherein said substituted alkyi R^"^ groups are substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from the group consisting of:
II

(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom (i.e.. only one -OH group can be bound to a carbon atom);
(2) -CM;
(3) -CF3;
(4) haiogen(e.g,. Br, ClorF);
(5) cycloalkyt;
(6) heterocydoalkyl;
(7) arylalkyi;
(8} heteroarylalkyl; and (9) heteroalkenyl; and wherein said substituted cycloalkyi, and substituted heterocycloalkyi R"^ groups are substituted with one or more (e.g. 1, 2 or 3) substituents independently selected from the group consisting of:
{1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom (i.e.. only one -OH group can be bound to a carbon atom);
(2) "ON;
(3) -CF3;
(4) halogen (e.g.. Br, CI or F);
(5) alkyl;
(6) cycloalkyi;
(7) heterocycloalkyi;
(8) arylalkyi;
(9) heteroarylalkyl;
(10) alkenyl;and
(11) heteroaIkenyl;and
wherein said substituted aryl, substituted heteroaryl and the aryl moiety of said substituted arylalkyi R^"^ groups have one or more (e.g. 1, 2 or 3) substituents independently selected from the group consisting of".
(1) -OH. providedthat when there is more than one-OH group then
each -OH group is bound to a different carbon atom (i.e., only one -OH group
can be bound to a carbon atom);

(2) -CN;
(3) -CFj;
(4) haiogen (e.g., Br, CI or F);
(5) alkyl;
(6) cycloalkyi;
(7) heterocycloaikyl; (8} arylalkyi;

(9) heteroarylalkyl;
(10) atkenyi;
(11) heteroalkenyl;
(12) aryloxy (e.g.. -0-phenyl); and
(13) alko)cy(e.g.,"OCH3);
R^^ is selected from the group consisting of: H. alkyl, pipendine Ring V, cycloalkyl. and -alky(-(piperidine Ring V) (wherein said pipendine Ring V is as described below, see, for example, paragraph (8) in the definition of R^\ R^ and R*^);
R"^ is selected from the group consisting of: alkyl and aryl;
R^", R^ and R""^ are independently selected from the group consisting of:
(1) -H;
(2) alkyl (e.g., methyl, ethyl, propyl, butyl ort-butyl);
(3) unsubstituted aryl, (e.g. phenyl);
(4) substituted aryl substituted with one or more substituents independently selected from the group consisting oft alkyl, haiogen, -CF3 and OH;
(5) unsubstrtuted cycloalkyl, (e.g. cyclohexyl);
(6) substituted cycloalkyl substituted with onepr^more substituents independently selected from the group consisting of: alkyl, halogen, -CF3 and OH;
(7) heteroaryl of the fonnula.



and

(8) heterocycloalkyi of the formula:

N
(i.e., piperidine Ring V) wherein R"" is selected from the group consisting of:
(a) -H,
(b) alkyl. (e.g., rriethyt, ethyl, propyl, butyl or t-fautyl);
(c) alkylcarbonyl (e.g., CHaClO)-);
(d) alkyloxy carbonyl (e.g.. -C{0)0-t-C4H9, -C{0)OC2H5. and -C(0)0CH3};
(e) haloalkyi (e.g., trifluoromethyl); and
(0 ~C(0)NH{R^");
(9) -NH2 provided that only one of R^\ R^, and R^^ group can be -NH;, and provided that when one of R^\ R^, and R"^ is -NH2 then the remaining groups are not-OH;
(10) -OH provided that only one of R^". R^. and R""^ group can be -OH. and provided that vi/hen one of R^\ R^. and R**^ is -OH then the remaining groups are not-NH2; and
(11) alkyl substituted with one or more substituents (e.g., 1-3, or 1-2. and preferably 1) selected from the group consisting of: -OH and -NH2, provided that there is only one -OH or one -NH2 group on a substituted carbon;
(12) alkQxy(e.g.,-0CH3}; or
(13) R^^ and R^^ taken together with the carbon tO-Which they are bound form a cyclic ring selected from the group consisting of:

(a) unsubstituted cydoalkyi (e.g., cyclopropyl, cyclobutyl, cyclopentyi, and cyclohexyl);
(b) cydoalkyi substituted with one or more substituents independently selected from the group consisting of: alkyl. halogen, "CF3 and OH;
(c) unsubstituted cydoalkenyi



cydoalkenyl substituted with one or more substituents independently selected from the group consisting of: alkyf, halogen, -CFa and OH;
(e) heterocycloalkyl, e.g., a piperidyl ring of the formula:

N
wherein R*^ is selected from the group consisting of:
(1) -H,
(2) alkyi. (e.g., methyl, ethyl, propyl, buty) or t-butyl);
(3) alkylcarbonyi (e.g.. CH3C(0)-);
(4) alkyloxy carbonyl {e.g., -C(0)0-t-C4H9. -C(0)OC2H5, and-C(0)OCH3);
(5) haloalkyi (e.g., trtfluoromethyl); and
(6) -C(0)NH(R^^);
(f) unsubstituted aryl (e.g., phenyl);
(g) aryl substituted with one or more substituents independently selected from the group consisting of: aikyl (e.g., methyl), halogen (e.g., CI. Br and F), -CN, -CFs, OH and alkoxy (e.g.. methoxy); and
(i) heteroaryl selected from the group coosistlng of:


and
R^"^is selected from the group consisting of:
(1) -H;
(2) aikyi (e.g., methyl, ethyl, propyl, butyl or t-butyl);
(3) alkoxy (e.g., methoxy. elhoxy, or propoxy);
(4) -CH2-CN;

(5) R":
(6) -CHzCOjH;
(7) -C(0)a!ky1: and
(3) CHsCOsalkyI:
R^^ is selected from the group consisting of:
(1) -H;
(2) -OH;
(3) alkyl (e.g., methyl, ethyl, propyl, or butyl); and
(4) alkoxy;
R"^ is selected from the group consisting of:
(1) alkyf (e.g. methyl, ethyl, propyl, or butyl); and
(2) alko)cy;
R^°. R^", R^^and R^ are independently selected from the group consisting of;
0) -H;
(2) -OH;
(3) -O;
(4) alkyl;
(5) aryl (e.g.. phenyl);
(6) arylalky! (e.g., benzyi);
(7) -OR^";
(8) -NHz;
(9) -NHR^;
(10) -N(R^)2 wherein each R^^ is independently selected;
(11) -Ms;
(12) -NHR^;and
(13) -N(R^)R^"=;
R^ is selected from the group consisting of:
(1) alkyl;
(2) unsubstituted heteroaryl;
(3) substituted heteroary; and
(4) amino;

wherein said substituents on said substituted H^° groups are independently selected from the group consisting of; alkyl (e.g., methyl, ethyl, propyl, and butyl); halogen (e.g.. Sr, CI, and F); and-OH;
R^" is selected from the group consisting of: H, and alkyl (e.g., methyl, ethyl, propyl, butyl and t-butyl); and
provided that: ■ (1) a ring carbon atom adjacent to a ring heteroatom in a substituted heterocycloalkyl moiety is not substituted with a heteroatom or a halo atom; and
(2) a ring carbon atom, that is not adjacent to a ring heteroatom. in a substituted heterocyctoalkyi moiety, is not substituted with more than one heteroatom; and
(3) a ring carbon atom, that is not adjacent to a ring heteroatom. in a substituted heterocycloalkyl moiety, is not substituted with a heteroatom and a halo atom; and
(4) a ring carbon in a substituted cycloalkyi moiety is not substituted with more than one heteroatom; and
(5) a carbon atom in a substituted alkyl moiety is not substituted with more than one heteroatom; and
(6) the same carbon atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms; and
(7) when A and B are independently selected from the group consisting of substituents (1) to (31) and (34) to (39), then R^ Is not H; and
(8) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39). and R® is (2.0), then R"*^ is selected from the group consisting of substituents (11) to (14); and
(9} when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R^ is (3.0). then R" is selected from the group consisting of substituents (11) to (14); and
(10) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R° is (4.0), then: (a) R"^ is selected from the group consisting of substituents (13) to (18), and R^^ is as defined above. or(b) R^^^ is selected from the group consisting of substituents (1) to (12), and R"^ is selected from the group consisting of: cycloalkyi, piperidine Ring V and alky!-(piperidine Ring V), or

(C)R"^ is selected from the group consisting of substitutents (13) to (18). and R"^ is selected from the group consisting of: cycloalky). piperidlne Ring V and a!kyl-(piperidine Ring V); and
(11) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R^ is (5.0), then at least one of R^", R^, and R""^ is selected from the group consisting of substituents (8)(g), (8)(h). (9). (10), (i1), (12} and (13); and
(12) when at least one of A and B (preferably B) is subsUtutenl (32) or (33) (preferably (32)), and R"^" to R^^ are selected from the group consisting of substituents (1) to (6), then R° is selected from the group consisting of:

(a) (2.0) wherein R" is selected from substituents (11) to (14),
(b) (3.0) wherein R^^ is selected from substituents (11) to (14),
(c) (4.Q) wherein (i) R"^ is selected from the group consisting of substituents (13) to (18), and R^^ is as defined above for fomnula 1.0, or (ii) R^^^ Is selected from the group consisting of substitutents (1) to (12), and R^^ is selected from the group consisting of; cycloalkyi, piperidine Ring V and alkyl-(piperidine Ring V), or (iii) R"^^ is selected from the group consisting of substituents (13) to (18). and R^^ is selected from the group consisting of: cycloalkyi, piperidine Ring V and alkyl-(piperidine Ring V), and
(d) (5.0) wherein at least one of R^\ R^. and R**^ Is selected from the group consisting of substituents (8)(g), (8)(h), (9), (10), (11), (12) and (13); and
(13) when at least one of A and B (preferably B) is substitutent (32) or (33)
(preferably (32)), and at least one of R^ to R^^ is -NH2 (i.e., substituent (8)). and R^ is
(2.0), then R^ is not

0^ o ^ ;and
(14) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^*^ to R" is-N3 (i.e., substituent (11)), and R^is (2.0), then R^ is not


O^ X
This invention also provides pharmaceutical compositions comprising an effective amount of a compound of this invention (e.g., a compound of formula 1.0) and a pharmaceutically acceptable carrier.
This invention also provides a method of inhibiting famesyt protein transferase in a patient In need of such treatment comprising administering to said patient an effective amount of at least one (usually one) compound of this invention (e.g.. a compound of formula 1.0).
This invention also provides methods of treating (or inhibiting) tumors (i.e., cancers) in a patient in need of such treatrfTgntxomprreing-^dmhTisterTrigtcnsa^^ patient an effective amount of at least one (usually one) compound of this invention (e.g., a compound of formula 1.0).
This Invention also provides methods of treating (or inhibiting) tumors (I.e., cancers) In a patient in need of such treatment comprising administering to said patient an effective amount of at least one (usually one) compound of this invention (e.g.. a compound of formula 1.0) in combination with at least one chemotherapeutic agent (also know in the art as antineoplastic agent or anticancer agent).
This invention also provides methods of treating (or inhibiting) tumors (i.e.,
cancers) in a patient in need of such treatment comprising administering to said
patient an effective amount of at least one (usually one) compound of this invention
(e.g., a compound of formula 1.0) in combination with at least one chemotherapeutic
agent (also know in the art as antineoplastic agent or anticancer agent) and/or
radiafcn. _ ___
This invention also provides methods of treating (or inhibiting) tumors (i.e., cancers) in a patient In need of such treatment comprising administering to said patient an effective amount of at least one (usually one) compound of this invention (e.g., a compound of formula 1.0) in combination with at least one signal transduction inhibitor.
In the methods of this invention the compounds of this invention (e.g., a compound of formula 1.0) can be administered concurrently or sequentially (i.e., consecutively) with the chemotherapeutic agents or the signal transduction inhibitor.

DETAILED DESCRIPTION OF THE INVENTION
As descdbed herein, unless otherwise indicated, the use of a dmg or compound in a specified period (e.g., once a week, or once every three v/eeks, etc.,) is per treatment cycle.
As used herein, the following terms have the following meanings unless otherwise described;
AD HPLC is a HPLC column from Chiral Technologies;
AUOrepresents"Area Under the Curve";
BOC-represents tert-butyloxycarbonyl;
CBZ-represents -C(0)OCH2C6H5 (i.e., benzyloxycarbonyl);
CH2Ct2-represents dichloromethane;
CIMS-represents chemical ionization mass spectnjm;
Cmpd-represents Compound".
DBU-represents 1,8-Diazabicyclo[5.4.0]undec-7"ene:
DEAD-represents diethytazodicarboxylate;
DEC-represents EDCI which represents 1-(3-dimethy!-aminopropyt)-3-
ethylcarbodiimide hydrochloride;
DMF-represents N,N-^Jmethylformamide;
DPPA-represents diphenylphosphoryl azide
Et-represents ethyl;
EtaN-represents TEA which represents triethylamine;
EtOAc-represents ethyl acetate;
EtOH-represents ethanol;
FAB-represents FABMS which represents fast atom bornbardment mass
spectroscopy;
HOBT-represents 1-hydroxybenzotriazole hydrate;
HRMS-represents high resolution mass spectroscopy;
IPA-represents isopropanol;
i-PrOH-represents isopropanol;
Me-represents methyl;
MeOH-represents methanol;

MH""■-represents the molecular ion pius hydrogen of the molecule in the mass spectrum:
MS-represents mass spectroscopy;
NMM-represents N-methylmorpholine;
00 HPLC is a HPLC column from Chirai Technologies;
PPh^-represents triphenyi phosphine;
Ph-represents phenyl;
Pr-represents propyl;
SEM-represents2,2-{Trimethy(silyl)ethoxymethyl;
TBDMS-representstert-butyldimethylsiiyl;
t-BUTYL-represents -C-(CH3)3;
TFA-represents trifluoroacetic acid;
THF-represents tetrahydrofuran;
Tr-represents trityl;
Tf-represents SO2CF3;
at least one- represents one or more-(e.g. 1 -6 ), more preferrabiy 1 -4 with 1, 2 or 3 being most preferred;
alkenyl-represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2-12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms;
aikoxy-represenls an alkyl moiety, alkyl as defined below, covalently bonded to an adjacent stnjcturat element through an oxygen atom, for example, methoxy. ethoxy. propoxy. butoxy and the like;
alkyl-represents sU-alght and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms, more preferably one to four cartxin atoms; even more preferably one to two carbon atoms;
alkylcarbonyl- represents an alkyl group, as defined above, covalently bonded to a carbonyl moiely (-CO-), for example, -COCH3;
alkyfoxycarbonyi- represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (-CO-) through an oxygen atom, for example, -C(0>-OC2H5;

atkynyt-represents straight and branched cart>on chains having at least one carbon to carbon triple bond and containing from 2-12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 2 to 4 carbon atoms;
amino-represents an-NH2 moiety;
antineoplastic agent-represents a chemolherapeutic agent effective against cancer;
afyt-represents a carbocydic group containing from 6 to 15 carbon atoms in the unsubstituted cartiocydic group and having at least one aroma^c ring (e.g., aryl is a phenyl ring), with al! available subsUtutable carbon atoms of the carbocydic group being intended as possible points of attachment of said aryl group, said aryl group being unsubstituted or substituted, said substituted aryl group having one or more (e.g., 1 to 3) substituents independently selected from the group consisting of; halo. alkyl. hydroxy, alKoxy. phenoxy, CF^, -C(0)N(R^^)a. -S02R^^ -S02N(R^^)2. amino,
23
alkylamino, dialkylamino, -COOR and -NO2 (preferably said substifutents are independently selected from the group consisting of: alkyl (e.g., Ci-Ce alkyt), halogen (e.g., CI and Br), -CF3 and -OH), wherein each R^^ is independently selected from the
23
group consisting of; H, alkyl, aryl, arylalkyl, heteroaryl and cydoalkyl, and wherein R is selected from the group consisting of: alkyl and aryl;
arylalkyl-represents an alkyl group, as defined at>ove, substituted with an aryl group, as defined above;
arylheteroalkyl" represents a heteroalkyi group, as defined below, substituted with an aryl group, as defined above;
aryloxy-represents an aryl moiety, as defined above, covalently bonded to an
adjacent stnjcturai element through an oxygen atom, for example, -O-phenyi (i.e.,
phenoxy); -":.
compound-wlth reference to the antineoplastic agents, includes the agents that are antibodies;
concurrently-represents (1) simultaneously in time (e.g., at the same time), or (2) at different times during the course of a common treatment schedule;
consecutively-means one following the other;
cycloalkenyt-represents unsaturated carbocydic rings of from 3 to 20 carbon atoms in the unsubstituted ring, preferably 3 to 7 carbon atoms, said cycloaikenyt ring comprising at least one (usually one) double bond, and said cycloalkenyl ring being

unsubstituted or substituted, said substituted cycloalkenyl ring having one or more (e.g., 1, 2 or 3) substituents independently selected from the group consisting of: alkyl (e.g.. methyl and ethyi), halogen, -CF3 and -OH;
cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms in the unsubstituted ring, preferably 3 to 7 carbon atoms, said cycloalkyi ring being unsubstituted or substituted, said substituted cycloalkyi ring having one or more (e.g., 1, 2 or 3) substituents independently selected from the group consisting of: alkyl (e.g., methyl and ethyl), halogen, -CF3 and -OH: for example, 1-substituted cycloalkyi rings, such as, for example,



or


or 1 , _, or
a"kyf "" alkyl a"kyi a» wherein said alkyl is generally a Ci-Cg alkyl group, usually a C1-C2 alky! group, and preferably a methyl group; thus, examples of cycloalkyi rings substituted at the 1-position with methyl include but are not limited to:
l-^ l-p l-p liD
cycloalkylalkyl-represents an alkyl group, as defined above, substituted with a cycloalkyi group, as defined above;
different-as used in the phrase "different antSneoplastic agents" means that
the agents are not the same compound or structure; preferably, "different" as used in
the phrase "different antineoplastic agents" means not from the same class of
antineoplastic agents; for example, one antineoplastic agent is a taxane, and another
antineoplastic agent is a platinum coordinator compound; ■"-
effective amount-represents a therapeutically effective amount; for example, the amount of the compound (or dmg), or radiation, that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor; for example, in the treatment of lung cancer (e.g., non small cell lung cancer) a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain; also, for example, a therapeutically effective amount of the FPT inhibitor is that amount which results in the

reduction of farnesylation; the reduction in famesylation may be determined by the analysis of phamnacodynamic markers such as Prelamin A and hDJ-2 (DNAJ-2) using techniques well known in the art;
tiaio {orhalogen)-represents fluoro, chloro, bromo or iodo;
haloalkyl-represents an alkyl group, as defined above, substituted with a halo group;
heteroatom-represents a O, N or S atom;
heteroaikenyi- represents straight and branched carbon chains having at least one cartwn to carbon double bond and containing from two to twenty cartron atoms, preferably two to six carbon atoms interrupted by 1 to 3 heteroatoms selected from the group consisting of:-0-, -S- and -N-, provided that when there is more than one heteroatom, the heteroatoms are not adjacent to one another;
heteroalkyl- represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms intenupted by 1 to 3 heteroatoms selected from the group consisting of:-0-, -S- and -N-, provided that when there is more than one heteroatom. the heteroatoms are not adjacent to one another;
heteroalkynyl- represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from two to twenty carbon atoms, preferably two lo six carbon atoms inlermpted by 1 to 3 heteroatoms selected from the group consisiting of: -0-, -S- and -N-provided that when there is more than one heteroatom, the heteroatoms are not adjacent to one another;
heteroaryl-represents unsubstituted or substituted cyclic groups, having at least one heteroatom selected from the group consisting of: 0, S or N (provided that any O and S atoms are not adjacent to one another), said heteroaryl group comprises O and S atoms, said heteroatom internjpting a carbocyclic ring stnjcture and having a sufficient number of deiocalized pi electrons to provide aromatic character, with the unsubstituted heteroaryl group preferably containing from 2 to 14 carbon atoms, wherein said substituted heteroaryl group is substitued with one or more (e.g., 1, 2 or 3) of the same or different R^^ (as defined for formula 1.1) groups, examples of heteroaryl groups include but are not limited to: e.g.. 2- or 3-fury!. 2- or 3-thienyI, 2-, 4-or 5-thia20lyI, 2-. 4- or S-imidazolyl. 2-, 4- or S-pyrimidinyj, 2-pyra2iny(. 3- or 4-pyridazinyl. 3-, 5- or 6-[1.2,4-triazinyl], 3- or 5-[1,2,4-thiadizolyl], 2-, 3-. 4-, 5-, 6- or 7-

benzofuranyl. 2-, 3-, 4-, 5-, 6- or 7-indolyl. 3-, 4- or S-pyrazolyl, 2-. 4- or S-oxazoiyl. triazolyl, 2-, 3- or 4-pyridyl, or 2-, 3- or 4-pyridy! N-oxide, wherein pyridyi N-oxide can be represented as:



or -I-
i- t
0
heteroarylalkenyt" represents an alkenyi group, as defined above, substituted with a heteroaryl group, as defined below:
heteroaryialkyi- represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined above;
heterocydoalkyfalkyl- represents an alkyl group, as defined above, substituted with a heterocycloalkyi group, as defined below;
heterocycloalkyl- represents a saturated carbocylic nng containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from the group consisting of:-0-, -S- or -
34 24
NR wherein R is selected from the group consisting of: H. aikyf. aiyl. and -C(0)N(R^^)2 wherein R"^ is as above defined, examples of heterocycloalkyl groups include but are not limited to: 2- or 3-tetrahydrofurany!, 2- or 3- tetrahydrothienyi, 2-, 3-or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2-, 3-, or 4- piperizin>d, 2- or 4-dioxanyl. morpholinyl, and
heterocydoalkylalkyl- represents an alkyl group, as defined above, substituted with a heterocycloalkyl group, as above;
"in association with"-means, in reference to the combination therapies of the invention, that the agents or components are adminstered concurrently or sequentially;
patient-represents a mammal, such as a human;
sequentially-represents (1) administration of one component of the method {(a) compound of the invention, or (b) chemotherapeutic agent, signal transduction inhibitor and/or radiation therapy) followed by administration of the other component or

components; after adminsitration of one component, the next component can be administered substantially Immediately after the first component, or the next component can be administered after an effective time period after the first component; the effective time period is the amount of time given for realization of maximum benefit from the administration of the first component.
The positions in the tricyclic ring system are:
5 6

A "+" or a "-" in Ring H in the compounds below/ indicates the "(+)-isomer" or ""(-)-isomer", respectively.
As well known in the art, a bond drawn from a particular-atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom. For example;


HO. =
represents

HoJ"^^^^



N

represents

N

and





N

CH-,





-N,

represents

-N,

H-iC




o ^o

CHa^N H3C"^0"^ O



e.g..

Those skilled in the art will appreciate that the numbers "1" and "2" in a formula.





-N,

and

-N,





N"

represent Isomers 1 and 2, respectively. One of the isomers is



-N.
N
and one of the isomers is:

R3° N.
-N,


For example, for the isomers



,N,

and

.N.




0 ^O



one isomers is


and one isomers is".

XFor the compounds of this invention. Isomer 1 means that the compound is the first isomer to be obtained from the separation column being used to separate the diastereomer mixture (e.g., the first isomer obtained by HPLC) or is a derivative of that first isomer. Isomer 2 means that the compound is the second isomer to be obtained from the separation column being used to separate the diastereomer mixture (e.g., the second isomer obtained by HPLC) or is a derivative of that second isomer.
In an embodiment of the compounds of formula 1.0, when-at least one of A and B (preferably B) is substilutent (32) (preferably (32)) or (33), then at least one of R^° to R^^ is selected from the group consisting of substituents (7) to (13).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) Is substitutent (32) or (33) (preferably (32)), then at least one of R^° to R^^ is selected from the group consisting of substituents (7), (9), (10), (12) and (13)-
In an embodiment of the compounds of formula 1.0. when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)). and at least one of R^ to

R is -NH2. and R^ is (2.Q), then R" is selected from tfie group consisting of substituents (3) to (10),
In an embodiment of the compounds of fomiula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), ar\d at least one of R^° to R^^ is -NH2, and R^ is (2.0), then R^" is selected from the group consisting of substituents(11)to(14).
In an embodiment of ttie compounds of fonnula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^° to R^^ is -N3, and R^ is (2.0), then R^" Is selected from the group consisting of substituents (3) to (10).
In an embodiment of the compounds of formula 1.0. when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^° to R^^ is -N3, and R^ is (2.0), then R" is selected from the group consisting of substituents (11) to (14).
In an embodiment of the compounds of formula 1.0. when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^° to R^ is -NH2, and R^ is (3.0), then R" is selected from the group consisting of substituents (1) to (14).
In an embodiment of the compounds of formula 1.0, when at least one of A and B {preferably B) is substitutent (32) or (33) (preferably (32)). and at least one of H^° to R^^ is -NH2, and R^ is (3.0), then R"^ is selected from the group consisting of substituents (3) to (14).
In an embodiment of the compounds of fomiula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^ to R^^ is -NH2, and R® is (3.0), then R" is selected from the group consisting of substituents (11) to (14).
In an embodiment of the compounds of fomiula 1.0. when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^° to R^^ is -N3, and R^ is (3.0). then R" is selected from the group consisting of substituents (1) to (14).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)). and at least one of R^ to

R^^ is -N3, and R^ is (3.0). then R^^ is selected from the group consisting of substituents(3)lo(14).
In an embodiment of \he compounds of fonnula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)). and at least one of R^"" to R^^ is -Na. and R^ is (3.0). then R" is selected from ttie group consisting of substituents(11) to(14).
In an embodiment of the compounds of formula 1.0, when at (east one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^° to R"^ is NH2, and R^ is (4.0), then; (a) R^"^ is selected from the group consisting of substituents (1)to (4) and (7) to (12), and R"^ is as defined above for fonmula 1.0. or
(b) R""" is selected from the group consisting of substrtutents (1) to (4) and (7) to (12),
and R"^ is selected from the group consisting of: cyctoalkyl. piperidlne Ring V and
a!kyi-(piperidine Ring V).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) {preferably (32)), and at least one of R^° to R^^ is NHa, and R^ is (4.0), then: (a) R"^ is selected from the group consisting of substituents (13) to (18), and R^^ is as defined above for fomiula 1.0, or (b) R^^^ is selected from the group consisting of substitutents (1) to (12), and R^^ is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyi-(piperidine Ring V), or
(c) R"^ is selected from the group consisting of substituents (13) to (18), and R"^ is
selected from the group consisting of: cycloalkyl, piperidine Ring V and
alkyl-(piperidine Ring V).
tn an embodiment of ttie compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^ to R^ is Na. and R* is (4.0), then; (a) R"^^ is selected from the group^consisting of substituents (1) to (4) and (7) to (12), and R" is as defined above for formula 1.0, or (b) R^"^ is selected from the group consisting of substitutents (1) to (4) and (7) to (12), and R"^ is selected from the group consisting of: cycloalkyl, piperidine Ring V and aikyl-(pipehdine Ring V).
In an embodiment of the compounds of fomnula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)). and at least one of R^ to R^ is Nj, and R^ is (4.0), then: (a) R"^ is selected from the group consisting of substituents {13} to (18), and R"^ is as defined above for fonnula 1.0. or (b) R"^ is

selected from the group consisting of substitutents (1) to {12}. and R"^ is selected from the group consisting of; cycloalkyi, piperidine Ring V and alkyl-(pipendin6 Ring V), or (c) R^""* is selected from the group consisting of substituents (13) to (18), and R"^ is selected from the group consisting of: cycloalkyi, piperidine Ring V and alkyi-{piperidine Ring V).
In an embodiment of the compounds of formula 1 .Q, wtien at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)}, and at least one of R^° to R^ is -NH2. and R^ is (5.0). then at least one of R^", R^, and R*^ is selected from the group consisting of substituents (8)(g). (a){h), (9), (10), (11), (12) and {13).
In an embodiment of the compounds of fomiula 1.0, when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)). and at least one of R^° to R^^ is -N3, and R^ is (5.0). then at least one of R^\ R^, and R*^ is selected from the gnoup consisting of substituents (8)(g). (8)(h), (9), (10). (11), (12) and (13).
In an embodiment of formula 1.0:
(1} when at least one of A and B (preferably B) is substitutent (32). and R^° and R^* are selected from the group consisting of substituents (1) to (6). then R^ is lelected from the group consisting of:
(a) (2.0) wherein R" is selected from substituents (11) to (14),
(b) (3.0) wherein R" is selected from substituents (11) to (14),
(c) (4.0) wherein (i) R"^ is selected from the group consisting of substituents (13) to (18), and R"^ is as defined above for formula 1.0. or (ii) R^^^ is selected from the group consisting of substitutents (1) to (12). and R"^ is selected from the group consisting of: cycloalkyi, piperidine Ring V and alkyl-(p!peridine Ring V), or (iii) R"^ is selected from the group consisting of substituents (13) to (18). and R^^ is selected from the group consisting of: cycloalkyi, piperidine Ring V and alkyl"(p"peridine Ring V), and
(d) (5.0) wherein at least one of R^", R^^, and R^^ is selected from the group consisting of substituents (8)(g).(8)(h), (9), (10). (11), (12) and (13); and

(2) when at least one of A and 6 (preferably 6) is substituent (32), and at least one of R^^ or R^" is -NHj (e.g.. R^^ is -NH? and R^" is H or alkyl (e.g., "0^3)), and R^ is (2.0). then R^ is not

O^ o ^ ;and
(3} when at least one of A and B (preferably B) is substitutent (32). and at least one of R^° or R^" is -N3 (e.g.. R^" is -N3 and R^^ Is H or alky! (e.g., -CH3)), and R^s (2,0), then R^ is not

o^ "O
In an embodiment of the compounds of fonnuta 1.0, when at least one of A and B (preferably B) is substitutent (32). then at least one of R^ or R^^ is selected from the group consisting of substituents (7), (9), (10), (12) and (13).
In an embodiment of the compounds of fonnula 1.0, when at least one of A and B (preferably B) is substitutent (32). and at least one of R^ or R^^ is -NH2 (e.g., R^" is -NH2 and R^" Is H or alkyl (e.g.. -CH3)). and R^ is (2.0), then R"^ is selected from the group consisting of substituents (3) to (10),
In an embodiment of the compounds of fonnula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R^ or R^^ is -NH2 (e.g., R^° is -NHz and R^^ is H or alkyl (e.g., -CH3)). and R*" is (2.0). then R"^ is selected from the group consisting of substituents (11) to (14).
In an embodiment of the compounds of ferula 1.0, when at least one of A and B (preferably B) is substitutent (32). and at least one of R^° or R^is -N3 (e.g.. R^° is -Nj and R^^ is H or alkyl (e.g., -CH3)), and R^ Is (2.0). then R^^ is selected from the group consisting of substituents (3) to (10).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R^ or R^\is -N3 (e.g., R^° is -N3 and R^^ is H or alkyl (e.g., -CHj)), and R° Is (2.0), then R" is selected from the group consisting of substituents (11) to (14).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R^ or R^" is -NH2 (e.g., R^" is

-NH2 and R^^ is H or alkyl (e.g., -GHa)), and R^ is (3.0), then R" is selected from the group consisting of substituents (1) to (14).
In an embodiment of the connpounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R"° or R^" is -NH^ (e.g.. R^" is -NH2 and R^^ is H or a!ky! (e.g., -CH3)). and R^ is (3.0). then R" is selected from the group consisting of substituents (3) to (14).
In an embodiment of tfie compounds of fonnuia 1.0. when at least one of A and B (preferably 8) is substitutent (32), and at least one of R^° or R^^ is -NH2 (e.g., R^° is -NH2 and R^^ is H or alkyl (e.g.. -CH3)), and R^ is (3.0). then R"^ is selected from the group consisting of substituents (11) to (14).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R^^ or R^^ is -Na (e.g., R^ is -Na and R^^ is H or alkyl (e.g., -CH3)). and R^ is (3.0), then R" is selected from the group consisting of substituents (1)to(14).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R^° or R^^ is -N3 (e.g., R^° is -N3 and R^" is H or alkyl (e.g., -CH3)). and R^ is (3.0), then R" is selected from the group consisting of substituents (3) to (14).
In an embodiment of the compounds of fonnuia 1.0, when at least one of A and B (preferably B) is substitutent (32). and at least one of R^° or R^^ is -N3 (e.g., R^° is -N3 and R^" is H or alkyl (e.g.. -CH3)). and R® is (3.0). then R^" is selected from the group consisting of substituents (11) to (14).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32), and at least one of R^° or R^^ is -NH2 (e.g., R^ is -NHa and R^^ is H or alkyl (e.g., -CH3)), and R* is (4.0), then: (a)|?^^^ is selected from the group consisting of substituents (1) to (4) and (7) to (12). and R^^ is as defined above for formula 1.0. or (b) R"^ is selected from the group consisting of substitutents (1) to (4) and (7) to (12), and R^^ is selected from the group consisting of: cydoalkyl, piperidine Ring V and alkyl-(piperidine Ring V).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably 8) is substitutent (32). and at least one of R^ or R^" is -NH2 (e.g., R^ is -NH2 and R^^ is H or alkyl (e.g.. -CHa)), and R^ is (4.0), then: (a) R"^" is selected from the group consisting of substituents (13} to (18). and R"^ is as defined above for

formula 1.0, or (b} R"^ is selected from the group consisting of substitutents (1) to (12), and R"^ is selected from the group consisting of: cycloalKyI, piperidine Ring V and alky(-(pipendine Ring V). or (c) R"^ is selected from the group consisting of substituents (13) to (18), and R"^ is selected from the group consisting of: cycloalky!, piperidine Ring V and alkyl-(piperidine Ring V).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably 8} is substitutent (32), and at least one of R^ or R^" is -N3 (e.g.. R^ is -N3 and R^" is H or alkyl (e.g., -CH3)}, and R^ is (4.0), then: (a) R"^ is selected from the group consisting of substituents (1) to (4) and (7) to (12), and R"^ is as defined above for formula 1.0. or (b) R^ ^^ is selected from the group consisting of substitutents (1) to (4) and (7) to (12), and R^^ is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl-(piperidine Ring V).
in an embodiment of the compounds of fonnula 1.0, when at least one of A and B (preferably 8) is substitutent (32), and at least one of R^° or R^" is ~Hz (e.g.. R^° is -N3 and R^" is H or alkyl (e.g.. -CH3)), and R^ is (4.0), then: (a) R"^ is selected from the group consisting of substituents (13) to (18), and R^^ is as defined above for fonnula 1.0, or (b) R^^^ is selected from the group consisting of substitutents (1) to (12). and R"^ is selected from the group consisting of: cycloalkyl. piperidine Ring V and a(kyt-(ptperidine Ring V), or (c) R"^^ is selected from the group consisting of substituents (13) to (18). and R^^ is selected from the group consisting of: cycloalkyl, piperidine Ring V and alkyl-(piperidine Ring V).
In an embodiment of the compounds of formula 1.0. when at least one of A and B (preferably B) is subsUtutent (32), and at least one of R^° or R^" is -NH2 (e.g., R^ is -NH2 and R^^ is H or alkyl (e.g.. -CH3)). and R^ is (5.0), then at least one of R^\ R^. and R"^ is selected from the group consisting of substituents (8)(^. (8)(h), (9), (10), (11). (12) and (13).
In an embodiment of the compounds of formula 1.0, when at least one of A and B (preferably B) is substitutent (32). and at (east one of R^° or R^" is -N3 (e.g.. R^ is -N3 and R^" is H or alkyl (e.g., -CH3)), and R^ is (5.0), then at least one of R^\ R^. and R*^ is selected from the group consisting of substituents (8)(g), (8}(h), (9), (10), (11), (12) and (13).


Those skilled in the art will appreciate that the compounds of formula 1.0 ara also represented by compounds of fomiula 1.1:
(I.I) or a pharmaceutically acceptable salt or solvate thereof, wherein:
(A) one of a, b, c and d represents N or N*0", and the remaining a, b. c, and d groups represent CR" (i.e., carbon with an R" group) wherein each R" group on each carbon is the same or different; or
(B) each a, b. c, and d group represents CR" (i.e.. cartxin with an R" group) wherein each R" group on each carbon is the same or different;
(C) the dotted lines (—) represent optional bonds;
(D) X represents N or CH when the optional bond (to 011} is absent, and represents C when the optional bond (to C11) is present;
(E) when the optional bond is present between carbon atom 5 (i.e., C-5) and
carbon atom 6 (i.e., OS) (i.e., there is a double bond between C-5 and C-6) then there
is only one A substituent txiund to C-5 and there is only one B substituent bound to
C-6, and A or Bis other than H; • -
(F) when the optional bond is not present between carbon atoms 5 and 6
(i.e., there is a single bond between C-5 and C-6) then:
(1) there are two A substituenls bound to C-5 wherein each A substituent is independently selected; and
(2) there are two 8 substituents bound to C-6 wherein each B substituent is independently selected; and
(3) at least one of the two Asubstituentsoroneof the two B substituents is H; and

(4) at least one of the two A substituents or one of the two B substituants is other than H; (i.e., when there is a single bond between C-5 and G-6 one of Ihe four substituents (A, A, B. and B) is H and one is other than H};
(G) A and B is independently selected from the group consisting of;
(1) -H;
(2) -R^;
(3) -R^-C(0>-R^;
(4) - R^-COr R^;
(5) -(CHslpR^^
(6) -C(0)N(R^)2, wherein each R^is the same or different;
(7) -C(0)NHR^
(8) -C(O)NH-CHrC(0)-NH3;
(9) -C(0)NHR2^;
(10) ^(CH2}pC(R">-0-R^;
(11) -(CH2)t^]CH(RV provided that p is not 0, and wherein each R^ is the same or different;
(12) -(CH2)pC(0)R^
(13) -(CH2)pC(0)R^^^
(14) -(GH2)pC(0)N(R^)2, wherein each R^ is the same or different;
(15) -(CH2)pC(0)NH(R^);
(16) -(CH2)pC{0)N(R^)2. wherein each R^^ is the same or different;
(17) -(CH2)pN(R^>R*" (e.g. -CH2-N(CH2-pyridine)-CHr imidazole):

(18) -(CH2)pN(R^^)2. wherein each R^ is the same or different (e.g., -(CH2)p-NH-CHrCH3);
(19) ^(CH2)pNHC(0)R^;
(20) -(CHz)pNHC(0)2R"°;
(21) -(CH2)cN(C(0)R^^^)2 wherein each R^^"* is the same or different;
(22) -{CH2)pNR^^C(0)R^^

(23) -(CH2)pNR^^C(0)R" wherein R^" is not H, and R^" and R^^ taken together with the atoms to which they are bound form a 5 or 6 membered heterocycioalkyl ring;
(24) -(CH3)pNR^^C(0)NR^^

(25) -(CH2)pNR^"C(0)NR" wherein R^" is not H, and R^" and R=" taken together with the atoms to which they are bound form a 5 or 6 membered heterocycloafkyl ring;
(26) -(CHa)pNR^"C(0)N(R^^^)2. wherein each R^"" is the same or different;
(27) -{CH2)pNHS02N(R^"")2, wherein each R^" is the same or different:
(28) -{CH2)pNHC02R^:
(29) -(CH2)pNC{0)NHR^";
(30) -{CH2)pC02R^^
(31) -NHR^:
(32)
"(CH2)p-—C~W
wherein R"^ and R"^" are the same or different, and each p is independently selected; provided that for each



group when one of R^° or R"*" is selected from the group consisting of: -OH, =0, -OR^. -NH2. -NHR"\ -N(R^h. -N3. -NHR^\ and -N(R^^)R^^ then the remaining R^" or R^^ is selected from the group consisting of: H. alkyl, aryi (e.g., phenyl), and arylalkyl (e.g., benzyl);
(33)
R30 f^32

-C-R"
-(CH2)p-(^
R^" R"
30
Wherein R^°. R^\ R^^ and R^^ are the same or different; provided that when one of R or R^^ is seiecled from the group consisting of: -OH. =0, -OR^, -NH2, -NHR", -N(R^)2. -N3, -NHR^, and -N(R^)R^^ then the remaining R^° or R^" is selected from the group consisting of: H. alkyl, aryi (e.g., phenyl), and arylalkyl (e.g., benzyl); and provided that when one of R"^ or R^^ is selected from Hie group consisting of: -OH, =0, -OR^, -NH2, -NHR^, -N(R^)2, -N3. -NHR^. and -N(R^)R^^ then the remaining

R^^ or R^^ is selected from the group consisting of: H, alkyl, aryi (e.g., phenyl), and arylalkyi (e.g., benzyl);
(34) -alkenyl-COsR^;

(35) -alkenyl-C(0)R-^
(36) -alkenyl-COaR^";
(3?) "alkeny(-C(0)-R^^";
(38) (CH2)p-alkenyl-C02-R^" ;
(39) -(CH2)pC=N0R"\- and
(40) -{CH2)p"Phthalimid;
(H) pisQ , 1,2,3or4;
(1) R" is selected from the group consisting of:
(1) H;
(2) halo;
(3) -CF3;
(4) -OR"^;
(5) COR"°;
(6) -SR";
(7) -S(0)tR";
(a) -n(R(9) -NO2;
(10) -OC(0)R"^
(11) COJR"";
(12) "OCO^R"^;
(13) -CN;
10 15
(14) -NR COOR ;
(15) -SR"^C(0)OR^^
(16) -SR N(R^ }2 wherein each R is independently selected from the
group consisting of: H and -C(0)OR , and provided that R"^ in -SR N(R )2 is
not -CH2;
(17) ben2otriazol-1-yloxy;
(18) tetrazohS-ylthio;

(19) substituted tetrazol-5-ylthio;
(20) alkynyl;
(21) aikenyl;
(22) alkyl;
(23) a/kyi substituted with one or more (e.g., 1. 2 or 3) substitutenfs
independently selected from the group consisting of: halogen, -OR and -CO,R"";
(24) aikenyl substituted with one or more (e^g-, 1, 2 or 3) substitutents
independently selected from the group consisting of: halogen, -QR and

-CO,R"°;
3A
(J) Each R is independei
(1) halo;
(2) -CFs;
(3) -OR";
(4) COR"^:
(5) -SR^°;
(6) -S{0)tR";
(7} "NiR\.
(8) -NOj;
(10) COSR"";
(11) -OCO^R"^
(12) -CN;
(13) -NR"°COOR^^
(14) -SR^^C(0)OR^^

(15) -SR N(R ), wherein each R is independently selected from the
"2
.15 ,5. ._15 13,
group consisting of: H and -C(0)OR""", and provided that R"^in -SR""N(R"^)2 is
not -GH2;
(16) benzotriazol-1-yloxy;
(17) tetra2ol-5-ylthio;

(18) substituted tetrazol-S-ylthio;
(19) alkynyl;
(20) alkenyl;
(21) alkyl;
(22) alky) substituted with one or more (e.g., 1, 2 or 3) substitutenls
10
independently selected from the group consisting of: haiogen, -OR and
-COjR^"; and
(23) alkenyi substituted with one or more (e.g., 1, 2 or 3) substitutents
10
independently selected from the group consisting of: halogen, -OR and
-CO^R"";
(K) mis 0.1 or2;
(L) tisO. 1or2
(M) R , R , R and R are each independently selected from the group consisting of:
(1) H;
(2) -CF3;
10
(3) -COR ;
(4) alkyl;
(5) unsubstituted aryl;
(6) alkyl substituted with one or more {e.g..1,2 or3) groups selected
from the group consisting of; -S(0)tR^^ -NR^^COOR^^ -C(0)R^^ and -CO2R ;
and
(7) aryl substituted with one or more (e.g., 1,2, or 3) groups selected
from the group consisting of; -S{0),R" , -NR COOR , -C{Q)R , and -COJR ;
or
(N) R together with R represents =0 or =S; (O) R^ is selected from the group consisting of:
(2.0) (3.0) ^
^ -^^ (5.0)

(P) R^ is selected from the group consisting ot:
(1) unsubstituted heteroaiyl;
(2) substituted heteroaryl;
(3) unsubstituted arylalkoxy;
(4) substituted arylalkoxy;
(5) heterocycioalkyt;
(6) substituted heterocycloalkyl;
(7) heterocycloalkylalkyl;
(8) substituted heterocycloalkylalkyl;
(9) unsubstituted heteroarylalkyl;
(10) substituted heteroaryialkyi;
(11) unsubstituted heteroarylalkenyl;
(12) substituted heteroarylalkenyl;
(13) unsubstituted heteroarylalkynyl and (U) substituted heteroaryl alky nyl;
wherein said substituted R^ groups are substituted with one or more (e.g., 1. 2 or 3} substituents independently selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom (i.e., only one -OH group can be bound to a carbon atom);
(2) -COjR"^
(3) -CH2OR",
(4) halogen (e.g., Br, CI or F),
(5) alky! (e.g. methyl, etfiyl. propyl, butyl or t-butyl);
(6) amino;
(7) tfityl;
(8) heterocycloalkyl;
(9) cycioalkyi, (e.g. cyclopropyl or cyclohexyl);
(10) arylalkyl;
(11) heteroaryl;
(12) heteroaryialkyi and
(13)


wherein R""* is independently selected from the group consisting of: H; aikyI; aryl, arylalkyt, heteroar/i and heteroarylalkyl;
(Q) R^ is selected from the group consisting of: alky and aryiaikyl;
(R) R^ is selected from the group consisting of:
(1) -C(0)R^;
(2) -SOaR^
(3) -C(0)NHR^^
(4) -C(0)OR^^ and
(5) -C(0)N(R%;
(S) Each R*" is independently selected from the group consisting of: H. alkyi and arylalkyt;
(T) R"° is selected from the group consisting of: H; alkyi; aryl and arylalkyl; (U) R*^ is selected from the group consisting of:
(1) alkyi;
(2) substituted aikyi;
(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyi;
(6) substituted cydoalkyi;
(7) unsubstituted heteroaryl; (3) substituted heteroaryl;

(9) heterocycloaikyl; and
(10) substituted heterocycloaikyl;
(11) unsubstituted aikeny! (e.g., -CH2CH=CH2);
(12) -N(aikyl)2 wherein each aikyI is independently selected (e.g., -N{CH3)2;
(13) unsubstituted arylalkyl; and
(14) substituted arylalkyl;
wherein said substituted alkyi R" groups are substituted with one or more (e.g. 1, 2 or 3) substltuents selected from the group consisting of:

(1) -OH. provided thatwhen there is more than one-OH group then each -OH group is tiound to a different carbon atom (i.e., only one -OH group can be bound to a carbon atom);
(2) halogen (e.g., Br, CI or F); and
(3) -CN; and
wherein said substituted cycloaikyl, and substituted heterocycloalkyi R" groups are substituted with one or more (e.g. 1, 2 or 3) substituents selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom (i.e., only one -OH group can be bound to a carbon atom);
(2) halogen (e.g., Br. CI orF); and
(3) alkyl; and
wherein said substituted aryl. substituted heteroaryl and the ary! moiety of said substituted arylalkyl R"^ groups are substituted with one or more (e.g. 1, 2 or 3) substituents independently selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom (i.e., only one -OH group can be bound to a carbon atom);
(2) halogen (e.g,. Br, CI or F};
(3) alkyl;
(4) -CF3;
(5) -CN; and
(6) alkoxy(e.g.,-OCH3);
(V) R"^ is selected from the group consisting of;
(1) H;
(2) OH;
(3) alkyi;
(4) substituted alkyl;
(5) unsubstituted aryl,
(6) substituted aryl;
(7) unsubstituted cycloaikyl;
(8) substituted cycloaikyl;

(9) unsubslituled heteroaryl;
(10) substituted heteroaryl;
(11) heterocydoalkyl;
(12) substituted heterocycloalkyi; (13} -OR^

(14) unsubstituted aryialkyi;
(15) substituted arylalKyI;
(16) unsubstituted atkenyt;
(17) unsubstituted arylacyl (e.g.. -C(0}pheny!);and
(18) unsubstituted heteroarylalkyl (e.g., -CHrPyndyl); and
wherein said substituted alkyl R"^groups are substituted with oneormore (e.g., 1,2 or 3) substituents independently selected from the group consisting of:
(1) -OH, provided thai when there is more than one -^H group then each -OH group is bound to a different carbon atom (i.e., only one -OH group can be bound to a carbon atom);
(2) -CN;
(3) -CF3;
(4) halogen (e.g.. Br, CI or F);
(5) cycloalkyi;
(6) heterocycloalkyi;
(7) aryialkyi;
(8) heteroarylalkyl; and
(9) heteroalkenyt;and
wherein said substituted cycloalkyi, and substituted heterocycloalkyi R^^^ groups are substituted with one or more (e.g. 1,2 or 3) substituents indepenctently selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom (i.e.. only one -OH group can be t>ound to a carbon atom);
(2) -CN;
(3) -CF3;
(4) halogen (e.g., Br, Ci or F);
(5) alkyi;

(6) cycloalkyl;
(7) heterocycioall (8) arylalkyi;
(9) he Eero arylalkyi;
(10) alkenyland
(11) heteroalkenyJ;and
wherein said substituted aryi, substituted heteroaryi and the aryi moiety of said substituted aryialkyl R"^ groups have one or more (e.g. 1, 2 or 3) substituents independently selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group Is bound to a different cartxjn atom (I.e., only one -OH group can be txiund to a carbon atom);
(2) -CN;
(3) -CF3:
(4) halogen (e.g., Br. CI or F);
(5) alkyl;
(6) cycloalkyl;
(7) heterocycloalkyf;
(8) arylalkyi;
(9) heteroarylalkyi;
(10) alkenyf;
(11) hetaroalkeny!;
(12) aryloxy (e.g., -0-phenyl); and
(13) alkoxy (e.g.,-OCH3);
(W) R^^ is selected from the group consisting of: H, alkyl, piperidine Ring V. cycloaikyi, and -alkyl-(piperidine Ring V) (wherein said piperidine Ring V is as described below, see, for example, paragraph (8) in the definition of R^\ R^ and R*^};
(X) R^^ is selected from the group consisting of: alkyl and aryi;
(Y) R^", R^ and R"*^ are Independently selected from the group consisting
of:
(1) H:
(2) alkyl (e.g.. methyl, ethyl, propyl, butyl ort-butyl);
(3) unsubstituted aryi (e.g. phenyl);

(4) substituted aryl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CFsandOH;
(5) unsubsfituted cydoalkyl. (e.g. cyciohexyi);
(6) substituted cydoalkyl sutistituted with one or more substituents independently selected from: alkyl, halogen. CF3 or OH;
(7) heteroaryl of the formula,

or
(8) piperidtne Ring V:



V N"
wherein R"" is selected from the group consisting of:
(a) H,
(b) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyt);
(c) alkylcartonyl {e.g.. CH3C(0)-);
(d) alkyloxy carbony! (e.g.. -C(O)0-t-C4H9. -C(0)OC2H5. and -C(0)OCH3);
(8) haloalkyi (e.g., trifluoromethyl); and (0 -C(0)NH(R5^);
(9) -NH2 provided that only one of R^\ R^, and R*^ group can be -NH2, and provided that when one of R^\ R^. and R^^ is-^H2 then the remaining groups are not-OH;
(10) -OH provided that only one of R^\ R^, and R*® group can be -OH, and provided that when one of R^\ R^, and R"^ is -OH then the remaining groups are not -NH2; and
(11) alkyl substituted with one or more substituents (e.g.. 1-3, or 1-2, and preferably 1) selected from the group consisting of: -OH and -NH2, and provided that there is only one -OH or one -NH2 group on a substituted carbon;

(12) alkoxy(e.g., -OCH3): or
(13} R^" and R^ taken together with the carbon to which they are bound form a cyclic ring selected from the group consisting of:
(a) unsubstituted cycloalkyi {e.g., cyclopropyi, cydobutyl, cyclopentyl, and cyclohexyl);
(b) cycloalkyi substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;
(c) unsubstituted cydoalkenyl


e.g..

