OA11820A - Functionalized heterocycles as chemokine receptor modulators. - Google Patents

Abstract

The present invention is a novel series of functionalized heterocycles as chemokine receptor modulators of Formula (I) useful as modulators of chemokine receptor activity. The compounds are useful in the treatment and prevention of the AIDS virus. Intermediates useful in the prepartion of the final products, pharmaceutical compositions containing the final products are also taught.

Description

-1- 11820

BACKGROUND OF THE INVENTION

The présent invention relates to fiinctionalized heterocycles useful asmodulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A,CCR-2B, CCR-3, CCR-4, CCR-5, CXCR1, CXCR2, CXCR-3, and/or CXCR4and to pharmaceutical compositions which include these compounds and apharmaceutically acceptable carrier. More particularly, the présent invention isdirected to methods for inhibiting HIV infectivity.

Chemokines médiate a range of proinflammatory effects on leukocytes,such as chemotaxis, degranulation, and intigran activation (Baggiolini et al., Adv.Immunol., 1994;55:97-179; Oppenheim et al., Annu. Rev. Immunol., 1991;9:617-48; Miller et al., Crit. Rev. Immunol., 1992;12:17-46). These effects aremediated by binding to the seven-transmembrane-sparming G-protein coupledreceptors (Baggiolini et al., Adv. Immunol., 1994;55:97-179; Murphy, Annu. Rev.Immunol., 1994;12:593-633; Schall et al., Curr. Opin. Immunol., 1994;6:865-73;Gérard et al., Curr. Opin. Immunol., 1994;6; 140-5; Mackay, Curr. Bio., In press).Chemokine receptors also serve as coreceptors for HIV-1 entry into ce!Is. Thiscame from observations that RANTES, ΜΙΡ-Ια, and MIP-Ιβ suppressed infectionof susceptible cells in vitro by macrophage-tropic primary HIV-1 isolâtes(Cocchi et al., Science (Wash. DC), 1995;270; 1811-5). The chemokine receptorCXCR-4 was found to support infection and cell fusion of CD4+ cells bylaboratory-adapted, T-tropic HIV-1 strains (Feng et al., Science (Wash. DC),1996;272:872-7). CCR-5, a RANTES, MIP-lcc, and MIP-Ιβ receptor, wassubsequently identified as the principle coreceptor for primary macrophage-tropicstrains (Choe et al., Cell, 1996;85:1135-48; Alkhatib et al., Science (Wash. DC),1996;272:1955-8; Doranz et al., Cell, 1996;85:1149-58; Deng et al., Nature(Lond.) 1996;381:661-6; Dragic et al., Nature (Lond.), 1996;381:667-3). Theimportance of CCR-5 for HIV-1 transmission was underscored by the observationthat certain individuals who had been repeatedly exposed to HIV-1 but remained 118 2 0 -2- uninfected had a defect in CCR-5 expression (Liu et al., Cell, 1996; 86:367-77;Samson et al., Nature (Lond.), 1996;382:722-5; Dean et al., Science (Wash. DC),1996;273:1856-62; Huang et al., Nature Med., 1996;2:1240-3). Thesenoninfectable individuals were found to be homozygous for a defective CCR-5 5 allele that contains an internai 32-base pair délétion (CCR-5 Δ32). The truncatedprotein encoded by this gene is apparently not expressed at the cell surface.CCR-5 Δ32 homozygous individuals comprise -1% of the Caucasian populationand heterozygous individuals comprise -20%. In studies of about 2700 HIV-1infected individuals, no Δ32 homozygotes were found. Individuals who are 10 heterozygous for Δ32 CCR-5 allele hâve been shown to progress more slowly toAIDS than wild-type homozygous individuals (Samson et al., Nature (Lond.),1996;382:722-5; Dean et al., Science (Wash. DC), 1996;273:1856-62;

Huang et al., Nature Med., 1996;2:1240-3). Thus, the identity of CCR-5 as theprinciple coreceptor for primary HIV isolâtes provides an opportunity to 15 understand disease pathogenesis, and more importantly to identify a new avenue for the treatment of HIV-1 infection.

The instant invention is a sériés of functionalized heterocycles that blockthe CD-4/GP-120 interaction with CCR-5 receptor, and thus can be useful in thetreatment of HIV infection manifested in AIDS.

20 SUMMARY OF THE INVENTION

The compounds of the invention are useful in a method of modulatingchemokine receptor activity in a patient in need of such modulation comprisingthe administration of an effective amount of the compound.

