Title of Invention

"FARNESYL PROTEIN TRANSFERASE OF FORMULA I "

Abstract ABSTRACT 315/CHENP/2003 "FARNESYL PROTEIN TRANSFERASE OF FORMULA I" The present invention discloses novel tricyclic compounds represented by the formula (1,0); a prodrug thereof, or a pharmaceutically acceptable salt or solvate of the compounds or of said prodrug useful for inhibiting famesyi protein transferase. Also disclosed are pharmaceutical compositions comprising such compounds their preparation as well as methods of using them to treat proliferative diseases such as cancer.
Full Text





-(CH2)pR2^;
(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)NHR2^;
(10) -(CH2)pC(R')-0-R^^;
(11) -(CH2)p(R%, wherein each R^ is the same or different;
(12) -(CH2)pC(0)R^;
(13) -(CH2)pC(0)R2'^;
(14)" -(CH2JpC(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)-CH2-imidazole);
(18) -(CH2)pN(R^%, wherein R^^ is the same or different (e.g., ~(CH2)p-NH-CH2-CH3);
(19) ~(CH2)pNHC(0)R^°;
(20) -(CH2)pNHC(0)2R^°;
(21) -(CH2)pN(C(0)R^^^)2 wherein each R^^^ is the same or different;

(22) -(CH2)pNR^^C(0)R^^, or R^^ and R^^ taken together with the atoms to which they are bound form a heterocycloalkyi ring consisting of 5 or 6 members, provided that when R^^ and R^ form a ring, R^' is not H;
(23) -(CH2)pNR^^C(0)NR^^ or R^^ and R^^ taken together with the atoms to which they are bound form a heterocycloalkyi ring consisting or 5 or 6 members, provided that when R^^ and R^' form a ring, R^^ is not H;
(24) -(CH2)pNR^^C(0)N(R^^^)2, wherein each R^^^ is the same or different;
(25) -(CH2)pNHS02N(R^^)2, wherein each R^^ is the same or different;
(26) -(CH2)pNHC02R^°;
(27) -(CH2)pNC(0)NHR^^
(28) -(CH2)pC02R^(29) -NHR^
(30)


same or different; (31)

wherein R^° and R^^ are the

R=^' R32
-(CH2)p-C C-R^
R^' R^^ , wherein R^^, R^', R^^ and R^ are the same or different;
(32) -alkenyl'COsR^^;
(33) -all (34) -alkenyl-COgR^';
(35) -alkenyl-C(0)-R2^^
(36) (CH2)p-alkenyl-C02-R^' ;
(37) -(CH2}pC=NOR^^or
(38) -(CH2)p-Phthalimid; p is 0, 1, 2, 3 or 4;
each R^ and R^ is independently selected from H, Halo, "CF3,
-0R^° COR^°, -SR^°, -S(0)tR^^ wherein t is 0, 1 or 2, -N(R^\, -NO2, -OC(0)R^°,
COgR^^, -OCOgR^^, 'CN, -NR^°COOR^^. -SR^^C(0)OR^^, -SR^^N(R^\ provided that
R^^ in -SR N(R )^ is not -CH2 and wherein each R is independently selected from
H or -C(0)OR , benzotriazol-l-yloxy, tetrazol-S-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or aikyi, said alkyl or alkenyl group optionally being substituted with
halogen, -0R^° or -CO2R °;
3 4
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, -CF^, -COR , alkyl or aryl, said atkyl or aryl optionally being substituted with -OR'°, -SR'°, -S(0),R'^ -NR'°COOR'^ -N(R'V -NOg. -C(0)R'°,
6

-OCOR °, -OCOgR^^, -COgR^^ OPOaR^", or R^ is combined.with R^to represent =0 or R^ is selected from:

22

H, o^'^" , I o=s=o O^C-R
(2.0) (3.0) (4.0) (5.0)
R^ is selected from:
(1) heteroaryl;
(2) substituted heteroaryl;
(3) arylalkoxy;
(4) substituted arylalkoxy;
(5) heterocycloalkyi;
(6) substituted heterocycloalkyi;
(7) heterocycloalkylalkyi;
(8) substituted heterocycloalkylalkyi;
(9) heteroarylalkyl;
(10) substituted heteroarylalkyl;
(11) heteroarylalkenyl;
(12) substituted heteroarylalkenyl;
(13) heteroarylalkynyl and
(14) substituted heteroarylalkynyl;
wherein said substituted R^ groups are substituted with one or more (e.g. 1,2 or 3) substituents selected from:
(1) -OH;
(2) -CO2R'*;
(3) -CHaOR^'*,
(4) halogen (e.g. Br. CI or F),
(5) alkyl (e.g. methyl, ethyl, propyl, butyl ort-butyl);
(6) amino;
(7) trityl;
(8) heterocycloalky!;
(9) cycloalkyi, (e.g. cyclopropyl or cyclohexyl);

(10) arylalkyi;
(11) heteroaryl;
(12) heteroarylalkyi and

(13) ■ V_/;
wherein R^" is independently selected from: H; alky!; aryl, arylalkyi, heteroaryl and heteroarylalkyi;
R^^ is selected from: alky or arylalkyi;
R^° is selected from; H; aikyI; aryl or arylalkyi;
R^' is selected from:
(1) alkyl;
(2) substituted alkyl;
(3) aryl;
(4) substituted aryl;
(5) cycloalkyi;
(6) substituted cycloalkyi;
(7) heteroaryl;
(8) substituted heteroaryl;
(9) heterocycloalkyi; and
(10) substituted heterocycloalkyi;
wherein said substituted R^^ groups have one or more (e.g. 1, 2 or 3) substituents selected from:
(1) -OH;
(2) halogen (e.g. Br, CI or F) and
(3) alkyl; R^^^ is selected from:

(1) H;
(2) OH;
(3) alkyl;
(4) substituted alkyl;
(5) aryl;
(6) substituted aryl;
(7) cycloalkyi;
7

(8) substituted cycloalkyl;
(9) heteroaryl;
(10) substituted heteroaryl;
(11) heterocycloalkyi; and
(12) substituted heterocycloalkyi;
wherein said substituted R^^^ groups have one or more (e.g. 1, 2 or 3) substituents selected from:
(1) -OH;
(2) -CN;
(3) -CFs; '
(4) halogen (e.g Br, CI or F);
(5) alkyl;
(6) cycloalkyl;
(7) heterocycloalkyi;
(8) arylalkyi;
(9) heteroarylalkyi;
(10) alkenyl and
(11) heteroalkenyl; R""^ is selected from: H, or alkyl; R""^ is selected from: alkyl or aryl;
R^\ R^ and R*^ are independently selected from:
(1) "-H;
(2) alkyl (e.g., methyl, ethyl, propyl, butyl or t-butyl);
(3) aryl, (e.g. phenyl);
(4) substituted aryl,
optionally substituted with one or more substituents selected from; alkyl, halogen, CF3 or OH;
(5) cycloalkyl, (e.g. cyclohexyl);
(6) substituted cycloalkyl;
optionally substituted with one or more substituents selected from: alkyl, halogen, CF3 or OH;
(7) heteroaryl of the formula,
s





(4) alkoxy; R^^^ is selected from:
(1) alkyl {e.g. methyl, ethyl, propyl, or butyl), and
(2) alkoxy;
R^^ , R^\ R^^ and R^^ is independently selected from:
(1) -H;
(2) -OH;
(3) =0;
(4) alkyl;
(5) aryl (e.g. phenyl) and
(6) arylalkyi (e.g. benzyl); R^° is selected from:

(1) alkyl;
(2) heteroaryl;
(3) substituted heteroaryl and
(4) amino;
wherein said substituents on said substituted R^° groups are independently selected from: alkyl (e.g. methyl, ethyl, propyl, or butyl); halogen (e.g. Br, CI, or F); and -OH; R^°^ is selected from:
(1) heteroaryl;
(2) substituted heteroaryl and
(3) amino;
R^^ is selected from: -H, or alkyl (e.g.;methyl, ethyl, propyl, butyl or t-butyl);
The compounds of this invention: (i) potently inhibit farnesyl 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 farnesyl acceptor but not by a form of transfonning Ras engineered to be a geranylgeranyl acceptor, (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnom:\al cell growth in culture induced by transforming Ras.

The compounds of this invention inhibit farnesyl protein transferase and the farnesyiation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount (e.g. a therapeutically effective amount) of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnomnal growth of cells, including transfonmed cells, by administering an effective amount (e.g. a therapeutically effective amount) of a compound of this invention. Abnormal growth of .cells refers to ceil growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (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 growth by administering an effective amount (e.g., a therapeutically effective amount) of the. tricyclic compounds, described herein, 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 (tumors), comprising administering an effective amount (e.g., a therapeutically effective amount) of a compound of the invention, described herein, to a mammal (e.g., a human) in need of such treatment in combination with (2) an effective amount of at least one anti-cancer agent i.e. a chemotherapeutic agent and/or radiation).
The present invention also provides a method of treating proliferative diseases, especially cancers (tumors), comprising administering an effective amount (e.g., a therapeutically effective amount) of a compound of the invention, described herein, to a mammal (e.g., a human) in need of such treatment in combination with (2) an effective amount of at least one signal transduction inhibitor.