(d) cydoalkenyl substituted with one or more substituents independently selected from the group consisting of; alkyl, halogen, CF3 and OH;
(e) heterocycloalkyl, e.g., a piperidyl ring of the fomnula:
wherein R*^ is selected from the group consisting of:
(1) -H.
(2) alkyl, {e.g., methyl, ethyl, propyl, butyl or t-butyi);
(3) alkylcarbonyl (e.g., CH3C(0H:
(4) alkyloxy carbonyl (e.g., -C(0J0-t-C4Hg,
-C(0)OC2H5, and-C{0)0CH3);
(5) haloalkyi (e.g., trifluoromethyl); and
(6) -<:>
(f) unsubstituted aryl (e.g., phenyl};
(g) aryl substituted with one or more substituents independently selected from the group consisting of; alkyl (e.g., methyl), halogen (e.g., CI, Brand F), -CN, -CFj. OH and alkoxy (e.g,, methoxy); and


(i) heteroaryl selected from the group consisting of:
V
and
(Z) R^^ is selected from the group consisting of;
(1) H;
(2) alkyl (e.g., methyl, ethyl, propyl, butyl or t-buty();
(3) alkoxy (e.g., methoxy, ethoxy, propoxy);
(4) -CHa-CN;
(5) R^;
(6) -CHECO^H;
(7) -C(0)alkyl and
(8) CHiCOaalkyl;
(AA) R^^ is selected from the group consisting of:
(1) H;
(3) alkyl (e.g., mettiyl, ethyl, propyl, or butyl), and
(4) alkoxy;
(AB) R^"^ is selected from the group consisting of:
(1) alkyl (e.g., methyl, ethyl, propyl, or butyl); and
(2) alkoxy;
(AC) R^, n^\ R^^ and R^^ are independently selected from the group
consisting of:
0) -H;
(2) -OH;
(3) =0;
(4) alkyl;
(5) aryl (e.g. phenyl);
(6) aryialkyi (e.g., benzyl);
(7) -OR^^
(8) -NH2;
(9) -NHR^^
(10) -N(R*")2 wherein each R^^ is independently selected;

(11) -N3;
(12) -NHR^^and
(13) -N(R"^)R*;
(AD) R^ is selected from the group consisting of:
(1) ail^yi;
(2) unsubstituted heteroaryl;
(3) substituted heteroaryl; and
(4) amino:
wherein sard substituents on said substituted heteroaryl group are independently selected from one or more (e.g., 1,2 or 3) substitutents selected from the group consisting of: alky! (e.g., methyl, ethyl, propyl, or butyl); halogen (e.g., Br, CI, or F); and -OH;
(AE) R^" is selected from the group consisting of: H and alkyl (e.g., methyl,
ethyl, propyl, butyl and t-buty(); and
(AF) provided that
(1} a ring carbon atom adjacent to a ring heteroatom in a substituted heterocycloalkyl moiety is not substituted with a heteroatom or a halo atom; and
(2) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloalkyl moiety, is not substituted with more than one heteroatom; and
(3) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloalkyl moiety, is not substituted with a heteroatom and a halo atom; and
(4) a ring carbon in a substituted cycloalkyl moiety is not substituted with more than one heteroatom; and _
(5) a carbon atom in a substituted aikyi moiety is not substituted with more than one heteroatom; and
(6) the same cartxin atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms; and
(7) when A and B are independently selected from the group consisting of substituents (1) to (31) and (34) to (39), then R** is not H; and

(8) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R^ is (2.0), then R"^ is selected from the group consisting of substituents (11) to (14); and
(9) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R^ is (3.0), then R" is selected from the group consisting ofsubsti{uenls(11)to (14); and

(10) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R^ is (4.0), then: (a) R"^ is selected from the group consisting of substituents (13) to (18), and R^^ is as defined above, or (b) R^"^ is selected from the group consisting of substituents (1) to (12), and R"^ is selected from the group consisting of; cycloalkyi, piperidine Ring V and all (11) when A and B are selected from the group consisting of substituents (1) to (31) and (34) to (39), and R^ is (5.0). then at least one of R^\ R". and R"*^ is selected from the group consisting of substituents (8)(g). (8)(h). (9), (10), (11), (12) and (13); and
(12) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)). and R^° to R^^ are selected from the group consisting of substituents (1) to (6), then R® is selected from the group consisting of:

(a) (2.0) wherein R" is selected from substituents (11) to (14),
(b) (3.0) wherein R" is selected from substituents (11) to (14).
(c) (4.0) wherein (i) R"^ is selected from the group consisting of substituents (13) to (18), and R"^ is as defined above for formula 1.0, or (ii) R^ ^^ is selected from the group consisting of substitutents (1) to (12), and R"*^ is selected from the group consisting of; cycloalkyi, piperidine Ring V and alkyl-(piperidine Ring V), or (iii) R^^^ is selected from the group consisting of substituents (13) to (18). and R^^ is selected from the group consisting of: cycloalkyi, piperidine Ring V and alkyl-(piperidine Ring V). and

(d) (5.0) wherein at least one of R^\ R^^ and R""^ is selected from the group consisting of substituents (8)(g), (8Kh). (9). (10), (11), (12) and (13); and (13) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^° to R^ is -NH2 (i.e., substituent (8)), and R^ is (2.0), then R^s not

O-^ "0" ^ ;and
(14) when at least one of A and B (preferably B) is substitutent (32) or (33) (preferably (32)), and at least one of R^° to R" is -N3 (i.e.. substituent (11)), and R^ is (2.0), then R^ is not

0^ "0
When there is a single bond between C-5 and C-6, then there are two A substituents bound to C-5 and there are two B substituents bound to C-6
A R A B
I.e., /TTTK represents /—C

and each A and each B are independently selected, and at least one of the two A
substituents or one of the two B substituents is H, and at least one of the two A
substituents or one of the two B substituants is other than H (i.e.. when there is a
single bond between C-5 and C-6 one of the four substituents (A. A, 6. and 8} is H
and one is other than H). -_
The substituted R^ groups can be substituted on any portion of the group that has substitutable carbon atoms. For example, a group that has a ring moiety (e.g., a heterocycloalkyi or heteroary! ring) bound to a hydrocarbon moiety (e.g., alkyl, alkenyi or alkynyl) can be substituted on the ring moiety and/or the hydrocarbon moiety. Thus, for example, substitued heteroarylalkyl can be substituted on the heteroaryl moiety and/or the alkyl moiety.
Piperidine Ring V includes the rings:



and

Examples of Ring V include, but are not limited to:




V3

C(0)CH3

N
C(0)CH3 V4






CO2C2H5
V6
Nv, and
C(0)NH2

-N.
V7

■CO2-I-BUTYL

One embodiment of this invention is directed to compounds of formula 1.1 wherein the C-5 to C-6 double bond is present. A is H, and B is the group:

R
,za

.(CH2)p-(—^—|R"
R"" /P wherein p of the -^CH2)p- moiety of said B group is 0, and wherein p of the
-,30 >
-,9

moiety of said B group is 1, and all other substitutents are as defined for formula 1.1. Preferably R^ is unsubstituted heteroaryl (e.g., imidazolyl) or substituted heteroaryi (e.g., substituted imidazolyl). Most preferably R^ is a substituted heteroaryl, more preferably substituted imidazolyl, even more preferably an N-alkylimidazoly!. and stilt more preferably


Preferably R"° is selected from the group consisting of; -OH. -NHz, -OR^"" (wherein R^^ is C^ to C3 alkyi), N3, and -NHR^"", and R^"* is selected from the group consisting of: H and alkyl (e.g., methyl). Most preferably (1) R^° is -OH and R^" is H; (2) R^° is -NH2 and R^" is H; (3) R^ is -OR^ (wherein R^ is d to C3 alkyi), and R^^ is H or alkyl (e.g., Ci-Cs, C]-C4, C1-C2, said alkyl group preferably being methyl), and preferably H; (4) R^ is N3, and R^" is H or alkyl (e.g., Ci-Cs. C1-C4, C1-C2, said alky! group preferably being methyl), and preferably H; or (5) R^° is -NHR* (wherein R^ is as defined for fomiula 1.1), and R^^ is H or alkyl (e.g., Ci-Cg, C1-C4, CrCs. said alkyl group preferably being methyl), and preferably H. More preferably R^" is -NH2 or -NHR^^ and R^" is H. Still more preferably R^° is -NHz and R^" is H. Preferably X is N. Preferably a is N. Preferably b is CR^herein RMS H. Preferably c is CR^ wherein R" is H or halo (e.g., Br or CI), and most preferably H. Preferably d is is CR"* wherein R^ is H. Preferably R^ R^, R^ and R^^ are H. Preferably m is 1 and R^"^ is halo (e.g., Br or CI), and most preferably CI. When m is 1. R^ is preferably at the C-B position, i.e., preferably R^* is 8-ha(o and most preferably 8-Cl. R^ is preferably 2.0. 3.0, 4.0 or 5.0. When R^ is 2.0. R"^ is preferably alkyl (e.g.. Ci to C4). most preferably t-butyl or isopropyl, and more preferably isopropyl. Preferably R^ is 2.0. Preferably the compounds of this embodiment have the stereochemistry shown in formulas 1.5A, 1.6Aor1.7A.
One embodiment of this invention is directed to compounds of fonnuia 1.1 having the formula:




wherein:

(1.2)

{1) a, b, c. d. R^^ R^. R^ R^ R^^ R^ and X are as defined for formula 1.1; (2) B is the group:

R30
-(CH2)P-(-C-|R"
R"/p -(3) in said B group:
(a) P of the-(CH2)p-moiety is 0;
(b) p of the
n

moiety is 1 to 3, preferably 1 to 2, most preferably 1 ; (c) when p is 1 for the moiety
R30,
-R^
o31
then R^" is selected from the group consisting of: -OH. or-NHs (preferably -OH), and R^" is alkyl. most preferably C.-C, alkyl more preferably C.C. alkyl, still more preferably C.C, alkyl, and even more preferably methyl; (d) when p is 2 or 3 for the moiety



then: (1) for one -CR^^R^"- moiety, R^° is selected from the group consisting of: -OH or -NH;, and R^^ is alkyl, most preferably Ci-Ce alkyl, more preferably C1-C4 alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl; and (2) for the remaining -CR^°R^^- moieties R^ and R^^ are hydrogen; and (e) R^ is unsubslituted heteroaryl (e.g., imidazotyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e.g., methyl), more preferably substituted tmidazolyl. still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR^R^^- moiety when R"^ is -OH or -NH2. Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:

R (1.3) wherein:
(1) R® and X are as defined for formula 1.0;
(2) B is the group;


-{CH:)P-.-C-IR"



(3) in said B group:
(a) P of the-{CHajp-moiety is 0; fb) p of the
moiety is 1 to 3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety
then R3O i3 3g,^^(g^ ^^^^ ^^^ ^^^p consisting of; -OH or-NH^. and R^^ is alkyl, most preferably C-Ce alkyl, more preferably C,-C4 alkyl, still more preferably CrC^ alkyl. and even more preferably methyl; (d) when p is 2 or 3 for the moiety

then: (1) for one -CR-R^"- moiety. R- is selected from the group consisting of; -OH or-NH,. and R^" is alkj^. most preferably C,-Ce alkyl, more preferably C,-C4 alkyl. still mor^ preferably Ci-C^ alkyl, and even more preferably methyi; and (2) for the remaining
-CR^R^i- moieties R^° and R^^ are hydrogen; and (6) R^ is unsubstituted heteroaryf (e.g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl. most preferably heteroaryl substituted with alkyl (e.g.. methyl), more preferably substituted imidazolyl. still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring

nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR^R^^- moiety when R^Ss-OHor-NHz;
(4) a is N;
(5) b, c and d are CR" groups wherein all of said R"" substituents are H, or one R" substituent is halo (e.g.. Br, CI or F) and the remaining two R^ substituents are hydrogen;
(6) m is 1. and R^"^ is halo (e.g., Sr or CI), or m is 2 and each R^ is the same or different halo (e.g., Br or C!); and
(7) R^ R^R^andR^^areH.
Another embodiment of this invention is directed to compounds of formula 1,1 having the formula:

(1.4)
wherein;
(1) R^ is as defined for formula 1.0;
(2) B is the group:
p.30
-(CH,U~C—VR"
R" /P
(3) in said B group:
(a) p of the -{CH2)p- moiety is 0;
(b) p of the



moiety is 1 to 3, preferably 1 to 2. most preferably 1; (c) when p is 1 for the moiety
,30>

then R^"^ is selected from the group consisting of: -OH or -NH2, and R"^" is alkyt, most preferably Ci-Cs alkyl, more preferably Ci-C4 alkyl, still more preferably C^•C2 alkyl, and even more preferably methyl; (d) when p is 2 or 3 for the moiety

then: (1) for one -CR^°R^^- moiety, R^° is selected from the group consisting of: -OH or -NH2, and R^^ is alkyl, nK>st preferably Cr Cg alkyl, more preferably CrC^ alkyl, still more preferably C1-C2 alkyl, and even more preferably methyl; and (2) for the remaining -CR^R^"- moieUes R^ and R^^ are hydrogen; and (e) R^ is unsubstituted heteroaryl {e.g., imidazolyl) or substituted heteroaryl. preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl {e.g., methyl), more preferably substituted imidazolyl, still more preferably irnidazolyt substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR^R^"- moiety when R^^is-OHor-NHa;
.) a is N;

(5) b, c and d are CR" groups wherein all of said R^ substituents are H, or one R" substituent is haio (e.g., Br. CI or F) and the remaining two R" substituents are hydrogen;
(6) m is 1, and R^^ is halo (e.g., Br or CI), or m is 2 and each R^ is the same or different halo {e.g., Br or CI);
(7) X!sNorCH;and
(8) R^ R^ R^ and R^^ are H.
Another emtiodiment of this invention is directed to compounds of formuia 1.1 having the formula:
B
(1.4A)

wherein:
0) (2)

a, b, c, d. R^*. R^ R^ R^ R"^ R° and X are as defined for formula 1.1; B is the group:



R

30

-(CHz)p4-C—K
R^" /P .

(3)

in said B group:
(a) p of the -(CH2)p- moiety is 0;
(b) p of the


moiety is 1 to 3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety



then
0} R^" is -OH, and R^" is H; or
(ii) R^° is -NH2, and R^" is H; or
(jii) R^ is selected from the group consisting of:
(1) -OR^ wherein R^ is Ci to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl, e.g., -OR^^ is-0CH3;
(2) -Na:
(3) -NHR^" wherein R^** is as defined for formula 1.1; and
(4) -/^(RS^IRS" wherein R^^ and R^^ is as defined for formula 1.1; and
R^" is selected from the group consisting of; H and alkyl {e.g.. Ci-Ce alkyl, CrC4 alkyl, C1-C2 alkyl. and methyl); (d) when p is 2 or 3 for the moiety
,30"


then:
0)

for one-CR^V-moiety
0) R"° is-OH. and R^Ms.Hi^or
(2) R"°is-NH2.andR3"isH;or
(3)
R"° is selected from the group consisting of: (a) -OR^ wherein R^ is C, to C3 alkyl. preferably C-Cs alkyl, and more preferably methyl, e.g., -OR^ is -OCH3; (b) -N3;

(c) -NHR^"" wherein R^ is as defined for formula 1.1; and
(d) -N(R^^)R^"" wherein R^ and R^ is as defined forformula 1.1; and
R^" is selected from the group consisting of: H and alkyl (e.g., C1-C6 alkyl, C,-C2 alkyl, and methyl); and (ii) for the remaining -CR^R^"- moieties R^° and R^* are hydrogen; and (e) R^ is unsubstituted heteroaryl (e.g., imidazolyS) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl {e.g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR^^R^"- moiety when R^"^ is selected from the group consisting of: -OH, -NHj, -OR^. -N3, and -NHR^^ Another emtKxJiment of this invention is directed to compounds of formula 1.1 having the formula:

(R"^)m
R

(1.4B)

wherein:
(1) R^ and X are as defined for formula 1.0;




(2) Bis the group:
(3) in said B group:
(a) p of the -(CH2)p- moiety is 0;
(b) p of the
moiety is 1 to 3. preferably 1 to 2. most preferably 1; (c) when p is 1 for the moiety
then
(i) R"° is -OH. and R^^ is H; or (ii) R"°is-NH2.andR^^-sH:or (iii) R"° is selected from the group consisting of:
(1) -OR^ wherein R^ is C, to C3 alkyl. preferably C-Cz alkyl, and more preferably methyl, e.g., -OR^ is-OCHa"
(2) -N3;
(3) -NHR^"" wherein R^"" Is as defined for formula 1.1; and .^
(4) -N[R^)R* wherein R^^ and R* is as defined for formula 1.1; and
R"^ is selected from the group consisting of: H and alky! (e.g.. C,-Cs alkyl. C,-C. alkyl. C,-C, alkyl. and methyl); (d) when p is 2 or 3 for the moiety


then:
(() for one -CR^"^R^"- moiety
(1) R^°is-OH.andR^MsH;or
(2) R^°is-NH2,andR^"isH:or
(a) -OR^ wherein R^^ is Ci to C3 alkyi. preferably C1-C2 alkyl, and more preferably methyl, e.g., -OR^^ is -OCH3;
(b) -N3;
(c) -NHR^" wherein R^ is as defined for formula 1.1; and
(d) -NCR^IR^" wherein R^ and R^" is as defined for formula 1.1; and
R-" is selected from the group consisting of: H and alkyl {e.g., Ci-Ce alkyl. C1-C2 alkyl, and methyl); and (ii) for the remaining -CR^°R^"- moieties R^ and R^" are hydrogen; and (e) R^ is unsubstituted heteroaryl (e.g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e.g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazoiyi substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR^R^^- moiety when R^° is selected from the group consisting of: -OH, -NH2. -OR^^, -N3, and -NHR*:

(4) a is N:
(5) b. c and d are CR" groups wherein all of said R" substituents are H. or one R" substituent is halo (e.g., Br, CI or F) and the remaining two R"" substituents are hydrogen;
(6) m is 1, and R^* is halo (e.g.. Br or CI), or m is 2 and eacti R^ is the same or different halo (e.g., Br or CI); and
(7) R^ R^ R^ and R^^ are H.
Another embodiment of this invention is directed to compounds of formula 1.1 having the formula:
e
(1.4C)
wherein:
(1) R" is as defined for fomiula 1.0:
(2) B is the group:
R30

-C—^R"
-(CH2)p.|- (J
R"VP

(3) ih said B group:
(a) p of the -(CH2)p- moiety is 0;
(b) p of the

moiety is 1 to-3, preferably 1 to 2, most preferably 1; (c) when p is 1 for the moiety


then
(i) R^°is-OH,andR^"isH;or
(ii) R^° is -NH2, and R^" is H; or
(iii) R-"° is selected from the group consisting of:
(1) -OR^ wherein R^ is C, to C3 alkyl, preferatJly CrC2 aikyl. and more preferably methyl, e.g., -OR^ is-OCHa;
(2) -Na;
(3) -NHR* wherein R^ is as defined for formula 1.1; and
(4) -N(R^)R^""wherein R^"and R^Ns as defined for formula 1.1; and
R^" is selected from the group consisting of; H and alkyl (e.g., CrCe alkyl. C^-Ci alkyl. C,-C2 alkyl. and methyl); (d) when p is 2 or 3 for the moiety

then:
(i) for one -^R^°R^^- moiety
(1) R^° is -OH. and R^" is-Ft^r
(2) R^° is -NHj, and R^^ is H; or
(3) R^° is selected from the group consisting of:

(a) -OR^" wherein R^ is Ci to C3 alkyl preferably C-Cz alkyl, and more preferably methyl, e.g., -OR^ is -OCH3;
(b) -N3;

(c) -NHR^ wherein R^ is as defined for fonnula 1.1; and
(d) -N(R^)R"""wherein R^" and R^ is as defined for formuia 1.1; and
R-*" is selected from the group consisting of: H and alkyl (e.g., C-Ce alkyi, C]-C2 alkyl, and methyl); and (ii) for the remaining -CR^R^"- moieties R^° and R^^ are hydrogen; and (e) R^ is unsubstituted heteroaryl (e.g.. imidazolyl) or substituted heteroaryl. preferably substituted heteroaryl. most preferably heteroaryl substituted with alkyl (e.g., methyl), more preferably substituted imidazolyl, still more preferably imidazoiyi substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR"^R^^- moiety when R^° is selected from the group consisting of: -OH, -NH2, -OR^, -N3. and -NHR*;
(4) a is N;
(5) b, c and d are CR^ groups wherein all of said R" substttuents are H, or one R^ substituent is halo (e.g., Br, CI or F) and the remaining two R" substituents are hydrogen;
(6) mis 1,and R^ls halo (e.g.. BrorCI), orm is2 and^ach R^is the same or different halo (e.g., Br or CI);
(7) X is N or CH; and
(8) R^R^R^andR^^areH.
Another embodiment of this invention is directed to compounds of formula 1.1 having the fomiula:


(R^^U
(1.4D)

wherein:
0) a, b, c.d.R^
a, b, c, d, R^, R^ R^ R^ R^", R^ and X are as defined for formula 1,1;
(2) B is the group:


-{CH,)p-~c—IR
— n9

(3) in said B group:
(a) P of the-(CHJV moiety is 0;
(b) p of the


301


(c)

moiety is 1;
0) R"°is-OH,andR^"isH;or
(ii) R""ts-NH2.andR^"isH;or
(iii) R"" is selected from the group consisting of:
(1) -OR^" wherein R^ is C^ to C3 alkyl, preferably C,-C2 alkyl, and more preferably methyl (e.g.. -OR^^ is-OCH^);
(2) -N3;
(3) -NHR^ wherein R^" is as defined for formula 1.1:and

(4) ^N(R^")R^" wherein R^ and R^" is as defined for formula 1.1; and R^" is selected from the group consisting of: H and alkyl (e.g., Ci-Ce alkyl. C-C^ alkyl. CpCa alkyl. and methyl); and (d) R^ is unsubstituted heteraary! {e.g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryi substituted with alkyl (e.g., methyl), more preferably substituted Imidarolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR^R^^- moiety when R^° is selected from the group consisting of-. -OH, -NH2, -OR^, -N3. and-NHR^. Another embodiment of this invention is directed to compounds of formula 1.4E having the fomiula:
B
(1-4E)
wherein:
(1) R^ and X are as defined for formula 1.0;
(2) Bis the group:
-(CH2)pi-C—V
(3) in said B group;

(a) p of the -(CHzIp- moiety is 0;
(b) p of the



moiety is 1;
(c)
(i) R^ is-OH, and R^^ is H; or
(ii) R^is-NH2. andR^"isH;or
(iii) R^ is selected from the group consisting of:
(1) -OR^^ wherein R^ is Ci to C3 alkyl. preferably Ct-C2 alkyl, and more preferably methyl (e.g., -OR^ is-OCHs);
(2) -N3:
(3) -NHR^ wherein R^" is as defined for formula 1.1; and
(4) -N{R^^)R^"= wherein R^ and R^"" is as defined forfomiula 1.1; and
R^" is selected from the group consisting of; H and alkyl (e.g., Ci-Cg alkyl, C1-C4 alkyl, C1-C2 alkyl, and methyl); and (e) R^ is unsubstituted heteroaryl (e.g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryl, most preferably heteroaryl substituted with alkyl (e.g.. methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl .substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryl group contains nitrogen in the nng, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR^°R^^- moiety when
D30 ; ,._._. c .1 :_.- r ^i i mi r^D^
R is selected from the group consisting of: -OH. -NH2, -0R~ -N3. and-NHR*;
(4) a is N;
(5) b, c and d are CR1 groups wherein all of said R" substituents are H, or one R" substituent is halo (e.g.. Br, CI or F) and the remaining two R" substituents are hydrogen;
(6) m is 1, and R1 is halo (e.g., Br or CI), or m is 2 and each R1""is the same or different halo (e.g., Br or CI); and
(7) R1R1R1andR1"areH.
Another embodiment of this invention is directed to compounds of formula 1.1 having the formula;


(iii) R1° is selected from the group consisting of;
(1) -OR1 wherein R1 is d to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g., -OR1" is-OCHa);
(2) -N3;
(3) -NHR1"" wherein R* is as defined for formula 1.1;and
(4) -N(R1)R1 wherein R1" and R1" is as defined for formula 1.1; and
R11 is selected from the group consisting of: H and alkyl (e.g., Ci-Cg alkyl, CrC1 alkyl. C1-C2 alkyl, and methyl}; and (e) R1 is unsubstrtuted heteroaryi (e.g., imidazolyl) or substituted heteroaryl, preferably substituted heteroaryt, most preferably heteroaryi substituted with alkyl (e.g., methyl), more preferably substituted imidazolyl, still more preferably imidazolyl substituted with alkyl, even more preferably imidazolyl substituted with methyl, yet more preferably imidazolyl substituted on a ring nitrogen with methyl, provided that when said heteroaryi group contains nitrogen in the ring, then said heteroaryi group is not bound by a ring nitrogen to the adjacent -CR1R11- moiety when R1° is selected from Ihe group consisting of; -OH, -NH2, -OR1, -N3. and -NHR*;
(4) a is N;
(5) b, c and d are CR" groups wherein all of said R" substituents are H. or one R" substituent is halo (e.g., Br, CI or F) and the remaining two R1 substituents are hydrogen;
(6) m is 1, and R1 is halo (e.g., Br or CI), or m is 2 and each R1 is the same or different halo (e.g., Br or CI);
(7) XisNorCH;and
(8) R1 R1 R1 and R1" are H.
Another embodiment of this invention is directed to compounds of fonmulas 1.2, I -3. 1.4, 1.4A, 1.48. 1.40, 1.4D. 1.4 E, and 1.4F wherein X is CH.

Another embodiment of this invention is directed to compounds of formulas 1.2. 1.3,1.4, 1.4A, 1,48, 1.40,1.40.1.4 E.and 1_4F wherein X is CH, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this; invention is directed to compounds of formulas 1.2. 1.3,1.4, 1.4A, 1.46, 1.4C, 1.4D, 1.4 E, and 1.4F wherein X is N.
Another embodiment of this invention is directed to compounds of formulas 1.2, 1.3, 1.4. 1.4A, 1.4B, 1.4C. 1.40, 1.4 E.and 1.4F wherein X is N. and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention Is directed to a compound of formula 1.4 wherein p is 1 for the moiety



and R1 is -NHj.
Another embodiment of this Invention Is directed to a compound of formula 1.4 wherein p is 1 for the moiety



R1*1 is-NH2, and X is N.
Another embodiment of this invention is directed to a compound of formula 1.40 wherein p is 1 for the moiety
,301

R1 is-NH2, R1"* is -CHa. X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1.46, or a compound of formula 1.4C wherein R "S -OH. and R1" is H,
Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1.4B, or a compound of formula 1.4C wherein R1° is -OH, R1" is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1.46, or a compound of formula 1.4C wherein R-"1 is -OH, R1" is H, X is N. and the optional bond between C5 and C6 is present {i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of fonnula 1.4A, or a compound of formula 1.48, or a compound of fonmula 1 AC wherein R1 is -NH2, and R11 is H.
Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 1.48, or a compound of formula 1.4C wherein R1° is -NH2, and R1" is H, and X is N.
Another embodiment of this invention is directed to a compound of fonnula 1.4A, or a compound of formula 1.46, or a compound of formula 1 AC wherein R1 is -NH2, and R11 is H, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed lo a compound of formula 1.4A. or a compound of formula 1.48. or a compound of fonnula 1.4C wherein R1° is selected from the group consisting of:
(1) -OR1 wherein R1 is Ci to C3 alkyl, preferably CrC2 slkyi, and more preferably methyl (e.g., -OR1 is-GCHs);
(2) -N3;
(3) -NHR1" wtierein R1" is as defined for formula 1.1; and
(4) -NR11 R1 wherein R1 and R* is as defined for fomiula 1.1; and
R1" is selected from the group consisting of: H and alkyl (e.g., Gi-Ce alkyl, CrCt, alkyl,
Ci"Ca alkyl, and methyl).
Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of formula 148, or a compound of formula 1.4C wherein R1°is selected from the group consisting of:.
(1) -OR11 wherein R1 is C, to C3 alkyl. preferably CrCz alkyl, and more preferably methyl (e.g., -OR1 is-OCHj);
(2) -N3;
(3) -NHR1 wherein R1" is as defined for formula 1.1; and
(4) -NR1" R1" wherein R11 and R1"" is as defined for formula 1.1; and

R1"is selected from the group consisting of; H and alkyt (e.g., Ci-Ce alkyi, CrC4 alkyi, C1-C2 alkyl, and methyl), and X is N,
Another embodiment of this invention is directed to a compound of formula 1.4A, or a compound of fonnula 1.48, or a compound of formula 1.4C wherein R1"" is selected from the group consisting of:
(1) -OR11 wherein R1 is C, to C3 alkyt, preferably d-Ci alkyl. and more preferably methyl (e.g., -OR11 is-OCHa):
(2) "N3;
(3) -NHR1" wherein R1 is as defined for formula 1.1; and
(4) -NR11 R1*1 wherein R1 and R1is as defined for fonnula 1.1; and
R1" is selected from the group consisting of: H and alkyl (e.g., Ci-Cg alkyl, C1-C4 alkyl,
CrG2 alkyl, and methyl), and X is N, and the optional bond between C5 and G6 is
present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.4D wherein R1° is-OH, and R11 is H.
Another embodiment of this invention Is directed lo a compound of formula 1.4D wherein R1° is-OH, R1" is H, and X is N.
Another embodiment of this invention is directed to a compound of formula 1.4D wherein R1 is ~OH, R11 is H, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.40 wherein R1"1 is -NH2. and R11 is H.
Another embodiment of this invention is directed to a compound of formula 1.40 wherein R1° is-NHz. and R1" is H, and X is N.
Another embodiment of this invention is directed to a compound of formula 1.4D wherein R1° is-NHa, and R11 is H, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of fonnula 1.4D wherein R1° is selected from the group consisting of:
(1) -OR1 wherein R1 is Ci to Cj alkyl, preferably C1-C2 alkyi, and more preferably methyl (e.g.. -OR11 is-OCHs);
(2) 1N3;
(3) -NHR1" wherein R1 is as defined for fomiula 1.1; and

(4) -NR1R11 wherein R1"and R1" is as defined for formula 1.1; and R1" is selected from the group consisting of: H and alky) (e.g., Cj-Cs alkyl, C1-C4 alkyi, C1-C2 alkyl, and methyl).
Another embodiment of this invention is directed to a compound of fonnula I.4D wherein R1° is selected from the group consisting of:
(1) -OR1 wherein R11 is C1 to C3 alkyl. preferably C1-C2 alkyl, and more preferably methyl (e.g., -OR1 is-OCH1);
(2) -N3;
(3) -NHR1 wherein R1 is as defined for formula 1.1; and
(4) -NR1 R* wherein R1 and R* is as defined for formula 1.1; and
R1" is selected from the group consisting of: H and alky) (e.g., Cj-Cs alkyl, C1-C4 alkyl,
CrC2 alkyl, and methyl), and X is N.
Another embodiment of this invention is directed to a compound of formula 1.4D wherein R""1 is selected from the group consisting of:
(1) -OR1 wherein R1 is Ci to C3 alkyl, preferably d-Ca alkyl, and more preferably methyl (e.g., -OR11 is-OCHa);
(2) -N3;
(3) -NHR1 wherein R1 is as defined for fonnula 1.1; and
(4) -NR1 R1 wherein R1" and R1"" is as defined for formula 1.1: and
R1" is selected from the group consisting of: H and alky! (e.g., Ci-Ce alkyl, C1-C4 alkyl,
C1-C2 alkyl, and methyl), and X is N, and the optional bond between C5 and C6 is
present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.4E wherein R1° is-OH, and R11 is H.
Another embodiment of this invention is directed to a compound of formula 1.4E wherein R1 is-OH, R11 is H, and X is N.
Another embodiment of this invention is directed to a compound of formula 1.4E wherein R1 is -OH. R11 is H, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.4E wherein R1° is -NH2. and R1" is H.
Another emtx>diment of this invention is directed to a compound of formula 1.4E wherein R1° is-NHj. and R1" is H, and X is N.

Another embodiment of this invention is directed to a compound of formula 1.4E wherein R1"* is-NH1, and R11 is H, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.4E wherein R1° is selected from the group consisting of:
(1) -OR11 wherein R11 is C, to C3 alkyl. P1"11erably C1-C2 alkyi, and more preferably methyl (e.g., -OR1 is-OCHj);
(2) -No;
{3} -NHR1" wherein R1 is as defined for formula 1.1; and
(4) -NR11 R1" wtierein R1 and R11 is as defined forfomiula 1.1; and
R1" is selected from the group consisting of: H and alkyl (e.g., CrCe alkyl. C1-C4 alkyi,
CrC2 alkyl, and methyl).
Another embodiment of this invention is directed to a compound of formula
1.4E wherein R1"1 is selected from the group consisting of;
(1) -OR11 wherein R1"" is Ci to Go alkyl, preferably d-C1 alkyl. and more preferably methyl (e.g.. -OR11 is-OCHa);
(2) -N3;
(3) -NHR11 wherein R1" is as defined for formula 1.1; and
(4) -NR1" R1" wherein R1 and R1"" Is as defined for formula 1.1; and
R1" is selected from the group consisting of; H and alkyl (e.g., Ci-Ce alkyf, G1-C4 alkyi,
C1-C2 alkyl, and methyl), and X is N.
Another embodiment of 1is tnvenfon is directed to a compound of fonmula 1-4E wherein R1*1 is selected from the group consisting of:
(1) -OR1 wherein R1 is Ci to C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl (e.g.. -OR1 is-0CH3);_
(2) -N3;
(3) -NHR* wherein R1"" is as defined for formula 1.1; and
(4) -NR1 R1"" wherein R1 and R1*" is as defined for formula 1.1; and
R11 is selected from the group consisting of; H and alkyl (e.g., CrCg alkyl, C1CA alkyl,
CrC2 alkyl, and methyl), and X is N, and the optional bond between C5 and 06 is
present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.4F wherein R1 Is-OH. and R11 is H.

Another embodiment of this invention is directed to a compound of formula 1.4F wherein R11 is-OH. R1" is H. and X is N.
Another embodiment of this invention is directed to a compound of formula 1 .4F wherein R1" is -OH, R11 is H, X is N. and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.4F wherein R1° is -JMH;. and R1" is H.
Another embodiment of this invention is directed to a compound of formula 1.4F wherein R1 is-NHz, and R1" is H. and X is N.
Another embodiment of this invention is directed to a compound of formula 1.4F wherein R1 is-NH;, and R11 is H, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to a compound of formula 1.4F wherein R"1"1 is selected from the group consisting of:
(1) -OR1 wherein R11 Is Ci to C3 alkyl. preferably CrC2 alkyl. and more preferably methyl (e.g.. -OR11 is-OCH3);
(2) -N3:
(3) -NHR1"" wherein R1" is as defined for formula 1.1: and
(4) -NR1" R* wherein R1 and R1"" is as defined for fonnula 1.1; and
R11 is selected from the group consisting of: H and alkyl (e.g.. Ci-Ce alkyl, Ci-C4 alkyl,
C1-C2 aiKyl, and methyl).
AnoUier embodiment of this invention is directed to a compound of formula 1.4F wherein R1° is selected from the group consisting of;
(1) -OR1 wherein R1 is Ci to Cj alkyi, preferably CrCa alkyl. and more preferably methyl (e.g., -OR11 is-OCHa);..
(2) -N3;
(3) -NHR1"" wherein R1*" is as defined for formula 1.1; and
(4) -NR1" R11 wherein R1 and R1 is as defined for formula 1.1; and
R1" is selected from the group consisting of: H and alkyi (e.g., Ci-Ce alkyl. Ci-C4 alkyl,
CrCa alkyl, and methyl), and X is N.
Another embodiment of this invention is directed to a compound of fomiuia 1.4F wherein R"1° is selected from the group consisting of:

(1) -OR11 wherein R1 is C, to C3 alkyl, preferably C1-C2 alkyl. and more preferably methyl (e.g.. -OR11 is-OCH3);
(2) -N3;
(3) -NHR* wherein R* is as defined for formula 1.1; and
(4) -NR1 R1"" wherein R11 aad R-"" is as defined for formula 1.1; and
R1" is selected from the group consisting of: H and alkyl (e.g., Ci-Ce alkyl, C1-C4 aikyI,
C1-C2 alkyl, and methyl), and X is N, and the optional bond between C5 and C6 is
present {i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of formula 1.40, 1.4E or 1.4F wherein R1 is -OR1 and R1" is H.
Another embodiment of this invention is directed to compounds of formula 1.40.1.4E or 1.4F wherein R1° is -OR1, R1" is H. and X is N.
Another embodiment of this invention is directed to compounds of formula 1.40, 1.4E or 1.4F wherein R1 is -OR1. R11 is H, X is N. and the optional bond between C5 and C6 is present (i.e., ttiere is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of formula 1.40, 1.4E or 1.4F wherein R1° is -N3 and R11 is H.
Another embodiment of this invention is directed to compounds of formuia 1.40,1.4E or 1.4F wherein R1° is -N3, R11 is H, and X is N.
Another embodiment of this invention is directed to compounds of formula 1.40,1.4E or 1.4F wherein R1 is -N3. R1" is H, X is N, and the optional bond between C5 and G6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of fomula 1.40,1.4E or 1.4F wherein R1 is -NHR* and R11 is H.
Another emt>odimenl of this invention is directed to compoj;nds of fomnuta 1.40, 1.4E or 1.4F wherein R1 is -NHR11 R11 is H, and X is N.
Another embodiment of this invention is directed to compounds of formula 1.40,1.4E or 1.4F wherein R1° is -NHR1*", R1" is H, X is N. and the optional bond between C5 and C6 is present (i.e.. there is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of formula 1.40, 1.4E or 1.4F wherein R1 is -NR1R* and R11 is H.
Another embodiment of this invention is directed to compounds of fomnula 1.40, 1.4E or 1.4F wherein R1° is -NR1R* R1" is H, and X is N.

Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R1 is -NR1R11 R1" is H, X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of formula 1.40, 1.4E or 1.4F wherein R1 is -OR1 and R11 is alkyl (e.g.. methyl).
Another emtrodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R1 is -OR11 R11 is alkyl (e.g., methyl), and X Is N.
Another embodiment of this invention is directed to compounds of fomiula 1.4D. 1.4E or 1.4F wherein R1 is -OR1, R1" is alkyl (e.g., methyl). X is N. and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of formula 1.4D. 1.4E or 1.4F wherein R1° is -N3 and R1"" is alkyl (e.g.. methyl).
Another embodiment of this invention is directed to compounds of formula 1.4D. 1.4E or 1.4F wherein R1"1 is-N3, R11 is alky! (e.g.. methyl), and X is N.
Another embodiment of this invention is directed to compounds of fonnula 1.4D, 1.4E or 1.4F wherein R1 is-N3.R1" is alkyl (e.g., methyl), X is N, and the optional bond between C5 and C6 is present (i.e., there is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of formula 1.4D, 1.4E or 1.4F wherein R1 is -NHR1"" and R1" is alkyl (e.g., methyl).
Another embodiment of this invention Is directed to compounds of formula 1.4D. 1.4E or 1.4F wherein R1° Is -NHR* R1" is alkyl (e.g., methyl), and X is N.
Another embodiment of this invention is directed to compounds of formula 1.40.1.4E or 1.4F wherein R1° is -NHR11 R1" is alkyl (e.g., meth>d). X is N. and the optional bond betv/een C5 and C6 is present (i.e.. there is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of fonnula 1.40, 1.4E or 1.4F wherein R1 is -NR1R1"" and R11 is alkyl (e.g., methyl).
Another embodiment of this invention is directed to compounds of formula 1.40. 1.4Eor 1.4F wherein R1° is —NR1R1"". R1" is alkyl (e.g.. methyl), and X is N.
Another embodiment of this invention is directed to compounds of formula 1.40,1.4E or 1.4F wherein R1" is —NR1R11 R11 is alkyl (e.g.. methyl), X is N, and the

optional bond between C5 and C6 is present (i.e.. there is a double bond between C5 and C6).
Another embodiment of this invention is directed to compounds of formulas 1.4D. 1.4E and 1.4F. wherein for the R1"1 substituent -NHR-1 9b is preferably --C{0)R11 and more preferably-C(0)R1 wherein R11 is alkyl.
Another embodiment of this invention is directed to compounds of formulas 1.4D, 1.4E and 1.4F, wherein for the R1° substituent -NHR1, 9b is preferably -C{0)R11 and more preferably -C(0)R1 wherein R1 is alkyf; and R1" is H.
Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R1 is formula 2.0 wherein R" is as defined for formula 1.0.
Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R1 is formula 3.0 wherein R"" is as defined forfomiula 1.0.
Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R1 is 4.0 wherein R"1 and R"1 are as defined for formula 1.0.
Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4Eand 1.4F wherein R1 is 5.0 wherein R1\ R1, and R""1 are as defined forfomiula 1.0.
Anottier embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, l.4Eand 1.4F, wherein R® is formula 2.0 wherein R" is alkyl (e.g., isopropyl ort-butyl).
Another embodiment of this invention is directed to any of the emhradiments directed to formulas 1.4D, 1.4E and 1.4F,whereir>R® is formula 2.0 wherein R1"is alkyl (e.g., isopropyl or t-butyl, and preferably isopropyl), R1° is -NH2 and R1" is H.
Another embodiment of this invention is directed to compounds of formulas 1.4D. 1.4E and 1.4F, wherein for the R1 substituent-NHR*. 9b is preferably -C(0)R11 and more preferably -e(0)R*" wherein R11 is alky), and R° is formula 2.0 wherein R" is alkyl (e.g., isopropyl or t-butyf).
Another embodiment of this invention is directed to compounds of formulas 1.40, 1.4E and 1.4F, wherein for the R1 substituent -NHR*, 9b is preferably

-C{0)R11 and more preferably-C(0)R11 wherein R11 is alkyl, and R1" is H, and R1 is formula 2.0 wherein R" is alky) (e.g., isopropyl ort-butyi).
Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.40,1.4E and 1.4F wherein substituent a in Ring I is N, and substituents b, c, and d in Ring I are CR1 groups, and all of said R" substituents are H.
Another embodiment of this invention is directed to any of the embodiments directed to fomiulas 1.4D, 1.4E and 1.4F wherein substituent a in Ring I is N, and substituents b, c, and d in Ring I are CR" groups, and said R" substituent at C-3 is halo and said R1 substituents at C-2 and C-4 are hydrogen.
Another embodiment of this invention is directed to any of the emtxJdiments directed to fomiulas 1.4D. 1.4E and 1.4F wherein m is 1 and R1 is halo.
Another emtxxJiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein m is 1 and R1"1isCl.
Another embodiment of this invention is directed to any of the embodiments directed to fomiulas 1.4D, 1.4£ and 1.4F wherein m is 1 and R1 is halo at the C-8 position.
Another emtxidiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1,4E and 1.4F wherein m is 1 and R1isCI at the C-8 position.
Another embodiment of this invention is directed to any of the emtwdiments directed to fonr1ulas 1.4D, 1.4E and 1.4F wherein m ts 2, and each R1 is the same or different halo, and said halo substitution is at the C-7 and C-6 position or the C-8 and C-10 position.
Another embodiment of this invention is directed to any of the emtwdiments directed to formulas 1.4D, 1.4E and 1.4F wherein R1 is unsubstituted heteroaryi or substituted heteroaryi.
Another emtxidiment of this invention Is directed to any of the emtwdlments directed to formulas 1.4D, 1.4E and 1.4F wherein R1 is substituted heteroaryi.
Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R1 is substituted heteroaryi wherein said heteroaryi is mono substituted.

Another embodiment of this invention is directed to any of the embodiments directed to fonnulas 1.4D, 1,4E and i .4F wherein R1 is unsubstituted imidazolyl or substituted imidazolyl.
Another embodifnent of this invention is directed to any of the embodiments directed to formulas 1.4D, 1.4E and 1.4F wherein R1 is substituted imidazolyl.
Another embodiment of this invention is directed to any of the embodiments directed tofonnulas 1.4D, 1.4Eand 1.4F wherein R1 is substituted imidazolyl wherein said imidazojy) is mono substituted and tfie substituent is alkyl (e.g., Ci to C3 alkyl, or Ci to C2 alkyl), and preferably said substituent is methyl.
Another embodiment of this invention is directed to any of the embodiments directed to formulas 1.40.1.4E and 1.4F wherein R1 is.
In another embodiment, R1 is 2.0 in fonnula 1.2 wherein R1" is as defined for formula 1.0.
In another embodiment, R1 is 3.0 In formula 1.2 wherein R1" is as defined for formula 1.0.
In another embodiment, R® is 4.0 in formula 1.2 wherein R"1and R"1 are as defined for fonmula 1.0.
In another embodiment. R1 is 5.0 in fonnula 1,2 wherein R1\ R1, and R**1 are as defined for formula 1.0.
In another embodiment, R* is 2.0 in fomnula 1.3 wherein R11 is as defined for formula 1.0.
In another embodiment, R® is 3.0 in formula 1.3 wherein-RiVis as defined for formula 1.0.
In another embodiment. R° is 4.0 in formula 1.3 wherein R1 "1 and R11 are as defined for formula 1.0.
in another embodiment. R1 is 5.0 in formula 1.3 wherein R1\ R1, and R"*1 are as defined for fomiula 1.0.
In another embodiment, R1 is 2.0 in formula 1.4 wherein R"1 Is as defined for formula 1.0.

In another embodiment, R1 is 3.0 in formula 1.4 wherein R""1 is as defined for formula 1.0.
In another embodiment, R1 is 4.0 in formula 1.4 wherein R"11and R"1are as defined for formula 1.Q.
In another embodiment, R® is 5.0 in fomiula 1.4 wherein R1", R1, and R"*1 are as defined for formula 1.0.
Preferably, in formulas 1-3 and 1.4, all R" substituents are H, or R"" at C-3 is halo and R1 at C-2 and C-4 is hydrogen, most preferably all R" substituents are hydrogen.
Preferably, in fomiuias 1.3 and 1.4, when m is 1 then R1 is preferably CI at the C-3 position.
In formulas 1.3 and 1.4, when m is 2, then the substitution is 7,8-dihalo, or 8,10-dihalo.
Preferably, in formulas 1.3 and 1.4, the optional double bond between C5 and C6 Is present, i.e., preferably there is a double bond between C5 and C6.
Preferably, in fomiuias 1.2 and 1.3 X is N.
Preferably, in formula 1.4 X is N.
Another embodiment of this invention is directed to compounds of formula 1.4 having the formula:
B

(1.5)
wherein ail substituents are as defined for formula 1.4. Preferably R1 is 2.0, most preferably 2.0 wherein R11 is alkyl, more preferably 2.0 wherein R11 is t-butyl or isopropyl, and even more preferably 2.0 wherein R" is isopropyl.

Another embodiment of the invention is directed to compounds of fomiula 1.5 having the formula:



3A
(R"1l
(R"1)m
or
(1.7)
wherein ail substituents are as defined for formula 1.4. Preferably R1 is 2.0, most preferably 2.0 wherein R" is alkyl, more preferably 2.0 wherein R" is t-butyl or isopropyl. and even more preferably 2.0 wherein R" is isopropyt.
Thus, one embodiment of the invention is directed to compounds of formuia 1.5 having the fonmula:


,30
R"VT1R1
wherein all substituents are as defined for formula 1.4. Preferably R1 is 2.0, most preferably 2.0 wherein R11 is alkyl, more preferably 2.0 wherein R1" is t-buty! or isopropyl, and even more preferably 2.0 wherein R" is isopropyl.

Another embodiment of the invention is directed to compounds of formula 1.5 having the fonriuta:


(R11U

wherein all substituents are as defined for formula 1.4. Preferably R1 is 2.0, most preferably 2.0 wherein R1" is alkyl, more preferably 2.0 wherein R" is t-butyl or isopropyl, and even more preferably 2.0 wherein R11 is isopropyl. lnfomiulas1.2. 1.3.1.4,1.5.1.6, and 1.7, R1 is preferably:
H3C

Another embodiment of this invention is directed to compounds of formula 1.40,1.4E or 1.4F having the fonnula-.


(1.5A)

wherein all substituents are as defined for fonmulas 1.40,1.4E or 1.4F. Compounds of formula 1.5A inciude compounds wherein R1 is 2.0, and include compounds

wherein R1 is 2.0 wherein R1" is alkyl (e.g.. Ci to C4. such as, isopropy or t-butyl). Preferably R1 is 2.0, R11 is isopropyl. R1 is -NH3, and R1" is H.
Another embodiment of the invention is directed to compounds of fonnula 1.5A having the formula:


(R1U
{R1"U

R"
R-
"-11
IV
7a
or

1y
-R
(1.7A)

wherein all substituents are as defined for foimulas 1.40,1.4E or 1.4F. Ck)mpounds of fomnula 1.5A include compounds wherein R1 is 2.0, and include compounds wherein R1 is 2.0 wherein R"1 is alkyl {e.g., Ci to C4, such as, isopropy or t-butyl). Preferably R1 is 2.0. R1" is isopropyl, R1° is -NH2, and R1" is H.
Thus, one embodiment of the invention is directed to compounds of formula 1.5A having the formula;


(R"")1

wherein all substituents are as defined for formulas 1.40, 1.4E or 1.4F. Compounds of fonnula 1,5A include compounds wherein R1 is 2.0, and include compounds

wherein R1 is 2.0 wherein R" is alkyi (e.g., C, to C4, such as, isopropy or t-butyl). Preferably R1 is 2.0, R" is isopropyl, R1° is -NH2. and R1" is H.
Another embodiment of the invention is directed to compounds of formula 1.5A having the formula;


(R"1)m

v/herein all substituents are as defined for formulas 1.4D, 1.4E or 1.4F. Compounds of formula 1.5A include compounds wherein R1 is 2.0, and include compounds wherein R* is 2.0 wherein R1"" is alky! {e.g., Ci to d, such as, isopropy or t-butyl). Preferably R1 is 2.0, R" is isopropyl, R1° is -NH2, and R11 is H.
The compounds of formula 1.0 include the R isomer
In formulas 1.4D, 1.4E, 1.4F. 1.5A. 1.6A, and 1.7A. R1 is preferably:



(R"1)m
or
(1.0 A)
wherein:
X is N or CH;
aisNorC(NorCR1 in 1.1A);and
the optional bond between C-5 and C-6 is present and B is H. or the optional bond between C-5 and C-6 is absent and each B is H.
The compounds of formula 1.0 also include the S isomer



= S
(R1L
/"X
-R"
or
,7a
IV J.
■R
R"
R" (I.OB)
wherein."
X is N or CH (preferably N);
a is Nor C (a is NorCR1 (n 1.16); and
the optional bond between C-5 and C-6 is present and A is H, or the optional bond between C-5 and C-6 is absent and each A is H (preferably the optional bond between C-5 and C-6 is present).

Inoneembodiment of the compounds of formula 1.0, R\ R1, R1 and R"* are independently selected from the group consisting of: H and halo, more preferably H, Br, F and CI, and even more preferably H and CI. Representative compounds of formula 1.0 include dihalo (e.g., 3,8KJihalo) and monohalo {e.g., 8-halo) substituted compounds, such as, for example: (a) 3-bromo-8-chloro, (b) 3,8-dichloro, (c) 3-bromo, (d) 3-chlorQ, (e) 3-fluoro, (f) 8-ch!oro or (g) 8-bromo.
In one embodimentof the compounds of formula 1.1, each R" is independently selected from the group consisting of: H and halo, most preferably H. Br, F and CI, and more preferably H and CI. Each R1 is independently selected from the group consisting of: H and halo, most preferably H, Br. F and CI, and more preferably H and CI. Representative compounds of formula 1.1 include dihalo (e.g., 3,8-dihalo) and monohalo (e.g., 3-halo or 8-halo) substituted compounds, such as, for example: (a) 3-bromo-8-chloro, (b) 3,8-dichloro, (c) 3-bromo, (d) 3-chtoro, (e) 3-fluoro, (f) 8-chloro or (g) 8"bromo.
In one embodiment of the invention, substituent a in compounds of formula 1.0 is preferably C or N, with N being preferred, and substituent a in compounds of formula 1.1 is CR1 or N, with N being prefen-ed.
In one embodiment of the invention, R° in compounds of fomiula 1.0 is selected from the group consisting of:

C1o1 - I „ . C1 N1 . and o1 c—R1
R" \1
1 1R" 0=S=0 J1 1R"1 1 X /1"R"
(2-0) (3.0)
(4.0) (5.0)
In one embodiment of the invention, R® in compounds of fonnuia 1.0 is 2.0 or 4.0; and preferably R1 is 2.0.
In one embodiment of the invention, for compounds of fonnula 1.0, R111 is selected from the group consisting of: alkyl, substituted alkyl, unsubstitufed aryl, substituted aryl, heleroaryl, substituted heteroaryl, unsubstituted cyioalkyi and substituted cycloaikyi, wherein:
(1) said substituted aryl and substituted heteroaryl R"1 groups are substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from the group consisting of: halo (preferably F or CI), cyano, -CFa, and alkyl;

(2) said substituted cydoalkyl R"1 groups are substituted with one or more {e.g., 1, 2 or 3) subslituents independently selected from the group consisting of: fluoro, cyano, -CF3. and alkyl; and
(3) said substituted alkyl R1"1 groups are substituted with one or more (e.g., 1.2 or 3) substituents selected from the group consisting of. fluoro, cyano and CF3.
In one embodiment of the invention, for compounds of formula 1.0, R"1 is selected from the group consisting of: alkyJ, unsubstituted aryl, substituted aryl, unsubstituted cyloalkyl, and substituted cydoalkyl, wherein:
(1) said substituted aryl is substituted with one or more (e.g.. 1, 2 or 3) substituents independently selected from the group consisting of: halo, (preferably F or CI). -CN and CF3; and
(2) said substituted cydoalkyl is substituted with one or more (e.g., 1. 2 or 3) substituents independently selected from the group consisting of: fluoro, -CN and CF3.
In one emtrodiment of the Invention, for compounds 1.0, R111 Is selected from the group consisting of: methyl, t-butyl, phenyl, cyanophenyl, chiorophenyl, fluorophenyt, and cydohexyi. In another embodiment, R"1 is selected from the group consisting of: t-butyl, cyanophenyl, chiorophenyl, fiuorophenyl and cydohexyi. In another embodiment, R111 is cyanophenyl (e.g., p-cyanophenyl).
In one embodiment of ttie invention, for compounds of formula 1.0, R11 is selected from the group consisting of alkyl, unsubstituted cydoalkyt, and substituted cydoalkyl. wherein said substituted cydoalkyl group is substituted with 1,2 or 3 substituents independently selected from the group consisting of: fluoro and alkyl (preferably methyl or t-butyl). Examples of R" groups include: methyl, ethyl, propyl, isopropyl, t-butyl, cydohexyi or substituted cydohexyi. In one embodiment of the invention, R"" is selected from the group consisting of: methyl, isopropyl. t-butyl, cydohexyi and fluorocydohexyl (preferably p-fluorocydohexyl). In one embodiment of the invention, R" is selected from the group consisting of: methyl, isopropyl, t-butyl, and cydohexyi. In one embodiment of the invention R11 is t-butyl or cydohexyi. in one embodiment of the invention R" is l-butyl for 2.0, and R11 is methyl for 3.0. In one embodiment of this invention R" is isopropyl.

(n one embodiment of the invention, for compounds of formula 1.0, R11 is selected from the group consisting of: H and methy!. In one embodiment of the invention, R11isH.
In one embodiment of the invention, for compounds of formula 1 -0, R1 R1, R1 and R""1 are H.
In one embodiment of the invention, for compounds of formula 1.0, R1 is selected from the group consisting of;
(1) unsubstituted heteroaryl;
(2) substituted heteroaryl;
(3) arylalkoxy;
(4) substituted aryjalkoxy;
(5) hetarocycloalkyl;
(6) substituted heterocydoalkyl;
(7) heterocycloalkyialky!;
(8) substituted heterocycloalkylalkyl;
(9) heteroarylalkyi;
(10) substituted heteroarylalkyi;
(11) heteroarylalkenyl and
(12) substituted heteroarylalkenyi;
wherein said substituted R® groups are substituted with one or more substituents (e.g., 1, 2, or 3) independently selected from the group consisting of:
(1) -OH;
(2) -CO2R". wherein R" is selected from the group consisting of: H and alkyl (e.g., methyl and ethyl), preferably alkyl, most preferably methyl or ethyl; , _
(3) alkyl substituted with one or more -OH groups (e.g.. 1, 2. or 3, preferably 1), for example, -(CH2)qOH wherein, q is 1 -4, with q = 1 being preferred;
(4) halo (e.g., Br. F.I, or CI);
(5) afkyi, usually Ci-Ce alkyl. preferably C1-C* alky! (e.g., methyl, ethyl, propyl, isopropyi, t-butyi or butyl, preferably isopropyl. or t-butyl);
(6) amino;
(7) tdtyl;

(8) heterocydoalkyi:
(9) ar/laikyi (e.g. benzyl);
(10) heteroaryl (e.g. pyridyl) and
(11) heteroarylalkyi;
In one embodiment of the invention, for the compounds of formula 1.0, R1 is selected from the group consisting of:
(1) heterocycloalKyl;
(2) substituted heterocycloalKyl;
(3) heterocycloalkylalkyl;
(4) substituted heterocycloalkylalkyl;
(5) unsubstituted heteroarylalkyl;
(6) substituted heteroarylalkyl;
(7) unsubstituted heteroarylalkenyl and
(8) substituted heteroarylalkenyl;
wherein said substituted R1 groups are substituted with one or more substituerits (e.g.. 1, 2. or 3) independently selected from the group consisting of:
(1) -OH;
(2) -CO2R"* wherein R1* is selected from the gnaup consisting of; H and alkyl (e.g., methyl or ethyl), preferably alkyl. and most preferably methyl and ethyl;

(3) aikyl, substituted vwth one or more -OH groups (e.g„1,2, or 3, preferably 1), for example -(CH2)qOH wherein, q is 1 - 4, with q = 1 being preferred.
(4) halo (e.g.. Br or CI);
(5) alkyl, usually CrCg alkyl. preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, tsopropyt, butyl or t-buty), most preferably t-but)1);
(6) amino;
(7) trityi;
(8) heterocycloalkyi;
(9) arylalkyi;
(10) heteroaryl and
(11) heteroarylalkyl;
In one embodiment of \he invention, for fomiula 1.0, R1 is selected from the group consisting of:

(1) heterocycloalk/t;
(2) substituted heterocycloatkyi;
(3) helGrocycloalkylalkyl;
(4) substituted heterocydoalkylalkyl;
(5) unsubstituted heteroarylalkyi;
(6) substituted heteroarylalkyi;
(7) unsubstituted heteroarylalkenyl and
(8) substituted heteroacyiaikenyl;
wherein said substituted R1 groups are substituted with one or more substituents (e.g., 1,2. or 3) independently selected from the graup consisting of:
(1) halo {e.g., Br. or CI);
(2) aikyl. usually Cj-Ce alkyl. preferably C1-C4 alkyl (e,g. methyl, ettiy!, propyl, isopropyi, buty! or t-butyl, most preferably
t-butylj;
(3) alkyt, substituted with one or more (i.e. 1,2, or 3, preferably 1) -OH groups, (e.g. -(CH2)qOH wherein q is 1-4, with q=1 being preferred).
(4) amino;
(5) trityl;
(6) arylalkyl. and
(7) heteroarylalkyi.
In one embodiment of the invention, R® is selected from the group consisting of;
(1) heterocydoalkylalkyl;
(2) substituted heterocydoalkylalkyl;
(3) unsubstituted heteroarylalkyi and
(4) substituted heteroarylalkyi;
wherein said substituted R1 groups are substituted with one or more substituents (e.g., 1,2, or 3) independently selected from the group consisting of:
(1) halo (e.g., Br, or CI);
(2) alkyl. usually Ci-Ce alkyl, preferably C,-C4 alkyl
(e.g. methyl, ethyl, propyl, isopropyi, butyl and t-butyl. most preferably t-butyl);
(3) amino; and

(4) trityl. In one embodiment of the invention, for formula 1 -0. R1 is selected from the group consisting of;
(1) heterocycioalkylalkyi;
(2) substituted heterocycioalkylalkyi;
(3) unsubstituted heteroarylalkyi and
(4) substituted heteroaryfalkyi;
wherein said substituted R1 groups are substituted with one or more substituents (e.g., 1, 2, or 3) independently selected from the group consisting of:
(1) halo{e.g.,Br,orCl);and
(2) alkyl. usually Ci-Ce alkyl, preferably C1-C1 alkyl
(e.g. methyl, ethyl, propyl, isopropyl, butyl or l-butyi. most preferably t-butyl). In one embodiment of the invention, for fomiula 1.0, R1 rs selected from the group consisting of:
(1) piperidinyl;
(2) piperizinyl;
(3) -{CH2)p-piperidinyI;
(4) -{CH2)p-pip9rizinyl;
(5) -(CH2)p-morpholinyl and
(6) KCH2)p-imida2olyi;
wherein p is 0 to 1, and wherein the ring moiety of each R® group is optionally substituted with one, two or three substituents independently selected from the group consisting of:
(1) halo {e.g., Br.or CI); and , _ .
(2) alkyl, usually Ci-Cs alkyl. preferably CrC4 alkyl (e.g. methyl, ethj1, propyl, isopropyl, butyl or t-butyl, most preferably t-butyt).
In one embodiment of the invention, for formula 1.0, R1 is selected from the group consisting of;
(1) -piperizinyl;
(2) -{CH2)p-piperidinyl;
(3) - (4) -(CH2)o-morpholinyl,

wherein p is 1 to 4, and the ring moiety of each R1 group is optionally substituted with one, two or three substituents independently selected from the group consisting of: methy!, ethyl, and isopropyl.
In one embodiment of the invention, for fomiula 1.0, R1 is selected from the group consisting of: -(CHzH"1"dazolyl, wherein said imidazolyl ring is optionally substituted with 1,2, or 3 substituants, preferably 1, independently selected from the group consisting of. methyl or ethyl.
In one embodiment of the invention, for fonnula 1.0, R® is -{CHzVta-methytHmidazolyl.
In one embodiment of the invention, for formula 1,0, at (east one of R1", R" and R11 is other than H or alkyl. In one embodiment of the invention, R1" and R1 is H and R*1 is other than H or alk>1. In one embodiment of the invention, R1" and R1 is H and R*® is selected from the group consisting of: heteroar/l and heterocycloalkyl.
In one embodiment of the invention, for fomiula 1.0, said heteroaryl groups for said R1\ R1 or R*1 are independently selected from the group consisting of: 3-pyridj1, 4-pyridyl. 3-pyridyl-N-Oxide and 4-pyridyl- N-Oxide. In one embodiment of the invention, said heteroaryl groups for said R1\ R1 or R*1 are independently selected from the group consisting of: 4-pyridyl and 4-pyridyI-N-Oxide. In one embodiment of the invention, said heteroaryl group for said H1\ R1 or R*1 is 4-pyridyl- N-Oxide.
In one embodiment of the invention, for formula 1.0, said heterocycloalkyl groups for R1", R1. or R** are selected from piperidines of Ring V;

X
V
N"
Wherein R"" is ~C{0)NHR1". In one embodiment of the invention, R1" is -C(0)NH2. In one embodiment of the invention, piperidine Ring V is:

.1.,..o51
and in one embodiment of the invention Ring V is:

nj-v/w

Thus, in one embodiment of the invention, for fonrnula 1.0, R1\ R1 and R**1 are Independently selected from the group consisting of:
(1) H;
(2) aryf (most preferably phenyl);
(3) heteroaryl and
(4) heterocycioalkyl (i.e., Piperidine Ring V)
wherein at least one of R1", R1, or R""1 is other than H, and In one emtiodiment of the invention R11 and R1 are H and R"*1 is other than H, and in one embodiment of the invention R1" and R1 are H and R*1 is selected from the group consisting of; heteroaryl and heterocycioalkyl, and in one embodiment of the invention R1" and R1 are H and R"*1 is Piperidine Ring V; wherein the definitions of heteroaryl and Piperidine Ring V are as described above.
In one embodiment of the invention, for fonmula 1.0, A and B are independently selected from the group consisting of;
(I) -H;
(3) -R1-C(0).R1
(4) -R1-COrR*":
(5) -C(0)NHR1;
(6) -C(0)NH-CH2-C(O>-NH2;
(7) ~C(0)NHR1;
(8) -(CH2)p(R1)2 wherein each R1 is the same or different;
(9) -{CH2)pC(0)R";
(10) -(CH2)pC(0)R1"1
(II) - (12) -{CH2)pC(0)NH(R1);
(13) -
(14) -(CH2)pNHC(0)2R1-
(15) -(CH2)pN(C(0)R2"1)2 wherein each R1"" is the same or different;
(16) -(CHz)pNR1"C(0)R11
(17) -(CH2}pNR1"C(0)R" wherein R1" is not H. and R1" and R". taken together with the atoms to which they are bound, fonm a 5 or 6 memebered heterocyctoalk>i ring;
(18) -(CH2)pNR1"C(0)NR1";
(19) -{CH2)pNR1"C(0)NR" wherein R1" is not H. and R1" and R1\ taken together with the atoms to which they are fctound. form a 5 or 6 membered heterocycloalkyl ring;
(20) -(CH2)pNR1"C(0)N(R111)2. wherein each R111is the same or different;
(21) -{CH2)pNHS02N(R1")2, wherein each R1" is the same or different;
(22) -(CH2)pNHC02R=1;

(23) -(CH2)pC02R"";
(24) -NHR1;
(25) 1 f f -(CHj)p-j -C-IR"
wherein R1° and R1" are the same or different and (26)
R30 f,32
-(CH2)p-C C-R1
wherein R1°. R11. R11 and R" are the same or different. In one embodiment of the invention, for formula 1.0, A and B are independently selected from the group consisting of:

0) -H;
(2) -R";
(3) -R1-C(0>-R5;
(4) -R1-C02-R51;
(S) -C(0)NHR3;

(6) -(CH2UR%, wherein each R1is the same or different-
(7) -(CH2}pC(0)R1-
(8) -(CH.)pC(0)N(R1),, wherein each R1 is the same or different-
(9) -(CH2}pC(0)NH(RS);
(10) -(CH2)pNR51C(0)R11:
(11) -(CH.)pNR-C(0)R- wherein R- is not H. and R- and R- taken ogether with the atoms to which they are bound, form a 5 or 6 membered
heterocycloalkyi ring;
(12) -(CH2)pNR51C(0)NR21;
(13) -{CH2)pNR="C(0)NR11 wherein R=" is not H, and R=1 and R11
taken together with the atoms tc which they are bound, form a 5 or 6 "
membered heterocycloalkyi ring;
(14) -NHR5;and
(15)


-(CH2)p-

wherein R1" and R11 are the same or different. Examples of A and B include but are not limited to;



N
"WW


01 1CH-,

X"
\ - -WW . 1 j111



NH




N1

and

wherein p is 0, 1,2, 3 or 4.
Examples of A and B also include but are not limited to:



. 0CH3N CH3

H3C
NHR1V.

Examples of A and B also include but are not limited to:





e.g.,
HiC

H,C

H,C






H3C \ NHR* N
HN n1 HN N1 "f1. "
N
1
1
■H
and

1
-N -

1N

YH3C
HN N
H,C
o-
" HN
HN t
1
HN N1 HN N " HN N-1 1\ "-1


and

Thus, examples of B include but are not limited to;



N
H " 1 H


-P. _ \ 1O H,N.

NHR1
5 I / ~7l «. HN
v-N, 1r1"i "11-SJi.
and
" "•1" N1 HN N1


Preferred examples of B include:
H3C
rt-v«


H3C e.g.. >-c-

O11O 1..1O HjN. 10

1 H
HN11O




, HN N.
11il
and

More preferred examples of B include:
lO


HjN11O


YH3C


HN1 1O
1\c

\JI,

A most preferred example of B is:



Examples of R® groups include, but are not limited to:


O1NH, O1N" 0-1N

H

H





H
o-

H

""\/W\j
H °






H

H

H

CN






CI
I

H

Br

o-

N H







OCK
O
1
O"

N H

O1

N H

H



H

o

H

H

, and

o1H" 1\ //*

Examples of R1 also include, but are not limited to:



O
O
0"

I
°1 o

"Uu-
1, OH

TJOP
°1", °1-, o11 o-K{ o1 o1









o
oW\"

o
NH2







1N
OCH.



, and

Ov
Examples of R1 also include, but are not limited to:


lA/1
° //
0

o

o

O-

0 I

0.

II 0

o

F




O1i
W //
I
6 1
o
o4-1/ 161\7 111"

W //

s-o






O;
w //
o
CI O:
W //
o
sA\ r-11 "1s-A //
Oc
o


// 0
\. //
s-A //
o
o

/
Br O-
0"


0 —-F
0

o



and

Examples of R« also include, but are not limited to:

O

,10-1 J1n- >.1 ,X1
O

OAyxru
O"
o1.






o
o
"\J\/\J\,
o
0=1





o1






o



©■

I







and

In one embodiment of the invention, for fomiula lo.when the optional bond between C-5 and C-6 is present (i.e.. there is a double bond between C-5 and C-6) »1en one of A or B is H and the other is R=. and R" is selected from the group consisting of:
(1) heteroaryl;

(2) substituted heteroaryl;
(3) arytalkyi;
{4} substituted arylalkyl;
(5) aryialkoxy;
(6) substituted aryialkoxy;
(7) heterocycloalkyi;
(8) substituted heterocycloalkyi;
(9) heterocycloalkylalkyt;
(10) substituted heterocydoalkylalkyl;
(11) unsubstituted heteroarylalkyl;
(12) substituted heteroarylalkyl;
(13) alkenyl;
(14) substituted alkenyl;
(15) unsubstituted heteroaryialkenyl; and
(16) substituted heteroaryialkenyl,
wherein said substituted R1 groups are substituted with one or more (e.g. 1, 2 or 3) substituents independently selected from the group consisting of:
(1) -OH;
(2) -CO2R";
(3) -CH20R1(4) halo.
(5) alkyl (e.g. methyl, ethyl, propyt, butyl or t-butyl);
(6) amino;
(7) trityl;
(8) heterocycloalkyi; -.__
(9) arylalkyf;
(10) heteroaryl aad
(11) heteroarylalkyl,
wherein R"** is independently selected from the group consisting of: H; and alkyl, preferably methyl and ethyl.
In one embodiment of the invention, for fonnula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R1 In one embodiment of the invention.

for formula 1.0, when there is a double bond between C-5 and
C-6, A is H and B is R1 wherein R1 is selected from the group consisting of;
(1) arvlalkyl;
(2) substituted arylalkyl;
(3) arylalkoxy;
(4) substituted arylalkoxy;
(5) heterocydoalkyl;
(6) substituted heterocydoalkyl;
(7) heterocydoalkylaikyl;
(8) substituted heterocydoalkylaikyl;
(9) unsubstituted heteroarytalkyl;
(10) substituted heteroarytalkyl;
(11) alkenyl;
(12) substituted alkenyl;
(13) unsubstituted heteroarylalkenyl; and
(14) substituted heteroarylalkenyl,
wherein said substituted R1 groups are substituted with one or more (e.g. 1, 2 or 3) substituents independently selected from the group consisting of;
(1) -OH;
(2) halo, (preferably Br);
(3) alkyl {e.g. methyl, ethyl, propyl, butyl, ort-butyl);
(4) amino; and
(5) trityl.
In one embodiment of the invention, forfonnula 1.0. when there is a double bond between C-5 and C-6, A is H and B is R1 wherein R1 is selected from the group consisting of:
(1) heterocydoatkylalkyi;
(2) substituted heterocydoalkylaikyl;
(3) unsubstituted heteroarylatkyt; and
(4) substituted heteroarylalki1;
wherein said substituents for said substituted R1 groups are the same or different alkyl groups (e.g.. C1-C4 alkyl).

In one embodiment of the invention, for formula 1.0, when there Is a double bond between C-5 and C-6, A is H and B is R1 wherein R1 is selected from the group consisting of;
(1) unsubstituted heleroaryl(C]-C3)aIky1; and
(2) substituted heleroaryl (CrC3)aIkyl;
wherein the substituents for said substituted R1 group are as defined atrove.
tn one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R1 wherein R1 is selected from the grooup consisting of:
(1) unsubstituted heteroaryl(Ci-C3)alkyl, with unsubstituted heteroaryl-CHr being prefen1ed; and
(2) substituted heteroaryl(Ci-C3)alkyl, with substituted heteroaryl-CHr being preferred;
wherein the substituents for said substituted R1 groups are selected from one or more (e.g. 1, 2 or 3, with one being preferred) of the same or different alkyl groups (e.g., -CH3, -C2H5, -C3H4, with -CHa being prefen-ed).

one embodiment of the invention, for fonnula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R1 wherein R1 is selected from the group consisting of;
(1) -CHz-imidazolyl;
(2) substituted imidazolyl-CHr;
(3) -(CH2Hmidazolyl;
(4) substituted im(dazoly1-(CH2)2-;
(5) -(CH2)rimida20lyi;
(6) substituted imidazolyl-CCHzV;
(7) -CHrpiperazinyl and , (8) -CHa-morpholinyl;
wherein the substituents for said substituted R1 groups are selected from one or more (e.g. 1, 2 or 3, with one being preferred) of the same or different aikyl groups (e.g., "CH3, -C2H5, -C3H4, with "CH3 being preferred). Preferably, the substituted imidazolyl groups are selected from the group consisting of:

■3
CH

l4 \JJ and yjj
with the substituted imidazolyl:
fy
"Ho CH3
being most prefenred.
In one embodiment of the invention, for formula 1.0, when there is a double bond between C-5 and C-6, A is H and B is R1 wherein R® is substituted imidazolyl-CHr. with
being preferred.
In one embodiment of the invention, for formula 1.0, when B is H and A is R1, and there is a double ttond between C-5 and C-6, the R® groups for A are those described above for B.
In one embodiment of the invention, for fomiuJa 1.0, when the optional bond between C-5 and C-6 is not present (i.e. there is a single bond between C-5 and C-6), each A and each B are independently selected and the definitions of A and B are the same as those described atiove when the optional bond is present, provided that when there is a single bond between C-5 and C-6 then one of the two A substituents or one of the two B substituents Is H (i.e., when there is a single bond between C-5 and C-6 one of the four substituents (A, A, B, and B) has to be H).
In one embodiment of the invention, for compounds of formula 1,0, there is a iouble bond between C-5 and C-6.
Compounds of fom:iula 1.0, having C-11 R- and S- stereochemistry include:






























































Another embodiment of this invention is directed to compounds selected from the group consisting of:

Lines drawn into the ng systems indicate that the indicated bond may be attached to any of the substitutable ring carlines atoms.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) fonns. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds
which possess a carboxyl or phenolic hydroxy! group. These compounds may form
pharmaceutically acceptable salts. Examples of such salts may Include sodium,
potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts
fornied with phannaceutically acceptable amines such as ammonia, alkyl amines,
hydroxyall^yiamines, N-methytglucamine and the like, " "
Certain basic tricyclic compounds also fork pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also fomi salts with weaker acids. E)ramples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, malerc, methanesuifonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the

conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicartjonate. The free base fonns differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the Invention-All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the con-espondlng compounds for purposes of the invention.
The compounds of the invention (e.g., compounds of formula 1.0) can exist in unsolvated as we!! as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the !il The compounds of this invention: (i) potently inhibit famesyl protein transferase, but not geranylgeranyl protein transferase I. in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a famesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a famesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor, and (iv) block abnormal cell growUi in culture induced by transforming Ras.
The compounds of this invention inhibit famesyl protein transferase and the famesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting famesyl protein transferase, (e.g., ras famesyl protein transferase) in mammals, especially humans, by the administration of an effective amount {e.g., a therapeutically effective amount) of one or more (e.g., one) compounds of this invention. The administration of the compounds of this invention to patients, to inhibit famesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells, including transfomied cells, by administering an effective amount (e.g., a therapeutically effective amount) of one or more (e.g., one) compourKls of this

invention. Abnomial growth of cells refers to cell growth independent of nonmal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of; (1) tumor ceils (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases In which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor (i.e., cancer) growth by administering an effective amount (e.g., a therapeutically effective amount) of one or more (e.g., one) compounds of this invention to a mammal (e.g., a human) in need of such treatment. In particular, this Invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount (e.g., a therapeutically effective amount) of the above described compounds.
The present invention also provides a method of treating proliferative diseases, especially cancers (I.e, tumors), comprising administering an effective amount (e.g., a therapeutically effective amount) of one or more (e.g., one) compounds of the invention, described herein, to a mammal (e.g., a human) in need of such treatment in combination with an effective amount of at least one and-cancer agent (i.e., a chemottierapeutic agent) and/or radiation.
The present invention also provides a method of treating proliferative diseases, especially cancers (i.e., tumors), comprising administering an effective amount (e.g., a therapeutically effective amount) of one or more (e.g., one) compounds of the invention to a mammal (e.g., a human) in need of such treatment in combination with an effective amount of at least one signal transduction inhitMtor.
Examples of proliferative diseases (tumors, i.e., cancers) which may be inhibited or treated include, but are not limited to:
(A) lung cancer {e.g., lung adenocarcinoma and non smalK:ell lung cancer);
(B) pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma);
(C) colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma);

(0) myeloid leukemias (for example, acute myelogenous leukemia
(AMI). CML, and CMML);
(E) thyroid follicular cancer;
(F) myeiodysplastic syndrome (MDS);
(G) bladder carcinoma;
(H) epidermal carcinoma;
(1) melanoma;
(J) breast cancer,
(K) prostate cancer;
(L) head and neck cancers (e.g., squamous cell cancer of the head and neck);
(M) ovarian cancer,
(N) gliomas;
(0) cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas);
(P) sarcomas;
(Q) tetracarcinomas;
(R) nuroblastomas;
(S) kidney carcinomas;
(T) hepatomas;
(U) non-Hodgkin"s lymphoma;
(V) mulUple myeloma; and
(W) anaplastic thyroid carcinoma. For example, embodiments of this invention include methods of treating cancer wherein said cancer is selected from the group consisting of: pancreatic cancers, lung cancers, myeloid leukemias. thyroid follicular tumors, myeiodysplastic syndrome, head and neck cancers, melanomas, breast cancers, prostate cancers, ovarian cancers, bladder cancers, gliomas, epidermal cancers, colon cancers, non-Hodgkin"s lymphomas, and multiple myelomas comprising administering to said patient an effective amount of a compound of this invention.
Also for example, embodiments of this invention include methods of treating cancer wherein said cancers are selected from the group consisting of: lung cancer (e.g.. non-small cell lung cancer), head and neck cancer (e.g.. squamous cell cancer

of the head and neck), bladder carreer, breast cancer, prostate cancer, and myeloid leukemias {e.g., CML and AML), non-Hodgkln"s lymphoma and multiple myeloma.
This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering a therapeutically effective amount of one or more (e.g., one) compounds of the invention and therapeutically effective amounts of at least two different antineoplastic agents selected from: {1) taxanes, (2) platinum coordinator compounds, (3) epidermal growth factor (EGF) inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) vascular endolithial growth factor (VEGF) inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), (8) anti-tumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors. (11) vinca alkaloids, (12) antibodies that are inhibitors of aVpS integrins, (13) small molecules that are inhibitors of aVp3 integrins, (14) folate antagonists, (15) ribonucleotide reductase inhibitors, (16) anthracyclines, (17) biologies; (18) thalidomide (or related imid), and (19) Gleevec.
This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of one or more (e.g., one) compounds of the invention and an antineoplastic agent selected from: (1) EGF inhibitors that are antibodies, (2) EGF inhibitors that are small molecules, (3) VEGF inhibitors that are antibodies, and (4) VEGF inhibitors that are small molecules. RadiaUon therapy can also be used in conjunction with the above combination therapy, i.e., the above method using a combination of compounds of the invention and antineoplastic agent can also comprise the administration of a therapeutically effect amount of radiation.
This invention also provides a method of treating leukemias-(e.g., acute myelokl leukemia (AML), and chronic myeloid leukemia (CML)) in a patient in need of such treatment comprising administering therapeutically effective amounts of one or more (e.g., one) compounds of the invention and: (1) Gleevec and interferon to treat CML; (2) Gleevec and pegylated interferon to treat CML; (3) an anti-tumor nucleoside derivative (e.g.. Ara-C) to treat AML; or (4) an anti-tumor nucleoside derivative (e.g., Ara-C) in combinaUon with an anthracycline to treat AML.
This invention also provides a method of treating non-Hodgkin"s lymphoma in a patient in need of such treatment comprising administering therapeutically effective

amounts of one or more (e.g., one) compounds of the invention and: (1) a biologic (e.g., Rituxan); (2) a biologic (e.g., Rituxan) and an anti-tumor nucleoside derivative (e.g., Fludarabine); or (3) Genasense (antisense to BCL-2).
This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of one or more (e.g., one) compounds of the invention and: (1) a proteosome inhibitor (e.g.. PS-341 from Millenium); or (2) Thalidomide (or related imid).
This Invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this
invention, e.g., a compound of formula 1.0);
(b) at least two different antineoplastic agents selected from the
group consisting of:
(1) taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF inhibitors that are antibodies;
(6) VEGF kinase inhibitor that are small molecules;
(7) estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumor nucleoside derivatives;
(9) epothilones;
(10) topoisomerase inhibitors;
(11)vinca alkaloids;
(12) antibodies that are inhibitors of aVp3 integrins;
(13) small molecule inhibitors of aVp3 integrins
(14) folate antagonists;
(15) ribonucleotide reductase inhibitors;
(16) anthracyclines;
(17) biologies;
(18) Thalidomide (or related Imid); and

(19)Gleevec. This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts
of:
(a) an FPT inhibitor of this invention {i.e., a compound of this
invention, e.g., a compound of fomiula 1.0);
(b) at least two different antineoplastic agents selected from the
group consisting of:
(1) taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF inhibitors that are antibodies;
(6) VEGF kinase inhibitors that are small molecules;
(7} estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumornucleoside derivatives;
(9) epothilones;
(10) topoisomerase inhibitors;
(ll)vincaalkafQids;
(12) antilxxlies that are inhibitor of aVp3 integrins; or (13} small molecule inhibitors of aVp3 integrins
(14) folate antagonists;
(15) ribonucleotide reductase inhibitors; (16)anthracycrrnes; -

(17) biologies; and
(18) Thalidomide (or related Imid).
This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this
invention, e.g,, a compound of formula 1.0);

(b) at least two different antineoplastic agents selected from the group consisting of:
(1)taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF Inhibitors that are antibodies;
(6) VEGF kinase inhibitors that are small molecules;
(7) estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumor nucleoside derivatives;
(9) epothilones;
(10) topoisomerase inhibitors;
{11 )vinca alkaloids;
(12) antibodies that are inhibitors of aVp3 integrins; or
(13) small molecule inhibitors of aVp3 integrins
(14) folate antagonists;
(15) ribonucleotide reductase inhibitors;
(16) anlhracydines; and
(17) biologies.
This invention also provides a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this
invention, e.g., a compound of formula 1.0); . „
(b) at least two different antineoplastic agents selected from the
group consisting of:
(1) taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF inhibitors that are antibodies;
(6) VEGF kinase inhibitors that are smail molecules;

(7) estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumor nucleoside derivatives:
(9) epothiiones;
(10}topoisom6rase inhibitors;
(11) vinca alkaloids;
(12) antibodies that are inhibitors of aVp3 integrins; and
(13) small molecule inhibitors of aVp3 integrins.
This invention also provides a method of treating non small cell lung cancer comprising administenng to a patient in need of sudi treatment therapeutically effective amounts of;
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of formula 1.0);
(b) at least two different antineoptaslic agents selected from the group consisting of:
(1)taxanes;
(2) platinum coordinator compounds:
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF inhibitors that are antibodies;
(6) VEGF kinase Inhibitors that are small molecules;
(7) estnagen receptor antagonists or selective estrogen receptor modulators;
(8) anli-tumor nucleoside derivatives;
(9) epothiiones;

(10) topoisomerase inhibitors;
(11) vinca alkaloids;
(12) antibodies that are inhibitors of aVjJS integrins; and
(13) small molecule inhibitors of aVp3 integrins.
This invention also provides a method of treating non small cell lung cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of:

(a) an FPT inhibitor of this invention (i.e., a compound of this
invention, e.g., a compound of formula 1.0);
(b) at least two different antineoplastic agents selected from the
group consisting of:
(l)taxanes;
(2) platinum coordinator compounds;
(3) anti-tumor nucleoside derivatives;
(4) topoisomerase Inhibitors: and
(5) vinca alkaloids.
This invention also provides a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of fomiuia 1.0);
(b) cartioplatin; and
(c) paditaxel.
This invention also provides a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of fomiuia 1.0);
(b) cisplatin; and
(c) gemcitabine.
This invention also provides a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of fomnula 1.0);
(b) carbopiatin; and
(c) gemcitabine.
This invention also provides a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of:

(a) an FPT inhibitor of this invention (i.e., a compound of this invention, eg., a compound of formula 1.0);
(b) Carbcpjatin; and
(c) Docetaxel.
This invention also provides a method of treating cancer in a patient in need of such treatment comprising administering therapeutically effective amounts of.
(a) an FPT Inhibitor of this invention (i.e., a compound of this invention, e.g.. a compound of fomiula 1.0);
(b) an antineoplastic agent selected from the group consisting of:

(1) EGF inhibitors that are antibodies;
(2) EGF inhibitors that are small molecules;
(3) VEGF inhibitors that are antibodies; and
(4) VEGF kinase inhibitors that are small molecules.
This invention also provides a method of treating squamous cell cancer of the head and necK, in a patient In need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this
invention, e.g., a compound of fomiuia 1.0);
(b) one or more antineoplastic agents selected from the group
consisting of;
(1)taxanes:and
(2) platinum coordinator compounds.
This invention also provides a method of treating squamous cell cancer of the
head and neck, in a patient in need of sudi treatment comprising administering
therapeutically effective amounts of: . ^ .
(a) an FPT inhibitor of this invention (i.e., a compound of this
invention, e.g., a compound of formula 1.0);
(b) at least two different antineoplastic agents selected from the
group consisting of:
(1) taxanes;
(2) platinum coordinator compounds; and
(3) anti-tumor nucleoside derivatives (e.g., S-Fluorouracil).