Examples of proliferative diseases (tumors) which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinomaandcolonadenoma), myeloid leukemias (forexample, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for. inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as,a result of oncogenic mutation in other genes--f.e., the Ras gene itself is not activated by mutation to an oncogenic form~with said inhibition or treatrfient being accomplished by the administration of an effective amount (e.g. a therapeutically effective amount) of the tricyclic compounds described herein, 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 tricyclic compounds useful in the methods of this invention inhibit or treat the abnonmal grovdh of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as Ras p21, by blocking G-protein isoprenylation, 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 transformed cells.
DETAILED, DESCBIP-TION .OF THE JNVENTION
As used herein, the following tenns are used as defined below unless othenwise indicated:
MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
BOC-representstert-butyloxycarbonyl;
CBZ-represents -C(0)OCH2C6H5 (i.e., benzyloxycarbonyl);

CHaCla-representsdichioromethane; CIMS-represents chemical ionization mass spectrum; DBU-represents 1,8-DiazabicycIo[5.4.0]undec-7-ene; DEAD-representsdiethylazodicarboxyJate;
DEC-represents EDCI which represents 1-{3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride; DMF-represents N,N-dimethylformamide; Et-represents ethyl; EtOAc-represents ethyl acetate; EtOH-represenls ethanol;
HOBT-represents 1-hydroxybenzotriazole hydrate; IPA-represents isopropanol; i-PrOH-represents isopropanol; Me-represents methyl; MeOH-represents methanol; MS-represents mass spectroscopy;
FAB-represents FABMS which represents fast atom bombardment mass spectroscopy;
HRMS-represents high resolution mass spectroscopy; NMM-represents N-methylmorpholine; PPh3-represents triphenyl phosphine; Ph-represents phenyl; . . -Pr-represents propyl;
SEM-represents2,2-(Trimethylsilyl)ethoxymethyl; TBDMS-representstert-butyldimethylsilyl; EtsN-represents TEA which represents triethylamine; 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 preferrably 1-4 with 1, 2 or 3 being most preferred;
1^

alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms, more preferably one to four carbon atoms; even more preferably one to two carbon atoms.
arylalkyl-represents an alkyl group, as defined above, substituted with an aryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;
a I koxy-re presents an alkyl moiety, alkyl as defined above, covalently bonded.to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy and the like;
phenoxy represents an alkoxy moiety, as defined above, wherein the covalently bonded moiety is an aryl group, as defined below, for example, -O-phenyl;
alkenyl represents straight and branched carbofi chains haviiTg 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;
alkynyl represents straight and branched carbon 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;
aryl-(inciuding the aryl portion of arylalkyi and heteroarylalkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one or more (e.g., 1 to 3) of halo, alkyl. hydroxy, alkoxy, phenoxy, CF3, -C(0)N(R^^)2, -SOaR^^, -S02N(R^^)2, amino,
alkylamino, dialkylamino, -COOR or-NOg, wherein R^^ represents H, alkyl, aryl,
23
arylalkyi, heteroaryl or cycloalkyl and R represents alkyl or aryl;
cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms, said cycloalkyl ring being optionally substituted with one or more (e.g., 1, 2 or 3) of the same or different alkyl groups (e.g., methyl or ethyl);
cycloalkylalkyi- represents an alkyl group, as defined above, substituted with a cycIo group, as defined above, such that the bond from another substituent is to the alkyl moiety;
lis

heterocycloalkylalkyl- represents an alkyl group, as defined above, substituted with a heterocycloalkyi group, as defined below, such that the bond from another substituent is to the alkyl moiety;
halo- represents halogen i.e. fluoro, chloro, bromo and iodo;
haloalkyl- represents an alkyl group, as defined above, substituted with a halo group, as defined above, such that the bond from another substituent is to the alkyl moiety;
heteroarylalkyi- represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;
heteroaryialkenyl- represents an alkenyl group, as defined above, substituted with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;
heteroalkyl- represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from ~0-, -S- and -N-;
heteroalkenyl- represents straight and branched carbon chains having at
least one carbon to carbon double bond and containing from one to twenty carbon
atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected
from-0-,-S-and-N-; . .^
heteroalkynyl- represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from -0-, -S- and -N-;
arylheteroalkyi- represents a heteroalkyl group, as defined above, substituted with an aryl group, as defined above, such that the bond from another substituent is to the alkyl moiety;
alkyicarbonyl- represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (-CO-), for example, -COCH3;
alkyloxycarbonyl- represents an alkyl group, as defined above, covalently bonded to a carbonyl moiety (-CO-) through an oxygen atom, for example, -C(0)-OC2H5;






More preferably R^ is 2.0 or 4-0; and most preferably R^-is4.G: Preferably, R"^ is selected from: alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyloalkyl or substituted cycloalkyi; wherein, said substituted aryl, heteroary, and cycloalkyi, R^""^groups are substituted with substituents independently selected from: halo (preferably F or CI), cyano, -CF3, or alkyl; and wherein said substituted alkyl R"*^^ groups substituted with substituents selected from halo, (preferably F or CI), cyano or CF3. Most preferably, R""^^ is selected from: alkyl, aryl, substituted aryl, cyloalkyl, or substituted cycloalkyi, wherein, said substituted aryl and substituted cycloalkyi groups are substituted with substituents independently selected from: halo, (preferably F or CI), CN or CF3. More preferably, R"*""^ is selected from methyl, t-butyl, phenyl, cyanophenyl, chlorophenyi, fluorophenyl, or cyclohexyl. Still more preferably, R^^^ is selected from: t-butyl, cyanophenyl, chlorophenyi, fluorophenyl or cyclohexyl. Even more preferably, R^^° is selected from cyanophenyl, with p-cyanophenyl being even still more preferred. Preferably, R^\ is selected from alkyl, cycloalkyi, or substituted cycloalkyi, wherein said substituted cycloalkyi group is substituted with 1, 2 or 3 substituents independently selected from: halo (preferably chloro or fluoro), or alkyUpreferably methyl or t-butyl). Examples of R^^ groups include: methyl, ethyl, propyl, t-butyl, cyclohexyl or substituted cyclohexyl. More preferably, R^^ is selected from methyl, t-butyl, cyclohexyl, chlorocyclohexyl, (preferably p-chlorocyclohexyl) or fluorocyclohexyl. (preferably p-fluorocyclohexyl). Most preferably, R^^ is selected from: methyl, t-butyl, or cyclohexyl, with t-butyl or cyclohexyl being still more preferred.

Preferably, R^ is selected from H or methyl. Most preferably, R^^j^^ R^ R^ R^ and R^^ are preferably H. Preferably, R^ is selected from:
(1) heteroaryl;
(2) substituted heteroaryl;
(3) arylalkoxy;
(4) substituted arylalkoxy;.
(5) heterocycloalkyi;
(6) substituted heterocycloalkyi;
(7) heterocycloalkylalkyi;
(8) substituted heterocycloalkylalkyi;
(9) heteroarylalkyi;
(10) substituted heteroarylalkyi;
(11) heteroarylalkenyl and
(12) substituted heteroarylalkenyl;
wherein said substituted R^ groups are substituted with one or more substituents (e.g., 1, 2, or 3) independently selected from:
(1) -OH;
(2) -GOaR^";
wherein, R^'* is selected from: H or alkyl (e.g., methyl or 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, orCl);
(5) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl (e.g. methyl, ethyl, propyl, or butyl (preferably isopropyl, or t-butyl));
(6) amino;
(7) trityl;
(8) heterocycloalkyi;
(9) arylalkyi (e.g. benzyl);
(10) heteroaryl (e.g. pyridyl) and
(11) heteroarylalkyi (piperidine-CHa);

Most preferably, R^ is selected from:
(1) heterocycloalkyi;
(2) substituted heterocycloalkyi;
(3) heterocycloalkyla)kyl;
(4) substituted heterocycloalkylalkyi;
(5) heteroarylalkyl;
(6) substituted heteroarylalkyl;
(7) heteroaryialkenyl and.
(8) substituted heteroaryialkenyl;
wherein said substituted R^ groups are substituted withsubstituenTs-independently selected from:
(1) -OH;
(2) -COsR^^;
wherein, R^'* Is selected from: H or alkyl (e.g., methyl or ethyl), preferably aikyi, and 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 or CI);
(5) alkyl, usually C1-C6 alkyl, preferably C1-C4 alkyl
(e.g. methyl, ethyl, propyl, isopropyl, butyl ort-butyl, most preferably t-butyl);
(6) amino;
(7) trityl;-
(8) heterocycloalkyi;
(9) arylalkyl;
(10) heteroaryl and
(11) heteroarylalkyl;
More preferably, R^ is selected from: ,