This invention also provides a method of treating CML In a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of fomiula 1.0);
(b) Gleevec; and
(c) interferon (e.g., intron-A).
This invention also provides a method of treating CML in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPT inhibitor of this invention (i.e.. a compound of this invention, e.g., a compound of formula 1.0);
(b) Gleevec; and
(c) pegyiated interferon (e.g., Peg-lntron, and Pegasys).
This invention also provides a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of fomnula 1.0);
(b) an anti-tumor nucleoside derivative (e.g.. Cytarabine (i.e., Ara-C)).
This invention also provides a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of fomiula 1.0);
(b) an anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-0)); and
(c) an anthracycline.
This invention also provides a method of treating non-Hodgkin"s Ivmphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of this Invention (i.e., a compound of this invention, e.g., a compound of fomiula 1.0);
(b) Rituximab (Rituxan).

This invention also provides a method of treating non-Hodgkin"s lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of formula 1.0);
(b) Rituximab (Rituxan); and
(c) an anti"tumor nucleoside derivative (e.g.. Fludarabine (i.e., F-ara-A).
This invention also provides a method of treating non-Hodgkin"s lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g.. a compound of formula 1.0);
(b) Genasense (antisense to BCL-2).
This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of formula 1.0);
(b) a proteosome inhibitor (e.g.. PS-341 (Millenium)).
This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of this inventton (i.e.. a compound of this invention, e.g., a compound of formula 1.0);
(b) Thalidomide or related imid.
This invention also provides a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPT inhibitor of this invention (i.e., a compound of this invention, e.g.. a compound of formula 1.0};
(b) Thalidomide.

This invention is also directed to the methods of treating cancer described herein, particulariy those described above, wherein in addition to the administration of the FPT inhibitor and antineoplastic agents radiation therapy is also administered prior to, during, or after the treatment cycle.
it is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are abenrantly activated as a result of oncogenic mutation in other genes-i.e.. the Ras gene itself is not activated by mutation to an oncogenic fomi-with said inhibition or treatment being accomplished by the administration of an effective amount (e.g. a therapeutically effective amount) of one or more (e.g., one) compounds of the invention to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, Ick, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The compounds of the invention useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed thai these compounds may function through the inhibition of G-prolein function, such as Ras p21, by blocking G-protein isoprenylatlon, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras famesyl protein transferase, and thus show antiproliferative activity against ras transfomied cells.
The method of treating proliferative diseases (cancers, i.e., tumors), according to this invention, includes a method for treating (inhibiting) the abnormal grofwth of celts, including transformed cells, in a, by administering, concun-ently or sequentially, an effective amount of a compound of this invention and an effective amount of a chemotherapeutic agent and/or radiation.
In preferred embodiments, the methods of the present invention include methods for treating or inhibiting tumor growth in a patient in need of such treatment by administering, concurrently or sequentially, (1) an effective amount of a compound of this invention and (2) an effective amount of at least one antineoplastic agent, microtubule affecting agent and/or radiation therapy. For example, one embodiment

of these methods is directed to a method of treating cancers selected from the group consisting of: lung cancer, prostate cancer and myeloid leukemias.
The methods of treating proliferative diseases, according to this invention, also include a method for treating (inhibiting) proliferative diseases, both benign and malignant, wherein ras proteins are aben"antly 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. This method comprises administering, concurrency or sequenlJaHy, an effective amount of a compound of this invention and an effective amount of an antineoplastic agent and/or radiation therapy to a patient in need of such treatment. Examples of such proliferative diseases which may be treated include: the benign proliferative disorder neurofibromatosis, or tumors in which ras Is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, IcK, !yn, fyn).
For radiation therapy, y-radlation is preferred.
The methods of treating proliferative diseases (cancers, i.e., tumors), according to this invention, also include a method for treating (inhibiting) the abnomial growth of cells, including transfomied cells, in a patient in need of such treatment, by administering, concurrently or sequentially, an effective amount of a compound of this invention and an effective amount of at least one signal transduction Inhibitor.
Typical signal transduction Inhibitors include but are not limited to:
(i) Bcr/abI kinase inhibitors such as, for example. STt 571 (Gleevec);
(ii) Epidermal growth factor (EGF) receptor inhibitor such as, for example. Kinase inhibitors (Iressa, OSI-774) and antibodies {Imclone: C225 [Goldstein et at. (1995), Clin Cancer Res, 1:1311-1318], and Abgenix: ABX-EGF) and
(iii) HER-2/neu receptor inhibitors such as. for example. Herceptin® (trastuzumab).
Embodiments of the metfiods of treatment of this invention are directed to the use of a combination of dnjgs (compounds) for the treatment of cancer, i.e., this invention is directed to a combination therapy for the treatment of cancer. Those skilled in the art will appreciate that the dnjgs are generally administered individually as a phamiaceutical composition. The use of a pharmaceutical composition comprising more than one dnjg is within the scope of this invention.

The antineoplastic agents are usually administered in the dosage forms that are readily available to the skilled clinician, and are generally administered in their normally prescribed amounts (as for example, the amounts described in the Physician"s Desk Reference, 56"" Edition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645-1742 the disclosure of which is incorporated herein by reference thereto), or the amounts described in the manufacture"s literature for the use of the agent).
For example, the FPT Inhibitor can be administered orally (e.g., as a capsule), and the antineoplastic agents can be administered intravenously, usually as an IV solution. The use of a pharmaceutical composition comprising more than one drug is within the scope of this invention.
The FPT inhibitor and the antineoplastic agents are administered in therapeutically effective dosages to obtain clinically acceptable results, e.g., reduction or elimination of symptoms or of the tumor. Thus, the FPT inhibitor and antineoplastic agents can be administered concurrently or consecutively in a treatment protocol. The administration of the antineoplastic agents can be made according to treatment protocols already known in the art.
The FPT inhibitor and antineoplastic agents are administered in a treatment protocol that usually lasts one to seven weeks, and is repeated typically from 6 to 12 times. Generally the treatment protocol lasts one to four weeks. Treatment protocols of one to three weeks may also be used. A treatment protocol of one to two weeks may also be used. During this treatment protocol or cycle the FPT inhibitor is administered daily while the antineoplastic agents are administered one or more times a week. Generally, the FPT inhibitor can be administered daily (i.e., once per day), preferably twice per day, and the antineoplastic agent is administered once a week or once every three weeks. For example, the taxanes (e.g., Paclitaxel (e.g., Taxol®) or Docetaxel (e.g.,Taxotere®)) can be administered once a week or once every three weeks.
However, those skilled in the art will appreciate that treatment protocols cart be varied according to the needs of the patient. Thus, the combination of compounds (drugs) used in the methods of this invention can be administered in variations of the pnDtocols described above. For example, the FPT inhibitor can be administered discontinuously rather than continuously during the treatment cycle. Thus, for

example, during the treatment cycle the FPT inhibitor can be administered dally for a week and then discontinued for a week, with this administration repeating during the treatment cycle. Or the FPT inhibitor can be administered daily for two weeks and discontinued for a week, with this administration repeating during the treatment cycle. Thus, the FPT inhibitor can be administered daily for one or more weeks during the cycle and discontinued for one or more weeks during the cycle, with this pattern of administration repeating during the treatment cycle. This discontinuous treatment can also be based upon numbers of days rather than a full week. For example, daily dosing for 1 to 6 days, no dosing for 1 to 6 days with this pattern repeating during the treatment protocol. The number of days (or weeks) wherein the FPT inhibitor is not dosed does not have to equal the number of days (or weeks) wherein the FPT inhibitor is dosed. Usually, if a discontinuous dosing protocol is used, the number of days or weeks that the FPT inhibitor is dosed is at least equal or greater than the number of days or weeks that the FPT inhibitor is not dosed.
The antineoplastic agent could be given by bolus or continuous infusion. The antineoplastic agent could be given daily to once every week, or once every two weeks, or once every three weeks, or once every four weeks during the treatment cycle. If administered daily during a treatment cycle, this daily dosing can be discontinuous over the number of weeks of the treatment cycle- For example, dosed for a week (or a number of days), no dosing for a week (or a number of days, with the pattern repeating during the treatment cycle.
The FPT inhibitor can be administered orally, preferably as a solid dosage fofm, more preferably a capsule, and while the total therapeutically effective daily dose can be administered in one to four, or one to two divided doses per day, generally, the therapeutically effective dose is given once or twic^a day, preferably twice a day. The FPT Inhibitor can be administered in an amount of about 50 to about 400 mg once per day, and can be administered in an amount of about 50 to about 300 mg once per day. The FPT inhibitor is generally administered in an amount of about 50 to about 350 mg twice a day, usually 50 mg to about 200 mg twice a day. preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day.
If the patient is responding, or is stable, after completion of the therapy cycle, the therapy cycle can be repeated according to the judgment of Uie skilled clinician.

upon completion of the therapy cycles, the patient can be continued on the FPT inhibitor at the same dose that was administered in the treatment protocol, or, if the dose was less than 200mg twice a day, the dose can be raised to 200 mg twice a day, This maintenance dose can be continued until the patient progresses or can no longer tolerate the dose (in which case the dose can be reduced and the patient can be continued on the reduced dose).
The antineoplastic agents used with the FPT inhibitor are administered in their normally prescribed dosages during the treatment cycle (i.e., the antineoplastic agents are administered acconding to the standard of practice for the administration of these dojgs). For ejcample: (a) atiout 30 to about 300 mg/m^ for the taxanes; (b) about 30 to atx>ut 100 mg/m^ for Cisplatin; (c) AUG of about 2 to about 8 for Carboplatin; (d) about
2 to about 4 mg/m^ for EGF inhibitors that are antibodies; (e) about 50 to about 500 mg/m^ for EGF inhibitors that are small molecules; (f) atiout 1 to about 10 mg/m^ for VEGF kinase inhibitors that are antibodies; (g) about 50 to about 2400 mg/m^ for VEGF inhibitors that are small molecules; (h) about 1 to about 20 mg for SERMs; (i) about 500 to about 1250 mg/m^ for the anti-tumor nucleosides 5-F!uorouracil, Gemcitabine and Capecitabine; (j) for the anti-tumor nucleoside Cytarabine (Ara-C) 100-200mg/m^/day for 7 to 10 days every 3 to 4 weeks, and high doses for refractory leukemia and lymphoma, i.e., 1 to 3 gm/m^ for one hour every 12 hours for 4-8 doses every 3 to four weeks; (k) for the anti-tumor nucleoside Fludarabine (F-ara-A) 10-25mg/m^/day every 3 to 4 weeks; (I) for the anti-tumor nucleoside Decltabine 30 to 75 mg/m^ for three days every 6 weeks for a maximum of 8 cycles; (m) for the anti-tumor nucleoside Chlorodeoxyadenosine (CdA, 2-CdA) 0.05-0.1 mg/kg/day as continuous infusion for up to 7 days every 3 to 4 weeks; (n) about 1 to about 100 mg/m^ for epothilones; (o) about 1 to about 350 mg/m^ for topoisomerase Inhibitors; (p) about 1 to about 50 mg/m^ for vinca alkaloids; (q) for the folate antagonist Methotrexate (MTX) 20-60 mg/m^ by oral, IV or IM every 3 to 4 weeks, the intemiediate dose regimen is 80-250 mg/m^ IV over 60 minutes every 3 to 4 weeks, and the high dose regimen is 250-1 OOOmg/m^ IV given with leucovorin every 3 to 4 weeks; (r) for the folate antagonist Premetrexed (Alimta) 300-600 mg/m^ (10 minutes IV infusion day 1) every
3 weeks; (s) for the ribonucleotide reductase inhibitor Hydroxyurea (HU) 20-50 mg/kg/day (as needed to bring blood cell counts down); (t) the platinum coordinator compound Oxaliplalin (Eloxatin) 50-100 mg/m^ every 3 to 4 weeks (preferably used for

solid tumors such as non-small cell lung cancer, colorectal cancer and ovarian cancer); {u) for the anthracycline daunombicin 10-50 mg/m^/day IV for 3-5 days every 3 to 4 weeks; (v) for the anthracycline Doxonjbicin (Adriamycin) 50-100 mg/m^ IV continuous infusion over 1-4 days every 3 to 4 weeks, or 10-40 mgW IV weekly; (w) for the anthracycline Idambicin 10-30 mg/m^ daily for 1 -3 days as a slow iV infusion over 10-20 minutes every 3 to 4 weeks; (x) for the biologic interferon (Intron-A, Roferon) 5 to 20 million lU three times per week; (y) for the biologic pegyiated interferon (Peg-intron, Pegasys) 3 to 4 micrograms/kg/day chronic sub cutaneous (until relapse or loss of activity); and (z) for the biologic Rituximab (Rituxan) (antibody used for non-Hodgkln"s lymphoma) 200-400mg/m^ IV weekly over 4-8 weeks for 6 months.
Gleevec can be used orally in an amount of about 200 to about 800 mg/day.
Thalidomide (and related imids) can be used orally In amounts of about 200 to about 800 mg/day. and can be contiuously dosed or used until releapse or toxicity. See for example f*/litsiades et al., "Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells;therapeutic implications". Blood, 99(12):4525-30, June 15, 2002. thedisclosureofwhich is incorporated herein by reference thereto.
For example, Paclitaxei (e.g., Taxoi® can be administered once per week in an amount of about 50 to about 100 mg/m^ with about 60 to about 80 mg/m^ being prefen-ed. In another example Paclitaxei (e.g., Taxol® can be administered once every three weeks in an amount of about 150 to about 250 mg/m^ with about 175 to about 225 mg/m^ being preferred.
In another example, Docetaxel (e.g., Taxotere®) can be administered once per week in an amount of about 10 to about 45 mg/m^. Ih another eicample Docetaxel (e.g., Taxotere®) can be administered Once every three weeks in an amount of about 50 to about 100 mg/m^
In another example Cisplatin can be administered once per week in an amount of about 20 to about 40 mg/m^. In another example Cisplatin can be administered once every three weeks in an amount of about 60 to about 100 mg/m^.
In another example Carboplatin can be administered once per week in an amount to provide an AUG of about 2 to about 3. in another example Carboplatin can

be administered once every three weeks in an amount to provide an AUG of about 5 to about 8.
Thus, in one example {e.g., treating non small cell lung cancer):
(1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day:
(2) Paclitaxel {e.g., Taxol®) is administered once per week in an amount of about 50 to about 100 mg/m^ with about 60 to atiout 80 mg/m^ being preferred; and
(3) Carboplatin is administered once per week in an amount to provide an AUG of about 2 to about 3.
In another example {e.g., treating non small cell lung cancer):
{1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day;
{2) Paclitaxel {e.g., Taxol®) is administered once per week in an amount of about 50 to about 100 mg/m^ with about 60 to about 80 mg/m^ being prefen-ed; and
(3) Cisplatin is administered once per week in an amount of about 20 to about 40 mg/m^.
In another example {e.g., treating non small cell lung cancer):
{1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day:
{2) Docetaxel {e.g., Taxotere®) is administered once per week in an amount of about 10 to about 45 mg/m^; and
{3} Carboplatin is administered once per week in an amount to provide an AUG of about 2 to about 3.
In another example {e.g., treating non small cell lung cancer):
{1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day;
(2) Docetaxel (e.g., Taxotere®) is administered once per week in an amount of about 10 to about 45 mg/m^; and

(3) Cisplatin is administered once per week in an amount of about 20 to about 40 mg/m^.
Thus, in one example {e.g., treating non small cell lung cancer):
(1} the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day;
(2) Paclitaxel {e.g., Taxol*) is administered once every three weeks in an amountof about 150 to about 250 mg/m^ with about 175 to about 225 mg/m^ being preferred, and with 175 mg/m^ being most preferred; and
(3) Carbopfatin is administered once every three weeks in an amount to provide an AUG of about 5 to about 8, and preferably 6.
In a preferred example of treating non small cell lung cancer:
(1) the FPT inhibitor is administered in an amount of 100 mg administered twice a day;
(2) Paclitaxel (e.g., Taxol®^ is administered once every three weeks in an amount of 175 mg/m^; and
(3) Carboplatin is administered once every three weeks in an amount to provide an AUG of 6.
In another example {e.g., treating non small cell lung cancer):
(1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day;
(2) Paclitaxel (e.g., Taxol*) is administered once every three weeks in an amount of about 150 to about 250 mg/m^, with about 175 to about 225 mg/m^ being prefeffed; and -
(3) Cisplatin is administered once every three weeks in an amount of about 60toabout100mg/ml
In another example {e.g., treating non small cell lung cancer):
(1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, atmut 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day;
(2) Docetaxe! (e.g., Taxotere®) is administered once every three weeks in an amount of about 50 to about 100 mg/m^: and

(3) Carboplatin is administered once every three weeks in an amount to provide an AUG of about 5 to about 8.
In another example (e.g., treating non small cell lung cancer):
(1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day;
(2) Docetaxel {e.g., Taxotere®) is administered once every three weeks in an amount of about 50 to about 100 mg/m^; and
(3) Cisplatin Is administered once every three weeks in an amount of about 60 to about 100 mg/m^.
In a preferred example for treating non small cell lung cancer using the FPT inhibitor. Docetaxel and Carboplatin:
(1) the FPT inhibitor Is administered in an amount of about 50 mg to about 200 mg twice a day. preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day;
(2) Docetaxel (e.g., Taxotere®) is administered once every three weeks in an amount of about 75 mg/m^; and
(3) Carboplatin Is administered once every three weeks in an amount to provide an AUC of about 6.
In the above examples the Docetaxel (e.g., Taxotere®) and Cisplatin, the Docetaxel (e.g., Taxotere®) and Carboplatin, the Paciitaxel (e.g., Taxol®) and Carboplatin, or the Paciitaxel (e.g., Taxol®) and Ctsplatin are preferably administered on the same day.
In another example (e.g., CML):
(1) the FPT inhibitor is administered in an amount of about 100 mg to about 200 mg administered twice a day;
(2) Gleevec is administered in an amount of about 400 to about 800 mg/day orally; and
(3) interferon (Intron-A) is administered In an amount of about 5 to about 20 million lU three times per week.
In another example (e.g., CML): (1) the FPT inhibitor is administered in an amount of about 100 mg to about 200 mg administered twice a day;

(2) Gleevec is administered in an amount of about 400 to about 800 mg/day orally; and
(3) pegylated interferon (Peg-lntron or Pegasys) is administered in an amount of about 3 to about 6 micrograms/kg/day.
In another example {e.g., non-Hodgkin"s lymphoma);
(1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; and
(2) Genasense (antisense to 6CL-2) is administered as a continuous IV infusion at a dose of about 2 to about 5 mg/kg/day (e.g., 3 mg/kg/day) for 5 to 7 days every 3 to 4 weeks.
In another example (e.g., multiple myeloma):
{1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day, and most preferably about 100 mg administered twice a day; and
(2) the proteosome inhibitor (e.g., PS-341 - Millenium) is administered in an amount of about 1.5mg/m^ twice weekly for two consecutive weeks with a one week rest period.
In another example (e.g., multiple myeloma):
(1) the FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, preferably, about 75 mg to about 125 mg administered twice a day. and most preferably about 100 mg administered twice a day; and
(2) the Thalidomide (or related imid) is administered orally in an amount of about 200 to about SOO mg/day, with dosing being continuous until relapse or toxicity.
In the above examples the Taxotere and cisplatin, the Taxotere and carboplatin, tfie Taxol and carboplatin, or the Taxol and cisplatin are preferably administered on the same day.
Antineoplastic agents that can be used in combination with the FPT inhibitor are:
(1) taxanes such as paclilaxel (TAXOL®) and/or docetaxel (Taxotere®);
(2) platinum coordinator compounds, such as, for example, carboplatin, cisplatin and oxaliplatin;

(3) EGF inhibitors that are antibodies, such as: HER2 antibodies (such as, for example Irastuzumab (Herceptin"^, Genentech, Inc.), Cetuximab (Erbitux, IMC-C225, ImClone Systems). EMD 72000 (Merck KGaA), anti-EFGR monoclonal antibody ABX (Abgenix), TheraCIM-h-R3 (Center of Molecular Immunology), monoclonal antibody 425 (Merck KGaA), monoclonal antibody ICR~62 (ICR, Sutton, England); Herzyme (Elan Pharmaceutical Technologies and Ribozyme Pharmaceuticals). PK! 166 (Novartis). EKB 569 (Wyeth-Ayerst). GW 572016 (GlaxoSmithKIine), C11033 (Pfizer Global Research and Development), trastuzmab-maytansinoid conjugate (Genentech, Inc.), mitumomab {Imclone Systems and Merck KGaA) and Melvax II (Imclone Systems and Merck KgaA);
(4) EGF inhibitors that are small molecules, such as, Tarceva (TM) (OSI-774, OSI Phannaceuticals. Inc.), and Iressa (ZD 1839, Astra Zeneca);
(5) VEGF intiibttors that are antibodies such as: bevacizumab (Genentech. lnc,).andlMC-1C11 (ImClone Systems). DC 101 (a KDR VEGF Receptor 2 from ImClone Systems);
(6) VEGF kinase inhibitors that are small molecules such as SU 5416 and SU 6688 (both from Sugen, Inc.);
(7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), such as tamoxifen, idoxifene, raloxifene, trans-2,3-dihydroraloxifene, levormeloxifene, droloxifene, WDL 103,323, and acolbrfene (Schering Corp.);
(8) anti-tumornucleoside derivatives such as 5-fiuorouracil, gemcitabine or capecitabine;
(9) epothilones such as BMS-24755Q (Bristol-Myers Squibb), and EPO906 (Novartis Pharmaceuticals);

(10) topoisomerase inhibitors such as topotecan (Glaxo-Sm"rthKiine). and Camptosar (Pharmacia);
(11) vinca alkaloids, such as, navelbine (Anvar and Fabre, France), vinchstine and vinblastine; and
(12) antibodies that are inhibitors of aVp3 integrins, such as, LM-609 (see. Clinical Cancer Research, Vol. 6, page 3056-3061, August 2000, the disclosure of which is incorporated herein by reference thereto).
Preferred antineoplastic agents are selected from: paclitaxel, docetaxei. cartwplatin, cisplatin. gemcitabine, tamoxifen, Herceptin, Cetuximab, Tarceva, Iressa,

bevacizumab, navelbine, IMC-1C11, SU5416 or SU6688. Most prefen-ed antineoplastic agents are selected from: paclitaxel, docetaxel, carboplatin, cisplatin. navelbine, gemcitabine, or Herceptin.
In general when more than one antineoplastic agent is used in the methods of this Invention, the antineoplastic agents are administered on the same day either concurrently or consecutiveiy in their standard dosage form. For example, the antineoplastic agents are usually administered intravenously, preferably by an IV drip using IV solutions well known in the art (e.g., isotonic saline (0.9% NaCI) or dextrose solution (e.g., 5% dextrose)).
When two or more antineoplastic agents are used, the antineoplastic agents are generally administered on the same day; however, those skilled in the art will appreciate that the antineoplastic agents can be administered on different days and in different weeks. The skilled clinician can administer the antineoplastic agents according to their recommended dosage schedule from the manufacturer of the agent and can adjust the schedule according to the needs of the patient, e.g.. based on the patient"s response to the treatment. For example, when gemcitabine is used in combination with a platinum coordinator compound, such as, for example, cisplatin, to treat lung cancer, both the gemcitabine and the cisplatin are given on the same day ■ on day one of the treatment cycle, and then gemcitabine is given alone on day 8 and given alone again on day 15
Thus, one embodiment of this invention is directed to a method of treating cancer comprising administering to a paUent in need of such treabnent therapeutically effective amounts of the FPT inhibitor, a taxane. and a platinum coordination compound.
Another embodiment of this invention is directed to a metiiod of treating cancer comprising administering to a patient in need of such treatment therapeuticaliy effective amounts of the FPT inhibitor, a taxane, and a platinum coordination compound, wherein said FPT inhibitor is administered every day, said taxane is administered once per week per cycle, and said platinum coordinator compound is administered once per week per cycle. Preferably the treatment is for one to four weeks per cycle.
Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically

effective amounts of the FPT Inhibitor, a taxane, and a platinum coordination compound, wherein said FPT inhibitor is administered every day. said taxane is administered once every three weeks per cycle, and said platinum coordinator compound is administered once every three weeks per cycle. Preferably the treatment is for one to three weeks per cycle.
Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, paclitaxel, and carboplatin. Preferably, said FPT inhibitor is administered every day, said paclrtaxel is administered once per week per cycle, and said cartwplatin is administered dnce per week per cycle. Preferably the treatment is for one to four weeks per cycle.
Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, paclitaxel. and carboplatin. Preferably, said FPT inhibitor is administered every day, said paclitaxel is administered once every three weeks per cycle, and said cartjoplatin is administered once every three weeks per cycle. Preferably the treatment is for one to three weeks per cycle.
Preferably, non small cell lung cancer is treated in the methods described in the above embodiments.
Another embodiment of this invention is directed to a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering daily a therapeutically effective amount of the FPT inhibitor, administering a therapeutically effective amount of carboplatin once a week per cycle, and administering a therapeutically effective amount of paclitaxel once a week per cycle, wherein the treatment is given for one to four weeks per cycle. Preferably said FPT inhibitor is administered twice per day. Preferably said carboplatin and said paclitaxel are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said paclitaxel.
Another embodiment of this invention Is directed to a mefriod for treating non small cell lung cancer in a patient in need of such treatment comprising administering daily a therapeutically effective amount of the FPT inhibitor, administering a therapeutically effective amount of carboplatin once every three weeks per cycle, and

administering a therapeutically effective amount of paclitaxel once every three weeks per cycle, wherein the treatment is given for one to three weeks. Preferably said FPT inhibitor is administered twice per day. Preferably said carboplatin and said paclitaxe! are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said paclitaxel.
Another embodiment of this invention is directed to a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering about 50 to about 200 mg of the FPT inhibitor twice a day, administering carboplatin once per week per cycle in an amount to provide an AUG of about 2 to alx)ut 8 (preferably about 2 to about 3), and administering once per week per cycle about 60 to about 300 mg/m^ (preferably about 50 to 100mg/m^. more preferably about 60 to about 80 mg/m^) of paclitaxel, wherein the treatment is given for one to four weeks per cycle. In a more preferred embodiment said FPT inhibitor is administered in amount of about 75 to about 125 mg twice a day, with about 100 mg twice a day being preferred. Preferably said cartxiplatin and said paclitaxel are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said " paclitaxel.
In a preferred embodiment, this invention is directed to a method for treating non small celt lung cancer in a patient in need of such treatment comprising administering about 50 to about 200 mg of the FPT inhibitor twice a day, administering cartx)platin once every three weeks per cyde in an amount to provide an AUC of about 2 to about 8 (preferably about 5 to about 8, most preferably 6), and administering once evei7 ttiree weeks per cycle about 150 to about 250 mg/m^ (preferably about 175 to about 225 mg/m^, most preferably 175 mg/m^) of paclitaxel, wherein the treatment is given for one to three weeks. In a more preferred embodiment said FPT inhibitor is administered in an amount of about 75 to about 125 mg twice a day, with about 100 mg twice a day being preferred. Preferably said carboplatin and said paclitaxel are administered on the same day, and more preferably said carboplatin and said paclitaxel are administered consecutively, and most preferably said carboplatin is administered after said paclitaxel.

Other embodiments of this invention are directed to methods of treating cancer as described in the above embodiments except that in place of paciitaxel and carboplatin the taxanes and platinum coordinator compounds used together in the methods are; (1) docetaxel (Taxotere®) and cisplatin; (2) paciitaxel and cisplatin; and (3) docetaxel and cartx)platir. In the methods of this invention cisplatin is preferably used in amounts of about 30 to about 100mg/m^. In the methods of this invention docetaxel is preferably used in amounts of about 30 to about 100 mg/m^.
In another embodiment this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, a taxane, and an EGF inhibitor that is an antibody. Preferably the taxane used is paciitaxel, and preferably the EGF inhibitor is a HER2 antitiody (more preferably Herceptin) or Cetuximab, and most preferably Herceptin is used. The length of treatment, and the amounts and administration of the FPT inhibitor and the taxane are as described in the emt>odiments above. The EGF inhibitor that is an antitwdy is administered once a week per cycle, and is preferably administered on the same day as the taxane, and more preferably is administered consecutively with the taxane. For example, Herceptin is administered in a loading dose of about 3 to about 5 mg/m^ (preferably about 4 mg/m^), and then is administered in a maintenance dose of about 2 mg/m^ once per week per cycle for the remainder of the treatment cycle (usually the cycle is 1 to 4 weeks). Preferably the cancer treated is breast cancer.
In another embodiment this invention Is directed to a method of treating cancer comprising administering to a patient In need of such treatment therapeutically effective amounts of;
(1) the FPT inhibitor
(2) a taxane; and
(3) an antineoplastic agent selected from:

(a) an EGF inhibitor that is a small molecule;
(b) a VEGF inhibitor that is an antibody; or
(c) a VEGF kinase inhibitor that Is a small molecule.
Preferably, the taxane paciitaxel or docetaxel is used. Preferably the antineoplastic agent is selected from: tarceva, Iressa, bevacizumab, SU5416 or SU6688. The length of treatment, and the amounts and administration of the FPT inhibitor and the taxane

are as described in the embodiments above. The VEGF kinase inhibitor that is an antibody is usually given once per week per cycle. The EGF and VEGF inhibitors that are small molecules are usually given daily per cycle. Preferably, the VEGF inhibitor that is an antibody is given on the same day as the taxane, and more preferably is administered conojrrently with the taxane. When the EGF inhibitor that is a small molecule or the VEGF inhibitor that is a small molecule is administered on the same day as the taxane, the administration is preferably concurrently with the taxane. The EGF or VEGF kinase inhibitor is generally administered in an amount of about 10 to about 500 mg/m^. Preferably the cancer treated is non small cell lung cancer.
In another embodtment this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, an anti-tumor nucleoside derivative, and a platinum coordination compound.
Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, an anti-tumor nucleoside derivative, an AnoUier embodiment of this Invention is directed to a method of treating cancer comprising administering to 3 patient in need of such treatment therapeutically effective amounts of the FPT Inhibitor, an anti-tumor nucleoside derivative, and a platinum coordination compound, wherein said FPT Inhibitor is administered every day, said an anti-tumor nucleoside derivative is administered once per week per cycle, and said platinum coordinator compound is administered once every three weeks per cycle. Although the treatment can be for one to four weeks per cycle, the treatment is preferably for one to seven weeks per cycle.
Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, gemcitabine, and cisplatin. Preferably, said FPT inhibitor is administered every day, said gemcitabine is administered once per

week per cycle, and said cisplatin is administered once per week per cycle. Preferably the treatment is for one to seven weeks per cycle.
Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, gemcitabine, and cisplatin. Preferably, said FPT inhibitor is administered every day, said gemcitabine is administered once per week per cycle, and said cisplatin is administered once every three weeks per cycle. Preferably the treatment is for one to seven weeks.
Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the FPT inhibitor, gemcitabine, and carboplalin. Preferably, said FPT inhibitor is administered every day. said gemcitabine is administered once per week per cycle, and said carboplatin is administered once per week per cycle. Preferably the treatment is for one to seven weeks per cycle.
Another embodiment of this invention is directed to a method of treating cancer comprising administering to a patient In need of such treatment therapeutically effective amounts of the FPT inhibitor, gemcitabine, and carboplatin. Preferably, said FPT inhibitor is administered every day, said gemcitabine is administered once per week per cycle, and said carboplatin is administered once every three weeks per cycle. Preferably the treatment is for one to seven weeks per cycle.
Preferably, non small cell lung cancer is treated in the methods using gemcitabine in the embodiments described above.
(n the above embodiments using gemcitabine, the FPT inhibitor and the platinum coordinator compound are administered as described above for the embodiments using taxanes. Gemcitabine is administered in an amount of about 500 to about 1250 mg/m^ The gemcitabine is preferably administered on the same day as the platinum coordinator compound, and more preferably consecutively with the platinum coordinator compound, and most preferably the gemcitabine is administered after the platinum coordinator compound-
Another embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient the FPT inhibitor and an antineoplastic agent selected from: {1) EOF inhibitors that are antibodies, (2) EGF inhibitors that are small molecules, (3) VEGF inhibitors that are

antibodies, and (4) VEGF kinase inhibitors that are small molecules all as described above. The treatment is for one to seven weeks per cycle, and generally for one to four weeks per cycle, The FPT inhibitor is administered in the same manner as described above for the other embodiments of this invention. The small molecule antineoplastic agents are usually administered daily, and the antibody antineoplastic agents are usually administered once per week per cycle. The antineoplastic agents are preferably selected from: Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, IMC-1C11, SU5416orSU6688. Preferably non small cell lung cancer is treated.
In the embodiments of this invention wherein a platinum coordinator compound is used as well as at least one other antineoplastic agent, and these dnjgs are administered consecutively, the platinum coordinator compound is generally administered after the other antineoplastic agents have been administered.
Other embodiments of this invention include the administration of a therapeutically effective amount of radiation to the patient in addition to the administration of the FPT inhibitor and antineoplastic agents in the embodiments described above. Radiation is administered according to techniques and protocols well know to those skilled in the art.
Another embodiment of this invention is directed to a pharmaceutical composition comprising at least two different antineoplasUc agents and a pharmaceutically acceptable carrier for intravenous administration. Preferably the pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e.g., 6% dextrose).
Another embodiment of this invention Is directed to a phamiaceufical composition comprising the FPT inhibitor and at least two different antineoplastic agents and a pharmaceutically acceptable carrier for tntravenous^dministration. Preferably the pharmaceutically acceptable earner is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e.g., 5% dextrose).
Another embodiment of this invention is directed to a pharmaceutical composition comprising the FPT inhibitor and at least one antineoplastic agent and a pharmaceutically acceptable carrier for intravenous administration. Preferably the phamiaceutically acceptable carrier is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e.g., 5% dextrose).

in the method of treating embodiments, and in the pharmaceutical composition embodiments, the FPT inhibitor is preferably a compound selected from the compounds of formulas 1.4.1.4D, 1.4E. 1.4F, 1.5.1.5A. 1.6, 1.6A, 1.7, and 1.7A.
Those skilled in the art will appreciate that the compounds (drugs) used in the methods of this invention are available to the skilled dinician in phaimaceutical compositions (dosage forms) fnom the manufacture and are used In those compositions. So, the recitation of the compound or class of compounds in the above described methods can be replaced with a recitation of a phamiaceuticat composition comprising the particular compound or class of compounds. For example, the embodiment directed to a method of treating cancer comprising administering to a patient in need of such treatment ttierapeutically effective amounts of the FPT inhibitor, a taxane, and a platinum coordination compound, includes within its scope a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a pharmaceutical composition comprising the FPT inhibitor (1.0), a pharmaceutical composition comprising a taxane, and a pharmaceutical composition comprising a platinum coordination compound.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Detemiination of the proper dosage for a particular situation is within the skill of the art
The amount and frequency of administration of the FPT inhibitor and the antineoplastic agents will be regulated according to the judgment of the attending clinician (physician) considering such factors as age. condition and size of the patient as well as severity of the cancer being treated.
The antineoplastic agent can be administered according to.lherapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the antineoplastic agent can be varied depending on the cancer being treated and the known effects of the antineoplastic agent on that disease. Also. in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the obsen/ed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the cancer to the administered therapeutic agents.

The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
The particular choice of antineoplastic agent will depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol.
The detemiination of the order of administration, and the number of repetitions of administration of the antineoplastic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the cancer being treated and the condition of the patient.
Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of an antineoplastic agent according to the individual patient"s needs, as the treatment proceeds. All such modiJications are within the scope of the present invention.
The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of cancer-related symptoms (e.g., pain, cough {for lung cancer), and shortness of breath (for lung cancer)), inhibition of tumor grovirth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help Judge effectiveness of treatment.
CHEMOTHERAPEUTIC AGENTS Classes of compounds that can be used as chemotherapeutic agents (antineoplastic agent/microtubuie affecting agents) include but are not limited to: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and si^thetlcs. Examples of compounds within these classes are given t>elow.
Alkylating agents (including nitrogen mustards, elhyienimine derivatives, alkyl sulfonates, nitrosoureas and triazenes)-. Uracil mustard, Chlomiethine.

Cyciophosphamide (Cytoxan®), llosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine. and Temozolomide.
Antimetabolites (including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): Methotrexate, 5-Fluorouracil, Fioxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.
Natural products and their derivatives (including vinca alkaloids, antitumor antibiotics, enzymes, lymphoklnes and epipodophyllotoxins): Vinblastine, Vincristine, Vtndeslne, Bleomycin, Oactinomycin, Daunorubicin, Doxombicin, Epirubicin, ldan;bicin, paclitaxel (paclitaxel is commercially available as Taxol® and is described in more detail below in the subsection entitled "Microtubule Affecting Agents"), paclitaxel derivatives (e.g. taxotere), Mithramycin, Oeoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide.
Hormones and steroids (including synthetic analogs): 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone^ Prednisone, Fluoxymesterone. Dromostanolone propionate, Testoladone, Megeslrolacetate, Tamoxifen, Methyl prednisolone. Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene. Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoiadex.
Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatm, Carboplatin. Hydroxyurea, ArTisacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.
Other chemotherapGutics include Navelbene, CPT-11, Anastrazole. Letrazole, Capecitabinbe, Reloxafine, and Droioxafine.
Particularly preferred are the antineoplastic agents selected from Cydophasphamide, 5-FluorouraciI, Temozolomide, Vincristine, Cisplatjn, CartMplatin, and Gemcitabine. Most prefen-ably, the antineoplastic agent is selected from Gemcitabine, Ctsplatin and Carboplatin.
Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Pbysidans" Desk

Reference" (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA); the disclosure of which is incorporated herein by reference
thereto.
MICROTUBULE AFFECTING AGENTS
As used herein, a microtubule affecting agent (e.g., paciitaxel, a paditaxel derivative or a paclitaxel-like compound) is a compound that interferes with cellular mitosis, i.e., having an anti-mitotic effect, by affecting microtubule formation and/or action. Such agents can t>e, for instance, microtubule stabilizing agents or agents which disrupt microtubule formation.
Microtubule affeding agents useful in the invention are well known to those of skill in the art and include, but are not limited to allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchidne (NSC 757), colchidne derivatives (e.g., NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858). rhizoxin (NSC 332598), paciitaxel (Taxol®, NSC 125973). paditaxel derivatives (e.g., Taxotere. NSC 608832), thiocolchlcine (NSC 361792). trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothilone, and discodemiolide (see Service. (1996) Science, 274:2009) estramustine, nocodazole, MAP4. and the like. Examples of such agents are also described in the sdent/fic and patent literature, see. e.g., Bulinski (1997) J. Ceil Sd. 110:3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997) Cancer Res. 57:3344-3346; Nicolaou (1997) Nature 387:268-272; Vasquez (1997) Mol. Biol. Cell. 8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812.
Particulariy preferred agents are compounds with paditaxel-like activity. These indude, but are not limited to paditaxel and paciitaxel derfvaUves^paditaxel-like compounds) and analogues. Paditaxel and its derivatives (e.g. Taxol and Taxotere) are available commercially. In addition, methods of making paciitaxel and paditaxel derivatives and analogues are well known to those of skill in the art (see, e.g., U.S. Patent Nos: 5,569,729; 5,565.478; 5,530,020; 5,527.924; 5,508,447; 5.489,589; 5,488.116; 5,484,809; 5,478,854; 5.478.736; 5,475.120; 5,468.769; 5,461.169; 5,440.057: 5.422.364; 5.411.984; 5.405,972; and 5,296,506).
More specifically, the term "paditaxel" as used herein refers to the drug commercially available as Taxol® (NSC number 125973). Taxol® Inhibits eukaryotic

cell replication by enhancing polymerization of tubulin moieties into stabilized microtubule bundles that are unable to reorganize into the proper stnjctures for mitosis. Of the many available chemotherapeulic doigs, paditaxel has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Havv"kins (1992) Oncology, 6:17-23, Honwitz (1992) Trends Pharmacol. Sd. 13: 134-146, Rowinsky (1990) J. Natl. Cane. Inst. 62:1247-1259).
Additional micnDtubule affecting agents can be assessed using one of many such assays known in the art, e.g., a semiautomated assay which measures the tubulin-polymerizing activity of paditaxel analogs in combination with a cellular assay to measure the potential of these compounds to block cells in mitosis (see Lopes (1997) Cancer Chemother. Pharmacol. 41:37-47).
Generally, activity of a test compound is determined by contacting a cell with that compound and determining whether or not the cell cycle is disaipted, in particular, through the inhibition of a mitotic event. Such inhibition may be mediated by disruption of the mitotic apparatus, e.g., disnjption of normal spindle formation. Cells in which mitosis is intenupfed may be characterized by altered morphology (e.g., microtubule compaction, increased chromosome number, etc.).
Compounds with possible tubulin polymerization adivity can be screened in vitro. For example, the compounds are screened against cultured WR21 cells (derived from line 69-2 wap-ras mice) for inhibition of proliferation and/or for altered cellular morphology, in particular for microtubule compaction. In vivo screening of positive-testing compounds can then be performed using nude mice bearing the WR21 tumor cells. Detailed protocols for this screening method are described by Porter (1995) Lab. Anim.Sci.,45(2):145-150.
Other methods of screening compounds for desired activity are well known to those of skill in the art. Typically such assays involve assays for inhibition of microtubule assembly and/or disassembly. Assays for microtubule assembly are described, for example, by Gaskin et al. (1974) J. Molec. Biol.. 89: 737-758. U.S. Patent No. 5,569,720 also provides in vitro and in vivo assays for compounds with paclitaxel-like activity.
Methods for the safe and effective administration of the above-mentioned microtubule affecting agents are known to those skilled in the art. In addition, their

administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians" Desk Reference" (cited above).
General Preparative Schemes
The following processes may be employed to produce compounds of the invention.
Pvridvl Tricyclic Compounds -One skilled in the art will appreciate that the compounds of the invention represented by Formula 1, wherein one of a, b. c or d is N or N*-0" can be prepared according to the following schemes:

Scheme 1:

The synthesis of 5-bromo tricyclic compound lb begins with bridgehead olefin la (J. Med Chem (1998). 41,1561-1567) which is treated with dibromo dimethylhydantoin in triflic acid media. Further treatment of the vinylbromide with potassium t-butoxide in the presence of the appropriate secondary amine gives the 5 and 6-substituted enamine adducts. Y^ represents -CH2-, -O- or -NH-. When Y^ is NH (prperazine case), acylations, sulfonylations and amide formation can be carried out using standard procedures. Treatment of these amine adducts with HCI(aq) at the apprcipriate temperatures results in the fomnation of the 5 and 6 azaketones, If and 1e respectively.



Synthesis of 3-cartion spaced analogs can be prepared as outlined in Scheme 3. Thus, subjecting tricyclic vinyl bromide 1 b to a Heck type reaction using ethyl
acrylate and catalyzed by Pd^ gives the a-p un-saturated ester 3a. Reduction of the conjugated double bond was carried out using copper chloride-sodium borohydride reducing reagent. The ester was further reduced to alcohol using lithium aluminum hydride. Treatment of the alcohol with methanesulfonyJ chloride in an appropriate aprotic solvent, followed by displacement with an appropriate sodium salt resulted in the desired imidazole targets. In most cases, separation of isomers were effected at this point. Where the R^ group of 3e was a BOC group, deprotection using HCI-dioxane gave the hydrochloride salts of amines. Using standard chemistry, these amines were converted to ureas, carbamates, sulfonamides and amides.
Those skilled in the art will recognize that when a metal hydride, such as NaH. is used in the conversion of 3d to 3e in Scheme 3, reduction of the C5-C6 double bond can take place. This is exemplified in Preparative Example 59 Step 8.

Scheme 4; PREPARATION OF 6-SUBSTITUTED CARBON ANALOGUES



"Vci PhN{Tr)2



EtO^O
Pd(0Ac)2 cat
BU4NBr 4h
O^OEt
CuCI NaBH4 MeOH O"C
1. KiisCl
2. Imidazole
Separate (wherein R" represents H or alky! (e.g., methly and ethyl).
Preparaten of 6-subsWuted 3-cartjon spaced imidazole compounds was carried out as outlined in scheme 4. A mixture of ketones 1 f and 1 i were treated with N-phenytrifluoromethane sulfonimide to give a separable mixture of 5 and 6-tricyclic triflate compounds. The 6-triIate adduct was converted to the desired 3-caition spaced analogs using similar protocol as described for the 5-bromo tricyclic compounds outlined in scheme 3.

Scheme 5: SYNTHESIS OF 2-CARBON SPACER ANALOGUES



Tri-2-furylPhosphine \ NMP
LiCt
Buli (10 % mol) THF 120"C Sealed tube
OTf

R",
X^N
HN
J/

5b
(wherein R" represents H or alkyl (e.g.. methly and ethyl).
Two carbon spaced analogs were prepared as outlined in scheme 5. Thus, triflate 4b was subjected to Stille chemistry, by reacting with tributylvinyl stannate catalyzed by an appropriate Pd° to afford the tricyclic vinyl compound 5b. The 2-carbon spaced compounds were obtained by treating the tricyllc compound with the appropriate imidazole that had been previously treated with Buli-THF in a sealed tube and refluxed at 120 °C. Further funtlonalization was carried out as previously described. Suberane compounds were prepared In a similar way.
Scheme 6:



Hydrazine

HjN



3d

6a

Acylaled sulfonylated " etc
Products
Scheme 6 illustrates a method of making amine 6b through phthalimido displacement of a mesylate followed by hydazine hydrolysis of the phthalimido moiety.

Amine 6b can be converted to targets that have acyl, sufonyl. carbamoyl and urea functionalities.
Scheme 7



TEA O

Lactams 7a can be prepared from amine 6b by reacting with bromo butanonyl acid chloride as outlined in Scheme 7.

Scheme 8: PREPARATION OF CYCLIC UREAS MsO-

Cyclic urea can be prepared from the mesylate shown above by treating with the salt of the cyclic urea 8a as outlined in scheme 8.

^^^^^^^^^^-eSEPARAIiON^^
EtO. ^O

PROeAN0!CAClD_DERIVAIiyES;
DEC-HOBT
Vci °"(^ooh


DEC-HOBT R^—N^/^0 CI or {C0a)2 (R^)2NH
*"" Citric Acid

HO^/O
Amides from 3-carbon spaced carboxylic acic
as
mediated protocol or from the
cpdcea carDoxylic acid 9a and 9c can be prepared outlined in Scheme 9 using either DEC-HOBT mediated nmtrsr-r^t ^r
^"^^"^^"^—^^^^^i^aM^^a^^



R^-^
72a

12b






12c


Scheme 10;
Preparation of piperazine compounds off the bridgehead starts from mesylate aa which is reacted with CBZ-protected plperazine. The BOC group is then removed and the resulting amine 10c is functionalized appropriately. Removal of CBZ group off the piperazine is effected with TMSI.
Mesylate aa is prepared by first carbonyiating compound H from Scheme 14 using P(i°, triphenyl phosphine, cariDon monoxide, DBU, in methanol to give the cartioethoxy product. The carfaoethoxy product is then reduced with lithium aluminum hydride to give the resulting alcohol. This alcohol is converted to the mesylate aa using mesyl chloride and triethyiamine.



R^-^-:
Ms-Cl
12c ■• ^
{Et)3N

12a


Compound 12a is reduced with DIBAL In an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12bjvlth an appropriately substituted and trityiated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichloromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxy! group to an appropriate leaving group such as a mesylate, tosylate. or halide. using methanesulfonyt chloride, p-toluenesulfonyl chloride, orthionyl chloride, followed by elimination using an appropriate base such as triethylamine gives 12e. Removal of the trityl group with acid such as trifluoroacetic acid or hydrochloric acid gives the double bond compound 12f which is then hydrogenated using an appropriate catalyst such as

platinum oxide under from 1 to 55 psi of hydrogen in an appropriate solvent such as ethanol gave the desired product 12g.
Alternatively the ester 12a can be saponified with an appropriate base such as lithium hydroxide to obtain the acid 12h. Converting the acid 12h to the "Vi/einreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichloromethane at ambient temperature yields the adduct 12c (shown in Scheme 12 below).




12a

I2h





N(Me)OMe
EDC "R^ HOBt


12h

12t


H3CO
R—Vc.

HiC

12t

Rr N
\^
N
I
Tr
ElUgBr

12c

Scheme 1?a:

R—^
12c

12j



R^^\^
R^-^^
12j



R^-^^
R"^^

Compounds of type 12L were prepared as shown above. Oxidation of the hydroxy! compound 12c can be accomplished with the Dess Martin periodinane to obtain 12j. Reaction with a grignard reagent gave 12k. The trityl group is removed under standard conditions mentioned above to give the desired compound 12L.

Scheme 13: C-Substituted Imidazole Single Methylene Bridgehead Compounds

HO B,
H"^"^
NBS, PPH3

13A

13b



1. ")^^_Rii



Single methylene bridgehead C-lmidazole derivatives (13c) were prepared as shown above. Compound 13a was first converted to bromide 13b. Treatment of compound 13b with C-imidazole cuprates (prepared from corresponding rodo imidazole) yielded the adduct 13c.

Scheme 14: Preparation of one-methylene piperazJnes
Ketone A is brominated with brominating reagents such as NBS, with a small amount of an activator such as benzoyl peroxide, in solvents such as dichloromethane at elevated temperature, such as 80-100° C to give dibromo compound B.
Bf^ ,Br

° O
A B
Dibromo compound B is reacted with a base such as DBU in a solvent such as dichloromethane at temperatures from CC to room temperature to give vinylbromides C and D. These vinylbromides are separated by chromatography such as silica gel flash chromatography using solvents mixtures such as ethyl acetate and hexane. Alternatively, vinylbromides C and D can be separated by crystallization from solvents
such as dichloromethane.
er.


The ketone groups of separated vinylbromides C and D are reduced to the con-esponding alcohols E and F with a reducing agent such as NaBH4 in solvents such as methanol or ethanol at temperatures of OX to room temperature.
Br, .Br


The resulting alcohols functions of E and F are converted to a leaving group, such as a haltde. with reagents such as SOCIa in solvents such as dichloromethane ointaining a base such as 2.6-lutidine and running the reaction at 0°C to room temperature. The resulting intennediate halides are reacted, without purification, with

piperazine or a protected plperazine, such as BOC-piperazine in a solvent such as dichloromethane at room temperature giving intermediates G and H.




The vinylhalide intemiediates are carbonylated with CO gas under a pressure of about 100 psi and a temperature of SOX to lOOX using a palladium catalyst such as PdClj and friphenyl phosphine in toluene and containing DBU and an alcohol such as methanol. If methanol is used, methyi esters ! and J are obtained.


H3CO2C

COsCHa

The ester functions are of I and J are reduced to hydroxymethyl functions of K and L. This can be done directly by first removing the protecting BOC group with TFA or HCI-dioxane and then reducing with a reducing agent such as D(BAL-H, followed by reintroduction of the BOC group with di-tert-butyl dicarbonate. Aitemativety, the ester function is hydrolyzed with LiOH and water followed by neutralization with citric acid. The resulting carboxylic acids are then converted into a function that is easily reduced, such as a mixed anhydride oran acyl imidazole. This is done by reacting the resulting carbocylic acids with a chlorofonnate to form the mixed anhydride or with carfaonydilmidazole to form the acyi imidazole (Synlett. (1995). 839). The resulting activated carboxylic acids are reduced with NaBH^ in solvents such as methanol, ethanoi or aqueous THF.




The hydroxy functions of K and L are converted into leaving groups such as a methanesulfonate or an ar^sulfonate such as a tosylate. by reacting with the appropriate sulfonyl chloride in dichloromethane containing a base such as triethylamrne. The sulfonate leaving groups can be displaced by nucleophtles such amines. The nucloephile (Nuc in structures O and P below) can also be basic heterocydes such as imidazole or a substituted imidazole. In the case of an imidazole, the anion of the imidazole is first formed with NaH in DMF and then reacted with the above sulfonate. Displacement of the sulfonates with a nucleophile gives O and P, which can be converted to the compounds of this invention 1.0, by first removing the BOC protecting group and then forming the desired amide, urea, carbamate or sulfonamide on the resulting amine by methods well known in the art.


Nuc

Nuc



Formula (1.0)

Formula (1.0)

R^^^
R^-\^
GOC
X is Br or -OSO2CF3

Scheme 15: Preparation of one-methylene piperidenes X


H3CO2C

CO2CH3

The vinylhalide or vinyltriflate intermediates A^ and B^ (Scheme 10) are cart)ony(atBd with CO gas under a pressure of about 100 psi and a temperature of 8p°C to lOQ"C using a palladium catalyst such as PdCb and triphenyl phosphine in toluene and containing OBU and an alcohol such as methanol. If methanol is used, methyl esters C" and D^ are obtained. Intennediates C^ and D" are reacted as are intermediates 1^ and J^ {see Scheme 15a below) following essentially the same procedure as in Scheme 14 to yield compounds of Formula 1.0 of this invention.

Scheme 15a:



R"^V^
Sn(Bu)3
EtO Sn(8u)3
oet

Alternatively, Intemiediates A" and B^ can be reacted with tin vinylether E\ in the presence of PdCl2. as described in Tetrahedron. (1991). 47,1877, to yield vinylethers F^ and G" (Scheme 15a). Allowing F" and G^ to stand until aldehyde is visible by NMR (at least two weeks) and then reacting with Hg(0Ac)2, Kl followed by NaSH4, as described in J. Chem. Soc, Perkin Trans., (1984), 1069 and Tet. Lett., (1988), 6331, yields mixtures H\ i" and J\ and K\ Intennediates H^ and j" are separated and reacted, as are intemiediates K" and L\ following essentially the same procedure as in Scheme 14 to yield compounds of Fonnula 1.0, of this invention.

R^^^
R^--^

H0-„(H2C}

BOC

(CHs^-OH



H":n = 1

J\- n = 1 K":n = 2

Those skilled in the art will appreciate that Schemes 11,12,12a, 13,14,15 and 15a using reactants having the moieties



R^"-"V^
R^-^V^




R^-Vc:.
Nps f ^X and «" ^„

"\J\jA,ro

(related to formula 1.0), for example, are also representative of moieties:

reactants having the



"\rj\j\.

(R"* ).

"\f\r\f\j

(R"" U





">y\/\>Tj

(R"*)m
and

(R"^U

{related to compounds of fomiula 1.1).

Scheme 16: Branching on the methylene chain



R30R31

1.Pd(0Ac)2
Bu4NBr K2CO3
DMF; 100°


LAH
imidazole 2. KOtSu
V-ci .JS >r^^
31
R^^"R

TosNHNH 2 DBU toluene reflux

(wherein R represents R^, and R" represents R"°) -
In Scheme 16, compounds with substitution along the chain can be synthesized starting with a substituted ethyi acrylate derivative. Addition of imidazole across the olefin followed by reduction gives the terminal all^ene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituted olefin gives the saturated derivative.

Scheme 17: C-iinked imidazoles



\^^l PdfOAc);
CI TosNHNHj f
0

Tr
PhjPCHjSr
/? >■
" nBuU

Tr

Bu4NSr KaCOa
DMF
DBU

{wherein R represents R°)
In Scheme 17, the synthesis of the C-linked imidazoles proceeds through the Heck reaction of the appropriately substituted vinyl imidazole with the appropriate vinyl bromide. Selective reduction of the resulting di-substituted olefin gives the target compound. A similar procedure can be carried out with differentially N-substituted imidazoles to give N-alkyI imidazole derivatives.
Suberyl Compounds One skilled in the art will appreciate that the compounds of the invention represented by Formula 1.0, wherein a, b,c and d are C (or a, b, c, and dare CR^ in formula 1.1) can be prepared according to Scheme 18:

Scheme 18: Preparation of suberyi analogues

NaOH "^ MeOH
(+)-lsofner
(-)-lsonner -♦

Chiral AD
V 4i
Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. si (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was earned out with NaBH4. The alcohol was converted to chloride 4d and then treated

with N-methylpiperidine Grignard reagent to give piperidine derivative 4e. Demethylation was effected with ethyl chloroformate followed by acid hydrolysis and subsequent derivitization (i.e sulfonylation, acylation and carbomylation etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycyclic bridgehead was carried out in a similar way as described in scheme 3.
Scheme 19:


1) UOH
2) EDCI, NfOMe)Me.HCl. HOBt ^
3) MeMgBr
COjMe


1)TFA
2) Chiral Chrom.
3) (Boc)20



0 BrMg"^"^t^
2) Chiral Chromatography

-N =
I
Boc

+

Scheme 20:



CI AD column
50%


1)1.2eq. n-BuLi
""■^}
o -78 °C

0
I Boc

+

0
I Boc




1) Silica Col.
2) OD Column

-N I
I
Boc

-N =
6
I
~ Boc

Scheme 21:



Chirai HPLC




2) 0,
I) n-BuLi

•*-

■N I
N.
r Boc




(Me)3S I
NaH, DMSO

■N I
o
N I Boc



l)Li(Et)3BH
2} Chirai Chrom.

C")
N 1
Boc

+

c")
N I Boc



{isomer 1)

{isomer 2)

Ratio of {Isomer 1):( isomer 2) is about 10:1
Preparation of substituted 5-acelyl-rmidazoies


.N.
N.
, -^ CF3TMS/CSF y ^- R^°MgBr
»»■

MeO(Me)N—^
F3C—^ O
P.

Scheme 22:




I

-N.

•Tf
I.NaH.Mel 2.TFA
-♦-
3. (BDC}20, TEA
or introduction of Rg
4. OD HPLC

,N.
N"
^oA.

Re

* Chiral center, formula represents Isomer 1 or Isomer 2


DPPA, DBU
-N,

CHaPh

,N.



I ^^

I

0" ^O



-N.
I N""^

1.TFA
2. Introduction
ofRg
3. AD HPLC

I

Chiral center, formula represents Isomer 1 or Isomer 2





-N.

2.THF/H2O

-N,



"N"

or SnCVMeOH

"N"







* Chirai center, formula represents Isomer 1 or Isomer 2,
wherein Isomer 1 of the amine is obtained from Isomer 1 of the azide,
and Isomer 2 of the amine is obtained from Isomer 2 of the azide
Scheme 24:


-N.
I N^

Attachment of H

9t) ^N
* Q

TFA



o" ^o

1020



.N,

Attachment of R*

-N,



N HTFA
1021

"N"

1022
* Ghiral center, formula represents Isomer 1 or Isomer 2, wherein Isomer 1 of 1022 is obtained from Isomer 1 of the starting amine, and Isomer 2 of 1022 is obtained from Isomer 2 of the starting amine
Each isomer (Isomer 1 and Isomer 2) of the starting amine was reacted vwth an
acid chloride or anhydride to obtain an amide group, with an isocyanate to obtain a
urea, with an chlorocarbonate to obtain a carbamate, with a sulfonylchloride to obtain
a sulfonamide in an appropriate solvent such as dichioromethane and an equal
equivalent of base such as triethylamine to obtain the desired product compound
1020. Compound 1020 can then be treated with trinuoroacetic acid to obtain
compound 1021. Compound 1021 can then be reacted with an acid chloride or
anhydride to obtain an amide group, with an isocyanate to obtain a urea, with an
chlorocarbonate lo obtain a cartiamate, witfi a sutfonyichloride to obtain a sulfonamide
in an appropriate solvent such as dichioromethane and an equal equivalent of base
such as triethylamine to obtain the desired product compound 1022.




















Attachement of R

9b
-»-

wherein the R® group is attached using the corresponding isocyanate, chlorofomiate, sulfonyl chloride or acid chloride of the group to be attached, and wherein the R^"" group is attached using the corresponding isocyanate. chloroformate, sulfonyl chloride or acid chloride of the group to be attached.
Compounds of this invention are exemplified in the following examples, which should not be constnjed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. Compounds of the invention can be made according to the procedures described herein and those described in WO 02/18368 A1 published March 7,2002.

PREPARATIVE EXAMPLE 2
Step A




11
Compound 6 from Preparative Example 1, Step D, of WO 02/18368 A1, (10 g. 21.7 mmol) was hydrolyzed in the same manner as described in Preparative Example 1, Step A, of WO 02/18368 A1, to give the title compound (11). MH+ = 389.
StepB





11

12

To the amine product from Preparative Example 2, Step A (20 g. 0.5 mol) and triethylamine (10.4 g, 14.4 mL, 1.02 mol) dissolved in anhydrous dichloromethane (100 mL) was added methanesulfonyl chloride (8.8 g, 6mL, 0.77 mol). After stining at room temperature overnight, the solution was diluted with dichloromethane, washed with saturated NaHCOs and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo afforded the crude product that was purified by flash

chromatography on a silica gel column, eluting with 1 % CH30H(saturated with ammonia)-CH2Cl2to give the title compound (12). MS (FAB) m/z469 (MH+}.
StepC



12



13

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manner as described in Preparative Example 1, Step E, of WO 02/18368 A1,to give 22.2 g of a mixture of compounds (13) and (14). MS (473)
(MH*).

SteoD



CH3O2S

13

14



CHaO^S

15

16

The product from Preparative Example 2, Step C (22.5 g) was dissolved in 150 mL of Gonc. HCI and stirred for 16 h. The reaction mixture was poured into ice, basified with cone. NH4OH and then extracted with CH2CI2 to give a mixture of
compounds (15) and (16). MS (FAB) m/2 405 (MH+).

PREPARATIVE EXAMPLE 2A
Step A



12



CH3O2S

17

18

Separation of compound of Preparative Example 2 Step B by HPLC using a Chiralpack AD column eluting with 40-50% isopropano 1:60-50% hexane-0.2% diethyiamine gave enantiomeric amines (17) and (18).
Compound 17: mp = 118-119; [a]"^ =+ 136.9" (9.00 mg/2mL, MeOH); MS (FAB)m/2 469(MH-*-).
Compound 18: mp = 119-120; [a]^ = -178.2" (9.90 mg/2mL. MeOH); MS (FAB)m/2 469CMH+).

StepB





32

product 17 from Preparative Example 2A, Step A (21.25 g. 45.3 mmol) was treated in the same manner as described in Preparative ExampleJ, Step E, of WO 02/18368 A1, to give 22.2 g of a mixture of compounds (31) and (32). MS (473) (MH*).

PREPARATIVE EXAMPLE 4
Step A



11

To a solution of title compound (11) from Preparative Example 2, Step A (20 g, 51.32 mmole) in CH3OH/H2O (400 ml, 50:1) was added di-tert-butyl dicarbonate (16.8 g, 77.0 mmole). The pH was adjusted to 9 and the mixture was stin-ed for 4 h. The solvent was removed, tlien water was added. The mixture was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness affording the title compound (23). MS 491 (MH+).
StepB



24

Following a similar procedure as in Preparative Example 3. Step A, of WO 02/18368 A1. the title compound (24) was prepared. MS 509 (MH+}.
StepC





24

25

To a solution of the title compound from Preparative Example 4, Step B (19.62 g. 38.5 mmole) in ethanol (150 ml) was added platinum (IV) oxide (1.962 g). The reaction stirred over night at room temperature under H2 balloon pressure atmosphere. After monitoring the reaction, an additional 2% (by weight) of platinum (IV) oxide was added and the reaction stirred for 6 more hours, under H2 balloon pressure atmosphere. The mixture was filtered through celite and concentrated to dryness to afford the tide compound (25) as a white solid. MS 511 (MH*).

StepD

Dissolved product from Preparative Example 4, Step C (2.0 g, 3.9 mmole) in THF (30 ml) and cooled to 0°C in an ice bath. To the reaction was added diisobutylaluminum hydride (7.8 ml, 7.8 mmole). The reaction was allowed to stir and come to room temperature over night. The reaction did not go to completion. The mixture was cooled in an ice bath (0°C) and fresh diisobutylaluminum hydride/toluene (7.8 ml) was added. After the reaction stirred for 4 more hours, it was still not complete. The reaction mixture was cooled to CC, and an additional 3.9 ml of diisobutylaluminum hydride as added. The reaction stined for3 nnbre hours. The cnjde reaction mixture was then extracted with ethyl acetate;10% citric acid, and 1.0 N NaOH. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to afford the desired title compound (26). MS 471 (MH*).

step E




Following a similar procedure described In Preparative Example 3. Step C, of WO 02/18368 A1, the title compound (27) was prepared. MS 549 (MH*).
StepF

To a solution of the title compound from Preparative Example 4. Step E (1 6 g 3.01 mmole) in DMF (50 ml) was added imidazolytsodium (Aldrich) (0.407 g. 4.52

mmole). The reaction mixture was heated to 90°C for 2 h. The reaction was cooled and the OMF was removed. Saturated sodium bicarbonate was added and the mixture was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified by column chromatography eluting with 2% CH3OH; saturated with ammonia-CHaCIj. to afford the title compound (28). MS 519 (MH*).
Step G

Dissolved the product from Preparative Example 4, Step F (0.55 g, 1.08 mmoie) in 4 N dioxane/HCl (20 ml). The reaction mixture was stirred for 3 h at room temperature and then concentrated to dr^ess to afford the title compound (29) as a light yellow solid. HRMS 419 (MH"").

EXAMPLE 506 Diasteromeric separation of product (795.1):

from Example 489. Step B, of WO 02/18368 A1, was done by PREP HPLC using the Prep Chiralcei 00 Column and eluting with 20% lPA/HEXANES+0.2% DEA (iniUal mobile phase), then 25%IPA/HEXANES + 0.2% DEA (final mobile phase) to give 795.1 isomer-1 (i.e., 795.1a) and 795.1 isomer-2 (i.e., 795.1b).
Isomer-1 -MH+=536.1 (CDCL3. 400 MHz) 8.437 (d.1H). 8.22 (d,1H), 7.54 (S.1H), 7.49 (d.lH). 7.37 (d.lH). 7.31 (d,1H), 7.19(m,1H), 7.10 (s,1H), 6.57 (s.1H).4.57 (s,1H).3.86 (s,3H),3.21( br. s, 4H), 2.24 (m.2H). 1.98 (m,2H), 1.90 (s.3H).1.41 (s,9H). m.p. 195-197 °C.
Isomer-2 - MH+=536.1 {CDCL3.400MHz) 8.47(d.1H), 7.64 (d.lH) 7.64 (d.1H).7.54 (s,1H).7.5(s.1H).7.35(d,1H),7.23(m.1H).7.21(m.1H). 7.22 (m,1H), 7.14 (S,1H).6.8 (d,1H). 4.59 (s,1H). 3.76 (s.3H). 3.23 (br.s.4H), 2.23 (m.2H),1.99 (m.2H),1.87(s,3H),1.41 (s,9H). m.p. 206-208 °C.

Example 507


H3C OH N^
-N.
N"
795.1b CH,

TFA
OH2CI2 2hr

H,C
„3C OH ^^
0
I
H 795.2b




H^C PH N-
-N.
"N"
795.1a CH3

TFA
CH2CI2 2hr

H3C
H3C OH N-
0
I
H
795.2a

Compound 795.1b (isomer 2,0.093g ,0.173 mmoles) was converted to 795.2b by reacting it with CHaCl2(5.0ml)/TFA(1.0 ml) at room temperature under N2.
The same procedure was used to prepare 795.2a (isomer 1) from 795.1a.


AD COLUMN
50%

EXAMPLE 508 Br

Separations of enantiomers 365a and 365b is accomplished by chiral HPLC using a Chiralpak AD column and eiuting with iPA (20%) hexanes (80%) ■*• 0.2% DEA.
Isomer 365a; retention time = 7.65 min; MH*= 492.
Isomer 365b: retention time = 12.16 min; MH""= 492. m.p. 95-100 °C. (For compound 365 see WO 02/18368 A1).
PREPARATIVE EXAMPLE 73
Step A



IM LiOH
^ OH
THF


SSO

8S1

Dissolve (880) (2eq.14.2mmoi) in THF (20ml). add tM LiOH(16ml) and stir at room temperature for 1 hour or until reaction Is complete, evaporate to dryness, then evaporate 3x with toluene, to obtain crude (881) as a solid.
StepB



>J>i(OMe)Me
p
DEC/HOBT/NMM
DMF

Take crude (881) from Step A, and dissolve in DiVIF (60m(}, and add NH{OMe)Me(3.14g), DEC(6.14g),HOBT{2.16g), NMM(11mI}, and stir at room temperature over night Add 1.0 N HCL until acetic (pH=2). wash with diethyl ether. Add. while stining, K2CO3 until basic -pH=8, saturate witti NaCI, and extract with (4x).CH2Ci2. Dry with MgSOi, filter and evaporate to obtain product (882) (3.23g).
StepC



MeMgBr
THF

O


883

Took crude (882) (14.2mmol), and dissolve in THF (100m!). Cool in an iced bath and add MeMgBr (3 Mofar in diethyl ether); {22.2ml), dropwisa over 10 minutes, under N;. Let warm to 40^0 and stir for 4 hours or until reaction is complete. Cool in an iced bath and add saturated NH4CI. Extract v«th ethyl acetate and then 3x with CH2CI2 Dry with MgS04, filter and evaporate. Store under vacuum to obtain crystals -(833X1,78g.74%).
StepP



o.

N

N

883

HO 795.1

Dissolve 365 (0.24g.0.49mmot) in THF (2.5ml). Cool under N2 to -78^0, add (1) (BuLi. 2.5M, 0,2m!) and stir the resulting dark bnawn solution for 15 minutes. Dissolved 883 (Q.116g) from Step C in 0.5 mL of THF and add to reaction and stir at

-78°C for 3 hours. Add reaction mixture to brine and extract with ethyl acetate(2x). Dry with MgS04, filter and evaporate to obtain a yellow solid. Purified crude (0.29g) by Prep Plate Chromatography to afford 0.0.15g, 42% yield of the desired product
(795.1).
EXAMPLE 509



OD Column


795.1
Isomer-1 (i.e., 795.1a)

795.1 Isomer -2 (i.e.. 795.1b)

Compound 795.1 is separated into the two diasteromers (isomer-1 and isomer-2) by chrral HPLC using a Chiralpak OD column and using IPA (20%) hexanes (80%) + 0.2% DEA as described in EXAMPLE 506.
EXAMPLE 510
Step A


365a

S-Formyl-1-Melhy Umidazole
1 \ ^N
H
-^-
o-BuLi/2.5N in Hexanes 56% THF
-75V (acwne/dry ice)

-N
"N
8S4
365a [0.9g, 1.83 mmol] was dissolved in dry THF (15ml) and cooled to -75^C (dry ice/acetone bath). (N-BuLi)[(2.5N in Hexanes); 0.24g, 1.5ml, 3.74mmoi], was added dropwise at -75°C and stirred for - 20 minutes. 5-Formyl-1-Methyl tmidazole (0.3g. 2.75 mmol in 2ml THF was added quickly and stin-ed at "75°C for 3 hours. TLC with (HaO-Ethyl Acetate). Reaction completed. Worked up by adding 10ml of H2O and extracted with Ethyl Acetate and washed with brine, dried overMgSO*. filtered and evaporated to give crude product. Crude was puhfied by Flash Chromatography (silica gel column) using CH2CI2 / 5% CH3OH (15% NH4OH) to give 0.54g of compound 884, 56% yield.
Step B.



N
0^0
884

Mnoi
90%

Starting material 884 (0.54G) was dissolved in CHzCb, and MnOa (5g) was added and stirred at room temperature overnight. TLC in 75% CH2Cl2/25% EtoAc/ 5% M0OH (15% NH4OH). Filtered off the inorganics and evaporated to dryness to give 0.49g of 885, 90% yield.

StepC


885

+ (CH3)jS^r DMSO-THF ^
+ NaH -^,-
886
0.35g, 1.71 mmol of (CH3)3 S* f was dissolved in dry DMSO {5ml) and THF (5mt). Sodium hydride (0.068 g, 1.71 mmol) was added, stirred for 10 minutes. The mixture was cooled to G°C. Starting material 885 (0.3g, 0.577 mmol) in (DMSO-THF 1:1, 5 ml) was added and stirred at 0*^0 for 6 hours and then stored in the refrigerator for 18 hours. Quench with H2O. Extracted with Ethyl Acetate and washed with brine, dried over MgS04, filtered and evaporated to give 0.310g of product, 886.
StepD




.N
Q
I Boc
886

Li (EOjBH
THF 66%

0
887

Dissolved 886 {0.28g, 0.48 mmol) in THF(5ml), added Li (Et)3BH ( 0.8ml, O.Smmol). After stining for 1 hour, added to reaction ~ 1Dml of IN HCL and stin-ed for 5 min. Added saturated sodium bicarbonate slowly until basic, and extracted with Ethyt Acetate (3X). Organic was dried over MgSO^, filtered and evaporated to give

crude product. Column chromatography on 12g of silica and eluting with 2% to 4% WeOH NHjOH / CHjCbto gave 170 mg, 66% yield of pure product, 887.




Chiral OD Column
Prep HPLC 20% I PA/HEX/0.2%DEA
0
887

887 was separated by Chiral Prep HPLC using a Chiral Technologies OD column and eluting with 20% lsopropanol/Hexanes/0.2% DEA to give Compounds; 888a and 888b.

EXAMPLES 511-513 Each isomer, 795.2a and 795.2b from Example 507 was dissolved in CHsClz. treated with tiie corresponding isocyanates and stirred at room temperature overnight. The crude product was purified directly by silica gel preparative thin layer chromatography or silica gel chromatography to afford compounds of the fonnula:
.N,
.N,
H,C PH N-

"N" 1 R

N
I R

wherein R is defined in Table 55 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.
Table 55

Example R Isomer 1 Data Isomer 2 Data
511 H m.p. 200-202 "C m.p. 197-200 "C
512 H m.p. 185-190 "C m.p. 200-205 ""C
513 H ra.p. 210-214""C m.p. 185-190 °C
EXA^ IPLE 536
Each isomer, 795.2a and 795.2b from Example 507, was dissolved in anhydrous DMF at room temperature under nitrogen, followed by addition of the corresponding carboxylic acids, and the appropriate reagents: EDC, HOST, and NMM. Reactions were then stirred at room temperature overnight. Soivents were removed via rotary evaporator yielding an oiiy residue. Residue was taken up in dichloromethane and washed with 1.0 N NaOH. t3ry over NaaSO*. filtered and concentrated. Crudes were purified by Prep TLC using dichloromethane/methanol to give compounds of the formulas:

H3C OH N-

0" "
i
R
wherein R is defined in Table 57 and the numbers 1 and 2 in the fomiulas represent isomers 1 and 2, respectively.
Table 57

Example R Data Isomer 1 Data Isomer 2
536 i
0^ m.p. 175-180 "C
EXAMPLES 566-567 Each isomer, 795.2a and 795.2b from Example 507, was dissolved in anhydrous CHzCbfollowed by EtaN. Reactions were ttien treated with the corresponding sulfonyl chlorides and stirred at room temperature over night. Quench reaction with 1.0 N NaOH and extracted with CH2CI2. Organic layer was dried over MgS04, filtered and concentrated. Purification by column chromatography eluting with methanoi-CHaCb afforded compounds of the formula:



HX OHN-
H,C OH N-

wherein R is defined in Table 59 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.
Table 59

Example R Data Isomer 1 Data Isomer 2
566 1
0 mp = 215.4-217.5 "C m.p. 185-188 "C
567 0 -CI * mp = 182-186^C
*lsomer 1 for Example 567 would be obtained if one were to follow the described
procedure. ■ -
.EXAMPLES 590-603 Each isomer, 795.2a and 795.2b from Example 507, was dissolved in anhydrous methylene chloride at room temperature. The reaction was cooled to Q°C and TEA was added in. The respective chloroformates were then added dropwise, and reactions were stirred at 0°C for until completed. Reactions were basified with 1.0 N NaOH to pH = 8-10 followed by extraction with dichlorom ethane. Organic layer was combined, dried with MgS04, filtered and concentrated to yield crude products.

Purification by Prep TLC using methylene chloride /acetone (95%/5%) afforded the compounds:



-N.

-N.



N
1 R

N
I
R

wherein R is defined in Table 61 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.
Table 61

Example R Data Isomer 1 Data Isomer 2
590 1 /
591 * 179.8-182.4"C
592 195-200 "C - 193.5-197.5 ""C
593 * 165.9-167.9 ""C

594 163.8-186.6""C mp=173-175°C
595 * 173.9-176.2*^0
596 180-182 °C 172-174""C
597 "\r\j\/\r r ^ 165-170 °C 185-188.5""C
598 ° CCI3 184.3-186.6 "C 191.2-192.9 "C
599 °^oX, * 179.8-182.5 "C
600 175-180 °C 175-178 ""C
601 O^oV" 175-177 °C 173-176""C
602 0^0-P 177-180 °C 175-177^0
603 169.4-173.2 "^C 164.4-167.2 "C

"Isomer 1 for these examples would be obtained if one were to follow the described procedure.
PMR data for Example 592, isomer 1. {CD3CI) 8.44 (d, 1H), 8.23 (d, 1H), 7.54 {s, 1H), 7,48 (d, IH), 7.37 {d, 1H), 7.32 (dd, IH), 7.18 (dd, IH). 7.10 (s, IH). 6.58 (s, IH), 4.87 (m. 1H), 4.58 (s, 1H). 3,86 (s. 3H), 3.25 (br s, 4H). 2.26 (br s, 2H). 1.99 (m, 2H), 1.90 (s,3H), 1.21 (d. 6H).
PREPARATIVE EXAMPLE 74 0
cAci
R"-~H
"^^ ^ 1 R
CH2C12 O^^O"
R.TJO.N.
(wherein R is alkyl (e.g., ettiyt) or cycloalkyi (e.g., cyclohexyl))
Dissolve Phosgene (3mL, 1.93M in Toluene) in anhydrous ethyl ether and cooled to 0°C. A mixture of cyclohexyl alcohol (200 mg, 2 mmol) and pyridine (0.18 mL. 2.2 mmol) in ethyl ether (4 mL) was added in dropwise. After addition, reaction was allowed to wami to room temperature while stirring overnight MgS04 was then added into reaction and the mixture was stirred for 5 min. After filtration, Njwas bubbled into the solution for 30 min. It was then concentrated to 0.5 mL. diluted with CHsPh (10 mL) and stored as a stock solution at 4°C.
PREPARATIVE EXAMPLE 75

15.4 g (115 mmole) of CuCU and 17 mL (144 mmol) of t-butyl nitrite was added to 400 mL of dry CH3CN. The reaction mixture was cooled to 0° C and 25 g of ketone

(564)? was added. The reaction was warmed to room temperature and stirred for two days. The mixture was concentrated under vacuum. Then 1N HCi was added to the residue until the pH was neutral, then NH4OH was added until the pH was basic. After ejdraction with ethyl acetate, the organic layer was dried over fMgSO* and concentrated under vacuum to give compound 890. Altemativety, the corresponding alcohol of 889 can be reacted as above followed by oxidation with MnOz in CH2CI2 to give compound 890.
StepB

892 Compound 890 from Step A above was reacted in essentially the same manner as in Preparative Example 23. Steps A-D, of WO 02/18368. to get Compounds 891 and 892.

StepC

891 was separated into the respective enantiomers 891a and 891b using a Chiral AD Prep HPLC Column as described in Example 508.

StepP



CI CI
fjj ^ AD Column
!
BOC
892

892b
The 6-bromo substituted Compound 892 was separated into the enantiomers 892a and 892b using a Chiral AD Prep HPLC Column as described in Example 507.

Step A

PREPARATIVE EXAMPLE 76




:")
N 1 80C
891a


N^

N I BOC
893

Reacted 891 a wUh the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 893.
StepB



CI CI
893

OD Column

. .^
893a

Chromatograph 893 by chiral HPLC using a Chiralcel OD column and eluting with IPA (20%) and hexanes (80%) with 0.2% DEA to obtain 893a (i.e., isomer 1), and ) 893b (i.e., isomer 2).
PREPARATIVE EXAMPLE 77
Step A




ive Example 73 using essentially the
Reacted ,891bwith the product of Preparati
same procedure in Example 510 to obtain 893.
StepB

V-CI CI
OD COLUMN

N-^.

^N^

wim iHA (20%) and hexanes (80%) with 0 ^v ncA . u* ■
894b (i.e.. isomer 2). ^ *° °"*"" """^ ^*-^- "^°^«^" )• and

PR_EPARATIVE EXAMPl F 7fl
■Step A



Reacted 892a with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 895.
SteoB


OD Column

HO ,N-n

Chromatograph Compound 895 by chiral HPLC using a Chiralcel OD column and etuting with IPA (20%) and hexanes (80%) with 0.2% DEA lo obtain 895a (i.e., isomer 1), and 895b (i.e., isomer 2).
PREPARATIVE EXAMPLE 79
Step A


892b

N-

896

Reacted B92b with the product of Preparative Example 73 using essentially the same procedure in Example 510 to obtain 896.

StegB


CI c;
OD Column
CI

HO /-n

Wit. ™"rr """ "" *" """" ""^ ^ ^^"^^"=^" °° -™" -
PREPARATIVE EXAMPLE 80


^N-^N


HO \=:z/
TFA HaC-^ 1
CHzC\2 *■ ci- xiDc
2hr ^N I ^
N,
H
897a



TFA
CH2CI2
2hr

Compound 893a. and 893b. are converted to 897a. and 897b, by reacting them with CH2CI2/TFA at room temperature under N2, for 2 hours. Concentrated under vacuum. Dissolve residue in CH2CI2, and wash with 1.0 NaOH. Dry over MgSO^, filter and concentrate to give 897a (i.e., isomer 1) and 897b (i.e.. isomer 2).

EaEPARATiyEEXAMPLEa-



TFA
C( - P,
CH2CI2 ^"
2hr

N-^


N^



894b

898b

(i-e., isomer 2, "" """""""* "^«^ ("-■ --^^ 1) ^nd 898b

PREE^RATiyE_EMMPLE82




TFA
CH2CI2 2hr

Using essentially the same procedure as in Preparative Example 80, 895a and 895b were individually reacted with TFA/CH2CL2 at room temperature under N2, for 2 hours, to get compounds: 899a (i.e.. isomer 1) and 899b (i.e., isomer 899b).

PREPARATIVE EXAMPLE 83


^^. /1




TFA CI
CHjCI;
2hr

Using essentially the same procedure as in Preparative Example 80.896a and 896b were individually reacted with TFA/CHjCLz at room temperature under N2, for 2 hours, to get compounds: 900a (i.e.. isomer 1) and 900b (i.e., isomer 2).
PREPARATIVE EXAMPLE 84


1)DBU,Ph:,P, PdCl2/toluene
2)CO,100psi
MeOH, 80°C

COzMe

starting material 901 (25g, 78 mmol) was combined with DBU (15.7 ML, 105.3mmol, 1.35 eq.); Ph3p (9.44g 0.39mmol, 0.5 eq.); PdCl2(1.38g, 7.8mmol, 0.1 eq.): MeOH (50ML)/Toluene (200ML) in a flask and reacted in a Parr Shaker under CO, 100 psi at SO°C. When completed, the reaction was treated with H2O and extracted with Ethyl Acetate. Dried over MgSO* and evaporated to get a black syrup. (71g) Column chromatography (silica gel) and eluting with Hexanes, then 20%Ethy! Acetate/ Hexanes to 40% E/H to give producct 902, (39g).
PREPARATIVE EXAMPLE 85


C02Me

1)(Bu)4NN0.
2)TFAA CH2CI2

COjMe

Dissolve (BujjNNOj (21.15g) In CH2Cl2(220ML)and cool in an ice bath under N2 and dripped in TFAA(9.8ML) and stir for 15 minutes.The resulting yellow solution is added slowly to a solution of starting material 902. (18.97g) in CH2CI2 (200ML) while cooling in an ice bath (O^C). Stir at 0°C for 15- 20 minutes, then allowed to war to room temperature for 3 hours. Reaction was treated with saturated NaHCOa and extracted with CH2C)2- Isolated the organic layer and dried over MgS04, evaporated to dryness t give product as a syrup. Crude was chromatograph (twice) on Si02 using Hexanes, then eluting with 20% & 40% Ehyl Acetate/Hexanes). 3040% yield of product 903 (7.89g).
PREPARATIVE EXAMPLE 86


COjMe

Ci H2U
1) Ra-Ni(50% in H2O)
H2 MEOH

COsMe

Ra-Ni ((50%ln HzO). 50g), is washed with ETOH (5X, then decanted), the washed with MeOH (3X), then added to starting materia! 903 {7,89g) in MeOH (80ML), the resulting mi>cture is stirred under H2 (balloom) overnight. Reaction is monitored by TLC. Added more RaNi {25g. washed 5X with ETOH, then 3X w/ MeOH). When completed reaction is filtered, the insoluble dark solid is washed with CH2CL2/MeOH until the color of the washings became light, combined filtration and evaporated to dryness to get a brown solid 904 (3.88g of product).
PREPARATIVE EXAMPLE 87

H,N
CI B^
1 )CuBr/t.BuONO
^-
CH3CN

COoMe

COjMe

Suspend starting material 904 (0.5g) in CH3CN (20ML), add CuBr (0.42g) and cool in an ice bath under N2. Add t-BuONO (0.28g) and allow to stir and wann to nDom temperature. After 2 hours stir at 75° C, stir ~ 2 hours. After reaction is complete, add reaction to 1N HCL and stir. Then add Cone. NH4OH until blue (basic). Extract with CHaCla. isolate the organic layer, dried over MgS04, filter and concentrated to give product 905.
PREPARATIVE EXAMPLE 88

CI Br
1)NaBH4/MGOH

CO,Me

,CO,Me



905

906

Starting material 905 (3g. 7.92mmol) is stirred In MeOH( 100ML) atO°C in an ice/H20 bath, then NaBH4 is added to the:coId solution in portions- Stir at O"^C for 1 hour, then at room temperature for 1 hour. Add (20ML) of 1.0 N HCL. stir for 10

minutes, basifJed with saturated NaHC03, added to brine, extract with Ethyl Acetate, dried over MgS04, filtered and evaporated to dryness to give 3.6g of compound 906.



Cl Br
1)S0C(2
CH2CI;
PREPARATIVE EXAMPLE 89 COjMe

COaMe

SOCb (2.1 ML) was added to the solution of 906 (3.5g) in CH2CI2 (50ML), stirred at room temperature for 5 hours. Additional (1.0 ML) of SOCI2 was added, stirred for 2 hours, then overnight Monitored reaction progress by TLC. Reaction mixture was evaporated to dryness and dried under vacuum to give 3.6g of crude product 907.

PREPARATIVE EXAMPLE 90


CI ^"
Soc-Piperazine
CO,Me

TEA
CH3CN 80°C

COjMe

Boc-Piperazine (2.2g, 2.5 eq.) was added to a mixture of starling material 907 (1.78g. 4.68mmol)and TEA (1.9ML, 3 eq) was stirred in CH3CN (100ML). under N2. heat to 80°C for 5 hours. TLC Ihen stirred at 80"^C over the weekend. Reaction is treated with 1 .ON HCl and extracted with ethyl acetate, wash with brine followed by 1 .ON NaOH, dried over MgS04. Filter and evaporated reaction to dryness to give cmde 908 {62% yield).
PREPARATIVE EXAMPLE 91


10%LiOH/MeOH
908

COjMe

60°C

12ML of a 10% LiOH solution (~4M) was added to a solution of starting material 908 (1.6g) in MEOH (5QML) and reaction was stirred at 60°C. A solid precipitated out. Mixture is stirred overnight. Reaction became a clear- yellow solution. Reaction was treated with 10% K2HPO4. and extracted with ethyl acetate, washed with brine, dried over Mg304, and evaporated to dryness to give 1.5g of compound 909.

PREPARATIVE EXAMPLE 92


1) NHCH3OCH3.HCL. NMM.
HOBT, DMAP/CHjCij
2) EDC
93%
909

Combined starting materials 909 (1.5g. -7.8mmol); NHCH3OCH3.HCI; NMM; HOBT; & DMAP in CH2Cl2(20ML) and stirred for 10 minutes, then EDC (0.64g. 1.2 eq.) was added and stirred overnight at room temperature. Reaction was treated with IN HC!, extracted with ethyl acetate, washed with brine foliowed by 1N NaOH. dried over MgSOi. filtered and evaporated the filtrate to dryness to give 1.45g) crude compound 910.
PREPARATIVE EXAMPLE 93


CHaMgBr/THF
910

Quant.

A 3M solution of CHsMgBr/Ether {3.8 ML. 4.5 eq) was added dropwlse to a solutionof 910(1.45g, 2.5mmol)inTHF (50ML), a dark brown solution resulted.

Reaction was stin-ed under N2 at room temperature for 2 hours. Reaction was then treated with a saturated NH^Cl solution and extracted with ethyl acetate. Washed with brine and dried over MgS04, filtered and evaporated to dryness to get a yellow solid compound, which after column chromatography gave 1.33g of compound 911 as a racemic mixture,
PREPARATIVE EXAMPLE 94



TFA/ CH2C12

912

Starting material 911 (0.90g) was dissolved in CH2Cl2{35ML) and TFA (35MLJ and stin-ed at room temperature overnight. Washed with 1.0 N NaOH, dried over MgS04, filtered and evaporated to dryness to give compound 912.