(1) heterocycloalkyi;
(2) substituted heterocycloalkyi;
(3) heterocycloalkylalkyi;
(4) substituted heterocycloalkylalkyi;
(5) heteroarylalkyi;
(6) substitutedmeteroarylalkyl;
(7) heteroarylalkenyl and
(8) substituted heteroarylalkenyl;
wherein substituents for said substituted R^ groups are each independenjiy selected from:
(1) halo (e.g., Br, or CI);
(2) alkyi, usually C1-C6 alkyl, preferably C1-C4 alkyl
(e.g. methyl, ethyl, propyl, isopropyl, butyl ort-butyl, most preferably t-butyl);
(3) alkyl, 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) arylalkyi, and
(7) heteroarylalkyi.
Even more preferably, R^ is selected from:
(1) heterocycloalkylalkyi;
(2) substituted heterocycloalkylalkyi;
(3) heteroarylalkyi and
(4) substituted heteroarylalkyi;
wherein substituents for said substituted R^ groups are each independently selected
from:
(1) halo(e.g., Br, orCl);
(2) alkyl. usually C1-C6 alkyl. preferably C1-C4 alkyl
(e.g. methyl, ethyl, propyl, Isopropyl, butyl ort-butyl, most preferably
t-butyl);
(3) amino and
(4) trityl.

still more preferably, R^ is selected from:
(1) heterocycloalkylalkyi;
(2) substituted heterocycloalkylalkyi;
(3) heteroarylalkyi and
(4) substituted heteroarylalkyi;
wherein substituents for said substituted R^ groups are each independently selected from:
. (1) halo (e.g., Br,or CI) and ,,(2). alkyj, usually.C1-C6alkyJ,.pre.fera^^^^^
(e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl, most preferably t-butyl). Yet even more preferably, R^ is selected from:
(1) piperidinyl;
(2) piperizinyl;
(3) -(CH2)p-piperidinyl;
(4) -(CH2)p-piperizinyl;
(5) -(CH2)p-morpholinyl and
(6) -(CH2)p-imida20lyl;
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:
(1) halo(e.g., Br,orCl)and
(2) alkyl, usually C1-C6 alkyl, preferably C1-C4 aikyl
(e.g. methyl, ethyl, propyl, isopropyl, butyl ort-butyl, most preferably t-butyl). Still more preferably, R^ is selected from:
(1) -piperizinyl;
(2) -(CH2)p-piperidinyi;
(3) -(CH2)p-imidazolyl; and
(4) -(CH2)p-morpholinyl,
wherein p is 1 to 4, and the ring moiety of each R^ group is optionally substituted with one, two or three substituents independently selected from: methyl, ethyl, and isopropyl.
«



Thus, R^\ R22 and R"^ are preferably independently selected from; 0) H;
(2) aryl (most preferably phenyl);
(3) heteroaryl and
(4) heterocycloalkyl (i.e., Piperidine Ring V)
wherein at least one or H^\ R^, or R"^ is other than H, and most preferably R^^ and R^are H and R"*^ is other than H, and more preferably R^^ and R^^ are H and R"^ is selected fronn heteroaryl or heterocycloalkyl, and still more preferably R^' and R^ are H and R'^ is Piperidine Ring V; wherein the preferred definitions of heteroaryl-and Piperidine Ring V are as described above.
Preferably, A and B are-independently selected from:
(1) -H;
(2) -R';
(3) -R^-C(0)-R^;
(4) -R^-C02-R^^ - (5) -C(0)NHR^;

(6) -C(O)NH-CH2-C(0)-NH2; ■
(7) -C(0)NHR2^"'
(8) -(CH2)p(R^)2, wherein each R^ is the same or different;
(9) -(CH2)pC(0)R';
(10) -(CH2)pC(0)R^'^;
(11) -(CH2)pC(0)N(R^2, wherein each R^ is the same or different;
(12) -(CH2)pC(0)NH(R');
(13) -(CH2)pNHC(0)R^°;
(14) -(CH2)pNHC(0)2R^=

(15) -(CH2)pN(C(0)R^^^)2 wherein R^^^ is the same or different;
(16) -(CH2)pNR^'C(0)R^\ optionally. R^^ and R^^ taken together with the atoms to which they are bound, forni a heterocycloalkyl ring consisting of 5 or 6 members, provided that when R^^ and R^^ form a ring, R^^ is not H;

■ (17) -(CH2)pNR^^C(0)NR2^ optionaiiy, R^^ and R^^ taken together with the atoms to which they are bound, form a heterocycloatkyi ring consisting or 5 or 6 members, provided that when R^^ and R^^ fonn a ring, R^^ is not H;
(18) -(CH2)pNR^^C(0)N(R2%, wherein each R^^^ Is the same or different;
(19) -(CH2)pNHS02N(R^')2, wherein each R^^ Is the same or different;
(20) -(CH2)pNHC02R^;
(21) -(CH2)pC02R^^;
(22) -NHR^
(23)
,30


l-R'
31 /
^ ' P wherein R^° and R^^ are the same or different and

R
,30

,32

-(CH2)p-C C-R"
R^' R^ , wherein R^°, R^^, R^^ and R^^ are the same or
different.
Most preferably, A and B are independently selected from:
(1) -H;
(2) -R';
(3) -R'-C(0)-R';
(4) -R'-COa-R^';
(5) -C(0)NHR^;
(6) -(CH2)p(R^)2, wherein each R^ is the same or different;
(7) -(CH2)pC(0)R^;
(8) -(CH2)pC(0)N(R^)2, wherein each R^ is the same or different;
(9) -(CH2)pC(0)NH(R^;
(10) -(CH2)pNR^^C(0)R^, optionaiiy, R^' and R^^ taken together with the atoms to which they are bound, fomi a heterocycloalkyl ring consisting of 5 or 6 members, provided that when R^^ and R^'^ fomi a ring, R^^ is not H;





heteroaryialkenyl and
(16) substituted heteroaryialkenyl,
wherein the substituents for said substituted R^ groups are each independently selected from:
(1) -OH;
(2) -COsR^'^;
(3) -CHsOR'^
(4) halo,
(5) alkyl (e.g. methyl, ethyl, propyl,,butyl ort-butyj);
(6) amino;
(7) trityl;
(8) heterocycloalkyi;
(9) arylalkyi;
(10) heteroaryl and
(11) heteroarylalkyi,
wherein R^'* is independently selected from: H; or alkyl, preferably methyl or ethyl.
More preferably, when there Is a double bond between C-5 and C-6, A is H and B is R®. Most preferably, when there is a double bond between C-5 and C-6, A is H and B is R® wherein R^ Is selected from:
(1) arylalkyi;
(2) substituted arylalkyi;"
(3) arylalkoxy;
(4) substituted arylalkoxy;
(5) heterocycloalkyi;
(6) substituted heterocycloalkyi;
(7) heterocycloalkylalkyi;
(8) substituted heterocycloalkylalkyi;
(9) heteroarylalkyi;
(10) substituted heteroarylalkyi;
(11) aikenyl;
(12) substituted aikenyl;
(13) heteroaryialkenyl and
^^

(14) substituted heteroarylalkenyl,
wherein the substituents for said substituted R^ groups are independently selected from;
(1) -OH;
(2) halo, (preferably Br);
(3) alkyl (e.g. methyl, ethyl, propyl, butyl, or t-butyl);
(4) amino and
(5) trityl.
Still more preferably, when there is a double bond between C-5 and C-6, A Is H and B is R^ wherein R^ is selected from;
(1) heterocycloalkylalkyi;
(2) substituted heterocycloalkylalkyi;
(3) heteroaryialkyl and .
(4) substituted heteroaryialkyl,
wherein said substituents for said substituted R^ groups are the same or different alkyl groups (e.g., C1-C4 alkyl).
Even more preferably, when there is a double bond between C-5 and C-6, A is H and B is R^ wherein R^ is selected from:
■ (1) heteroaryl(C1-C3)alkyland
(2) substituted heteroaryl(C1 -C3)alkyl, wherein the substituents for said substituted R^ group are as defined above.
Yet still more preferably, when there is a double bond between C-5 and C-6, A is H and B is R^ wherein R® is selected from:
(1) heteroaryl(C1-C3)alkyI, with heteroaryl-CHa- being preferred and
(2) substituted heteroaryl(C1-C3)alkyl, with substituted heteroaryl-CH2- being preferred,
wherein the substituents for said substituted R^ 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 -CH3 being preferred.
Even still more preferably, when there is a double bond between C-5 and C-6, A is H and B is R^ wherein R^ is selected from:
(1) -CHa-imidazolyl;
(2) substituted imidazolyl-CH2-;
30



When B is H and A is R^ and there is a double bond between C-5 and C-6, the R^ groups for A are those described above for B.
When the optional bond between C-5 and 0-6 is not present (i.e, there is a single bond between C-5 and G-6), each A and each B are independently selected and the definitions of A and B are the same as those described above 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).
Preferably, there is a double bond between C-5 and C-6.

















Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. 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 hydroxyl group. These compounds may form phannaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable.amines such as ammonia, aikyl amines, hydroxyalkylamlnes, N-methylglucamine and the like.
Certain basic tricyclic compounds also form phannaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may fomn salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochioric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base forni 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 bicarbonate. The free base forms 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 phannaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
The compounds of formula 1.0 can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with phannaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.