PREPARATIVE EXAMPLE 95



AD COLUMN
912

912b
912 was separated into its enantiomers by Chiral Prep HPLC using a Chiral AD Column and eluting with 10% IPA/ 90% Hexanes+0.2% DEA to give compounds 912a and 912b.

PREPARATIVE EXAMPLE 96



913a
Starting material 912a {0.284g 0.656mmol) was dissolved in CH2Ci2 (5ML). TEA (1.83WL, 2.0 eq.) and (BOOzO (0.215g, 1.5eq), and stirred at room temperature overnight. Reaction was evaporated and crude was purified by column chromatography using 10% & 25 Ethyl Acetate/Hexanes to give 0.3g of compound 913a.
PREPARATIVE EXAMPLE 97



(B0C)2)
912b

TEA

913b
Starting material 9121 b (0.254g 0.587mmol) was dissolved in CH2CI2 (51^1). TEA (1.64ML. 2.0 eq.) and (B0C)20 (0.192g, 1.5eq), and stin-ed at room temperature Q^emight. Reaction was evaporated and crude was purified by column

chromatography using 10% & 25 Ethyl Acetate/Hexanes to give 0.255g of compound 913b.
PREPARATIVE EXAMPLE 98 Step A

N

N-CHs J

914

^^ + CHJ dry THF

915 " rt/N2 g^g

Suspended commercially available (from Acres) 915 (30g, 68,8 mmol) in dry THF (600ml) under dry N2. Stirred at room temperature under N2 until it fomied a dear solution. Added CH3I (50mM14g, 803.2mmol) at room temperature, dropwise. under dry Nj. Stirred the suspension at room temperature under N2 for 4 days, followed t)y TLC- (10% MeOH-2M NH3/ CH2CI2). Filtered the suspension, washed solid with dry THF. Dried the solid under house Vacuum at 40°C to give 31.11g of a brown solid, compound 916.

StepB

Tr-N-^^_CH3 ^ 50%HOAC/H,O . "^^.^-
"I f
916 914

Suspended 916 (31.1g, 53.79 mmol) in 200ML of 50%HOAC/H20 and heat under reflux overnight. Follow by TLC. When completed, allowed to cool to room temperature, filtered the resulting suspension. Washed with 50%HOAC/H2O. Evaporated to dryness. Suspended the solid in CHaCts. Basified to pH 10-11 with 1N NaOH. Separated CH2Ct2 layer and extracted the aqueous phase 3x with CH2CL2.

Combined organic layers and washed with Saturated NaCl solution. Dried over MgS04, evaporated to dryness to give 914 {8.68g of an off-white solid).
PREPARATIVE EXAMPLE 99
Step A



Cl Br
^j N"^ N-CH3 (914)
913a

2) EtMgBr {3M in EtsO) CICH2CH2CI

917

EtMgBr (3Molar in Et20) solution (2.89mmol, 963uL, 5,5eq.) was dripped into a solution of 914 (0.656g, 3.15mmol, 6eq.) in CICH2CH2CI (6ML) for 30 minutes. To ttie white suspended mixture, 913a (0.280g, 0.525mmol) was then added and stirred at 60°C for 3 hours. Reaction was treated with saturated NH4CI at 0°C by pouring the reaction into the cold NH4CI. Extracted with Ethyl Acetate, dried over MgS04 and evaporated to dryness. Column Chromatography (SiOz) eluted with 1%, 2% & 3% MEOH/ CH2CI2 gave 0.054g of compound 917.

StepB


OD Chirai Caiumn
917
917b
917 was separated by HPLC using a Chirai OD Column and eluting with 20%IPA/Hexanes to give 917a (isomer 1) and 917b {isomer 2).

PREPARATIVE EXAMPLE 100



CI Br
1) w^ N-CH3 (914)
913b

2) EtMgBr (3M in EtjO) CICH2CH2CI

EtMgBr (SMolar in EtiO) solution (791 uL), was dripped into a solution of 914 (0.518g, 3.15mmol, 6eq.) in CICH2CH2CI (6ML). for 30 minutes. To the white suspended mixture, 913b (0.280g. O.525mmo!) was then added and stirred at 60°C for 3 hours. Reaction was treated with saturated NH4CI at 0°C by pouring the reaction Into the cold NH4CI. Extracted with Ethyl Acetate, dried over MgSOi and evaporated to dryness. Column Chromatography (Si02), eluted with 1%, 2% & 3% MEOH/ CHjClagave 0.054g of compound 918,


StepB
918 was separated by HPLC using a Chiral OD Column and eluting with 20%IPA/Hexanes to give Isomers 918a ^H NMR (400MH2, CDCI3, TMS) 6 1.419 (s, 9H). 1.457 (s, 1H), 1.894 (s. 3H}, 2.05-1.87 (m. 2H). 2.30-2.15 (m, 2H), 3.214 (broad. 1H), 3.540 (s, 1H), 3.738 (s, 1H), 3.760 (s, 1H), 3.888 (s, 3H), 4.540 (s, 1H), 6.479 (s, 1H), 7.128 (s, 1H), 7.260 (d, 1H), 7.340 (s, 2H), 7.627 (d, J=2.4H2, 1H}, 8.221 (s, 1H). 8.486 (d. J=2.8Hz, 1H). (21) Mp = 188-190 °C, and 918b.

PREPARATIVE EXAMPLE 101

Compound 917a was converted to 919a by reacting with CH2Cla/TFA at room temperature under N2, for 2 hours. Reaction was then concentrated, and the residue taken up in CHaC);, and washed with 1.0 NaOH. Isolated organics are dried over MgS04, filtered and concentrated to give compound 9l9a.
PREPARATIVE EXAMPLE 102

Compound Camien 917b was converted to 919b by reacting with CH2CI2/TFA at room temperature under N2, for 2 hours. Reaction was then concentrated, and the residue taken up in CH2CI2; and washed with 1.0 NaOH. Isolated organics are dried over MgS04, filtered and concentrated to give compound 919b.

PREPARATIVE EXAMPLE103

N-^

N^.

Compound 918a, was converted to 92Qa, by reacting with CH2CI2/TFA at room temperature under N2, for 2 hours. Reaction was then concentrated, and the residue taken up in CH2CI3, and washed with 1.0 NaOH. Isolated organics are dried over MgSOd. filtered and concentrated to give compounds 920a.
PREPARATIVE EXAMPLE 104

TFA
Cl ^ Br
CH2CI2 W
2hr

918b

N^.

N-^.

Compound 918b was converted to 920b by reacting with CH2CI2/TFA at room temperature under N2, for 2 hours. Reaction was then concentrated, and the residue taken up in CH2CI2, and washed with 1.0 NaOH. Isolated organics are dried over MgSOj. filtered and concentrated to give compound 920b.

PREPARATIVE EXAMPLE 105
Step A

922
Compound 921 was reacted in essentially the same manner as In Preparative Example 23, Steps A-D, of WO 02/18368, to get compound 922.
StepB

923
In essentially the same manner as in Preparative Example 42, Step A, of WO
02/18368, using.922 as the starting material, compound 923 is prepared.


PREPARATIVE EXAMPLE 106
.N,
H
924b
Compound 923 from Preparative Example 105 Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get 924a (i.e.,
isomer 1) and 924b (i.e., isomer 2).


PREPARATIVE EXAMPLE 107
925b
Compound 923 from Preparative Example 105 Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get 925a (i.e., isomer 1) and 925b (i.e., isomer 2).
EXAMPLE 1295 Following essentially the same procedure as Examples 590-603 (wherein the chlorofomiates are prepared following the procedure in Preparative Example 74) using 924a and 924b compounds of the formula:





.N.

-N,

N N
I I
R R
were prepared wherein R is defined in Table 91 and the numbers 1 and 2 in the
formulas represent isomers 1 and 2, respectively.
Table 91

Example R Isomer 1 isomer 2
1295 "HNMR (400MHz, CDCI3,
0^0^ TMS)8 1.417 (S.9H), 1.454 (d.

J=1.6H2,1H), 1.857 (s, 3H). 2.20-
2.05 (m, 4H), 3.205 (broad, 1H). mp=
3.432 {s, 1H), 3.612 (s, 1H), 3.731 (d. J=6.4Hz, 1H), 3.653 (s, 3H), 4.575 (S.1H). 6.538 (s. 1H). 7.086 (s. 1H). 7.114 (S.1H), 7.262 (d, 2H), 7.540 (s, 1H), 8.530 (d, J=2.0Hz, 1H), 8.876 (d.J=2.0H2. 1H). 184-185 °C
EXAMPLE 1314 Following essentially the same procedure as Examples 590-603 (wherein the chloroform ates are prepared following the procedure in Preparative Example 74) using 924a and 924b compounds of the formula:


were prepared wherein R is defined in Table 93 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.
Table 93

Example R Isomer 1 Isomer 2
13U .K-k "H NMR (400MHz, CDCI3, TMS) mp=

5 1.418{S, 9H), 1.456 (s, 1H), 183-184 °C
1.859 (s, 3H), 2.20-2.05 (m, 4H), 3.205 (broad, 1H), 3.612 (s. 1H). 3.692 (s. 1H), 3.740 (s, 1H), 3.854 (s, 3H), 4.576 (S.1H), 6.541 (s.
1H), 7.090 (s,1H), 7.116 (s.lH), 7.262 (d.2H). 7.548 (s,1H), 8.530 (d. J=2.0Hz, 1H).8.864 {d. J=2.0Hz. 1H)

PREPARATIVE EXAMPLE 108
Step A

0^0-^
926
In essentially the same manner as in Preparative Example 23, Steps A-D, of WO 02/18368, use compound 234a (from Step B) to prepare 926.
StepB

In essentially the same manner as in Preparative Example 42, Step A, of WO 02/18368, use 926 to prepare 927.

StepC



928a

928b

Compound 927 from Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get compounds 928a and 92ab.
StepD

927
Compound 927 from Step B was reacted in essentially the same manner as in Preparative Examples 91-104 to get compounds 929a and 929b.

EXAMPLE 1573


HO

Step A


o

r x)
-N-
882

React 882. from Preparative Example 73 Step B. with ethylmagnesium bromide following the procedure described in Preparative Example 73 Step C.
StepB




931

HO
React 365a with 931 (from step A) following essentially the same procedure as in Preparative Example 73. step D, to give the 930 as a white solid, mp = 163.165°C.

EXAMPLE 1574
HO
Step A



F.C

Dissolve 880 (1.4g, 10 mol), CF3TMS {1.46g, 10.25 mol). and CsF (15.2 mg, O.lmmol) in 15 ml THF. Stir at room temperature ovemlght, then concentrate under vacuum. Flash chromalograph the residue on silica gel using 0.5%-1% methanol in methylene chloride to obtain 933.

StepB




FiC

React 365a with the 933 (from Step A) following essentially the same procedure as in Preparative Example 73. Step D, to give 932, mp = 189.9-190. rc.
EXAMPLE 1575

934
React 372 {Example 167 of WO 02/18368) (0.06g. 0.097mmol) with 5 equivalents {0.019g. a.48mmol) of NaH (60% in oil) in 2ml of dry THF at 0°C for 5 min. Add 0.027g (O.llmmol) of 4-(bromomethyl) pyridine. Raise temperature to 60-65°C and continue to add NaH and 4-(bromomethyl) pyridine until reaction is complete by TLC (5% CH3OH in CH2CI2 containing NH4OH. Partition between ethyl acetate and

brine. Dry organic layer over Na2S04, concentrate and chromatograph on silica gel, eiuting with 1%-4% CHaOH in CHjCb containing NH4OH. to give 934 as a light yellow solid.
EXAMPLE .1576 Following essentially the same procedure as in Example 1575, compound 372 was reacted with 2-{ bromomethyl}pyridJne.HBr to afford compound 935 identified in Table 105 below.
EXAMPLE 1577 Following essentially the same procedure as In Example 1575, compound 372 was reacted with 3-( bromomethyl)pyridine.HBr to afford compound 936 identified in Table 105 below.
EXAMPLE 1578 Following essentially the same procedure as In Example 1575. compound 372 was reacted with benzyl bromide to afford compound 937 identified in Table 105 below.
EXAMPLE 1579 Following essentially the same procedure as in Example 1575, compound 372 was reacted with CH3I to afford compound 938 Identified in Table 105 below.
Table 105




Step A

To a 125 ml flask, was added 4-hydroxymethyl ptperidine (940) (1g, 8.68mmol) and 20 mi of MeOH. cool to 0°C, then added Boc-anhydride {2.84g,13.02mmol. 1.5 eq.), and adjust to pH 8.5-9.5 over 1 hour with I3ml, 13.0 mmol,1.5eq. of 1.0 N NaOH. Reaction was allowed to warm to room temperature and stirred for 1 hour. TLC with 20% EtoAc/CH2Ci2. Removed most WeOH via evaporation. Added CH2CI2 and washed with HjO. brine and filtered through Na2S04. The solvent was evaporated to give 1.82g of a clear oil. Oily product crystallized upon standing to give a white solid product 941.

941 (0.3g. 1.395mmol) was transferred into a flask and dissolved in anhydrous CH2CI2. CooltoO"^C. Added 129ul, 1.67 mmol. 1.2eq.,ofmethanesulfonyl chloride and triethy1amine(129ul, 2.09 mmol, 1.5eq.). Allowed to wami to room temperature while stirring for 1 hour. TLC with 20% EtoAc/CH2Cl2- Added saturated NaHCOs, and stir 3-4 minutes, separated the CH2Cb layer, washed with H2O. brine and fittered

r through NaaSOi. Solvent was evaporated to give 0.423g of a clear oil, compound
942.

942 (Q-1 g, 3.413mmo!) was transferred into a reaction flask and added anhydrous CHsCb (1ml), followed by addition of (1) 4-aminobenzonitrile (0.040g.3.4 ■ mmo[)and triethy(amine(61ul. 4.4 mmol, 1.3 eq.) and stir at room temperature for 10 minutes. TLC with 10% EtoAc/CH2Cl2. reaction still did not complete. Stir for 1V2 hour, TLC again, reaction stopped. Removed solvent to dryness. Added toresidufe, (1ml) of anhydrous THF at room temperature, then added 0.0136g, 3.4 mmot of NaH (60% in oil Disp.). Let stir for % hour, followed reaction progress by TLC. Added to reaction mixture additional NaH (0.0136g, 3.4 mmol), stirred for Vz hour, monitored reaction by TLC, then heated reaction mixture to 60°C in an oil bath for 45 minutes then overnight. Removed solvent in rotary evaporator under vacuum. Residue was dissolved in CHaClaand washed with H2O, then brine. Filtered through NajSOi, removed solvent to dryness to give 0.125g of cmde product. Crude was purified by flash chromatography using (silica gel) and eluting with CHzCli then with 1-5% EtoAc/ CH2CI2. Isolated 0.035g of product, 943.


943 (0.034g, 0.11 mmol) was transferred into a reaction flask and dissolved in CH2CI3 (3 ml) and cooled to O^C. TEA {60ul, 0.43 mmol, 4 eq.) was added, followed by (213ul, 0.0427g, 0.43 mmol, 4 eq.) of a 20% phosgene/toluene solution. Reaction was allowed to stir at 0°C for 1 "/a hours. After 1V2 hours, Na was bubbled into the reaction for ~ 10 minutes, then added 0.056g, 0.12 mmol. 1,1 eq., of starting material (2)-compound 371a (Preparative Example 42. Step F, of WO 02/18368) followed by triethylamine (33ul, 0.24 mmol, 2.2 eq.) in 1ml of CH2CI2. Allowed to stir at O"^C for 1V2 hours. Reaction mixture was washed with NaHCOa, then H2O, then brine and organic layer was filtered through Na2S04. Removed solvent to dryness to give 0.083g of crude product. Purified on flash silica gel column eluting with 2,4, 6, .8%(10%NH4OH/CH3OH)/CH2Cl2). Isolated product gave 0.039g of 939, MH* = 747.


EXAMPLE 1581
939 1
939 was reacted in the same manner as Compound 360a (Preparative Example 40, Step G, of WO 02/02/18368), using (0.118g, 0.25 mmol) of 939 and (5 ml) of 4N HCI in dioxane to give 0.252g of 944, MH* = 647.

EXAMPLE 1582


944

NH . HCl

In a 100 ml flask was added 944 (0.073g, 0.067024mmol) and 5 ml of anhydrous CHaClaand stirred followed by addition of TEA (37u(. 4 eq.) and trimelhylsilyl isocyanate {90ul, 0.07 mmol, lOeq.). Reaction was allowed to stir at room temperature for 1 hour. TLC with 7% (10% NH4OH/CH3OH) /CHaCb- Stir 1 Vj hours, then added saturated NaHCOa and stirred for 10 minutes, separated CH2CI2 layer, and washed with HjO, brine and dried over Na2S04, filtered and concentrated filtrate to dryness to give 0.056g of crude product. Purified on Flash silica gel column eluting with CH2CI2, then with 1-7 %(10% NH4OH/CH30H)/CH2Cl2. Isolated 0.038g of the desired product, 945, MH* = 690.

EXAMPLE 1583



O^N^"^"

NH . HCI
944

■OH

946
In a 50ml reaction flask was added (0.0092g. 0.0882mmol, 1.05 eq.) of 2-hydroxy isobutyric acid (CAS 594-61-61 i" 1 f^" of anhydrous DMF and 1 ml of anhydrous CH2CI2followed by addition of NMM (46ul,0.42 mmol, 5 eq.); HOST (0.0178g, 0.11 mmol, 1.3 eq.). DEC (0.024g, 0.13mmol, 1.5 eq.}. Reaction mixture was allowed to stir at room temperature for - 10 minutes, then added 944 (0.084g, 0.08 mmol, 1 eq.) in 1 ml of DMF and 1 ml of CH2CI2. Reaction was allowed to stir at room temperature overnight. Removed solvent in rotary evaporator, added EtoAc and washed with saturated NaHCOa. then 3{X) with H2O, then with Brine, Organic layer was filtered through Na2S04. evaporated filtrate to dryness to give 0.087g of crude product, purified crude on a Flash silica gel column elutlng with CH2CI2-1-5% {10%NH4OH/CH3OH)/ CH2CI2. to give 0.048g of a white solid Compound 946. MH* = 733.

EXAMPLE 1584



NH.mHCL
944

947
In a 50 ml flask was transferred (0.084g, 0.084mmol) of 944 and 2 mi of anhydrous CH2CI2 followed by addition of triethylamine (50ul. 4.2mmol, 5 eq.) and methanesulfonylchloride (7.8ul. 0.10 mmol, 1.2eq.). Reaction was allowed to stir at room temperature overnight. Tic with 5% (10%NH4OH/CH3OH)/CH2Cl2. Added saturated NaHCOj and stirred vigorously 5-10 minutes. Separated CH2CI2 layer and washed with H2O, Brine and filtered through Na2S04. Filtrate was evaporated to dryness to give 0.080g of crude product. Purified crude on a Flash silica gel column eluting with CH2Clr 1-4% (10%NH4OH/CH3OH)/ CH2Cl2.to give 0.041 g - compound 947.MH* = 725.

EXAMPLE 1585



O^N-O""^""
944
NH . HCI

948
In a 50 ml flask was transfen-ed (0.084g, 0.084mmol) of 944 and 2 mi of anhydrous CH2CI2followed by addition of triethylamine (58ul. 4.2mmol, 5 eq.)and triflic anhydride (16.9ul, O.IOOammol, 1.2eq.). Reaction was allowed to stir at room temperature overnight. TLC with 5% (lOyoNHaOH/CHjOHyCHzCb- Added saturated NaHG03 and stirred vigorously 5-10 minutes. Separated CH2CI2 layer and washed with H2O, brine and filtered through Na2S04. Filtrate was evaporated to dryness to give 0.065g of crude product Purified cnjde on a Flash silica gel column eluting with CH2CI2-1-4% {10%NH4OH/CH3OH)/ CH2CI2, to give 0.028g - compound 948. MH*=779.

EXAMPLE 1586



V-ci
371a

O^^N^"^"^

OH
949

Step A


I
H2N

H
"tj^c.



950

OH

951

4-aminoben2onitriIe (O.lg, 0.85 mmol) was dissolved in {5ml) of CHzClz. To this solution was added isobutyiene oxide (61mg, 0.85mmol) and 1g of silica gel. Reaction mixture was stirred at room temperature for 16 hours, isobutyiene oxide (0.75ul, 8mmol) was added and reaction was heated to 60°C for 16 hours. 4-aminobenzonitrile (200mg, 1.6mmol) and Isobutyiene oxide(0.75ul, 8mmol) was added and reaction refiuxed for another 7 hours. Volatile solvents evaporated and material chromatographed on silica gel column, elufing with 1-9% ethyl acetate/ CH2Cl2.tQ give 295mg of the desired prQduct-951.
StepB
BOC


A>-
//
CN
M

CN



OH

951

OH

952

Compound 951 from Step A was N-protected with a Boc group using standard conditions to give 952.
STEPC

BOC

BOC




OH

"1^c;
952


-N
OTBDMS 953

//

CN

Compound 952 from Step B was 0-protected using tetrabutyldimethyl-silyl{TBDMS) to give 953.
StepD
BOC


I
//
//

1
-N

CN

"CN



OTBDMS
953

OTBDMS 954

The Boc group of 953 Step C was deprotected using HCl-Dioxane to give 954.
StepE


y/
OTBDMS
954

CN

OTBDMS
955

Compound 954 from Step D was treated in a similar way to compound of Example 1580, Step D, to give 955.
StepF

/"^CN

955

QTBDMS

-*-

O^NA,/

OH
949

Compound 955 from Step E, was deprotected by treatment with tetrabutyIammoniumnuoride(TBAF) to give the title compound 949.
EXAMPLE 1587





956

957

956 and 957 were prepared in a similar manner to 949 using the appropriate substituted starting epoxide.

PREPARATIVE EXAMPLE 109
Step A


958

I.BuLi, a;0
. k^
2. 0 DMF
H
A
N"

959

To a stirred solution of 1,2-dimethyiimidazole. compound 958 (1.92g,1eq. 20 mmol) in 50 ml of EtzO , was added BuLi (2.5 M in Hexanes,1eq. 20 mmol.S ml) and stirred at room temperature, a yellow suspension results. Stin-ed for 1.5 hr. more precipitate forms. Reaction mixture was treated with 3.5 ml of DMF , slin-ed for 2-5 hours or until reaction was complete. Quench reaction with NH^Ci solution and extract with CH2CI2, wash organic 3x with brine. Isolate organic and evaporate to dryness to obtain product as a crude. Purification from Prep Plate Chromatography 10:1 CH2Ct2 ; MeOH : 2N NH3 afforded 0.52 g of compound 959, -21%.
StepB



1)
.N.
C_.)
N
365a ^

BuU
■N
^1 I
959

Following essentially the same procedures as in Example 510 (Step A), but using compound 959 (0.25g, 2mmol) as the intermediate, compound 960 was prepared. Yellow solid (0,54g). 50% yield.

SlepC


MnO;
960
Following essentially the same procedures as in Example 510 (Step B) but using Compound 960 (0.45g, 0.84mmol) as the starting material, compound 961 was prepared. Light yellow solid (0.372).
StepP



NaH
THF/DMSO
CH3-S|—I H3C

Following essentially the same procedures as in Example 510 (Step C) but using Compound 961 (0.267g, O.Smmol) as the starting material,Compound 962 was prepared.

StepE



Ll [ Et)3BH

963

Following essentially the same procedures as in Example 510 (Step 0) but using Compound 962 (O.Smmoi) as the starting material, compound 963 was prepared. (0.18g).
StepF



OD COLUMN

Following essentially the same procedures as in Example 510 {Step E), Compound 963 was separated by Chirai HPLC to give compounds 963a and 963b. Chirai OD Prep HPLC Column, eluting with IPA (10%) hexanes (80%) + 0.2% DEA Isomer 1, compound 963a: retention time = 7.61 min Isomer 2, compound 963b: retention time = 10.56 min

PREPARATIVE EXAMPLE 11Q
Step A



964


K2C03
CH
ACETONE
3" 965

To a stirred solution of 964 (Ethyl 4-methyl-5-imidazole carboxylate, 7.7g, SOmmol) in 100ml of acetone at room temperature, was added K2CO3 ( 6.9g, 50 mmol) portionwise. Stin"ed at room temperature for 25 minutes, added in Mel (5 ml, SOmmol) stirred for ZVz h. (monitored reaction by TLC). Additional K2CO3(3.09g, 22mmo() and Mel (3ml) were added. Stirred reaction for 16h, then filtered reaction mixture and rinsed with acetone (80ml). A clear filtrate obtained. Filtrate was evaporated and the residue was chromatographed (eluent methylene chloride/methanol (60:1) to afford 1.8g of solid. This solid was purified by Prep Plate chromatography ((20:1) CHzClaiMeOH NH3}. compound still impure. Another column chromatography ((50:1) CHsCl^iMeOH NH3) was done to afford 383 mg of the desired product, compound 965.
SteoB



LAH
THF
965
To a stirred solution of compound 965 (680mg) in 10 ml THF at-78"C was added dropwise 1 .OM LAH in THF (5.0ml). Reaction was stined and allowed to wann to room temperature overnight. Cooled reaction mixture to 0°C then added 5ml of H2O dropwise. Aiiowed reaction to warm to room temperature while stirring for 1hr. Filtered through celite and rinsed with 20ml THFMOmI H2O. A clear filtrate obtained. Filtrate afforded compound 966.

step C


/
MnOa
-■^n
956
To a stin"ed solution of compound 966 (~4mmol) at room temperature was added (3.0g) of Mn02, a suspension resulted. Heated reaction mixture to a gentle reflux for 18hr. Additional MnOs/THF was added (6.0g/20ml). Stirred at reflux for 24hr. Cooled to room temperature, fittered through celite and rinsed with 50ml MeOH, Solvent was evaporated and azeotroped residue with toluene to affonj cnjde product. Cmde was purified by column chromatography (20:1 CHjCb/MeOH), then (8:1 CH2CI2: MeOH) to elute out desired product as a white solid, compound 967.
Step D


365a
968

If one were to follow essentially the same procedures as in Example 510 (Step A), but using compound 967 as the intermediate, then one could prepare compound 968.

StepE



WnO,

-*-

If one were to follow essentially the same procedures as in Example 510 (Step B). but using compound 968 as the starting material, then one could prepare compound 969,
StepF




If one were to follow essentially the same procedures as in Example 510 (Step C), but using compound 969 as the starting material, then one could prepare compound 970.

StepG



U ( Et)38H

If one were to follow essentially the same procedures as in Example 510 (Step D, but using Compound 970 as the starting material, then one could prepare compound 971.
StepH

OD COLUMN
CI ^

971b If one were to follow essentially the same procedures as in Example 510 (Step E), then compound 971 could be separated by Chiral HPLC to give compounds 971a and 971b.

PREPARATIVE EXAMPLE 111
Step A



972

NsH
Mel THF

To a stirred solution of 972 {ethy! 4-methyI-5-imida20le carboxylate, 3.08g, 20fnmot) in 30ml of THF, at room temperature, was added NaH (0.8g, 20 mmol) portionwise. Stirred at room temperature for 10 minutes, then cooled to 0°C. Added in Me! (1.5 ml, 24 mmol) stirred for 2 h, quenched with saturated NH4CI, extracted with ethyl acetate (2x), and washed with brine. Purified crude by column chromatography using a 20:1 CH2CI2; MeOH, to afford product, compound 973.
Steps



-ueti

To a stirred solution of compound 973 (0.9g) in 15 ml THF, was added 3ml of a 10% UOH solution and stirred reaction for 2 days. Evaporated solvent, azeotroped once with toluene, evaporated solvent to afford product, compound 974.
StepC


1)HN^HC1
OCH3
2) DEC
974 " 3) HOST

4)NMM
To a stirred solution of compound 974 (-5.4 mmol) in 40ml of anhydrous DMF at room temperature under N2, was added, 1.05g, 10.8 mmol of (1); 2.07g, 10.8 mmol of (2); 0.72gg, 5.4 mmof of (3); and 5.5 ml, 50mmot of (4). Reaction mixture was stirred

at room temperature for 5 hours. Reaction progress was monitored by TLC. Added IN HCI until pH StepD



975

LAH
1.0MTHF

To compound 975 (0.590g, 3.2 mmol) in 5 ml of toluene at -70°C. was added {3.6ml, 3,6mmol of LAH (IM in THF}) dropwise. Reaction mixture was stirred at temperatures ranging from -/O^C to -50°C for 30 minutes. Quenched reaction with 4ml brine, and stirred at room temperature for 20 minutes. Reaction was eluted through a cake of celite with ethyl acetate/ CH2CI2. Dried filtrate, evaporated solvent to afford 0.162g of product (yellow oil), compound 976.
StepE


HO
N^

BuU

1)
2)
976
977
365a
Following essentially the same procedures as in Example 510 (Step A), reacting compound 365a {0.612g, 1.25 mmol) but using compound 976 (0.152g) as the intermediate, compound 977 was pre pared. (Yellow solid, 0.408g).

StepF


N=
977
MnO?
978
If one were to follow essentially the same procedures as in Example 510 (Step B), but using Compound 977 as the starting material, then one could prepare compound 978.
StepG

N=N=^

NaH
THF/DMSO CHa
CH3-S|"—r
H3C
If one were to follow essentially the same procedures as in Example 510 (Step C), but using compound 978 as the starting material, then compound 979 osuid be prepared.

StepH


N=
Ll (EtJaBH



980

If one were to follow essentially the same procedures as in Example 510 (Step D). but using Compound 979 as the starting material, then one could prepare compound 980.
Step


980b
00 COLUMN

N=
r^=
Ifone were to follow essentially the same procedures as in Example 510 {Step E), compound 980 could be separated by Chiral HPLC using a Chiral OD Prep HPLC column to give compounds 980a and 980b.

Step A

PREPARAI!VE_EXAMPLE 112


EtMgBr
DMF

"N
4-lodo-1-Trity!-1H.|mlda2ole

Rep. Org. Prep. Proceed Int. {"1996) 28{6). 709-710.

To a stirred solution of 4-iodo-1-trityi-1H-imidazole (4.36g, 10mmol)inTHF (100ml) was added EtMgBr (4ml, 12 mmol) and let stir for 30 minutes, DMF (0.93mi, 12mmol) was added and let stir for 1 hour. The reaction was poured into saturated ammonium chloride and extracted with EtOAc. The organic layer was dried with MgS04. filtered, and concentrated under vacuo to yield 3.5g of light yellow solid.
StepB

M—Tr

365a
Following essentially the same procedures as in Example 510 {Step A), but using compound 981 (0.72g) as the intemiediate and MgBr.Et20 (2.58g in 50ml THF, 7.5ml), crude compound 982 was obtained. The crude material was purified via preparative plate chromatography (1-3% MeOH with NH3/CH2CI2) to obtain pure product, compound 982 (0.29, 39%).

f^=N—Tr
N—Tr

StepC

982



MnO".

983

Following essentially the same procedures as in Example 510 (Step B), tfut using compound 982 (0.29g) as the starting material, compound 983 was prepared (0.29g).

The crude material was purified via preparative plate chromatography (2% MeOH with NHyCH^CI,) to yield 0,237g of pure product, compound 983.
Step D

N—Tr
N—Tr
NaH

Q N=>

THF/DMSO H3C

P N=^

Following essentially the same procedures as in Example 510 (Step C) but using compound 983 (230m9) as the starting material, compound 984 was prepared {222mg).
StepE




N—Tr
N—Tr
LI (Et)3BH
^

984

9S5a

985b

Following essentially the same procedures as in Example 510 (Step D) but usmg compound 984 (0.2g) as the starting material, ca^de isomers 985a and 985b were prepared. The isomers were purified and separated via preparative plate chromatography (5% MeOH with NHyCH^CI.) ,o obtain 0.16g of pure 985a and 0 06g
of pure 985b.

PREPARATIVE EXAMPLE 113



N—Tr
HO N^

NaH.Me!

To compound 982 (390mg) dissolved in THF (3m!) was added NaH (60% in mineral oil, 2Smg). After 5 minutes, iodomethane was added and let stir for several hours. The reaction was concentrated under vacuo and ca^^ed on cojde to the next reaction.
PREPARATIVE EXAMPLE 114
Step A


SEM-CI

SEM

98S
987
To a stirred solution of 987 (2-methyl-1H-imidazole-4-cartK>xaldehyde.1g, 9.09mmol) in 10 ml of DMF at 0°C was added NaH (60% in mineral oil (0.36g)) portionwise. Stiaed mixture for Va hr, then added SEM-CI (2.02ml, 9.9fnmol). Stirred reaction until completed. Added reaction mixture to brine and extracted with CH2CI2 (3x). Evaporated solvent to get an oil. Column chromatography (CH2Cla(1Q0% - 2% MeOHNH3/ CHzClz) afforded 1.68g of product, compound 988 (77%).

StepB

Following essentially the same procedures as in Example 510 {Step A), reacting compound 365a {0.12g, 0.25mmoi) but using compound 988 (0.1g) as the intermediate, compound 989 was prepared {96mg, 56%).
StepC

Following essentially the same procedures as in Example 510 {Step B), but using Compound 989 {0.52g, 0.79mmoi) as the starting material, compound 990 was prepared.

StepD



NaH THF/DMSO
CH3
+
CH3-S
H-iC

Following essentially the same procedures as in Example 510 (Step C), but using compound 990 (0.5lg, 0.79mmoi) as the starting materia), compound 991 was prepared.
Steal



LI ( EOjBH

Following essentially the same procedures as in Example 510 (Step D), but using Compound 991 (0.79mmol) as the starting material, compound 992 was prepared.

StepF



TBAF

To compound 992 (0.1g) dissolved in THF (5ml) at room temperature under Nz. was added 0.2ml of tetrabutylammonium fluoride 1M solution in THF (TBAF). Stin-ed reaction for 2fir. Additional TBAF was added (0.2ml), monitored reaction by TLC. No reaction after 4 hours. Reaction was treated with 0.5ml of TBAF and heated to 85°C. After 2hr, reaction completed. Cooled reaction and added to brine and extracted with CH2CI2 (3x), dried organic over MgS04, filter and evaporated solvent to give crude product. Purification by Prep Plate Chromatography using 95% CHjCb/MeOH ■ NH3 (5%) afforded 0.12g of product, compound 993.
StepG



^,| 00 COLUMN
993b
If one were to follow essentially the same procedures as in Example 510 (Step E), then compound 993 could be separated by Chiral HPLC to give compounds 993a and 993b, using a Ctiiral OD Prep HPLC Column.

PREPARATIVE EXAMPLE 115
Step A


SEM-Cl
994
To a stirred solution of 994 (3.08g, 20mmol) in 15 ml of DfvlF at O"^C was added NaH (60% in mineral oil. O.SOg) portionwise. After stirring for several minutes, SEM-Cl (3.54ml, 20mmol) was added and let the reaction stir overnight. Brine was added to the reaction and ejdracted with EtOAc. The organic layer was washed with water and brine, dried with MgS04. filtered and concentrated under vacuum. Purified fay flash elute column chromatography (CH2Cl2/MeOH. 50:1 to 20:1) to afford 4.54g of yellow oil, compound 995.
StepB


LiOH
/ ^ 997
996

To a Stirred solution of compound 995 (3.5g) in THE (50ml) was added a LiOH solution (1M, 24ml) and stirred for 2 days. The reaction was not complete; therefore, 25mt of MeOH and another 10ml of the LiOH solution was added and the reaction was heated to 40°C for 2 hours. The reaction was concentrated under vacuo, azeotroped once with toluene, and evaporated to dryness to afford compound 996, which was carried on directly without further purification.

StepC


MeO.
^CH3
-N
V \-)
1)HN^HCI
997
^ ^biC 2} DEC
996 / f 3) HOBT
4}NMM
Following a similar procedure to that described In Preparative Example 111 Step C, but using compound 996, compound 997 was prepared (5.37g crude).
StepD

MeO.
."^">
LAH
V°v^/
N O /\ /
997
Si-/
1.0MTHF
998 "" ""
Following a similar procedure to that described in Preparative Example 111 Step D, but using compound 997 (4.2g), compound 998 was prepared.
PREPARATIVE EXAMPLE 116
Step A


365a

1) 1.2eq.nBuLi
O
2)
N.
Vs
N
H
998
SEM


N-Cl
999
^ fi-r

X

If one were to follow a similar procedure as described in Example 610 (Step A), but using compound 998 as the intennediate, then compound 999 could be prepared.

StepB



If one were to follow a similar procedure as described in Example 510 (Step B), but use Compound 999, then compound 1000 could be obtained.
Step C

NaH

THF/DMSO CHa-Sr—I
1000 \ ^3^
If one were to follow a similar procedure as described in Example 510 (Step C), but using compound 1000 as the starting material, then compound 1001 could be prepared.

StepD

N 1002 If one were to follow a sinnilar procedure as described in Example 510 {Step D), but using compound 1001, then one could obtain compound 1002.
Sjep E


If one were to follow a similar procedure as described in Preparative Example 114 (Step F), but using compound 1002, then one could obtain compound 1003.

SteoF


+
0 0-t^
1003a If one were to follow a similar procedure as described in Example 510 (Step E), then compound 1003 could be separated by Chiral HPLC to give compounds 1003a and 1003b.
EXAMPLE 1588 Compound 963a (Isomer 1) and compound 963b (Isomer 2) were converted to compound 1004a and compound 1004b by following a similar procedure as described in Example 507.


TFA
Cn2Cl2 2hr


Q
H 1004e



TFA
CH2CI2 2hr

1004b

EXAMPLE 1589 Compound971a(lsomer1) and compound 971b (Isomer 2) were converted to compound 1005a and compound 1005b by following a similar procedure as described In Example 507.



TFA
2hr

1005a




\ HO f""^.
971b

TFA
CH2CI2 2hr

\ HP N-
1005b

EXAMPLE 1590
Compound 980a (Isomer 1) and compound 980b (Isomer 2) were converted to compound "1006a and compound 1006D by following a similar procedure as described in Example 507.


N^

TFA
CHjCIa 2hr

HO
1006a




N^
TFA
CH2CI2
2hr

HO N-
1006b

EXAMPLE 1591 Isomers 985a and 985b were converted to compound 1007a and compound 1007b by following a similar procedure as described In Example 507.



,^=^
N—Tr
0" 0-985a
TFA

1007a


N—Tr
N^

TFA

1007b

EXAMPLE 1592 To the product from Preparative Example 113 dissolved in CH2CI2 (5ml) was added trifluoro acetic acid (1 ml) and let stir for 1 hour. The reaction was concentrated under vacuo and carried on crude to the next reaction.



N—Tr
THF
TFA

1008

EXAMPLE 1593 Compound 993a (Isomer 1) and compound 993b (Isomer 2) were converted to compound 1009a and compound 1009b by following a similar procedure as in
Example 507.



TFA
CHjCI? 2hr

1009a





TFA
CH2CI2 2hr

1009b

EXAMPLE 1594 If one were to follow a similar procedure as described in Example 507, then compound 1003a {Isomer 1) and compound 1003b (Isomer 2) can be converted to compound 1010a and compound 1010b.



TFA
CH2CI2

1010a



TFA
CHjCl;

1010b



Step A

PREPARATIVE EXAMPLE 117




NaH
CH3
H3C"S+—I CH3

1011

Following the same procedure as described in Example 510 Step C, but using compound 795 (3g) from Example 489 of WO 02/18368, the desired caide product was obtained (3.3g).
StepB






(Isomer A)

(Isomer B)

The cnjde material above (1011) was separated by flash column chromatography (40% EtOAc/Hex) to yieid pure isomer A (1011a) (1.23g) and an impure isomer B (1011b} (1,64g), Impure Isomer B was triterated In CHaCla/MeOH and filtered to give pure isomer lOllb (0.7g).
StepC




2-MethylimidazoIe(1.1g) was dissolved in dry DMF (15mi) followed by the addition of NaH (60% in mineral oii, 300mg). After stirring for 20 minutes, compound 1011b(1.2g) was added and the solution was heated to 90°C for 4 hours. The reaction was concentrated under vacuo, dissolved in CH2Ct2 and washed with brine. The organic layer was dried, concentrated under vacuo and purified via flash column chromatography (6% MeOH/CH2Cl2 + NH4OH) to give the desired product (1.47g).
StepD


1012

Compound 1012(1.4g) was converted to compound 1013 (1.09g) by foilowing the procedure set forth in Example 507.

Step A

PREPARATIVE EXAMPLE 118



C^ 0-
1011a
Following the same procedure as described in Preparative Example 117 Step C, but using compound 1011a (696mg), the desired compound was obtained (903mg).
StepB




Compound 1014 (O.gg) was converted to compound 1015 (0.58g) by following the procedure set forth in Example 507.

EXAMPLES 3157-3162
Compound 1015

1015 from Preparative Example 118 Step B was reacted in essentially the same manner as in Example 511-513 to afford the compounds in Table 134,
Table 134

Example Compound
3157 0



3161 0
3162 0
EXAMPLES 3163-3168
Compound 1013

1013 from Preparative Example 117 Step D was reacted in essentially the same manner as in Examples 511 -513 to afford the compounds in Table 135.

Iab!e 135




EXAMPLE3256



-N.

-N.

■Tr




O" ^^0 1016


1017
Tr


1018




1018

I.NaH, Wei
2. TFA
3. (Boc)20, TEA

-N.
1019a/1019b
78 c for 1.5 hrs, the reaCon mixture was participated between ethy, acetate and The comb,ned ethyl acetate layers was dried and concentrated /. .ac.o The
; ""^P™"^ ^"18 (834 mg) was obtained as a light yellow solid Compound 1018 (390 .g, 0.52 mmol, was dissolved in THF (3 mL, a. room
Mel (1.0 mL) 5 mm later. After stirrina fnr 70 hr. .h ■.
. ^"9 "°"^20 hrs, the mixture was evaporated to
one hour later, the mixture was evaporated to dryness. Thecordewas

retaken up in CH2C12 and made to PH>8 by addition of triethyl amine (ca. 0.6 mL). {Boc)20 (320 mg, 1.5 mmol) was then added. After stirring for 30 mi"ns, the solvents were removed in vacuo and the residue was participated between CHzCI; and H2O. The organic layer was dried and concentrated- The crude was purified with prep TLC plates using 10% methanol (2MNH3)/CH2Cl2 to yield a light yellow solid (121 mg). The product was separated by a semi-prep OD HPLG column eluting with 30% IPA/Hexane/0.2% DEA to give pure isomers 1019a {44.8 mg, isomer 1, MH* = 536) and 1019b (53.6 mg, isomer 2. MH* = 536).
EXAMPLE 3257



,N,

HCl/dioxane CHjClj

-N.




■N"
1019a

N
I
H
1020a





,N.

HCI/dioxane CH2CI2

-N.

I H
1020b
I N
-0 1019b
Compound 1019b (isomer 2) was converted to 1020b by reacting it with 20%
4M HCI(dioxane)/CH2Cl2 at room temperature under N2 overnight.
TVie same procedure was used to prepare 1020a (isomer 1) from 1019a.

EXAMPLES 3258-3260 Each isomer. 1020a and 1020b from Example 3257 was dissolved in CHzCla.. TEA was added in till PH >8 and followed by the corresponding isocyanates. Once TLG indicated the complete consumption of starting material, the solvent was concentrated in vacuo. The residue was purified by silica gel preparative thin layer chromatography or silica gel chromatography to afford connpounds of the formulas;



and

-N.

-N.



I R

1 R

wherein R is defined in Table 140 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.
Table 140

EXAMPLE R Isomer 1 Data Isomer 2 Data
3258 MH" 535 UH* 535
3259 oK-O MH* 561 MH^ 561
3260 oK-Or-"" MH" 580 MH* 580

EXAMPLES 3261-3263 Isomer 10203 from Example 3257 was dissolved in CHsClsat room temperature under nitrogen, followed by addition of the corresponding carfaoxylic acid, and the appropriate reagents: EDC, HOBt and NMM. Reaction was then stined overnight and added in 1N HCI till pH = 2. After stirring for 5 min, it was then basicified with sat. NaHCOa followed by extraction of CH2CI3, The orgariic solvent was concentrated In vacuo and the residue was then purified t>y silica ge) column to give compounds of the formula:

1
R
wherein R is defined in Table 141 and the number 1 in (he formula represents isomer 1.
Table 141

EXAMPLE R Isomer 1 Data
3261 1 MH* 522
3262 }
OH MH*5B4
3263 HO" V MH* 584
EXAMPLE 3264 Isomer 1020b from Example 3257 was dissolved in CH2Cl2at room mperature under nitrogen, followed by addition of diisopropylethyl amine to pH>8.

Reaction was then treated with the coaesponding sulfonyl chloride and stin-ed at room temperature till TLC indicated the completion of reaction. Quench reaction with brine and extract with CH2CI2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give a compound of the formula:



0
t
R
Wherein R Is defined in Table 142 and the number 2 in the formula represents isomer 2.

Table 142
EXAMPLE R Isomer 2 Data
3264 J
O"S=0
1" MH* 514
EXAMPLES 3265-326 7
Isomer 1020b from Example 3257 was dissolved in CH2Cirat room temperature under nitrogen, followed by addition of TEA. Reactions were then treated with the respective chloroformates (made from the corresponding alcohols according to Preparative Example 74) and stin-ed at room temperature till TLC indicated the completion of reactions. Quench reactions with brine and extract with CH2CI2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the fonnula:



0
t
R
wherein R is defined in Table 142 and the number 2 in the formula represents isomer 2.
Table 142

EXAMPLE R Isomer 2 Data
3265 " 1 MH" 522
3266 oK-G MH" 562
3267 oKxy MH* 564

791
{Preparative Example 65) of WO 02/18368

Compound 791 was separated by AD HPLC column eluting with 15% - 30% IPA/Hexanes/0.2% DEA to give pure isomers 791a (isomer 1. MH* = 547.1) and 79lb (isomer 2, MH* = 547.1).
EXAMPLE 3269



-N.

HCI/dioxane
CH2CI2



-N.




791a

N I H
1021a





791b

HCI/dioxane CH2CI2

Compound 791b (isomer 2) was converted to 1021b by reacting it with 20% 4M HC!(dioxane)/CH2Ci, at room temperature under N2 0vemlght.
The same procedure was used to prepare 1021a (isomer 1) from 791a.
■EXAMPLE 3?7n Each isomer. 1021a and 1021b from Example 3269 was dissolved in CH.CI,
TEA was added in till PH>8 and followed by the corresponding isocyanate Once " TLC indicated the complete consumption of starting material, the solvent was

concentftted in vacuo. The residue was purified by silica gel preparative thin layer chromatography or silica gel chromatography to afford compounds of the formulas



-N.

and

-N.

wherein R is defined in Table 144 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.
Table 144

EXAMPLE R Isomer 1 Data Isomer 2 Data
3270 H ^^ MH* 591 MH* 591
EXAMPLE 3271 Each isomer. 1021a and 1021b from Example 3269 was dissolved in CH2Cl2at room temperature under nitrogen, followed by addition of the corresponding carboxyfic acid, and the appropriate reagents: EDC, HOBt and NMM. Reaction was then stirred overnight and added in IN HCI till pH = 2. After stining for 5 min, it was then basicified with sat. NaHCOa followed by extraction of CHsCb- The organic solvent was concentrated in vacuo and the residue was then purified by silica gel column to give compounds of the formulas:



,N.

and

-N.

wherein R is defined in Table 145 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.
Table 145

EXAMPLE R Isomer 1 Data Isomer 2 Data
3271 I
POH fvlH* 533 MH^ 533
EXAMPLE 3272 Each isomer, 1021a and 1021b from Example 3269 was dissolved in CH2Cl2at room temperature under nitrogen, followed by addition of diisopropylethyl amine to PH>8. Reactions were then treated with the con-esponding sulfony! chloride and stirred at room temperature till TLC indicated the completion of reactions. Quench reactions with brine and extract with CH2CI2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the fonnulas:



and

-N.

-N,

k k
wherein R is defined in Table 146 and the numbers 1 and 2 in the formulas represent isomers 1 and 2, respectively.
Table 146

EXAMPLE B isomer 1 Data isomer 2 Data
3272 •1-o=s=o MH* 525 MH* 525
EXAMP LE 3273
Each isomer, 1021a and 1021bfrom Example 3269 was dissolved in CH2Cl2at room temperature under nitrogen, followed by addition of TEA. Reactions were then treated with the respective chloroformate (made from the corresponding alcohols according to Preparative Example 74) and stirred at room temperature till TLC indicated the completion of reactions. Quench reactions with brine and extract with CH2CI2. Organic layer was dried and concentrated. The residue was purified by silica gel column to give compounds of the formulas:



and

-N.

,N.

k k
wherein R is defined in Table 147 and the number 1 and 2 in the formulas represent Isomers 1 and 2, respectively.
Table 147

EXAMPLE

R

. Isomer 1 Data

Isomer 2 Data



3273

,C=o

MH* 533

UH* 533

EXAMPLES 3274-3277



SnCb
MeOH

M.

.N.



1 R

I R



.N.

SnCI;
MeOH

,N,

N N
1 1
R R
Each isomer from Examples 3268 and 3270-3273 was dissolved in MeOH at roam temperature under nitrogen, followed by addition of excess SnCb. Reactions were stirred at room temperature overnight and then concentrated in vacuo. The residue was stiaed in a mixture of 1N NaOH and ethyl acetate for 30 mins. Extract with ethyl acetate several times and wash the organic layer with brine. Organic layer was dried and evaporated to dryness. The crude was purified by silica gel column to give compounds of the formulas:



and

,N.

,N,

^N N
k k
wherein R is defined in Table 148 and the numbers 1 and 2 in the fonnulas represent isomers 1 and 2, respectively.
Table 148

EXAMPLE R Isomer 1 Data Isomer 2 Data
3274 oK^ MH* 521 MH* 521

3275 H MH* 565 f\4H* 565
3276 "1" 0=3=0
! MH" 499 MH* 499
3277 °^OH * tvlH* 507
"Isomer 1 of Example 3277 was not made.
EXAMPLES 3278-3279 Following a procedure similar to that of Example 3270 the azlde compound



.N.
I R
is prepared wherein R is


NH
X-O

or

o

and the number 2 in the formula represents isomer 2.
Then, following a procedure similar to that of Examples 3274 to 3278 the amino compounds of formula:



0
I
R
is prepared from the azide compound wherein R is defined in Table 149 and the number 2 in the formula represenst isomer 2.
Table 149

EXAMPLE R Isomer 2 Data
3278 o^Ij-O MH+ 547
3279 "0> NH MH+ 521
EXAMPLE 3280



-N.

I.TFA.CH2CI2
2. isopropyl
chlorofomiate, TEA, CH2CI2

-N,



0 ^0 1032
791 Isomers




SnClg, MeOH ^
-0
1032 1033
Isomer 2 of Compound 791 {70 mg, 0.13 mmol) was dissolved in CH2CI2 (5 mL) at room temperature. TFA (1 mL) was added in. After the reaction mixture was stirred under N2 for 1 hour, it was evaporated to dryness with CHaPh. The residue was retaken up in CH2Ct2 (5 mL) and the solution was made to pH>8 by addition of Iriethyl amine (ca. 0.2 mL). Isopropyl chloroformate (0.13 mL, 1.0 M in CHgPh) was then added In dropwise. After stining for 1 hr, the reaction was quenched with water and the mixture was extracted with CH2CI2 twice. The organic layer was dried and concentrated. The crude was purified with prep TLC plates using 10% methanol {2M NH3)/CH2Cl2 to give Compound 1032 as a light yellow solid (50 mg). MS M-t-1 533. Compound 1032 (160 mg, 0.3 mmol) was dissolved in f^eOH (5 mL) at room temperature and SnCb (150 mg, 0.79 mmol) was added in. After 3 hrs, majority of solvent was removed in vacuo. To the residue was added 30 mL 1N NaOH and 20 mL ethyf acetate. The turbid solution became clear after stirring for 20 min. Extract ttie aqueous layer once with ethyl acetate. The combined organic layer was dried and concentrated. The crude was purified by prep TLC plates using 10% methanol {2M NHa) /CH2CI2 to give compound 1033 as a light yellow solid (90.0 mg). M.P. ISa-ISS^C. MS M+1 507.

EXAMPLE 3281





M.

M.



I f^

i







-N.

-N,

To a solution of compound 792 (Example 486 of WO 02/18368) (0.052 gm, 0.1 mmole) in 5 ml of dry dichloromethane was added 0.02 gm of triethylamine and 0.01 g of methyf-chlorofonmate. After stirring for two hours under dry nitrogen the reaction mixture was washed with brine and the organic phase separated, dried over Magnesium sulfate, filtered and evaporated to obtain a crude mixture. The cnjde mixture was chromatographed on silica gel using 10% methanol/dichloromethane as the eluent to obtain 0.019 gm of final product. I^H+ 579 {Isomer 1) and MH+ 579 (Isomer 2).
EXAMPLES 3282-3287f Following a procedure similar to that in Example 3281, but using the corresponding suifonyl chloride, isocyanate, chloroformate or acid chloride of the R^" substituent, compounds of the fonnulas;



-N,

and

-N.



i

!

were prepared wherein R* is defined in Table 150 and the numbers 1 and 2 in the fonnulas represent Isomers 1 and 2, respectively.
Table 150

R
Example

w

Isomer 1 Data

Isomer 2 Data



3282

o

MH+ 563

MH+ 563



3283

H,N
O

MH+ 564

MH+ 564



3284

MH+ 592

MH+ 592

HN


3285




MH+ 599

MH+ 599



3286

MH+ 607

MH+ 607






3287

O


MH+ 620

MH+ 620



3287a

0

MH+ 593.1

o

3287b

0

MH+ 606.1

.-"

N H



3287c

o

MH+ 589.1







3287d

o

MH+591.3




3287e

MH+ 605.1



OMe
3287f

X

MH+ 593.3

EXAMPLE 3288



.N.

O" ^^O

TFA

-N
I
H

)





-toot
To a solution of the compound of Example 3282 (Isomer 2) (150 mg) was added 10 mi of dichloromethane and 2 mi of trifluoroacetic acid. The mixture was stirred for 1.5 hrs and ther^ evaporated to dryness. The mixture was azeotroped with dichloromethane two times and rendissolved in 15 ml of dichtoromethane and 0.5 ml of triethyi amine. To 0.08 mmol of the resulting compound was added 15 mg of 4-cyanophenyiisocyanate. The reaction was stin-ed for 1 hr and then concentrated. The

residue was chromatographed on silica gel using 10% methanol/dichloromethane to obtain 0.033 gm of product. MH-t- 607 (Isomer 2).
EXAMPLES 3289-3291 Following a procedure similar to that in Example 3288 compounds of the formula:



0
I
R
were prepared using the conesponding chioroformate or isocyanate for substituent R, wherein R is defined in Table 151, and the number 2 in the formula represents Isomer 2.
Table 151

Example

R

Isomer 2 Data



3289

"VT-P."-""

MH+549



^0

-^o




3290

o

MH+ 562



■"woxixr
3291

O ^O

MH+ 591

EXAMPLES 3292-3297 Using the compound of Example 3287 (Isomer 2) and following a procedure sirnilarto that in Example 3288 compounds of the formula:

-N.
I R
were prepared using the con-esponding Isocyanate, sulfonyi chloride, or chloroformate for substituent R, wherein R is defined in Table 152, and the number 2 in the formula represents Isomer 2.
Table 152

Example R Isomer 2
Data
3292 H ° MH+654
3293 0 MH+598


3294 O"""^^ OA-^UV f^H+648
o ^0-^0
3295 " H MH+619

"
j\rw
3296

N ^O
H

MH+645




3297

"
s\-!^

MH+606

EXAMPLES 3298-3302 Using the compound of Example 3285 (Isomer 2) and following a procedure similar to that in Example 3288 compounds of the fomnula:

0
I
R
were prepared using the corresponding isocyanate, sulfony! chloride, or chloroformate for substituent R. wherein R is defined in Table 153. and the number 2 in the fomiula represents Isomer 2.
Table 153

Example R isomer 2 Data
3298 1 H MH+ 598
3299 X MH+542

3300 MH+ 585
3301 f^H+ 627
3302 0 MH+ 577
EXAMPLES 514-3255
If one were to follow procedures similar to those of Examples 511-513, or 536. or 566-567 or 590-603, then one would obtain compounds of the fomiuias described below, wherein R is defined in Table 153A, and the numbers 1 and 2 in the formulas represent isomers 1 and 2. respectively:
(1) Examples 514-535,537-544, 546-565. 568, 570-573,575-589, and 604-614, the compounds of these examples would have the formulas:



• N,

.N.



N
I
R

N
I
R

(2) From isomers 897a and 897b-. Examples 615-639, 715^732 (see Preparative Example 74 for preparation of chloroform ates), 787-814, 899, 900, 902-905, 907-913, and 915-922. the compounds of these examples would have the formulas;



CI CI

(3) From isomers 898a and 898b: Examples 640-664, 733-750 (see Preparative Example 74 for preparation of chloroformates), 815-842, 923, 924,926-929, 931-937, and 939-94, the compounds of these examples would have the formulas:




(4) From isomers 899a and 899b: Examples 665-689, 751-768 (see Preparative Example 74 for preparation of chlorofomfiates), 843-870. 947, 948,950-953, 955-961, and 963-, the compounds of these examples would have the formulas:




(5) From isomers 900a and 900b: Examples 690-714, 769-786 (see Preparative Example 74 for preparation of chloroformates), 871-898, 971, 973-977, 979-985, 987. and 989-995, the compounds of these examples would have the fomiulas:

HO /^

(6) From isomers 919a and 919b: Examples 996-1020.1046-1073,1103-1121 (see Preparative Example 74 for preparation of chloroformates). 1140,1141, 1143,1144-1146,1148-1154, and 1156-1163, the compounds of these examples would have the formulas:

(7) From isomers 920a and 920b: Examples 1021-1045.1075-1102,1122-
1139 (see Preparative Example 74 for preparation of chloro formates), 1164-1165.
" 1167-1170,1172-1178, and 1180-1187, the compounds of these examples would have the formulas:

(8) From isomers 924a and 924b: Examples 1188-1212,1239-1266.1296-
1313 (see Preparative Example 74 for preparation of chloroformates), 1333-1334,
1336-1339, 1341-1347, and 1349-1356, the compounds of these examples would
have the formulas:


(9) From isomers 925a and 925b; Examples 1213-1221,1223-1238,1267-
1294,1315-1332 (see Preparative Example 74 for preparation of chloroformates),
"" 1357-1358.1360-1363,1365-1371, and 1373-1380, the compounds of these examples would have the fomiulas:

(10) From isomers 928a and 928b: Examples 1381-1405.1432-1459,1432-
1459, 1488-1505 (see Preparative Example 74 for preparation of chloroformates),
1525-1529,1531. 1533-1539, and 1541-1548, the compounds of these examples would have the formulas:



"N"
I R

,N.
1 R

(11) From isomers 929a and 929b: Examples 1406-1409, and 1411-1431, 1460-1487,1506-1524 (see Preparative Example 74 for preparation of chloroformates), 1549-1550,1552-1555,1557-1563, and 1565-1572, the compounds of these examples would have the formulas;




(12) From isomers 1004a and 1004b: Examples 1595-1619, 1620-1647, 1648.1650-1654.1656-166Q, 1662-1671, and 1672-1690 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas:




(13) From isomers 1005a and 1005b: Examples 1691-1715,1716-1743. 1744-1745, 1747-1750, 1752-1758. 1760-1767. and 1768-1786 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas:




(14) From isomers 1006a and 1006b: Examples 1787, and 1788-1811.1812-1839, 1840-1845. 1847-1861. and 1862-1880 (see Preparative Example 74 for preparation of chlorofomiates), the compounds of these examples would have the
fonnulas:

HO N:


(15) From isomers 1007a and 1007b: Examples 1881-1905. 1906-1933, 1935-1940. 1942-1956, and 1957-1975 (see Preparative Example 74 for preparation of chloroformate), the compounds of these examples would have the formulas:




(16) From isomers 1009a and 1Q09b: Examples 1976-2000.2001-2028, 2028a. 2029-2033,2035-2049. and 2050-2068 (see Preparative Example 74 for preparation of chloroformates), the compounds of these examples would have the formulas:




(17) From isomers 1010a and 1010b: Examples 2069-2093, 2094-2099, 3000-3021, 3022-3027. 3029-3043, and 3044-3062 (see Preparative Example 74 for preparation of chlorofomnates), the compounds of these examples would have the fomiulas;




(18) From compound 1008; Examples 3063-3087, 3088-3115. 3116-3121. 3123-3137. 3138-3156 (see Preparative Example 74 for preparatTon of chlorofomiates). the compounds of these examples would have the formulas;


;and
(19) From compounds 1013 and 1015; Examples 3169-3187. 3188-3215. 3216-3221. 3223-3237, 3237a, and 3238-3255 (see Preparative Example 74 for preparation of chloroformates). the compounds of these examples would have the formulas:




TABLE 153A

Examples

R-Isomer 1 and Isomer 2



514, 615, 640. 655, 690, 996. 1021, 1188,1213,1381,1406,1595. 1691, 1787,1881.1976,2069,3063,

d^NH,



O
515, 616, 641, 666. 691, 997, 1022. 1189, 1214. 1382. 1407, 1596. 1692, 1788,1882.1977, 2070. 3064, 3169

:^=^N"
H























































I o a CHaCb (5 n,L) solution of compound 1033 (Example 3280) (35 mg 0 07
unde r/ r " "™"- """ """""°" "- ^"^-"" ^" ™- t-pe.a.ur
times. The combined organic solution was dried (MgSO.) and
evaporated to dryness Tho rooi^ .^ V"«you4j and
ryness. The residue was punfied by prep TLC plates using 10%

methanol {2M NH3) /CH2CI2 to give compound 5001 as an off white solid (15.0 mg). M.P. 152-155 °C (dec). MS M+l 593.
ASSAYS
FPT activity was determined by measuring the transfer of f H] famesyl from pH] farnesyl pyrophosphate to a biotinylated peptide derived from the C-terminus of H-ras (biotin-CVLS). The reaction mixture contains: 50 mM Tris pH7.7, 5 mM MgCl2. 5 fif\^ Zn^. 5 mM DTT. 0.1% Triton-X, 0.05 ^M peptide, 0.03 nM purified human farnesyl protein transferase. 0.180 IAM [^H] famesyl pyrophosphate, plus the indicated concentration of tricyclic compound or vehicle control in a total volume of 100 ^1. The reaction was incubated in a Vortemp shaking incubator at 37°C. 45 RPM for 60 minutes and stopped with 150 ^I of 0.25 M EDTA containing 0.5% BSA and 1.3 mg/ml Streptavidin SPA beads. Radioactivity was measured in a Wallach 1450 Microbeta liquid scintillation counter. Percent inhibition was calculated relative to the vehicle control.
COS Ceil iC50 (Cell-Based Assay) were detennrned following the assay procedures described In WO 95/10516, published April 20, 1995. GGPTIC50 (inhibition of geranyigeranyl protein transferase, in vitro enzyme assay). Cell Mat Biochemical assay and anti-tumor activity (in vivo anti-tumor studies) could be determined by the assay procedures described in WO 95/10516. The disclosure of WO 95/10516 is incorporated herein by reference thereto.
Various tumor cells (5 x 10^ to 8 x 10^) were innoculated subcutaneously into the flank of 5-6 week old athymic nu/nu female mice. Three tumor cell models were used: mouse fibroblasts transformed with H-Ras; HTB-177 human non small cell lung cancer cells or LOX human melanoma cells. Animals were treated with beta cyclodextran vehicle only or compounds in vehicle twice a day (BID) or once a day (QD) for 7 days per week for 1 (x1), 2 (x2} or 3 (x3) weeks. The percent inhibition of tumor growth relative to vehicle controls were determined by tumor measurements. The results are reported in Table 155.

Table 155

Compound No. Tumor Dose (MPK) Route and Schedule Average % Tumor Inhibition
(372) H-Ras fibroblasts 40 po, BID, x2 92
K H-Ras fibroblasts 10 po. BID, x2 70
H H-Ras fibroblasts 80 po, QD, x2 91
•* H-Ras fibroblasts 20 po, QD, x2 65
"* H-Ras fibroblasts 60 po, BID. x2 98
•4 H-Ras fibroblasts 20 po, BID, x2 59
H H-Ras fibroblasts 6.6 po. BID, x2 19
u HTB-177 60 po, BID, x3 87
" HTB-177 20 po. BID. x3 43
M HTB-177 120 po. QD, x3 54
U HTS-177 40 po. QD. x3 11
>* HT6-177 80 po, BID, x3 96
" HTB-177 40 po, BID, x3 79
u HTB-177 20 po, BID, x3 47
" LOX 15 po, BiD, x1 20.9
■A LOX 30 po, BID, x1 54.8
u LOX 60 po. BID, x1 90.3
(The schedule "po, BID, x3", for example, means orally, twice a day for 7 days (14 times per week) for 3 weeks).
Soft Agar Assay:
Anchorage-independent growth Is a characteristic of tumorgenic cell lines. Human tumor cells can be suspended in growth medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor. The solution can be overlayed onto growth medium solidified with 0.6% agarose containing the same concentration of famesyl transferase inhibitor as the top layer. After the top layer is solidified, plates can be incubated for 10-16 days at 37""C under 5% CO2 to allow colony outgrowth. After incubation, the colonies can be stained by overfaying the agar

with a solution of MTT (3-[4,5-dimethyI-thiazol"2-yi]-2.5-diphenyltetrazolium bromide, Thiazolyl blue) (1 mg/mL in PBS). Colonies can be counted and the ICso"s can be
determined.
There are compounds of this invention have an FPT IC50 in the range of 0.05 nM to 100 nM and a Soft Agar IC50 in the range of The compound of Example 4916 had an FPTIC50 of 1.2 nM.anda Soft Agar ICsoof For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersibie granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known In the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of phamiaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.). Remington: The Science and Practice of Pharmacy, 20** Edition, (2000). Lippincott Williams & Wilklns, Baltimore, MD,
Liquid form preparations include solutions, suspensions and einulsions. As an exaoiple may be mentioned water or water-propylene glycol solutions for parenteral Injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid fonn preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharniaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid fonn preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the fonn of creams, lotions, aerosols and/or

emulsions and can be included in a transdemial patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such forni, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 600 mg, and most preferably from about 0.01 mg to about 250 mg according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.
The chemotherapeutic agent and/or radiation therapy can be administered in association with the compounds of the present invention according to the dosage and administration schedule listed in the product infomiation sheet of-the approved agents, in the Physicians Desk Reference (PDR) as well as therapeutic protocols well known in the art. Dosages and dosage regimens are exemplified in the embodiments of this invention. Additional examples of dosages and dosage regimens of chemotherapeutic agents useful in this invention are given in Table 156,

TABLE 156 Exampiary Chemotherapeutic Agents Dosage and Dosage Regimens
Cisplatin: 50 -100 mg/m^ every 4 weeks (IV)*
Carboplatin: 300 - 360 mg/m^ every 4 weeks (IV)
Taxotere: 60 -100 mg/m^ every 3 weeks (IV)
"(jVHntravenously
It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered chemotherapeutic agents (i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
in an example of combination therapy In the treatment of pancreatic cancer, an FPT inhibitor of this invention (i.e., a compound of this invention, e.g„ a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the antineoplastic agent, gemcilabine. which is administered at a dosage of from 750 to 1350 mg/m^ weekly for three out of four weeks during the course of treatment.
In an example of combination therapy in the treatment of lung cancer, an FPT inhibitor of this invention {i.e., a compound of this invention, e.g., a compound of Fomiula (1.0)) is administered orally in a range of from 50 to 40O mg/day, in two divided doses, in association with the antineoplastic agent, paclitaxel, which is administered at a dosage of from 65 to 175 mg/m^ once every three weeks.
In an example of combination therapy in the treatment of gliomas, an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of Fonnula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two

divided doses; in association with the antineoplastic agent, temozolomide, which is administered at a dosage of from 100 to 250 mg/m^.
In another example of combination therapy in the treatment of cancer, an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day. in two divided doses, in association with the antineoplastic agent, cisplatin, which is administered intravenously in a range of from 50 to 100 mg/m2 once every four weeks.
In another example of combination therapy in the treatment of cancer, an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the antineoplastic agent, carboplatin, which is administered intravenously in a range of from 300 - 360 mg/m2 once every four weeks.
In another example of combination therapy in the treatment of cancer, an FPT inhibitor of this invention (i.e.. a compound of this invention, e.g., a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in association with the chemotherapeutic agent, carboplatin, which is administered intravenously in a range of from 300 to 360 mg/m2 once every four weeks and the chemotherapeutic agent, pactitaxel, which Is administered at a dosage of from 65 to 175 mg/m^ once every three weeks.
In another example of combinatron therapy in the treatment of cancer an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses, in associatkin with the chemotherapeutic agent,-Cisplatin, which is administered intravenously in a rang© of from 50 to100 mg/m2 once every four weeks and the chemotherapeutic agent, Gemcitablne, which is administered at a dosage of from 65 to 175 mg/m^ once every three weeks.
The signal transduction inhibition therapy can be administered according to the dosage and administration schedule listed in the product rnfonmation sheet of the approved agents, in the Physicians Desk Reference (PDR) as well as therapeutic protocols well known in the art. Examples of ranges of dosage and dosage regimens of some signal transduction inhibitors are given Table 167.

TABLE 157 Examplary Signal Transduction Inhibitors Dosage and Dosage Reoimens
Iressa (ZD1839) - EGF receptor kinase inhibitor: 150 - 700 mg/day (oral)
OSI-774 - EGF receptor kinase inhibitor. 100 -1000 mg/day (oral)
Herceptin - HER-2/neu antibody: 100-250 mg/m^/week (IV)*
C225 - EGF receptor antibody: 200 - 500 mg/m%eek (IV)
ABX-EGF - EGF receptor antibody: 0.2 - 2 mg/kg every 2 weeks (IV)
Gleevec (STI-571) - ba/abi kinase inhibitor: 300 -1000 mg / day (oral)
•(IV}-intravenously
It will be apparent to those skilled in the art that the administration of the signal tranduction inhibitor can be varied depending on the disease being treated and the knovm effects of the signal transduction inhibitor therapy on that disease. Also, in accordance with the knowledge of the skilled dinician. the therapeuOc protocols (e.g., dosage amounts and times of administration) can be varied in view of the obsen/ed effects of the administered signal transduction inhibitors on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
In another example of combination therapy in the treatment of cancer, an FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of Formula (1.0)) is administered orally in a range of from 50 to 400 mg/day, in two divided doses in association with the signal tranduction inhibitor, EGF receptor kinase inhibitor. Iressa (ZD1839). which is administered orally in the range of 150 - 7O0 mg/day.
The FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of Formula (1.0)). the chemoiherapeulic agent, signal transduction inhibitor

and/or radiation can be administered by different routes. For example, the FPT inhibitor can be administered orally, while the chemotherapeutic agent may be administered intravenously. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician .
The particular choice of the chemotherapeutic agent, signal transduction inhibitor and/or radiation to use with the FPT inhibitor of this invention wili depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol.
The FPT inhibitor of this invention (i.e.. a compound of this invention, e.g., a compound of Fonnula (1.0)). chemotherapeutic agent, signal transduction inhibitor and/or radiation may be administered concurrently (e.g., simuitaneously. just prior to or after, or within the same treatment protocol) or sequentiallyi. Determination of the sequence of administration can be determined by the skilled clinician. Some factors that the skilled clinician can use to determine the treatment protocol are the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent, signal transduction inhibitor and/or radiation to be administered In conjunction (i.e., within a single treatment protocol) with the FPT inhibitor.
If the FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of Fomiula {1.0)). chemotherapeutic agent, signal transduction inhibitor and/or radiation are not administered simultaneously then the FPT inhibitor may be administered first followed by the administration of the chemotherapeutic agent, signal transduction inhibitor and/or radiation, or the chemotherapeutic-agent, signal transduction inhibitor and/or radiation can be administered first followed by the administration of the FPT inhibitor. This alternate administration may be repeated during a single treatment protocol until the treatment protocol is completed. The determination of the order of administration, and the number of repititions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

Thus, in accordance with experience and knowledge, the practising physician can modify each protocol for the administration of a component (therapeutic agent-l.e., FPT inhibitor of this invention (i.e., a compound of this invention, e.g., a compound of Fom^ula (1.0)), chemotherapeutic agent, signal transduction inhibitor or radiation) of the treatment according to the individual patient"s needs, as the treatment proceeds.
The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radio-logical studies, e.g., CAT or MRI scan, and successive measure-ments can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
Additional phanmaceutical and method of treating embodiments of this invention are set forth below.
An embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a compound of this invention in combination with a pharmaceuticatly acceptable earner.
An embodiment of this invention is directed to a phamiaceutical composition comprising an effective amount of a compound of formula 1.0 in combination with a pharmaceutically acceptable canier.
An embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of compound of formula 1.4 in coRibination with a pharmaceutically acceptable carrier.
An embodiment of this invention is directed to a method for treating the abnormal growth of cells in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of this invention (e.g.. a compound of formula 1.0).
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering to said patient an effective amountof a compound of this invention (e.g., a compound of formula 1.0).

An embodiment of this invention is directed to a method of treating tumors expressing an activated ras oncogene in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of thisinvention (e.g., a compound of fonnula 1-0).
An emirodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment vjherein said tumors are selected from the group consisting of: pancreatictumors, lung tumors, myeloid leukemias, thyroid follicular tumors, myelodysplastic syndrome, head and neck tumors, melanomas, breast tumor, prostate tumors, ovarian tumors, bladder tumors, glioma tumors, epidermal tumors and colon tumors, comprising administering to said patient an effective amount of a compound of this invention {e.g., a compound of fonnula 1.0).
An embodiment of this invention is directed to a method of inhibiting ras farnesyl protein transferase in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of this invention (e.g.. a compound of formula 1.0).
An embodiment of this invention is directed to a method of treating tumors, wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, in a patient in need of such treatment comprising administering to said patient an effective amount of a compound of this invention (e.g., a compound of fomnuia 1.0).
An embodiment of this invention is directed to a method of ti"eating tumors in a
patient in need of such treatment comprising administering concurrently or
sequentially to said patient, an effective amount of a compound of this invention (e.g.,
a compound of fomiula 1.0) in combination vwth an effective amount of at least one
chemotherapeutic agent and/or radiation. - -
An embodiment of this Invention Is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of thisinvention (e.g., a compound of formula 1,0) In combination with an effective amount ofat least one chemotherapeutic agent and/or radiation, wherein said tumors are selected from the group consisting of: pancreatic tumors, lung tumors, myeloid leukemias, thyroid follicular tumors, myelodysplastic syndrome, head and neck tumors, melanomas.

breast tumor, prostate tumors, ovarian tumors, bladder tumors, glioma tumors, epidermal tumors and colon tumors.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e.g., a compound of fonnula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, w/herein said tumors are selected from the group consisting of lung cancer, head and neck cancer, bladder cancer, breast cancer, prostate cancer and myeloid leukemias.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concuaentlyor sequentially to said patient, an effective amount of a compound of this invention (e.g., a compound of fonnula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein said chemotherapeutic agent is an antineoplastic agent selected from: Uracil mustard, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethlophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Temozolomide, Methotrexate, 5-Fluorouracil, Floxuridine. Cytarabine, 6-Mercaptopurine, 6"Thioguanine, Fludarabine phosphate, Pentostatine, Gemcitabine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Eptrubicin, Idarubicin, Taxol, Taxotere, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons, Etoposide, Teniposide 17a-Ethinyfestradiol, Diethylstilbestrol, Testosterone. Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethlmide. Estramustine, Medroxyprogesteroneacetate. Leuprolide. Fiutamide, Toremifene, goserelin, Cisplatin, CartJOplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole. Navelbene. CPT-11, Anastrazole, Letrazole. Capecitabine. Reloxafine, Droloxafine, and Hexamethylmelamine.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e.g..

a compound of formula 1.0) in combination witfi an effective amount of at least one chemotherapeutic agent and/or radiation, wherein said chemotherapeutic agent is a microtubule affecting agent selected from allocolchicine, Halichondrln B, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel, paclitaxel derivatives, Taxotere, thiocolchicine, trityl cysteine, vinblastine sulfate, vincristine sulfate, epothlione A, epothilone, discedermolide, estramustine, nocodazole and MAP4.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e.g., a compound of fomiula 1.0) in combination with an effective amount of at (east one chemotherapeutic agent and/or radiation, wherein said chemotherapeutic agent is selected from Gemcitabine, Cisplatin, Carboplatin, paclitaxel, paclitaxel derivatives, and Taxotere.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of formula 1.0 in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the compound of fomiula 1.0 is selected from the group consisting of:




-N,

-N.

,N,






N-^O
o-^o
"W

■N"
H

^N N-^0
H





NC

.N.
-N"
N-^r
H

N.

0=S=0

-N.
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NC

-N.
^N"
N-^f
H










H
N.
N.


N
o--^o

HN N.
-N,
-N"
N-^r
H

N
^N-^O H






, and



-N.

O" "-0
An emtK>diment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concun-ently or sequentially to said patient, an effective amount of a compound of this invention in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the compound of the invention is selected from the group consisting of;







-N.
"N"
0=S=0 I

-N.

I

N.
N



-N.



N.
NC

"N-
-N-^0
H

/^o--^o

O
I o=s=o






NC

-N.
■w
N^O
H




-N.

M.

-N.



N
o=s~o

1 ^


O^^^O







,N,

-N.


I
"N"
N-^O
H , and H
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprisir^ administering concurrently or sequentially to said patient, an effective amount ofa compound of fomiula 1.0 in combination with an effective amount of at least one diemottierapeutic agent and/or radiation, wherein the compound of fomiuia 1.0 is selected from the group consisting of:





-N,






.N.


NC

-N.
"N-
N-^O
H

-N.





-N.

-N.

-N.






"N-
N^O
H


O^^^O

NC

^N"
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0
I o=s=o

-N.
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■0-^c

-N.

H



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H






-N.

,N.

f 0=S=0

and ^ *0^ ^"O An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering concurrently or sequentially to said patient, an effective amount of a compound of formula 1.0 in combination with an effective amount of at least one chemotherapeufc agent and/or radiation, wherein the compound of formula 1.0 is selected from the group consisting of:





,N.

-N.



•^
1 ^N^

NC

-N"
■N^C
H






-N.

-N.



I o=s=o

-^x

1





-N.

,N.

"O
. and H
An embodiment of this invention is directed to a method of treating tumors in a patient ,n need of such treatment comprising administering concurrenUy or sequentially to said patient, an effective amount of a compound of fomiula 1 o in combination with an effect^a amount of at least one chemothe^peutic agent and/or

radiation, Vifherein the compound of formula 10 is selected from Ihe group consisling
of:
.0. .Q

I UIM *
HN N.

An embodiment of this invention is directed to a method of treating tumors in a patient in need ol such treatment comprising administering concun-ently or sequentially to said patient, an effective amount of a compound of this invention (e.g., a compound of fonnula 1 -0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the tumors treated are selected from the group consisting of: lung cancer, head and neck cancer, bladder cancer, breast cancer, prostate cancer and myeloid leukemias; wherein the chemotherapeutic agent is selected from the group consisting of: paciitaxel, a paciitaxel derivative, taxotere, cyclophosphamide, 5-fIuorouracil, temozolomide, vincristine, cisplatin, carbopjatin, and gemcitabine.
An embodiment of this invention is directed to a method of lung cancer in a patient in need of such treatment compnsing administering concurrently or sequentially to said patient, an effective amount of a compound of this invention (e.g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the chemotherapeutic agent is selected from the group consisting of: carboplatin, taxol and taxotere.
An embodiment of this invention is directed to a method of lung cancer in a patient in need of such treatment comprising administering concurrenUy or sequentially to said patient, an effective amount of a compound of this invention (e.g., a compound of formula 1.0) in combination with an effective amount of at least one chemotherapeutic agent and/or radiation, wherein the chemotherapeutic agent is selected from the group consisting of: gemcitabine and cisplatin.

An embodiment of this invention is directed to a method of treating tumors in a patient in need of suct^ treatment comprising administenng concurrently or sequentially to said patient, an effective amount of a compound of this invention (e.g., a compound of formula 1.0) in [Combination with an effective amount taxol and/or radiation, v/herein the tumors treated are selected from tile group consisting of: lung cancer, head and neck cancer, bladder cancer, breast cancer, prostate cancer and myeloid leukemias.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of this invention (e.g., a compound of formula 1.0) in combination with an affective amount of at least one signal transduction inhibitor.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentlaily, to said patient an effective amount of a compound of this invention (e.g,, a compound of fonmula 1.0} in combination with an effective amount of at (east one signal transduction inhibitor, wherein the tumors are selected from the group consisting of: pancreatic tumors, lung tumors, myeloid leukemias, thyroid follicutar tumors, myelodysplastic syndrome, head and neck tumors, melanomas, breast tumors, prostate tumors, ovarian tumors, bladder tumors, gliomas and colon tumors.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of this invention (e.g., a compound of formula 1.0) in combination with an effective amount of at least one signal transduction inhibitor, wherein the signal tranduction inhibitor is selected from the group consisting of: a bcr/ab! kinase inhibitor, an epidermal growth factor receptor inhibitor, and a HER-2/neu receptor inhibitor.
An embodiment of this invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of 3 compound of this invention (e.g., a compound of formula 1.0) in combination with an effective amount of at least one signal transduction inhibitor, wherein the signal tranduction inhibitor is selected from

the group consisting of: Gleevec, Iressa, OSI-774, Imclone C225, Abgenix A3X-EGF, and Herceptin.
An embodiment of (his invention is directed to a method of treating tumors in a patient in need of such treatment comprising administering, concurrently or sequentially, to said patient an effective amount of a compound of this invention (e.g., a compound of fonnula 1 -0) in combination with an effective amount of at least one signal transduction inhibitor, wherein the tumors treated are selected from the group conisting of: lung tumors, head and neck tumors, bladder tumors, breast tumors, prostate tumors and myeloid leukemias; and the signal transduction inhibitor is selected from the group consisting of: Gleevec, Iressa, OSI-774. Imclone C225, Abgenix ABX-EGF; and Herceptin.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g.. 1,4F wherein X is N) and at least two different antineoplastic agents selected from the group consisting of;
(1) taxanes;
(2) platinum coordinator compounds; (3} EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules,
(5) VEGF Inhibitors that are antibodies;
(6) VEGF kinase inhibitors that are small molecules;
(7) estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumor nucleoside derivatives;
(9) epothiiones;
(10) topoisomerase inhibitors;
(n)vinca alkaloids;
(12) antibodies that are inhibitors of aVp3 integhns; or
(13) small molecule inhibitors of aVp3 integrins
(14) folate antagonists;
(15) ribonucleotide reductase inhibitors;
(16) anthracyclines;
(17) biologies;

(18) Thalidomide (or related Imid); and
(l9)Gieevec. An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N) and at least two different antineoplastic agents selected from the group consisting of:
(1) taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF inhibitors that are antibodies;
(5) VEGF kinase inhibitors that are small molecules;
(7) estrogen receptor antagonists or selective estrogen receptor-
modulators,
(8) anti-tumor nucleoside derivatives;
(9)epothilones;
(10) topoisomerase inhibitors;
(11) vinca alkaloids;
(12) antibodies thai are inhibitors of aVp3 integrins; or
(13) small molecule inhibitors of aVp3 integrins
(14) folate antagonists;
(15) ribonucteotjde reductase inhibitors; (16)anthracyclines;

(17) biologies; and
(18) Thalidomide (or related Imid).
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of fonnula 1.4F (e.g., 1.4F wherein Xis N)and at least two different antineoplastic agents selected from the group consisting of:
(1) taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules,

(5) VEGF inhibitors that are antibodies;
(6) VEGF kinase inhibitors that are small molecules;
(7) estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumor nucleoside derivatives;
(9) epothilones;

(10) topoisomerase inhibitors;
(11) vinca alkaloids;
(12) antibodies that are inhibitors of aVp3 integnns; or
(13) small molecule inhibitors of aVp3 integrins
(14) folate antagonists;
(15) hbonucleolide reductase inhibitors;
(16) anthracyclines; and
(17) biologies.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g.. 1,4F wherein X is N) and at least two different antineoplastic agents selected from the group consisting of: (l)taxanes;
(2) platinum coordinator compounds;
(3) EGF inhibitors that are antibodies;
(4) EGF inhibitors that are small molecules;
(5) VEGF inhibitors that are antibodies;
(6) VEGF kinase inhibitors that are small molecules;
(7) estrogen receptor antagonists or selective estrogen receptor modulators;
(8) anti-tumor nucleoside derivatives;
(9) epothilones;

(10) topoisomerase inhibitors;
(11) vinca alkaloids;
(12) antibodies that are inhibitors of aVp3 integrins; and
(13) small molecule inhibitors of aVp3 integrins.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F {e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is selected from paclitaxel ordocetaxel, and said platinum coordinator compound Is selected from carboplatin or cisplatin.
An embodiment of this Invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is paclitaxel and said platinum coordinator compound is carboplatin.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein Xis N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is paclitaxel and said platinum coordinator compound is cisplatin.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F {e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is docetaxel and said platinum coordinator compound is cisplatin.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein Xis N) and

two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is docetaxel and said platinum coordinator compound is carboplatin.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula "1.4F (e.g., 1,4F wherein X is M) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is paclitaxel administered in an amount of about 150 mg to about 250 mg/m^ once every three weeks per cycle, and said platinum coordinator compound is carboplatin administered once every three weeks per cycle in amount of to provide an AUG of about 5 to about 8.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of fonnuia 1.4F (e.g., 1.4F wherein Xis N)and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is docetaxel administered in an amount of about 50 mg to about 100 mg/m^ once every three weeks per cycie, and said platinum coordinator compound is cisplatin administered in amount of about 60 mg to about 100 mg/m^ once every three weeks per cycle.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT lnhit)itor compound of fotmula 1.4F (e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the o;no, antineopiastic agent is a platinum coordinator compound, wherein said FPT inhibitor is administered In an amount of about 50 mg to about 200 mg twice a day.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of fomiula 1.4F {e.g., 1.4F wherein X is N) and tv;o antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineopiastic agent is a platinum coordinator compound, wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125 mg twice a day.























O. .0

,N.
I ^""
O" ^O
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of fonnula 1.4F (e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said FPT inhibitor
I HN

-N.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N) and tv/o antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein the treatment is given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1,4F (e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein non small cell lung cancer is treated.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F(e.g.. 1.4F wherein X is N}and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is an EGF inhibitor that is an antibody.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1,4F (e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is an EGF inhibitor that is an antibody, wherein said taxane Is paclitaxel and said EGF inhibitor is Herceptin.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound offonnula 1,4F(e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is an antinucieoside derivative, and the other antineoplastic agent is a platinum coordinator compound.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of fomiula 1.4F (e.g., 1.4F wherein X Is N) and two antineoplastic agents, wherein one antineoplastic agent is an antinucieoside derivative, and the other antineoplastic agent is a platinum coordinator compound, wherein said antinucieoside derivative is gemcitabine and said platinum coordinator compound is cisplatin.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N} and two antineoplastic agents, wherein one antineoplastic agent is an antinucieoside

derivative, and the other antineoplastic agenf is a platinum coordinator compound, wherein said antinudeoside derivative is gemcitabine and said platinum coordinator compound is carboplatin.
An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of fomiula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) paditaxe!.
An embodiment of this Invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of fontiula l.4F(e,g., 1.4F wherein XisN);and
(b) carboplatin; and
(c) paclitaxel.
wherein said FPT inhibitor is administered twice a day, said cartjoplatin is administered once every three weeks per cycle, and said paclitaxel is administered once every three weeks per cycle, said treatment being given for one to four weeks per cycle.
An embodiment of this invention is directed to a method of treating non small ceil lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) paditaxe!,
wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUG of about 5 to about 8. said paditaxel is administered once every three weeks per cycle in an amount of about 150 to about 250 mg/m^ wherein said carboplatin and said paclitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle.