The method of treating proliferative diseases (cancer), according to this
invention, includes a method for treating (inhibiting) the abnormal growth of cells,
including transformed cells, in a patient in need of such treatment (e.g., a mammal
such as a human), by administering, concurrently or sequentially, an effective amount
of a compound of this invention and an effective amount of a chemotherapeutic agent
and/or radiation. Abnormal growth of cells means cell growth independent of normal
regulatory mechanisms (e.g., loss of contact inhibition), including 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 preferred embodiments, the methods of the present invention include methods for treating or inhibiting tumor growrth in a patient in need of such treatment (e.g„ a mammal such as a human) 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. Examples of tumors which may be treated include, but are not limited to, epithelial cancers, e.g., prostate cancer, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for exan^iple, exocrine pancreatic carcinoma), breast cancers, colon cancers (e.g., colorectal carcinomas, such as, for • example, colon adenocarcinoma and colon adenoma), ovarian cancer, and bladder carcinoma. Other cancers that can be treated include melanoma, myeloid leukemias (for example, acute myelogenous leukemia), sarcomas, thyroid follicular cancer, and myelodysplastic syndrome. In particular, the proliferative disease (tumor) that may be treated is selected from lung cancer, pancreatic cancer, prostate cancer and myeloid leukemia. Preferrably for the methods of the present Invention, the disease (tumor) thai may be treated is selected from lung cancer and myeloid leukemia.
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 aberrantly activated as a result of oncogenic mutation in other genes - i.e., the ras gene itself is not activated by mutation to an oncogenic fomn. This method comprises administering, concurrently or sequentially, 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

(e.g., a mammal such as a human). 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, lyn, fyn).
For radiation therapy, y-radiatjon is preferred.
The methods of treating proliferative diseases (cancer), according to this invention, also include a method for treating (inhibiting) the abnormal growth of cells, including transformed cells, in a patient in need of such treatment (e.g., a mammal _such as.a hurnan), 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, STI 571 (Gleevec); ■
(ii) Epidermal growth factor (EGF) receptor inhibitor such as, for example, Kinase inhibitors (Iressa, OSI-774) and antibodies (Imcione: C225 [Goldstein et al. (1995), Clin Cancer Res. V.1311-1318], and Abgenix: ABX-EGF) and
(iii) Her~2/neu receptor inhibitors such as, for example, Herceptin© (trastuzumab).
As used herein the following terms have the following meanings unless indicated othenwise:
antineoplastic agent - a chemotherapeutic agent effective against cancer;
concurrently - (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule; and
- sequentially ^-(1)-administration of one component of the method t(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 componeht.
The term "in association with" as used herein in reference to the combination therapies of the invention means-the agents or components are adminstered concurrently or sequentially as defined above.
CHEMQTHERAPEUTIC AGENTS
Classes of compounds that can be used as chemotherapeutic agents (antineoplastic agent/microtubule affecting agents) include but are not limited to: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. Examples of compounds within these classes are given below.
Alkylating agents (including nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, 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-FluorouraciI, , Floxuridine, Cylarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.
Natural products and their derivatives (including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyilotoxins): Vinblastine, Vincristine, Vindesirie, Bleomycin, Daclinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, 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, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide.
Hormones and steroids (including synthetic analogs): 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanblone

propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex.
Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.
Particularly preferred are the antineoplastic agents selected from Cyclophasphamide, 5-Fluorouracil, Temozolomlde, Vincristine, Cisplatin, Carboplatin, and Gemcitabine. Most preferrably, the antineoplastic agent is selected from Gemcitabine, Cisplatin and Carboplatin.
Methods foir 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 "Physicians' 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 explained above, the present invention also provides methods of treating diseased cells by contacting the cells with an FPT inhibiting compound of the invention and a microtubule affecting agent (e.g., paclitaxel, a paclitaxel derivative or a paclitaxel-like compound). As used herein, a microtubule affecting agent is a compound that interferes with cellular mitosis, i.e., having an anti-mitotic effect, by affecting microtubule-foHnationand/or-action.-Suchagentscanbe.forinstance; microtubule stabilizing agents or agents which dismpt microtubule formation.
Wlicrotubuie affecting agents usefui in the invention are weH known to those ot skill in the art and include, but are not limited to allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®, NSC 125973), paclitaxel derivatives (e.g., Taxotere, NSC

608832), thiocolchicine (NSC 361792), trity! cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A/epothilone, and discodermolide (see Service, (1996) Science, 274:2009) estramustine, nocodazoie, MAP4, and the like. Examples of such agents are also described in the scientific and patent literature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997) CancerRes. 57:3344-3346; Nicolaou (1997) Nature 387:268-272; Vasquez (1997) Moi. Biol. Cell. 8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812.
Particularly preferred agents are compounds with paclltaxel-like activity^ These include, but are not limited to paclitaxel and paclitaxel derivatives (paclitaxel-like compounds) and analogues. Paclitaxel and its derivatives (e.g. Taxol and Taxotere) are available commercially. In addition, methods of making paclitaxel and paclitaxel 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 "paclitaxel" as used herein refers to the drug commercially available as Taxol® (NSC number: 125973). TaxoP inhibits eukaryotic cell replication by enhancing polymerization of tut)ulin moieties into stabilized microtubule bundles that are unable to reorganize into the proper structures for mitosis. Of the many available chemotherapeutic drugs, paclitaxel has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6:17-23, Honwitz (1992) Trends Pharmacol. Sci. 13:134-146, Rowinsky (1990) J. Nati. Cane. Inst. 82; 1247-1259).
Additional microtubule affecting agents can be assessed using one of many such assays known in the art, e.g., a semrautomated assay which measures the tubulin-polymerizing activity of paclitaxel 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 disrupted, in particular, through the inhibition of a mitotic event. Such inhibition may be mediated by

disruption of the mitotic apparatus, e.g., disruption of normal spindle formation. Cells in which mitosis is interrupted may be characterized by altered morphology (e.g., microtubule compaction, increased chromosome number, etc.).
In a preferred embodiment, compounds with possible tubulin polymerization activity are screened in vitro. In a preferred embodiment, 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 jjearing the Wp21 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 inhibitloh'of' microtubule assembly and/or disassembly. Assays for microtubule assembly are described, for example, by Gaskin et al. (1974) J. Molec. Bio!., 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" (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ
07645-1742, USA); the disclosure of which is incorporated herein by reference
thereto. i
General Preparative Schemes
The following processes may be employed to produce compounds ot the
invention.-— — ^ "
Pyridyl 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:





Synthesis ot 3-carbon spaced analogs can be prepared as outlined in scheme 3. Thus, subjecting tricyclic vinyl bromide 1b 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 aluminunn hydride. Treatment of the alcohol with methanesulfonyl 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.















Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").






Compound 12a is reduced with DIBAL in an inert solvent such as toluene or tetrahydrofuran to give 12b after acidic workup. Treatment of 12b with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c. Elimination of the hydroxyl group by converting the hydroxyl group to an appropriate leaving group such as a mesylate, tosylate, or halide, using methanesulfonyl 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 ethanoi 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 "Weinreb amide" followed by reaction with an appropriately substituted and tritylated imidazole iodide in the presence of ethylmagnesium bromide in solvents such as dichioromethane at ambient temperature yields the adduct 12c {shown in Scheme 12 below).



















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 alkene, which can be added to the appropriately substituted vinyl bromide under Heck reaction conditions. Selective reduction of the di-substituled olefin gives the saturated derivative (Scheme 16).

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-alkyl imidazoie derivatives (Scheme 17).



Tricyclic vinyl bromide azaketone 4b was prepared as described by Rupard et. al. (J. Med. Chem. 1989, 32, 2261-2268). Reduction of ketone to alcohol 4c was carried 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 carbomyjatlon etc.). Preparation of compounds with 3-carbon substituted imidazole moieties on the suberane trycycljc bridgehead was carriedjout in a similar way as described in scheme 3.

Loratadine® (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCI (1.4 L conc.HCl in 600 ml H2O) for 12h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2CI2 (1 X 4L, and 2 x 2.5L). The organic phase was washed with brine, dried over Na2S04 and MgS04 and then filtered. All the volatiles were then removed to give 368 g of the
title compound (2). MH+ = 311



To a solution of the title compound of Preparative Example 1, Step B (145 g) in 1L of CH2CI2 at 0°C was added ethylchloroformate (55 mL), dropwise. The reaction
mixture was stirred at room temperature overnight. It was further diluted with 1L CH2CI2 and stirred with 2L of dilute NaHCOg, pH ~ 7-8. The organic layer was separated and dried over MgS04 and Na2S04, filtered and concentrated to afford 174 g of a brown black gum. The crude compound was purified by silica gel column chromatography, eluting with 20-60% ethyl acetate-hexane to afford the title compound (4). MS (FAB) m/z 383 (MH+).
The title compound of Preparative Example 1, Step C (251 g, 0.65 mol) was dissolved in 1.65 L of CH2CI2 and dibromo dimethylhydantoin, (132 g, 0.462 mol)
was then added. The solution was stirred until the system was homogeneous. The solution was cooled to 0 ""C under N2 atmosphere and 174 mL of CF3SO3H were
added over 37 min. while keeping temperatures between "1 to 1°C. The reaction



To a solution of piperazine 0.186 g ( 2.2 mmol, 5 equiv.) in 5 mLof THF was added 0.20 g (0.4 mmol) of compound 6 (from Preparative Example 1, Step D. The reactants stirred at room temperature until everything was in solution. To this mixture was added potassium t-butoxide (0.243 g, 2.1 mmol, 5 equivalents) in one portion. The reaction mixture was stirred at room temperature for 2 h. All of the THF was removed by rotary evaporation and the resulting crude product was purified by flash chromatography eluting with 3-4% (10% CH3OH: saturated with NH40H)-CH2Ci2
to give a mixture of title compounds (7) and.(8). FAB nVz 467 (MH+).
(,
(
The mixture of compounds from Preparative Example 1, Step E (43.6 g) in 100 mL of cone. HCi was stirred at room temperature for 16 h. The reaction mixture was



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/z 469 (MH+).

Product from Preparative Example 2, Step B (21.25 g, 45.3 mmol) was treated in the same manneras described in Preparative Example 1, Step E, to give 22.2 g of a mixture of compounds (13) and (14). MS (473) (MH"").




Separation of compound of Preparative Example 2 Step B by HPLC using a Chiraipack AD column eluting with 40-50% isopropanol:60-50% hexane-0.27o diethylamine gave enantiomeric amines (17) and (18).
'i
22 Compound 17: mp = 118-119; [a]p =+ 136.9° (9.00 mg/2mU MeOH); MS
(FAB)m/z469(MH+).
22
Compound 18: mp = 119-120; [a]p = -178.2' (9.90 mg/2mL, MeOH); MS
(FAB)m/z469(MH+).



To a solution of the title compound from Preparative Example 2, Step B (2.0 g, 4.3 mmole) in DMF (50 ml) under nitrogen atmosphere, was added triethyl amine (17 ml), ethyl arcrylate (2.5 ml), potassium carbonate (3 g, 21.4 mmole), tetrabutylamonium bromide (2.8 g, 8.6 mmole) and palladium (II) acetate (0.1255 g, 0.56 mmol). The resulting mixture was heated to 100°C, and stirred for4 h then it was cooled to room temperature and the solvent was removed. To the residue was added CH2C/2 and water and the mixture was then extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified using pre-adsorbed flash silica column chromatography eluting with 30-50% ethyl acetate-hexane gradient to give the title compound (19). MS 487 (MH^).



bicarbonate and the mixture was extracted with CH2CI2. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford a mixture of the
reduced ester (20) and the alcohol (21) title compounds. This crude nnixture was taken on to the next step without purification.

To a solution of the products from Preparative Example 3, Step B (5.74 g) in CH2CI2 (100 ml) was added triethyl amine (2.4 mi). Slowly, methane sulfonyl chloride (0.8 ml) was added and the mixture stirred over night at room temperature. To the reaction was added saturated sodium bicarbonate and then it was extracted with CH2CI2. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product mixture was separated on a Biotage® column, eluting w/ith 30% ethyl acetate-CH2Cl2, to afford the desired title compound (22). MS 525 (MH*). (recovered unreacted ester (20))









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

Compound (20) from Preparative Example 3, Step B"(0.67 g, 1.37 mmole) was dissolved in THF (5 ml). To the mixutre was added 1N NaOH (6.9 ml) and the resulting solution stirred over night at room temperature. The reaction mixture was concentrated, acidified with 10% citric acid (w/v) and extracted with CH2CI2. The organic layer was drived over magnesium sulfate, filtered and concentrated to dryness to afford the title compound (30) as a yellow solid, mp 122.7-123.4°C; MS 461 (MH^.












To a solution of the title compound (22) from Preparative Example 3, Step C (1.0 g, 2.03 mmole) in DMF (20 ml) was added imidazolylsodium (0.257 g, 2.85 mmole). Tfie reaction mixture was heated to 90°C for 2 h. Cooled the reaction and removed DMF. Added saturated sodium bicarbonate and extracted with CH2CI2. Dried organic layer over magnesium sulfate, filtered and concentrated to dryness. Crude product was purified by Biotage column chromatography eluting with 3% CH3OH: (saturated with ammonia)-CH2Cl2, to afford the title compound as an enantiomeric mixture. The mixture was separated into pure enantiomers on Prep HPLC Chiral AD column eluting with 35-40% Isopropanol-Hexane: 0.2% Diethyl amine, to give the title compounds (43) and (44). MS 497 (MH"^)





temperature over night. The solvents were removed and then the residue was diluted with ethyl acetate (250 ml) and washed with 1.0 M NaOH {5 x 50 ml) and then brine (50 ml). The organic layer was dried over Na2S04, filtered and concentrated. The crude product (45.28 g, 0.141 mole) was dissoved in ethanol (100 ml) and 5 M aqueous HCI (100 ml) and stirred for 12 h. at 60°C. The solvent was removed and the residue was dissolved in distilled H2O. 5M aqueous NaOH was added until pH=:8, then the mixture was extracted with ethyl acetate. Combined organic layers and washed with brine, dried over Na2S04, filtered and concentrated. Purified by flash chromatography eluting with 70% Hexanes;Acetone to afford the product as a white solid. The amine was further reacted with NaH (1 equivalent) in DMF for 1 h. affording the title compound (49).

Compound (27) from PREPARATIVE EXAMPLE 4, STEP E was reacted in the same manner as EXAMPLE 8, substituting 4-methy!-2-phenyIsu!fanyl-1H-imJdaizole sodium (49), affording the title compound (50) as a light yellow solid. MS 643 (MH"^).















Following the same procedure as described in EXAMPLE 18 above, substituting the (-) enatiomer of the starting amine from EXAMPLE 17, afforded the title compound (63) as a white solid. MS 545 (MH"").

To a solution of compound (23) from Preparative Example 4, Step A (6.51 g, 13.29 mM), dichlorobis(trlphenylphosphine) palladium(II) (Alrich) (0.373 g, .53 mM), and tetrabutylammonium chloride (Aldrich) (3.69 g, 13.29 mM) in DMF (50 ml) was added compound (64) from PREPARATIVB EXAMPLE 6, STEP A. The reaction

stirred over night at 75-80°C under nitrogen atmosphere. The reaction was cooled to room temperature, then a solution of KF (.93 g, 15.94 mM) in H20 (70 ml) was added. A precipitate formed upon addition. The reaction mixture was stirred for fifteen minutes then added CH2CI2 and stirred an additional fifteen minutes. The reaction mixture was extracted with CH2CI2, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by silica gel column chromatography eluting with 1:3% -1:1% ethyf acetate-hexanes affording the title compound (65) as a yellow solid, mp 86-90°C.

To a solution of compound (65) from Preparative Example 6, Step B (3.25 g, 6.76 mM) in THF/H20 (33.7 mI/7.3 ml), was added mercury (II) acetate. The reaction stirred at room temperature for fifteen minutes during which time a precipitate formed. To the mixture was then added saturated Kl solution (70-80 ml) and was stinred for five minutes. Added CH2CI2 and stirred for 1 h. The reaction was extracted with CH2CI2 (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (66) as a light brown solid. MS 453 (MH*).


To a solution of compound (66) from Preparative Example 6, Step C (3.06 g, 6.8 mM) in ethanol (40 ml) was added sodium borohydride (0.31 g, 8.1 mM) in two portions over seven minutes. The reaction stirred for 45 minutes was then concentrated, taken up in ethyl acetate and washed with brine. Re-extracted brine layer with additional ethyl acetate and then combined organic layers, dried over magnesium sulfate, filtered and concentrated to a solid. Further purification by silica gel column chromatography eluting with 1:1-5:1 ethyl acetate-hexane afforded the title compound (67) as a white solid. MP range 120-130°C; MS 455 (MH"").








Compound (68) from Preparative Example 6, Step E, was reacted in the same manner as described in Example 8, Step B, resulting in the title compound (70) as a white solid, mp 94-101 °C.

To compound (69) from Preparative Example 6, Step F (0.3 g, .05 mM) in CH3CN (1 ml) was added imidazole (Aldrich) (0.014 g, .2 mM). The reaction was heated to 52°C and stirred over night. The reaction was cooled, concentrated, then diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by silica gel column chromatography eluting with 0-5% methanol/ saturated with ammonia:CH2Cl2 to afford the title compound (71)as a white solid, mp 95-104°C; MS 505 (MH"").
























Compound (93A) from above was dissolved in DIViF: Successively added, EtsN (29 eq.), Ethyl acrylate (5.4 eq.), K2CO3 (5 eq.), Bu4NBr (2 eq.) and Palladuim (11) acetate (0.13 eq.). The mixture stirred and heated to 100°C for 4 h. After cooling, the mixture was concentrated and the residue was taken up in CH2CI2 and extracted with CH2CI2/H2O. The organic layer was dried over Na2S04 then concentrated and the residue purfied by flash silica column chromatography to afford the title connpound (94).


Compound (94) was dissolved in EtOH cooled in an ice bath and reacted witli NaBH4 (15 eq.) for 3 min. Then added CuCI (2 eq) and stirred for 2 h. at room temperature. The mixture was filtered, concentrated and extracted with CH2CI2. Washed with water then brine, dried over Na2S04 and concentrated to a mixture of the title compound (95) and the hydroxy compound (96).



Dissolved compound (96) in CH2CI2, added EtsN (3 eq.) followed by methane sulfonylchioride {1.5 eq.). The mixture stirred at room temperature over night then diluted with CHzCk and washed with NaaCOs. Dried over NaS04 and concentrated to afford the title compound (97).