An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatnient comprising administering to said patient therapeutically effective amounts of;
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) paciitaxel,
wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said paciitaxel is administered once every three weeks per cycle in an amount of about 150 to about 250 mg/m^ said carboplatin and said paciitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle
An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) paciitaxel,
wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 5 to about 8, said paciitaxel is administered once every three weeks per cycle in an amount of about 150 to about 250 mg/m^, v/herein said carboplatin and said paciitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle.
An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) paciitaxel,
wherein said FPT Inhibitor is administered in an amount of about 100 mg twice a day, said carboplatin is administered once every three weeks per cycfe in an amount to provide an AUC of about 5 to about 8, said paciitaxel is administered once every three

weeks per cycle in an amount of about 175 to about 225 mg/m^, wherein said carboplatin and said paclitaxei are administered on the same day, and said treatmenl being given for one to fourweeks per cycle.
An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F(6.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) paclitaxel,
wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day. said cartxjplatin is administered once every three weeks per cycle in an amount to provide an AUC of about 6, said paclitaxel is administered once every three weeks per cycle in an amount of about 175 mg/m^, wherein said carboplatin and said paclitaxel are administered on the same day, and said treatment being given for one to four weeks per cycle.
An embodiment of this invention is directed to a method of treating non small cell (ung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and:
(b) cisptatin; and
(c) gemcitabine.
An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F(e.g., 1.4F wherein X is N); and:
(b) cisplatin; and
(c) gemcitabine
wherein said FPT inhibitor is administered twice a day, said cisplatin is administered once every three or four weeks per cycle, and said gemcitabine is administered once a v/eek per cycle, said treatment being given for one to seven weeks per cycle.
An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and:
(b) cisplatin: and
(c) gemcitabine
wherein said FPT Inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said cisplatin is administered once every three or four weeks per cycle in an amount of about 60 lo about 100 mg/m^, said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m^, and said treatment being given for one to seven weeks per cycle.
An embodiment of this invention is directed to a method of treating non small celi lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and:
(b) cisplatin; and
(c) gemcitabine
wherein said FPT inhibitor Is administered in an amount of about 75 mg to about 125 mg twice a day, said cisplatin is administered once every three or four weeks per cycle in an amount of about 60 to about 100 mg/m^. said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m^, and said treatment being given for one to seven weeks per cycle.
An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT Inhibitor of fomiula 1.4F (e.g., 1.4F wherein X is N); and:
(b) cisplatin; and
(c) gemcitabine
wherein said FPT inhibitor Is administered in an amount of about 100 mg twice a day, said cisplatin is administered once every three or four weeks per cycle in an amount of at>out 60 to about 100 mg/m^, and said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m^, and said treatment being given for one to seven weeks per cycle.
An embodiment of this invention is directed to a method of treating non small cei! lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:

(a) an FPT inhibitor of fonnula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) gemcitabine.
An emtx)diment of this invention is directed to a method of treating non small celt lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) gemcitabine,
wherein said FPT inhibitor is administered twice a day, said carboplatin is administered once every three weeks per cycle, and said gemcitabine is administered once a week per cycle, said treatment being given for one to seven weeks per cycle. An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) gemcitabine,
wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUG of about 5 to about B, said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m^, and said treatment being given for one to seven weeks per cycle.
An embodiment of this invention is directed to a method of treating non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) gemcitabine,
said treatment being given for one to seven weeks per cycle, wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUG of about 5 to about 8, and said gemcitabine is administered once a

week per cycle in an amount of about 750 to about 1250 mgW, and said treatment being given for one to seven weeks per cycle.
An embodiment of this invention is directed to a method of treating of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N); and
(b) cartjoplatin; and
(c) gemcitabine,
wherein said FPT inhibitor is administered in an amount of about 100 mg twice a day, said carboplatin is administered once every three weeks per cycle in an amount to provide an AUG of about 5 to about 8, said gemcitabine is administered once a week per cycle in an amount of about 750 to about 1250 mg/m^ and said treatment being given for one to seven weeks per cycle.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (e.g.. 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of:
(1) EGF inhibitors that are antibodies;
(2) EGF inhibitors that are small molecules;
(3) VEGF inhibitors that are antibodies; or
(4) VEGF kinase inhibitors that are small molecules.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of: Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, IMC-1C11, SU5416, and SU6688.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of:

(1) £GF inhibitors that are antibodies;
(2) EGF inhibitors that are small molecules;
(3) VEGF inhibitors that are antibodies; or
(4) VEGF kinase inhibitors that are small molecuies,
wherein the FPT inhibitor is administered twice a day, said antineoplastic agent that is
an antibody is administered once a week per cycle and said antineoplastic agent that
is a small molecule is administered daily, said treatment being given for one to four
weeks per cycle.
An embodiment of this invention is directed to a method of treating cancer
a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (c-g.. 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of:
(1) EGF inhibitors that are antibodies;
(2) EGF inhibitors that are small molecules;
(3) VEGF inhibitors that are antibodies; or
(4) VEGF kinase inhibitors that are small molecules,
wherein said FPT inhibitor is administered in an amount of about 50 mg to about 200
mg twice a day, and said antineoplastic agent that is an antibody is administered once
a week per cycle in an amount of about 2 to about 10 mg/m^. and said antineoplastic
agent that is a small molecule is administered daily in an amount of about 50 to about
2400 mg/m^, and said treatment being given for one to four weeks per cycle.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of:
(1) EGF inhibitors that are antibodies;
(2) EGF inhibitors that are small molecules;
(3) VEGF inhibitors that are antibodies; or
(4) VEGF kinase inhibitors that are small molecules,
wherein said FPT inhibitor is administered in an amount of about 75 mg to about 125
mg twice a day. and said antineoplastic agent that is an antibody is administered once

a week per cycle in an amount of about 2 to about 10 mg/m^, and said antineoplastic agent that is a small molecule Is administered daily in an amount of about 50 to about 2400 mg/m", and said treatment being given for one to four weeks per cycle.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of an FPT inhibitor compound of formula 1.4F (e.g., 1.4F wherein X is N) and an antineoplastic agent selected from the group consisting of:
(1} EGF inhibitors that are antibodies;
(2) EGF inhibitors that are smail molecules;
(3) VEGF inhibitors that are antibodies; or
(4) VEGF kinase inhibitors that are small molecules,
said treatment being given for one to four weeks per cycle, wherein said FPT inhibitor is administered In an amount of atraut 100 mg twice a day, and said antineoplastic agent that is an antibody is administered once a week per cycle in an amount of about 2 to about 10 mg/m^, and said antineoplastic agent that is a small molecule is administered daily in an amount of about 50 to about 2400 mg/m^, and said treatment being given for one to four weeks per cycle.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of an FPT inhibitor compound of formula 1-4F (e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is paciitaxel administered in an amount of about 150 mg to about 250 mg/m^ once a week per cycle, and said platinum coordinator compound is carboplatin administered once a week per cycle in an amount to provide an AUG of about 5 to about 8.
An embodiment of this invention is directed to a method of treating cancer in a patient in need of such treatment comprising administehng to said patient an effective amount of an FPT inhibitor compound of fonnula 1.4F(e.g., 1.4F wherein X is N) and two antineoplastic agents, wherein one antineoplastic agent is a taxane, and the other antineoplastic agent is a platinum coordinator compound, wherein said taxane is docetaxel administered in an amount of about 50 mg to atxiut 100 mgW once a week

per cycle, and said platinum coordinator compound is cisplatin administered in amount of about 60 mg to about 1Q0 mg/m^ once a week per cycle.
An embodiment of this invention is directed to a method of treating of non small cell lung cancer in a patient in need of such treatment comprising administering to said patient therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F {e.g., 1.4F wherein X is N); and
(b) carboplatin; and
(c) docetaxel.
An embodiment of this invention is directed to a method of treating squamous cell cancer of the head and neck, in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPTinhibitor of formula 1.4F (e.g., 1.4F wherein X Is N); and
(b) one or more antineoplastic agents selected from the group consisting of;
(1)taxanes; and
(2) platinum coordinator compounds. An embodiment of this invention is directed to a method of treating squamous cell cancer of the head and neck, in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);
(b) at least two different antineoplastic agents selected from the group consisting of:
(l)taxanes;
(2) platinum coordinator compounds; and
(3) anti-tumor nucleoside derivatives (e.g., 5-Fluorouracil).
An embodiment of this invention is directed to a method of treating CML in a patient in need of such treatment comprising administering therapeutically effective amounts of;
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);
(b) Gleevec; and
(c) interferon (e.g., intron-A),

An embodiment of this invention is directed to a method of treating CML in a patient in need of such treatment compnsing administering therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1,4F wherein X is N);
(b) Gleevec; and
(c) pegylaled interferon (e.g., Peg-!ntron, and Pegasys).
An embodiment of this invention is directed to a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);
(b) an anti-lumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)).
An embodiment of this invention is directed to a method of treating AML in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);
(b) an anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)); and
(c) an anthracycline.
An embodiment of this invention is directed to a method of treating non-Hodgkin"s lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F(e.g.. 1-4F wherein X is N);
(b) Rituximab (Rituxan).
An embodiment of this invention is directed to a method of treating non-Hodgkin"s lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1-4F (e.g., 1.4F wherein XisN);
(b) Rftuximab (Rituxan); and
(c) an anti-tumor nucleoside derivative (e.g., Fludarabine (i.e., F-ara-A).

An embodiment of this invention is directed to a method of treating non-Hodgkin"s lymphoma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g.. 1.4F wherein X is N);
(b) Genasense (antisense to BCL-2}.
An embodiment of this invention is directed to a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of fonmula 1.4F (e.g., 1.4F wherein X is N);
(b) a proteosome inhibitor (e.g., PS-341 (Millenium)).
An embodiment of this invention is directed to a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
. (a) an FPT inhibitor of formula 1 Af (e.g., 1.4F wherein X is N); (b) Thalidomide or related imid. An embodiment of this invention is directed to a method of treating multiple myeloma in a patient in need of such treatment comprising administering therapeutically effective amounts of:
(a) an FPT inhibitor of formula 1.4F (e.g., 1.4F wherein X is N);
(b) Thalidomide.
Other embodiments of this invention are directed to the embodiments described above using an FPT inhibitor of formula 1.4F (e.g.. 1.4F wherein X is N) wherein in addition to the administration of the FPT inhibitor and antineopiastic agents radiation therapy is also administered prior to, during, or after the treatment cycle.
For the embodiments of this invention using compounds of formula 1.4F(e.g., 1.4F wherein X is N), the compounds of formula 1.4F are preferably selected from the group consisting of;


























WE CLAIM:
1. A compound of the formula:

or a phamiaceutically acceptable or solvate thereof, wherein:
(A) a represents N or N*0", and the b, c. and d groups represent CR1 wherein each R1 group on each carbon is the same or
(ft) X represents N;



(3) when p is 1 for the moiety
then
(a) R1"is-OH.andR"MsHiar
(b) R1° Is -NHi. and R" is H; or
(c) R"* is selected from the group consisting of:
(i) -OR** wherein R1 is Ci to C3 alltyl;
(ii) -N3;
(iir) -NHR1iivherqinR1;and
(iv) -NtR1"lR"* therein R*1 ond R"|; and
R1" Is selected from the group consisting of: H and
alkyl:
(4) when p is 2 or 3 for ihe moiety
then:
(a) for one -CR1°R1"- moiety
(i) R1" is -OH. and R" is H; or
(ii) R"*"ls-NHi,andR"isH;or
(iii) R*" is selected from the group consisting of:
(1) -OR" wherein R"1 is C, to Cjalkyt;
(2) -Nj;
(3) -NHR11and
(4) -N(R*")R11 wherein R** and R1; and R*" is selected from the group consisting of: hi and alkyl; and
(b) for the remaining -GR*°R11- moieties R1" and R"
are hydrogen; and
(5) R1 is unsubstituled heteroaryl or substituted heteroaryl, provided
that when said heteroaryl group contains nitrogen in the ring, then

(24) alkenyl substituted wtt> one or more subslitutents independently selected from the group consisting of: halogen, -OR"" and -COJR""*;
1] Hach R is independently selected from the group consisting of: (1) halo:

(2) -CF,:
(3) -OR";
(5) -SR";
(6) -S(0)tR"*
(7) -N(R(8) -NO2;
(9) -OC(0)R":
{10) CO,R";
(11) -OCOjR1";
(12) -CN;
(13) -NR1COOR":
(14) -SR11C(0)0R"1
(15) -SR N(R )2 wherein each R Is independently sheeted from the group consisting of; H and-CfO)OR , and provided that R" In-SR N(R jjis not-CHz;
(16) benzotriazot-1 -ytoxy:
(17) tetrazol-S-ylthio:
(18) substituted tetrazol-S-ylthio;
(19) alkynyl;
(20) alkenyl;
(21) alkyl;
(22) alkyl substituted with one or more suhstitutents independently sheeted from the group consisting of: halogen, -OR and -CO2R ; and
(23) alkenyl substituted with one or more substitutents independently selected from the group consistinq of: haloaen.-OR" anri-rn.o" ■

said heteroarvl group is not bound by a ring nitrogen to the adjacent -CR"R"- moiety when R" IS selected from the group consisting of: -OH. -NHa, -OR1. -Na. and -NHR*. W*) R" is selected from the group consisting of: 0) H:

(2) halo;
(3) •CFj;
(4) -OR"1;
(5) COR";
(6) -SR"1
(7) •S(0)tR"":
(8) -m(9> -NO/.
(10) ■OC(0)R"°;
(11) COJR";
(12) -OCOJR":
(13) -CN:
(14) 1R"1COOR";
(15) -SR"C(0)OR";
(16) -SR"N(R"\ wherein each R" is independently selected from the
group consisting of: H and -CfOjOR", and provided that R"*in -SR N(R ); is
not -CHa;
(17) benzotriazoH-yloxy,
(18) tetrazoI-5-ylthio;
(19) substituted tetrazol-5"ylthio;
(20) alkynyl;
(21) alkenyl;
(22) alkyJ;
(23) afkyI substituted with one or more substitulents independently
selected from the group consisting of: halogen. -OR and -COjR ;

(f) mts0.lor2;
Q[) ris0,1or2
CH) R".I R , R and R " are each independently sslected from the group
consisfing of:
(1) H:
(2) -CF3:
(3) 1OR";
(4) alkyl;
(5) unsubstituted aryl;
(6) alkyl substituted with one or more groups selected from the group
consisting of: -S(0),R1*. -NR"1COOR". "C(0)R"1. and -COjR1*; and
(7) aryt substituted with one or more (e.g., 1,2, or 3} groups selected from the group consisting of: -S(0),R". -NR"1COOR"*. -C(0)R"*", and -COaR""; or
1) R* together with R1 represents =0 or =S;
0) R1 Is selected from the group consisting of;

H. O-
R" ■ " Y,, and i
•1O " iu ■ O1f ,1, O1C R* (5.0)
(2.0) (3.Q) j,,j

(jf) R1" is selected from the group consisting of: alk1and arylalKyI; Qj) R* is selected from the group consisyng of:
(1) 1©jR"1;
(2) -SOsR";
(3) 1(O)NHR*;
(4) -C(0)OR"*; and
(5) -C(0)N(R*)2:
i1) Each R°° is independently selected from the group consisting of: H. alkyl
and arylalkyi;
i1) R"" is selected from the group consisting of; H; afkyl; aiyl and arylalkyt; (o) R" is selected from the group consisting of; (1) alkyl;

(2) substituted all (3) unsubstltuted aryt;
(4) substituted aryt;
(5) unsubstituted cycloalkyi;
(6) substituted cycloalltyt;
(7) unsubstituted heteroaryl; (6) subs1ted heteroaryl;

(9) heterocycloalkyt; and
(10) substituted heterocyctoalkyl;
(11) unsubstituted alicenyl;
(12) -N(all(yl)2 vi1wrein each alkyi is independenUy selected;
(13) unsubstituted arytalkyt; and
(14) substftuted arylalkyi:
wherein said substituted atltyt R*1 groups are substituted with one or more subsQtuenU selected froni the group consisting ofi
(1) -OH, provided thai when there is more than one -OH group then each "-0H group is bound to a different carbon atom;
(2) halogen; and
(3) -CN; and
wherein said substituted cycloalkyi, and substituted heterocycloalkyt R" groups are substituted vwth one or more substituents selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bour>d to a different cartson atom;
(2) halogen; ana
(3) alkyl; and
wherein said substituted aryl, substituted heteroaryl and the aryi moiety of said substituted aryialkyl R1 * groups are substituted wnth one or more substituents independently selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then
each -OH group is bound to a different carbon atom;
(2) halogen;
{Z) alKyl;
(4) -CFa;

(5) -CN; and
(6) altexy.
(P) R"" is selected from the group consisting of:
(1) H;
(2) OH;
(3) alkyl;
(4) substituted alKyl;
(6) substituted aryl;
(7) unsubstituted cycloalkyt;
(8) substituted cyctoalky);
(9) unsubstituted heteroaryf;
(10) substituted helerodryf;
(11) heterocycloalkyl;
(12) substituted heteFocyOoatkyl;
(13) -OR"";
(14) unsubstituted arylatkyi;
(15) substituted arylalkyi:
(16) unsubstituted alkenyl;
(17) unsubstituted arytacyl:and
(18) unsubstituted heteroarytalk1: and
wherein setd substituted allcyt R"1 groups are substituted with one or more subsOtuents independently selected from the group consisting of:
(1) -OH. provided Ihat when there is more than one -OH group then each -OH group is bound to a different carbon atom;
(2) -CN;
(3) -CF3;
(4) halogen;
(5) cycloslkyV,
(6) heterocycloalkyi;
(7) arylalkyi;
(8) heteroarylalkyl; and
(9) hetero3ikenyl;and

wherein said substrtuted cydoalkyt, and substituted heterocydoalkyi R"" groups are substituted with one or more substltuents independently selected from the group consisting of:
(1) -OH, provided that when there ts more than one -OH group then each -OH group is bound to a different cartMn atom;
(2) -CN;
(3) -CF,;
(4) halogen;
(5) alkyl;
(6) cycloaikyi;
(7) heterocycloalkyl;
(8) afylatkyl;
(9) heteroarytalkyl;
(10) alkenyland
(11) heteroalkenyl;and
v1raln said sutistihited aryt, substituted heteroaryl and the apfi moiety of said substituted arylallcyl R1 "1 groups have one or more substltuents independently selected from ttie group consisting of:
(1) -OH, provided that when there Is more than one -OH group then each -OH group Is bound to a different carbon atom;
(2) -CN;
(3) -CFa:
(4) halogen;
(5) alkyl;
(6) cycloaikyi;
(7) heterocydoalkyl;
(8) aryialkyi;
(9) heteroarytalkyl;
(10} alkenyl;
(11) heteroalkenyl;
(12) aryloxy; and
(13) alkoxy;

Qd R" IS selected from the group consisting of; H, alkyl, piperidine Ring V,
cyctoalkyf. and -alkyl-(piperidine Ring V) (wherein said piperidine Ring V is as described below);
(ft) R" IS selected (J) R*", R1 and R11 are independently selected from the group consisting
of;
(1) H:
(2) alkyl;
(3) unsubstjiuted aryl;
(4) substituted aryl substituted with one or more substituents Independently selected from the group consisting of: alkyl, halogen, CFj and OH;
(5) unsubstituted cydoalkyt;
(6) substituted cycloalkyi substituted with one or more substKuents independently selected from: alkyl, halogen. -CFa or OH;
(7) heteroar)1 of the formula,

D

or

(8) piperidine Ring V:
A
wherein R*1 is selected from the group consisting of:
(a) H.
(b) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyl);
(0) alkylcarbonyt;
(d) alkyloxy carbonyl;
(e) hatoatkyt;
(0 -C(0)t1H(R="); and
0

(9J -MHz provided that only one of R*", R". and R** group can be -NHa, and provided that when one of R". R1, and R* (s -NHa then the remaining groups are not -OH;
(10) -OH provided that only one of R*". R1. and R** group can be -OH. and provided that when one of R", R1, and R*1 is -OH then the remaining groups are not -NHi",
(11) alkyl substituted with one or more substituents selected ftom the group consistir1 erf: -OH and -NH?, and provided that there is oniy one -OH or one -NHz group on a substituted carbon; and
(12) alkoxy; or
(13) R" and R" taken together with the carbon to which they are bound fbmi a cydtc ring selected from the group consisting of;

(a) unsut>stitut6d cyctoalkyi;
(b) cycloalkyi substituted with one or more substituents independently selected from the group consisting of: atkyt, halogen, CFa and OH;
(c) unsubstjtuted cycloatkenyt;
(d) cycloalken1 substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CF3 and OH;
(e) heterocycloatkyi;
(f) unsubstiUjled aryt;
(g) aryl substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, -CN. -CF3. OH and atKoxy; and
(i) hetaroaryl selected from the group consisting of;




fr) R" is selected from the group consisting of: H and alky); and

(U) alkenyi represents straight and branched carljon chains having at least one carbon to carbon double bond and containing from 2-12 carbon atoms;
alkoxy represents an alkyl moiety, alkyl as defined below, covalently bonded to an adjacent structural element through an oxygen atom;
alkyl represents straight and branched carbon chains and contains from one to twenty carbon atoms;
alkynyl represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from 2-12 carbon atoms;
aryl represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring;
arylalkyl represents an alkyl group, as defined above, substituted with an aryl group, as defined above;
cycloatkyi represents saturated carbocyclic rings of from 3 to 20 cartion atoms;
heteroalkyt represents straight and branched carbon chains containing from one to twenty caiton atoms, interrupted by 1 to 3 heteroatoms selected from the group consisting of: -0-, -S- and -N-, provided that when there is more than one heteroatom, the heteroatoms are not adjacent to one another;
heteroaryl represents unsubstituted or substituted cyclic groups, having at least one heteroatom selected from the group consisting of: O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character;
heterocycloalkyi represents a saturated carbocyclic ring containing from 3 to 15 carbon atoms, v/hich carbocyclic ring is Interrupted by 1 to 3 hetero groups selected from the group consisting of: -0-, -S- or NR" wherein R1* is selected from the group consisting of: H, aikyI, aryl, and -(0)N(R"1)2 wherein R1® is independently selected from the group consisting of: H, alkyi, aryl, arylalkyl, heteroaryl and cycloalkyi;
(V) provided that:
(1) a ring carbon atom adjacent to a ring heteroatom in a substituted heterocycloalkyi moiety is not substituted with a heteroatom or a halo atom; and

(?) a ting carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocydoalkyt moiety, is not substituted with more than one heteroatom; and
(3) a ring carbon atom, that is not adjacent to a ling hetmsatom, in a substituted heterocycloaikyi moiety. Is not substituted wth a Iwtefoaton) and a hafo atorn; and
(4) a ring carbon in a substituted cydoatkyi moiety is ntA substituted v1th more than one heteroatom; and
(5) a carbon atom in a siAistltuted alkyl moiety is not substituted with more ttian one heteroatom; and
(6) ttie same carbon atom in a substituted alkyi moiety is not substituted iiM} both heteroatoms and hah? atoms; and
(7) when R" to R1 are selected from the group consisting of substiUienIs (1} to (6), tf)en R" is selected from the group consisting of:

(a) (2.0) wherein R" is selected from substituents (11) to (14),
(b) (3.0) wherein R" Is selected from substituents (11) to (14),
(c) (4.0) therein (i) R11" is selected from the group consisOng of substituents (13) to (18). and R11 is as defined above, or (S) R"" is selected from the group consisting of substitutents (1) to (12), and R" fe selected from the group consistirig of; cycJoalkyl, piperidlne Rbig V and alkyt-(piperidine Ring V), or (lii) R"" is selected from the group consisting of substituents (13) to (18), and R1" is selected from the groifl) consisting oft cycioalkyi, ptperidine Ring V and alkyl-ftjiperidind Ring V), and
(d) (5.0) wherein at least one of R". R°, and R*" is selected from the group consisting of substituents (8)(g), (8Kh). (9), (10). (11). (12) and (13); and
(13) when at least one of R" to R" is -NHj. and R" is (2.0), then R1 is not
XJ<.> (14) when at least one of R" to R" is -N3, and R* is (2.0), then R* is not

x1
O"" "0
l.Tlie compound of clam 1 wherein:
(1) a is N;
(2) b, c and d are CR" groups wherein alt of said R" substftuerts are H. or one R1 substiiuent is halo and the remaining two R1 substituents are hydrogen;
(3) m is 1, and F1 is halo, or m is 2 and eac1 R" is the same or different halo; and
(4) R".R".R1andR1"areH.
3. The compound of claim 2 wherein R1 Is substituted imidaioly!.
1. The compound of ciaim 3 wherein said substituted imidazoli1 Is:
HjC
\
5" The compound of claim 4 wherein m is 1 and R is halo.
fo- The compound of claim 5 wherein said halo Is CI.
7. The compound of daim 6 vk1ereln said CI is bound to C4.
8. The compound of claim 7 wherein b. c and d are CR" groups wherein alt of said R1 substituents are H.
q. The compound of daim 8 wherein R1 is 2.0.
10. The compound of claim 1 wherein R" is alkyt.
11. The compound of daim 10 wherein said a5(1 is selected from the group consisting of: isoprop>4 and t-butyl.
12. The compound of claim 11 wherein said alkyl is isopropyl.

13. A compound of the fonnula:


{R1Xn
(1-4F)

or a pharmaceuticatly acceptable salt or solvate thereof, wherein; (A) B is the group:
-(CHi)H-(J-|R-
R1"/P .

wherein in said B group:
(1) p of the -{CH2)p- moiety is 0;
(2) p of the
c—h-f

(a>

moiety is 1;
(a) R*" is-OH. and R""Is H; or
{b) R"" is -NHz. and R1" is H; or
(c) R" is selected from the group consisting of;
(1) -OR* wherein R** is C, to Ca alkyl;
(2) -Na;
(3) -NHR"1and
(4) -NR*"R*;and
R" is selected fram the group consisting of: H and alkyl;

(4) R1 is unsut>5t(tuted heteroaryi or substituted heteroaryl, provided that when said heteroaryl group contains nitrogen In the ring, then said heteroaryl group is not bound by a ring nitrogen to the adjacent -CR"°R""- moiety whan R1 is selected from the group consisting of; -OH. -NHj, -OR*". -Ng, and -NHR*;
(B) a Is N;
(C) b. c and d are CR* groups wherein all of said R1 subsd&ients are H, or ono R" substibient is halo and Oie remaining two R1 substituents are hydrogen:
(D) m Is 1, and R1 is halo, or m is 2 and each R1 Is the same or different halo:
(E) XisNf9r6H:
(F) R",R".R".andR""areH:
(6) R" IS selected from the group consisting of:
1 °" " R" ■ " r,, and " ]
(2.0) (3.0) 1,_",j
(5.0)
(H) R* is selected from the group consisting of: alkyland arylalkyi; (1) R* is selected from the group consisting of:
(1) -C(0)R*:
(2) -SOzR*":
(3) -C(0)NHR*":
(4) -C(0)OR*: and
(5) -C(0)N(R*)2;
(J) Each R** is independently selected from the group consisting oft H, alkyl
and arylaticyl;
(K) R1" is selected from the group consisting of:
(1) alkyl;
(2) substituted alkyl;
(3) unsubstituted aryl;
(4) subs1uted aryl;
(5) unsubstituted cyctoalkyi;

(6) substituted cydoaikyt;
(7) un1jbstltuted heteroaryl;
(8) substituted heteroaryl;
(9) heterocycioalkyl; and
(10) substituted heterocycloajlcyl;
(11) unsubstituted altcenyl;
(12) •N(1)(yl}2 wherein each alkyl is independently sheeted;
(13) unsubstituted arytallcyl; and
(14) substituted arylalkyi;
wherein said substituted allc1 R11 groups are substituted with one or more substituents selected from the group con1sting of:
(1) -OH, provided fltat when there is more than one -011 group 1en eac1-OH group is bound to a different cartxin atom;
(2) halogen: and
(3) -CN; and
M11n said substituted cyctoalkyi, and substituted heterocycloaik1 R" groups are substituted with one or more substituents selected from the group consisting of:
(1) -OH, provided dial when 1ere is more than one -OH group then each -OH group is bound to a different cartxMi atom;
(2) halogen; and
(3) alkyl; and
wherebi said substituted aryl, substituted heteroaryl and the aryl moiety of said substituted arylalkyi R11 groups are substituted with one or more substituents Independently selected from the group consisting of:
(1) -OH. provided that when there is more than one -OH group then each -OH group Is bound to a different carbon atom;
(2) halogen;
(3) atkyi;
(4) -CFa:
(5) -ON; and
(6) alkoxy:
(L) R"" is selected from the group consisting of: (1) H;

{2) OH;
(3) alkyl;
(4) substituted alkyl;
(5) unsubstituted aryl;
(6) substituted aryl;
(7) unsubstrtuted cydoalkyi;
(8) substituted cycioalkyi;
(9) unsubsfituted heteroaryl;
(10) substituted heteroaryl;
(11) heterocydoalkirf;
(12) substituted heterocydoalkyl;
(13) -OR*";
(14) unsubstituted arytalkyi;
(15) substituted arytalkyi;
(16) unsubstrtuted alkenyi;
(17) unsubstituted arylacyl;and
(1Q) unsubstKuted heleroarylafkyl; and wherein said substituted alkyl R"** groups are substituted with one or more subst"rtuents independently selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom;
(2) -CN;
(3) -CF3;
(4) halogen;
(5) cycloalki1;
(6) heterocydoalkyl;
(7) arylalkyl;
(8) beteroarylafkyt; and
(9) heteroaIkenyl;and
wherein said substituted cycioalkyi, and substituted heterocydoalkyl R"* groups are substituted with one or more substituents independently selected from the group consisting of:

(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different cartoon atom;
(2) -CN;
(3) -CFj;
(4) halogen;
(5) alkyl;
(6) cydoalkyl;
(7) hetero11allcyt:
(8) aryialkyt:
(9) heteroarylaikyi;
(10) alkenyland
(11) heteroalKenyliand
M1iet1n said substituted ary), substituted heteroary1 and the aryi moieiy of said substitute] arylatkyl R"1" groups have one or more substituents independently selected from the group consisting of:
(1) -OH, provided that when there Is more than one -OH grwjp then each -OH group is bound to a different carbon atom;
(2) -CN;
(3) "CH
(4) halogen;
(5) alkyl;
(6) cydoalkyl;
(7) heterocycloalkyl;
(8) arylatkyl:
(9) heteroarylaikyi;
(10) alkenyt;
(11) heteroalkenyl;
(12) aryloxy; and
(13) alkoxy;
(M) R" is selected from the group consisting of: H, alkyl, piperidine Ring V. cydoalkyl, and -alkyl-(piperidine Ring V) (wherein sard piperidine Ring V Is as described below);

(N) R"\ R" aral R"* ars independently selected from Uie group consisting Of:
(1) H;
(2) alkyt;
(3) unsubsUluted aryl;
(4) substituted ar1 substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CFj and OH;
(5) unsubstHuted cycloalkyi;
(6) substituted cydoalkyl substituted with one or more substituents independently selected from; alkyl, halogen, •CFa or OH;
(7) heteroaryl of the fonnula.
(8) piperidine Ring V;

A



vrtier1n R** is selected from the group consisting of:
(a) H,
(b) alkyJ, {e.g., methyl, ethyl, propyl, butyl or t-butyi);
(c) alkylcarbonyl;
(d) alkyloxy carbonyl;
(e) haloalky);
(0 -C{0)NH(R11); and
(9) -NHj provided that only one of R1". R1, and R*1 group can be -NHz. and provided that when one of R1V R1. and R** is -NHj then the remaining groups are not -OH;
(10) -OH provided that only one of R". R". and R** group can be -OH, and provided that when one of R1", R1. and R*1 is -OH then the remaining groups are not -NHa;

(11) alkyl substituted with one or more substiluenls selected from the group consisting of: -OH and -NHi, and provided that there is only one -OH or one -NHj group on a substituted carbon; and
(12) alkoxy; or
(13) R1* and R1 taken together with the cartjon to which they are bound form a cyclic ring selected from the group consisting of:

(a) unsubslituted cycloalkyi:
(b) cycloalkyi substituted with one or more substituents independently selected from the group consisting of: alkyl, halogen, CFj and OH;
(c) unsubstituted cycloalkenyl;
(d) cycloalkenyl substituted with one or more substituents independently selected from the group consisting of: alk1i. halogen, CF3 and OH;
(e) helerocydoalkyl;
(0 unsubslituted aryl;
(g) aryl substituted wth one or more substituents independently selected from the group consisting of: alkyl. halogen, -CN, -CF3, OH and alkoxy; and
(t) heteroaryl selected from the group consisting of:


0

and

(0) R1" is selected from the group consisting of: H and alkyl: and (P) alkenyl, alkoxy, alkyl, alkynyl, aryl, aryialkyl, cycloalkyi, heteroalkyi, heteroaryl and heterocycloalkyl are as defined in claim 1; (Q) provided that:
(1) a ring carbon atom adjacent to a ring heteroatom in a substituted heterocycloalkyl moiety is not substituted with a heteroatom or a halo atom; and
(2) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycloafkyi moiety, is not substituted with more than one heteroatom: and

(3) a ring carbon in a substituted cycloalkyi moiety is not substituted with more than one heteroalom; and
(4) a carbon atom in a substituted a!k1 moiety is not substituted with more than one heteroalom; and
(5) the same cartwn atom in a substituted alkyl moiety is not substituted with both heteroatoms and halo atoms; and
(6) when R1 to R11 are selected from the group consisting o( substiluents (1) to (6), then R1 is selected from the group consisting of:

(a) (2.0) wherein R" is selected from substiluents {11) to (14),
(b) (3.0) wherein R" is selected from substiluents (11) to (14),
(c) (4.0) wherein (i) R"" is selected from the group consisting of substiluents (13) to (18), and R" is 3S defined above, or (ii) R""is selected from the group consisting of substttutents (1) to (12), and R"1 is selected from the group consisting of: cycloalkyi, piperidine Ring V and alkyHpiperidine Ring V), or (iii) R1"* is selected from the grciup consisting of substiluents (13) to (18), and R"1 is selected from the group consisting of: cycloaikyl. piperidine Ring V and alkyl-(piperidine Ring V). and
(d) (5.0) wherein at least one of R1\ R", and R*1 is selected from tiie group consisting of substiluents {8)(g), (8)(h), (9). (10), (11), (12) and (13); and
(13) when at least one of R" to R" is -NH1 and R1 is (2.0), then R* is not

Xk.
;and (14) when at least one of R1° to R" is -Nj, and R" is (2.0), then R1 is not
Xic

If. The compound of claim 13 wherein R1 is substituted imidazolyi.
IS. The compound of claim 14 wherein said substituted imidazolyi is:

VN

[jf. The compound of claim ISwhereinm is 1 and R1ishalo.
17. The compound of claim 16 wherein said halo is CI.
;-g The compound of claim 17 wherein said Ci is bound to C-8.
)(1, The compojnd of claim 17 wherein b, c and d are CR1 groups wherein
all of said R" substituenls are H.
20. The compound of claim 19 wherein R" is 2.0.
21. The compound of claim 20 wherein R1" is alkyl.
22. Thecompound ofanyoneofdaims U, 14, 19,20or2I
consisting of-OR*". -NHR* and -NR1R*.
23. The compound of claim 21 wherein said alkyl is selected from the group consisting of: isopropyl and t-butyl.
24. The compound of claim 23 wherein said alkyf is isopropyl.
25. The compound of claim 22 wherein R1° is -NHR*.
26. The compound of claim 25 wherein R1 is -C(0)OR1. wherein R* is
27. The compound of claim 27wheretn R" is H.
28. The compound of claim 27 wheftlVi is isopropyl.

29. The compound of claims 13 or 21 whereinR™ is selected from the group consisting of -NHz or -NHR*. and R1" is H.

*31,.
30. The compound of claims 13 or 21 wherein R is-NHz and R is H.
31. The compound of claim 21 wherein R"1 is -NHR*. and R1" is H.
32. The compound of claim 17 having Ihe structure-.

(R"")™
"-KV
,30
R"V3.R"

R"v4:«.
R"













(3) when p is one (or the moiety



then R"*" is selected from the group consisting of: -OH and -NHz, and R"" is alkyt; (d) when p is 2 or 3 for the moiety



then: (1) for one -CR11R1"- moiety, R1° is selected from the group consisting of; -OH and -NHj. and R1" is alkyl; and (2) for the remaining -CR"1R"- moieties R1° and R"" are hydrogen; and (e) R1 is unsubstituted heteroaryl or substituted heleroaryl. provided that when said heteroaryl group contains nitrogen in the ring, then said heteroaryl group is not bound by a ring nitrogen to (he adjacent -CR1R*1- moiety when R1° is -OH or -NH;;
(C) a is N;
(D) b, c and d are CR" groups wherein all of said R"" substituents are H, or one R" subsUtuent is halo and the remaining two R1 substituents are hydrogen;
{E) m is 1, and R" is halo, or m is 2 and each R1 is the same or different hato;
(F) X is N
(G) R", R1 R". and R"" are H;
(H) R* is selected from the group consisting of:

R" i., and
R" (5.0)
(2.0) (3,0)
R"1 U
(4.0) (I) R" is selected from the g"roup consisting of:

(3) unsubstituted aryl;
(4) substituted aryl;
(5) unsubstituted cycloalkyi;
(6) substituted cycloalltyl;
(7) unsubstituted heteroaryf;
(8) substituted heteroaiyl;
(9) heterocydoalkyi; and
(10) substituted heterocydoatkyt;
(11) unsubstituted alkenyl;
(12) -N(alkyi)z wherein each alkyl is independently selected;
(13) unsubstituted aryfafkyl; and
(14) substituted arytalkyt;
wherein said substituted alkyl R" groups are substituted with one or more substituents selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different cartran atom;
(2) halogen; and
(3) -CN; and
wherein said subslituted cydoalky!, and subslituted heterocycioalkyl R" groups are substituted with one or more substituents selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom;
(2] halogen; and
(3) alkyl; and wherein said substituted aryl. substituted heteroaryl and the aryl moiety of said substituted arylaikyl R1" groups are substituted with one or more substituents independently selected frorn the group consisting of:
(1) -OH. provided that when there is more than one -OH group then each -OH group is bound lo a different cartwn atom;
(2) hafogen;
(3) alkyl;

(6) alkoxy;
(J) R111 is sheeted from the group consisting of;
(1) H:
(2) OH:
(3) alkyl;
{4) substituted alkyl;
(5) unsubstituted aryl;
(6) substituted aryl;
(7) unsubstituted cydoalkyi;
(8) substituted cyctoalkyt:
(9) unsubstituted heteroaryl;
(10) substituted heteroaryl;
(11) heterocycloalkyi;
(12) substituted heterocycloalkyi;
(13) -OR*;
(14) unsubstituted arytalkyl;
(15) substituted arylalky(;
(16) unsubstituted alkenyl;
(17) unsubstituted arytacyl;and
(18) unsubstituted heteroarylalkyl; and
wherein said substituted alkyl R"1 groups are substituted with one or more subsfituents independently selected from the group consisting of:
(1) -OH. provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom;
(2) -CN;
(3) -CFa:
(4} halogen;
(5) cyctoalkyi;
(6) heterocycloalkyi:
(7) arylalkyt;
(8) heteroarylalkyl; and
iQ\ hfslfirnalkp.nul"anri

wherein said substituted cydoalkyl, and substituted heterocycloalkyi R"1 groups are substrtuted with one or more substituents tndependenlly selected from the group con1sting of:
(1) -OH. provided that when there is more than one -OH group then each -OH group is bound to a different carton atom;
(2) -CN:
(3) -CFj;
(4) halogen;
(5) alkyl;
(6) cycloalkyi;
(7) heterocycloalkyi;
(8) arylalkyl;
(9) heteroarylalkyl;
(10) alkenj1and
(11) hetero3lkenyl;and
wherein said substituted aryl, substituted heteroary! and the aryl moiety of said substituted arylalkyl R111 groups have one or more substituents independentiy selected from the group consisting of:
(1) -OH, provided that when there is more than one -OH group then each -OH group is bound to a different carbon atom;
(2) -CN;
(3) -CFs;
(4) halogen;
(5} alkyl;
(6) cycloalkyi;
(7) heterocycloalkyi;
(8) arylalkyl;
(9) heteroaiylaikyi;
(10) alkenyl;
(11) heteroalkenyt;
(12) aryioxy;and

(K) R" is selected from the group consisting of; H. alkyl. piperidine Ring V. cydoalkyi, and -alkyHpiperidine RingV) (wherein said piperidine Ring V is as desoibed below);
(L) R1\ R1 and R** are independently selected front the group consisting of:
(1) H;
(2) alkyt;
(3) unsubstituted aryi;
(4) substituted aryl substituted with one or more subsUtuents independently selected from the group consisHng of; atkyl. halogen, CFa and OH;
(5) unsubstituted cycloalk1;
(B) substituted cydoaJkj1 substituted with one or more substltuenls
independently selected from: a!k1, halogen, -CFj or OH; (7) heteroaryl of the fomiula,


D
(8) piperidine Ring V:

or

A
N
wherein R** is selected from the group consisting of:
(a) H.
(b) alkyl, (e.g., methyl, ethyl, propyl, butyl or t-butyl);
(c) alkylcarbonyl;
(d) alkyloxy carbonyt;
(e) haloalkyi;
(f) -C(0)NH(R"); and
(9) -NHj provided that only one of R1", R1, and R*® group can be -HHi. and provided that when one of R", R", and R** is -NH? then the remaining groups are not -OH;

(10) -OH provided that only one of R1\ R", and R*1 group can be -OH, and provided that when one of H1\ H1, and R*® is -OH then the remainirig groups are not -NH2;
(11) 3lky( substituted with one or more subslituents selected from the group consisting of: -OH and -NH3, and provided that there is only one -OH or one -NH2 group on a substituted cartjon; and
(12) alkoxy; or
(13) R" and R1 taken together with the cartwn to which they are bouf«J fomi a cydic ring selected from the group consisting of:

(a) unsubsfituted cycloatkyt;
(b) cydoalkyl substituted with one or more substituents independentiy sefectcd from the group consisting of: alkyl. halogen, CF3 and OH;
(c) unsubstituted cycloalkenj4;
(d) cyctoalkenyl substituted with one or more substituents independently selected from the group consisyng of: alkyt. halogen, CF3 and OH;
(e) heterocycloslkyi;
(0 unsubstituted aryl;
(i) heteroaryl selected from the group consisting of:




(M) R1"" is selected from the group consisting of: H and alkyl; and

(N) alkenyl, alkoxy, aikyI, alkynyl, aryl, arylalkyl, cycloalkyi, heteroalkyi. heteroaryf and heterocycloafkyl are as defined in claim 1; (0) provided that:
(1) a ring carbon atom adjacent to a ring heteroatom in a substituted heterocycloafkyl moiety is not substituted with a heteroatom or a hato atom; and
(2) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycfoalkyi moiety, is not substituted with more than one heteroatom; and

(3) a ring carbon atom, that is not adjacent to a ring heteroatom, in a substituted heterocycioalkyl moiety, is not substituled with a heteroatom and a halo atom; and
(4) a ring carbon in a substituted cycloalkyi moiety Is not substituted with more than one heteroatom; and
(5) a cartwn atom in a substituted alkyJ moiety is not substituled with more than one heteroatom; and
(6) the san:ie cartKsn atom in a substituted alky) moiety Is not substituted vnih both heteroatoms and halo atoms: and
(7) when R" to R" are selected from the group consisting of substituents (1) to (6), then R" Is selected from the group consisting of:

(a) (2.0) wherein R" is selected from substituents (11)to (14),
(b) (3.0) wherein R" is selected from substituents (11) to (14).
(c) (4.0) wherein (i) R"" is selected from the group consisting of substituents (13) to (IS), and R" is as defined above, or («) R11" is setected from the group consisting of substilutents 0)io (12), and R"* is seJecled from the group consisting of; cycloalkyi, piperidine Ring V and alkyl-(piperidine Ring V), or (iii) R"" is selected from the group consisting of substituents (13) to (IS), and R11 is selected from the group consisting of: cycloalkyi. piperidine Ring V and aikyl-(piperidine Ring V), and
(d) (5.0) wherein at least one of R". R", and R" is selected from the grtJup consisting of substituents (8)(g), (8)(h}. (9). (10), (11). (12) and (13); and
(13) when at least one of R1° to R" is -NHj, and R* is (2.0), then R1 is not

Xk.
;and (14) when at least one ifP lo R" is ~N3, lifds (2.0). then R* is not
x>

Documents:

1886-chenp-2004 abstract.pdf

1886-chenp-2004 assignment.pdf

1886-chenp-2004 claims-duplicate.pdf

1886-chenp-2004 claims.pdf

1886-chenp-2004 correspondence-others.pdf

1886-chenp-2004 correspondence-po.pdf

1886-chenp-2004 description (complete)-1.pdf

1886-chenp-2004 description (complete)-2.pdf

1886-chenp-2004 description (complete)-3.pdf

1886-chenp-2004 description (complete)-4.pdf

1886-chenp-2004 description (complete)-5.pdf

1886-chenp-2004 description (complete)-6.pdf

1886-chenp-2004 description (complete)-duplicate-1.pdf

1886-chenp-2004 description (complete)-duplicate-2.pdf

1886-chenp-2004 description (complete)-duplicate-3.pdf

1886-chenp-2004 description (complete)-duplicate-4.pdf

1886-chenp-2004 description (complete)-duplicate-5.pdf

1886-chenp-2004 description (complete)-duplicate-6.pdf

1886-chenp-2004 description (complete)-duplicate.pdf

1886-chenp-2004 description (complete).pdf

1886-chenp-2004 form-1.pdf

1886-chenp-2004 form-18.pdf

1886-chenp-2004 form-26.pdf

1886-chenp-2004 form-3.pdf

1886-chenp-2004 form-5.pdf

1886-chenp-2004 pct search report.pdf

1886-chenp-2004 pct.pdf

1886-chenp-2004 petition.pdf


Patent Number 221318
Indian Patent Application Number 1886/CHENP/2004
PG Journal Number 37/2008
Publication Date 12-Sep-2008
Grant Date 20-Jun-2008
Date of Filing 25-Aug-2004
Name of Patentee SCHERING CORPORATION
Applicant Address 2000 GALLOPING HILL ROAD, KENILWORTH, NEW JERSEY 07033-0530,
Inventors:
# Inventor's Name Inventor's Address
1 ZHU, Hugh, Y 38 Country Club Boulevard, Scotch Plains, NJ 07076,
2 COOPER, Alan, B 23 Natalie Drive, West Caldwell, NJ 07006,
3 GUZI, Timothy, J 48 Red Road, Chatham, NJ 07928
4 RANE, Dinanath, F 2 Hayground Court, Morganville, NJ 07751,
5 NJOROGE, F., George 11 Softwood Way, Warren, NJ 07059,
6 MINOR, Keith, P 7916 Glenway Drive, Dallas, TX 75249,
7 DOLL, Ronald, J 8 Concord Lane, Convent Station, NJ 07960,
8 GIRIJAVALLABHAN, Viyyoor, M 10 Maplewood Drive, Parsippany, NJ 07054,
9 SANTHANAM, Bama 10 Somerset Avenue, Bridgewater, NJ 08807,
10 PINTO, Patrick, A 34 Battle Ridge Road, Morris Plains, NJ 07950,
11 VIBULBHAN, Bancha 201 North 24th Street, Kenilworth, NJ 07033,
12 KEERTIKAR, Kartik, M 24 Columbia Avenue, East Windsor, NJ 08520,
13 ALVAREZ, Carmen, S 117 Dalton Street, Roselle Park, NJ 07204,
14 BALDWIN, John, J 621 Gypsy Hill Circle, Gwynedd Valley, PA 19437,
15 LI, Ge Room 201, Building 7, #815 Taolin Road, LuJiaZui Garden, 200135 Shang Hai,
16 HUANG, Chia-Yu 52 Ashford Drive, Plainsboro, NJ 08536,
17 JAMES, Ray, A 1036 Radcliffe Street, Bristol, PA 19007,
18 BISHOP, W., Robert 17 Hopper Avenue, Pompton Plains, NJ 07444,
19 WANG, James J-S 47 Unami Terrace, Westfield, NJ 07090,
20 DESAI, Jagdish, A 3 Forest Park Terrace, Monroe Township, NJ 08831,
PCT International Classification Number C07D 221/16
PCT International Application Number PCT/US2003/005479
PCT International Filing date 2003-02-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/085,896 2002-02-27 U.S.A.
2 10/325,896 2002-12-19 U.S.A.