To a solution of sodium imidazole (Aldrich) in DMF was added, NaH (2 eq.)-Stirred for 15 min. then added compound (97) (from above) (1 eq.) and stirred over night at room temperature. The reaction mixture was concentrated and then extracted with ethyl acetate. Washed with Na2C03, dried over NaSO*. filtered then concentrated.





























purified by flash chromatography using neat EtOAc then 5% MeOH in EtOAc as
eluent to give a pale yellow oil (184).
CIMS:MH^=137.

Pd(OAc)2 (0.023 g, 10 mol%) was added to a solution of the title connpound (184) from Preparative Example 11, Step C, (0.30 g, 2.0 eq.), compound (23)(0.50 g, 1.02 mmol). Bu4NBr (0.66 g, 2.0 eq.), TEA (2.84 mL, 20.eq.) and K2CO3 (0.70 g, 5.0 eq) in DMF(lb mL). The resulting solution was heated to 100 °C for 48 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (50 mL) and CHaCirCSO mQrieparated, and the aqueous layer extracted with CH2CI2 (2 X 25 mL). The combined organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography using an 8% MeOH in CH2CI2 solution as eluent to yield a 4 : 1 mixture of the compound (184) and coupled product (185). This mixture (0.27 g) was stirred in CH2CI2 : TFA (7.0 mL, 5 : 2) for 1.5 hours. The crude product was concentrated under reduced pressure, neutralized with NaOH (1N), and extracted with

CH2CI2 {3 X 20 mL). The combined organics were dried over Na2S04, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography using a 15% (10% NH4OH in IVleOH) solution in CH2CI2 as eluent to give the title compound (185) as a tan solid. LCMS: MH'= 445.

Methanesuifonyl chloride (0.005 mL, 1.3 eq) was added to a solution of Compound (185) from Preparative Example 11, Step D, (0.02 g, 0.045 mmol) and TEA (0.010 mL, 1.5 eq.) in CH2CI2 (1 mL). The resulting solution was stirred 12 hours at room temperature and diluted with saturated NaHCOa (5 mL). separated, and the aqueous layer extracted with CH2CI2 (3X10 mL). The combined organic layer was dried over Na2S04 and concentrated in vacuo. The crude product was purified by flash chronnatography using an 8% (10% NH4OH in MeOH) solution in CH2C12 as eluent to give the title compound (186) as a tan solid mp 124-129 °C; LCMS: MH-'^ 523.



Literature compound 1 H-imidazole-4rcarbaIdehydG was tritylated according to the literature procedure Keiley, et al.; J. Med. Ghem 20(5), (1977), 721 affording the title compound (188).

. nBuLi (2.00 mL, 2.2 eq; 1.7M in hexanes) was added dropwise to PhsPCHaBr (1.4 g, 2.3 eq) in THF (10 mL). The resulting orange solution was stirred 30 minutes at room temperature beiore cooling to -78 °C and adding the trityl protected 1 {3)H-imidazole-4-carbaldehyde (0.50 g, 1.48 mmol) in THF (7.0 mL). The resulting solution was warmed slowly to room temperature and stirred overnight. The reaction was quenched by the addition of water (20 mL) and extracted with CH2CI2 (3 X 20 mL). Th^ combined organics were dried over Na2S04 and concentrated in vacuo. The crude product was purified by flash chromatography using a 45% hexanes in EtOAc solution as eluent to yield the title compound (189) as a white solid.













deoxygenated 15 minutes before adding PdCl2(PPh3)2 (0.018g, 2.5 mol%) and Cul (0.002g, 1.0 mol%). The resulting solution was heated for 48 hours. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with CH2CI2. The combined organic layer was dried over Na2S04, filtered, and concentrated. The crude product was purified by flash chromatography using an 8% MeOH tn CH2CI2 solution as eluent. mp 109-112 °C; LCMS: 515 {MH"").

Compound (21) from Preparative Example 3, Step C, (2.83 g, 6.37 mmol) was dissolved in 120 ml of dichloromethane and 0.16 ml of de-ionized water. Dess-Martin periodinane (3.85 g, 9 mmol) was added as a solid at ambient temperature and the reaction mixture stirred for 4 hours. Then added a 20% Na2S203 solution (50 ml) and stirred for 15 minutes. The layers were separated and the dichloromethane layer washed with saturated NaHCOa, dried over magnesium sulfate, filtered and evaporated to obtain the title product (199). FABMS: 445 (MH^.



Compound (200) (0.6 gm) was dissolved in 10 ml of trifluoroacetic acid and stirred at ambient temperature.. After 7 hours tl^e reaction mixture was evaporated to dryness under vacuum and chromatographed on silica gel using 5% 2N methanol:ammonia/ dichioromethane to obtain title compound (201). FABMS; 514 . (MH^.

Compound (200) (0.5 g, 0.66 mmol) was dissolved in 5 ml of dichioromethane. Triethylamine (0.14 ml, 0.99 mmol) and.methanesulfonyl chloride (0.062 ml, 0.79 mmol) were added and the reaction mixture stirred for 18 hours. The reaction mixture was added to brine and extracted with dichioromethane three times. Dried over magnesium sulfate, filtered and concentrated to dryness under vacuum to give a residue which was chromatographed on silica gel using ethyl acetate as the eluent to obtain the title compound (202). FABMS: 537 (MH"").











Compound (211) (14 g, 29 mmol) prepared by NaOH hydrolysis of Compound (20) trom Preparative Example 3, Step B, was dissolved in 400 ml of DU^. ^ -{3-dimetfiylamino propyl)-3-etfiylcarbodiimide hydrochloride (8.3 g, 43 mmol), 1-hydroxybenzotriazole (5.9 g, 43 mmol), trietfiylamine (40 ml), and N.G-dimethylhydroxylamine hydrochloride( 3.8 g, 40 mmol) were added and the reaction mixture stirred at room temperature under a dry nitrogen atmosphere. After 24 hours the reaction mixture was poured into brine and the product extracted with ethylacetate two times. After drying over magnesium sulfate, filtration, and chromatography on silica gel using 10% ethyl acetate/hexanes the title compound (212) was obtained.

Compound (212) (0.53 g, 1.01 mmol) was treated as in PREPARATIVE Example 14, Step B to obtain the title compound (213) after silica gel chromatography.


Compound (213) (300 mg, 0.387 mmoi) was dissolved in methanol and sodium . borohydride (50 mg) was added portionwise while stirring. After 1 hour the mixture was added to 1N HCl Ibllowed by the addition ot 1 N NaOH and extracted with ethylacetate to obtain a crude product which was treated with neat trifluoroacetic acid for 5 hrs, and evaporated to dryness. The mixture was dissolved in methanol and reacted with di-tert.butyldicarbonate (0.2 gm) while maintaining the pH at 10 with 1N NaOH for 1 hour. The mixture was then treated with 2N Methanolic ammonia for 15 minutes followed by evaporation of the solvents and chromatography on silica gel. Further seperation of isomers was accomplished on a Chiral Technologies® AD HPLC column obtaining the pure isomers. (214) and (215). FABMS M+1=535



Compound (23) from Preparative Example 4, Step A (25.47 gm, 52 mmol) was dissolved in 300 ml of dry toluene and 39.5 ml of methanol. Palladium chloride (0.92 gm), triphenylphosphine (6.887 gm) and DBU (10.5 ml) were added and the reaction mixture transferred to a pressure reaction vessel. The reaction vessel was purged with carbon monoxide and then pressurized to 100 psi with carbon monoxide and the mixture stirred at 80 "C for 5 hours. The reaction was cooled in an ice bath and purged with nitrogen 3-4 times. The reaction mixture was transferred to a separatory funnel and 500 ml of ethylacetate was added. The mixture was washed with water three times, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum to give a dark brown gum. The gum was purified by column chromatography on silica gel using 12.5%-25% ethylacetate/hexanes to obtain 12.58 gm of pure title product (216) FABMS: 469 (MH^) and 9.16 gm of a mixture of two compounds.



Compound (65) from Preparative Example (6), Step B, was let stand for approximately two weeks at room temperature, after which time the pressence of some aldehyde was observed by NMR of the crude material. This material was then treated as in Preparative Example 6, Steps C and D to afford a mixture of Compounds (218) and (67). The crude mixture was separated on flash silica column chromatography eluting with 1:1 - 3:1 ethyl acetate;hexanes to afford pure Compound (218).
B. Preparation of Compound (219)

Compound (218) from Step A above, was combined with triethylamine (64.4 ml; .462 mmol) in CH2CI2 (4 ml) treated with methyl sulfonyl chloride (17.93 ml; .231 mmol) and let stir over night at room temperature. The reaction mixture was diluted with CH2CI2 (70 ml), quenched with brine (25 ml) and extracted. The organic layer was dried over MgS04, filtered and concentrated to give an off-white solid (219) (93 mg; 100%).







crude product was purified by flash silica column cfiromatography eluting with 2% (10% NH40H:MeOH)/CH2Cl2.

C. Product from Step B above (40.63 mg; 0.1896 mmol) was taken up in EtOH (2 ml) and CHgCIs (2 ml) and treated with 1M LiOH (.5 ml; .455 mmol). The reaction mixture was heated to 50°crand stirred for 5 hr. The reaction was cooled to room temperature treated with 1N HCI (.57 mi; .531 mmol) and stirred for 5 minutes. The resultant mixture was concentrated and dried under high vacuum for 4 days affording the title compound as a white solid. (223)

To a solution of Compound (221) from Preparative Example 20, Step D (51 mg; .126 mmol), 4-methylmorpholine (69.3 m!; .630 mmol), DEC (31.44 mg; .164 mmol), and HOBT (22.2 mg; .164 mmol) in DMF (2 ml) was added, 4-PyrJdylacetic Acid 1-N-Oxide (disclosed in US 5,719,148; 2/17/98). The reaction stirred for 3 hours at room

temperature. The reaction was diluted with CH2CI2 and washed two times with saturated aqueous NaHCOs. The organic layers were combined, concentrated and purified by preparative thin layer chromatography eluting with 95:5 CH2CI2: sat. MeOH/NHs affording the title compound as a white solid (224).

Compound (221) from Preparative Example 20, Step D (51 nng; .126 mmol) was combined with compound (223) from Preparative Example 21, Step C and reacted in the same manner as Example 84 to afford the title compound as a white solid. (145-155°C_dec.) MH^ 573.(225)









SOCI2 (1.8 ml; 24.6 mmol) was added and the reaction was allowed to stir and come to roon:i temperature over 3 hr. The reaction mixture was poured into 0,5 N NaOH (80 ml) extracted and concentrated In vacuo. The crude product was taken up in CH3CN and treated with 1,2,2,6,6-Pentamethylpiperidine (4.45 ml; 24.6 mmol) (Aldrich). The reaction was heated to 60-65°C treated with tert-butyl 1-piperazinecarboxyiate (2.32 g; 12 mmol) (Aldrich) and stirred over night under N2 atmosphere. The reaction mixture was concentrated to dryness, redissolved in CH2CI2 and washed with sat. aqueous NaCOs- The organic layer was dried over Na2S04, filtered and purified by flash silica gel column chromatography eluting with 1 ^A'^ -.2 EtOAc/Hexanes to alford the product as a white solid.

The BOC-protected bromo-compound (236) from Step D above (2 g; 4 mmol), triphenyl phosphine (.54 g; 2 mmol), and paHadium chloride (.0723 g; .4 mmol) were combined in MeOH (10 ml) and toluene (30 ml). To this mixture was added DBU (.835 ml; 5.5 mmol) and the mixture was sealed in a Parr bomb. The reaction mixture was stirred and subjected to 90 psi of CO at 80°C for 5 hr. The reaction was diluted with EtOAc (200 ml) and washed with 2 x 80 ml H2O. The organic layer was dried over MgS04, filtered and purified by flash silica column chromatography eluting with 1:3 EtOAc/Hexanes.



stirred over night at room temperature. The mixture was concentrated to dryness and used directly in the next step.

The alcohol {""^9) from Step G above was taken up in MeOH (50 ml) and H2O (5 mi) and treated v^^ . Boo anhydride (1.56 g; 7.14 mmol). The pH was adjusted to approximately 10 with 1N NaOH. The reaction mixture was concentrated, taken up In CH2CI2 and washed with H2O (2 x) The organic layer was dried over MgS04,.filtered and concentrated to a tan solid containing both product and an impurity.
Alternatively, compound (237) was converted to compound (240) by first preparing the acyl imidazole followed by NaBH4 reduction using the foKowing procedure:
Compound (237) from Step E above (7.0 mmol) was dissolved in a mixture of 15 mL methanol, 60 mL dioxane and 6 mL water containing 25 mL of 10% aqueous LiOH. The mixture was heated at 60° C for 4 hr, then it was concentrated under vacuum and the pH adjusted to 5.2 with 10% aqueous citric acid. The residue was dissolved in CH2CI2, washed with brine, dried over MgS04 and concentrated under vacuum to give the cartDoxylic acid. The acid was then dissolved in 20 mL THF containing 14 mmoi of 1,1'-carbonyl diimidazole and heated at 38° C for 18 hr. The mixture was then concentrated under vacuum to give the acyl imidazole. The residue was dissolved in a mixture of 21.2 mL of THF and 5.3 mL water and cooled to 0' C.

To the solution was added 35 mmol of NaBH4 and it was stirred for 1.5 hr. 5 mL brine and 25 mL CH2CI2 was then added The organic layer was dried over MgS04 and concentrated under vacuum to give compound (240) in essentially a quantitative yield.

■I The crude product (240) from Step H above (200 mg; 0.45 mmol) was taken up
in CH2CI2 (2 ml) and treated with triethyl amine (126 ml; 0.91 mmol) followed by
methanesulfonyl chloride (35 ml; 0.45 mmol). The reaction stirred over night at room
temperature. The mixture was diluted with CH2CI2 and quenched with sat. aqueous
NaCI. The organic layer was dried over MgS04, filtered and concentrated to afford
compound (241).
EXAMPLE 91 Preparation of Compound (242)



1 ID
mrr\o\) were combined in EtOH (42 ml) and stirred for 5 minutes. To the turbid mixture was added the dry NaCN (1.23 g; 25.1 mmol). An exothermic reaction was observed and after 5 minutes TLC showed consumption of starting material. The reaction was transferred to a sealed tube and used directly in the next experiment.

B. The crude product (243) from Step A above (25 mmol), was diluted up to 65 ml total volume with EtOH. To this mixture was added 7N NH3 in MeOH (100 ml) and the reaction was heated to 90°C over night (20 hr). The reaction was allowed to coo! to room temperature and stirred for 2 hr then concentrated to dryness. The crude product was purified by flash silica column chromatoghraphy eluting with a gradient of 1-5% MeOH(sat. NH3)/CH2Cl2 (244).

Propionaldehyde (1.5 g; 25.11 mmol) (ACROS) and tosylmethyl isocyanide (5 g; 25.6 mmol) were reacted in the same manner as Preparative Example 24 above to afford the title compound (245).






















1 N-Ben2yl-3(R) -hydroxy -pyrrolidines (5g, 28.21 mmol) and triethylamine (7.86 mL, 56.35 mmol) were dissolved in CH2CI2 (50 mL) and the mixture was stirred under nitrogen at 0°C . Methanesutfonylchloride (2.62 mU 33.87 mmol) was added and the solution was stirred at room temperature for 2 h. The solution was diluted with CH2CI2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSOfl), filtered and evaporated to dryness to give the (R) title compound (7.2g, 96.4 %). FABMS (M+1) = 256; ^HNMR (CDCI3) 2.2 (m, 1H). 2.3 (m, 1H), 2.52 (m, 1H), 2.7-2.85 (m, 3H), 2.95 (s, 3H), 3.65 (q, 2H), 5.16 (m, 1H), 7.3 (s, 5H).
In a similar way the (S) isomer was prepared from 1N-Ben2yI-3(S)-hydroxy-pyrrolidines (5g, 28.21 mmoles) to give the (S) title compound (7.15g, 98%).















over Na2S04, filtered, and concentrated to dryness to give a crude brown oil (15.5 g). To a solution of this crude oil (15.5 g) in acetonitrrle (200 ml) was added 2,6-Bis (dirr»ethyl)-1-methyl piperidine (10.81 g, 69.66 mmol) and N-Boc piperidine (6.49 g, 34.83 nnmof). The resulting mixture was warmed to 65 °C overnight. The mixture was evaporated to dryness, followed by extraction with CHaCla/saturated NaHCOs. The combined organic layer was dried over Na2S04, concentrated and purified by column chromatography on silica gel, eluting with 5% EtOAc/95% Hexane to give the protected N-Boc compound (281) (5.68 g, 36% yield, MH'=455).

To a solution of the N-Boc compound (281) from Step D (4.0 g, 8.78 mmol) in anhydrous toluene (100 ml) and methanol (20 ml) was added triphenylphosphine (1.15 g, 4.39 mmol), DBU (1.81 g, 11.9 mmol) and palladium (II) chloride (0.15 g. 0.88 mmol). The resulting mixture was purged with carbon oxide at 80 psi to 100 psi and heated to 78 ^C-82 ^C for 5 hours, followed by stirring at room temperature for overnight. The solution was then extracted with EtOAc. The combined organic layer was washed with water, brine, dried over Na2S04, filtered, evaporated and the crude product was purified by column chromatography on silica gel, eluting with 10% EtOAc/ 90% Hexane to give the ester compound (282) (2.1 g, 55% yield, MH'^=435):
\^3



filtered and concentrated to dryness to give the mesylate connpound (284) (0.53 g, 76% yield, M-CHaSOaH^SSQ.I).

To a stirred solution of 1 -methyl-imidazoie (1.04 g, 12.7 mmol) in DMF (10 ml) under nitrogen, was added NaH (0.305 g, 12.7mmol). The resulting solution was stirred at room temperature for 15 minutes, followed by the addition of the mesylate compound (284) from step G (2.05 g, 4.23 mmol). The reaction mixture was stirred at room temperature overnight, then evaporated to dryness, and extracted with an EtOAc-NaHCOa solution. The combined organic layer was dried over NagSOA, concentrated and the crude product purified by silica gel column chromatography


A solution of the product (285) from step H {0.3 g, 0.64 mmol) in 4M HCI in
dioxane (40 ml) was stirred at room temperature for 3 hours and then concentrated to
dryness to give the hydrochloride salt of the title product (286) (0.42 g, 100% yield,
MH^=371).
EXAMPLES 114 AND 115 Compounds (287) AND (288).
The racemic mixture of Preparative Example 33, Step H above was seperated into its pure isomers by HPLC, using a Chiral AD column eluting with 15% IPA/75% Hexane/0.2% DEA to afford the compounds in the table below:

EXAMPLES 116-119.
Starting with the piperazine compound (286) from Preparative Example 33 Step
I, and reacting it with the appropriate isocyanate or sulfonyl chloride, following
essentially the same procedure as indicated in the table below, the following
compounds were prepared: - - — - ~ ~ -






To a stirred solution of Corripound (293) from Step B above (42.9 g, 116.5 mmol) in toluene (400 mL) under nitrogen was added triethylamine (49 mL, 349.5 mniol). The resulting solution was heated to retux, followed by the dropwise addition of ethyl chloroformate (126 g, 1165 mmol). Continued to heat the solution at the reflux temperature for 2 hours. The reaction was then stirred at room temperature overnight, followed by extraction with an EtOAc-IN NaOH solution. The combined organic layer was dried over MgS04, filtered, concentrated to dryness and the crude product purified by column chromatography on normal phase silica gel, eluting with 30% EtOAc/70% Hexane to give a light yellow solid (294) (2.99 g, 12% yield, MH-'=426.3).
(
- - (
A solution of the ester (294) from step C above (3.34 g, 7.83 mmol) in 6N HCi
(20 mL) was heated to reflux overnight. The reaction was cooled to room temperature
and basified with NH4OH solution, followed by extraction with CH2CI2. The combined
organic layer was dried over MgS04, filtered, and evaporated to dryness to give a
crude free piperidine (2.80 g, 100% yield, MH"^=534)
To the crude" material (as obtained above) (2.77 g, 7.82 mmol) in 50%.
MeOH/1% H2O (200 mL) was added Di-tert-butyl dicarbonate (3.41 g, 15.64 mmol).
The reaction mixture was adjusted to pH=9 and stirred at room temperature for 4
hours, evaporated to dryness then extracted with CH2CI2-H2O. The combined organic
layer was dried over MgS04, filtered, concentrated to dryness and purified by HPLC,
using chiral AD column, eluting with 15%> IPA/75%. Hexane/0.2% DEA to give the pure
isomers of the N-Boc compounds (295a) and (295b) (3.42 g, 96% yield, MH-"=454).



To a stirred solution of the (+) or (-) isomer of the ester from Step E above, (1.2 g, 2.77 mmol) in THF (15 mL) at 0 °C was added 1M solution of DIBAL (16.62 mL, 16.62 mmoi). The resulting solution was stirred at room temperature for 4 hours. To the solution was then added 10% potential sodium tartarate, followed by extraction with EtOAc. The combined organic layer was dried over Na2S04, filtered, and

To a stirred solution of 1-methyl-imidazole (1.04 g, 12.7 mmol) in DMF (10 mL) under nitrogen, was added NaH (0.305 g, 12.7 mmol). The resulting solution was

stirred at room temperature for 15 minutes, followed by \he addition of the (+) or (-) isomer of the mesylate compound (299) from Step G above (2.05 g, 4.23 mmol). The reaction mixture was stirred at room temperature overnight then evaporated to dryness, followed by extraction with an EtOAc-NaHCOa solution. The combined organic layer was dried over Na2S04, concentrated and the crude product was purified by silica gel column chromatography, eluting with 2% MeOH/98% NH3-CH2Ci2 to give the product {299a) or {299b) (0.775 g, 39% yield, MH^=471).

A solution of the (+) or (-) isomer of the product from Step I above (0.3 g, 0.64 mmol) in 4M HCI in dioxane (40 mL) was stirred at room temperature for 3 hours and then concentrated to dryness to give the HCI salt of the product (300a) or (300b) (0.42 g, 100% yield, MH-'=371).
EXAMPLES 120 AND 121
Starting with the appropriate (+) or (-) isomer of Compound (300) and reacting in a similiar manner as in Example 13 using the appropriate isocyanate, the following compounds were prepared:



minutes, followed by the addition of tributyl (vinyl) tin (0.39 g, 1.24 mmol). The reaction was then heated to 85°C for 2 hours, followed by extraction with EtOAc-H20. The combined organiclayer was dried over MgS04, filtered, concentrated to dryness and purified by.column chromatography on normal phase silica gel, eluted with 10% EtOAc/90% CH2CI2 to give a light yellow liquid (303a) (0.06 g, 15% yield, MH'^=390).

To a stirred solution of 1- methyl imidazole (0.377 g, 4.6 mmol) in anhydrous THF (4mL) under nitrogen at -78°C, was added 2.5M n-BuLi/Hexane (0.33 mL). The resulting solution was stirred at-78°C for 30 minutes and then allowed to warm at room temperature. To this stirred solution was added the alkene compound (303a) from step A above,(0.78 g, 2.1 mmol) in THF. The resulting solution was then heated to 120°C overnight then cooled to room temperature, and extracted with EtOAc-H20. The combined organic layer was dried over MgS04, filtered, evaporated and purified by column chromatography on normal phase silica gel, eluted with 3% MeOH/97% NH3-CH2C(2 to give a light yellow solid (304a) (0.09 g, 10% yield, MH'=456.1).









Documents:

315-chenp-2003 abstract.pdf

315-chenp-2003 assignment.pdf

315-chenp-2003 claims.pdf

315-chenp-2003 correspondence others.pdf

315-chenp-2003 correspondence po.pdf

315-chenp-2003 description (complete)-1.pdf

315-chenp-2003 description (complete)-2.pdf

315-chenp-2003 description (complete)-3.pdf

315-chenp-2003 description (complete)-4.pdf

315-chenp-2003 description (complete)-5.pdf

315-chenp-2003 description (complete)-6.pdf

315-chenp-2003 description (complete).pdf

315-chenp-2003 form-1.pdf

315-chenp-2003 form-19.pdf

315-chenp-2003 form-26.pdf

315-chenp-2003 form-3.pdf

315-chenp-2003 form-5.pdf

315-chenp-2003 form-6.pdf

315-chenp-2003 petition.pdf


Patent Number 243167
Indian Patent Application Number 315/CHENP/2003
PG Journal Number 40/2010
Publication Date 01-Oct-2010
Grant Date 28-Sep-2010
Date of Filing 25-Feb-2003
Name of Patentee SCHERING CORPORATION
Applicant Address PATENT DEPARTMENT K-6-1 1990, 2000 GALLOPING HILL ROAD, KENILWORTH, NEW JERSEY 07033-0530
Inventors:
# Inventor's Name Inventor's Address
1 NJOROGE, F.GEORGE 11 SOFTWOOD WAY, WARREN, NJ 07059
2 GIRIJAVALLABHAN, VIYYOOR, MOOPIL, 10 MAPLEWOOD DRIVE, PARSIPPANY,NJ 07054
3 VIBULBHAN,BANCHA, 201 NORTH 24TH STREET, KENILWORTH NJ 07033
4 PINTO,PATRICK, A,., 34 BATTLE RIDGE ROAD,MORRIS PLAINS, NJ 07950
5 SANTHANAM, BAMA, 10 SOMERSET AVENUE, BRIDGEWATER, NJ 08807,
6 COOPER, ALAN, B. 23 NATALIE DRIVE, WEST CALDWELL, NJ07066
7 GUZI, TIMOTHY,J., 48 RED ROAD, CHATHAM, NJ 07928
8 RANE, DINANATH, F.. 2 HAYGROUND COURT, MORGANVILLE,NJ 07751
9 MINOR, KEITH, P., 7916 GLENWAY DRIVE, DALLAS, TEXAS 75259
10 DOLL, RONALD, J., 8 CONCORD LANE, CONVENT STATION, NJ 07960
11 ZHU, HUGH, Y., 38, COUNTRY CLUB BOULEVARD, SCOTCH PLAINS, NJ 07076
12 KEERTIKAR, KARTIK,M., 24 COLUMBIA AVENUE, EAST WINDSOR, NJ08520
13 ALVAREZ, CARMEN,S. 121 WALNUT STREET, LIVINGSTON, NJ 07039
14 BALDWIN, JOHN,J.. 621 GYPSY HILL CIRCLE, GWYNEDD VALLEY, PA 19437
15 LI,GE, BUILDING 7, ROOM 201, #815, LUJIAZUI GARDEN, 20135 SHANGHAI
16 HUANG, CHIA-YU, 52 ASHFORD DRIVE, PLAINSBORO,NJ 08536
17 JAMES,RAY, ANTHONY, 3263 STERLING PLACE, BENSALEM, PA 19024
18 BISHOP, WALTER, ROBERT, 17 HOPPER AVENUE, POMPTON PLAIN, 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/US01/26792
PCT International Filing date 2001-08-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/229,183 2000-08-30 U.S.A.