The présent invention is directed to the use of the foregoing substituted25 heterocycles as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, includingCCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR1,CXCR2, and/or CXCR-4. In particular, the compounds of the présent inventionare preferred as modulators of the chemokine receptor CCR-5. 11820 -3-

The compounds of the instant invention are those of Formula I which mayexist in both closed and open form.

or a pharmaceutically acceptable sait thereof wherein: A is O, S, and additionally A is NRj when X is C-R9; X is N when A is NRj or X is C-R9 wherein R9 is halogen, hydrogen, alkyl, -CF3, CHoF, CHF2,-(CH2)m’0Rb ary!’ arylalkyl, -(CH2)nrNR7R8> or (CH2)q

wherein ni is an integer of from 0 to 2 and 10 15 each occurrence of m is independently an integer of from 0 to 2,q is an integer of from 0 to 1, and r is an integer of from 0 to 3; Y is hydrogen, alkyl, arylalkyl, aryl, (CF^m-NR^Rs» "N(Ri)-(CH2)v-C(R7Rg)-aryl, or ORjq wherein Rjq is hydrogen, alkyl,cycloalkyl, cycloalkyl fused to an aryl ring, aryl, (CH2)saryl,-CH2CF3, (CH2)tC(R7R8)-(CH2)uaryl,

O R\/<CH2)mC-OR7 ,V^Aiyl

Aryl ^/^2)-^8

Aryl \/CH2)-C--NR7R8 118 2 0

Ri

Ri

Ri

Ri -4- Ο .(CH2) —NR7Rg R\/CH2>irC-OR7 Valkyl alkyl . i? <CH2>ÎTC_NR7R8 t alkyl R " R1 (CH2)-C-OR7 cycloalkyl ,(CH2)—nr7R8 cycloalkyl 0 II (CH2VÇ—NR7R8 cycloalkyl X V^CC13 ’ V C=N, ch3 >θΓ

wherein s is an integer of from 10 15 an integer of from 0 to 3, u is an integer of from 0 to 3, v is aninteger of from 1 to 3, and w is an integer of from 0 to 2; Z is CR or N;

Ri is hydrogen or alkyl and each occurrence of Rj is independentlyhydrogen or alkyl; R and R2 are each independently selected from:hydrogen,alkyl,halogen, -CN, -NO2, -(CH2)m-NR7R8,

118 2 0 -5- -(CH2)m-COOR7, -(CH2)m-CONR7Rg, (ch2)-n

r7 ’ -(CH2)mN-S-R7, -(CH2)m-OR7,-(CH2)m-SO2NR7Rg, and -(CH2)m-S(O)pR7 wherein each occurrence of R7 and Rg are eachindependently hydrogen, alkyl, aryl, arylalkyl, -CF3, or R7and Rg may be taken together to form a cyclic ring of from3 to 7 atoms which ring may hâve O, S, or NRj and p is aninteger of from 0 to 2; R3 is hydrogen or alkyl; R4 is hydrogen, alkyl, aryl, or aralkyl; R5 is alkyl, aryl, arylalkyl, acyl; or R4 and R5 are taken together with the atoms to which they are attached toform a cyclic ring of from 5 to 7 atoms;

Rg is hydrogen or alkyl; R5 when not taken together with R4 can be taken together with Rg withthe atoms to which they are attached to form a ring of from 5 to7 atoms; N-R5 is also the corresponding N-oxide;

Rl 1 is hydrogen or alkyl; n is an integer of from 1 to 3; j is an integer of from 1 to 2, and j is the integer 0 when Y is hydrogen,alkyl, arylalkyl, or aryl; -6- 11820 with the proviso that pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester is not included.

Preferred compounds are those of Formula 1 above wherein 5 R] is hydrogen.

Other preferred compounds are those of Formula 1 above whereinRj is hydrogen andX is C-Rç.

Still other preferred compounds are those wherein10 Rj is hydrogen and X is C-R9, wherein R9 is alkyl.

Still other preferred compounds are those whereinRj is hydrogen, X is C-R9, wherein R9 is alkyl; 15 R4 and R 5 are taken together with the atoms to which they are attached to form a ring of from 5-7 atoms; and Y is ORjo-

Still other preferred compounds are those whereinRj is hydrogen, 20 X is C-R9, wherein R9 is alkyl; R4 and R5 are taken together to form a 6-membered ring; and Y is OR10 wherein Riq is alkyl, aryl or -(CH2)saryl,-(CH2)t-C(R7R8)-(CH2)u-aryl.

Still other preferred compounds are those wherein25 Rl is hydrogen, X is C-R9, wherein R9 is Me; R4 and R5 are taken together to form a 6-membered ring; R5 is hydrogen;n is 2; and 118 2 0 -7- Y is ORjo wherein Rjo is alkyl, aryl or Rjq is -(CH2)t-C(R7Rg)-(CH2)u-aryl wherein t is 0, R7 and Rg can eachindependently be H, alkyl, -(CH2)vOH or (CH2)uCOOR7, and -(CH2)vNRiR2where u and v are as defined above.

More preferred compounds are those of Formula 1 and selected from:Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, methyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-bromo-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, propyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methylpropyl ester,

Pyrrolo[3 ’,2 ’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2-dimethylpropyl ester;Pyrrolo[3’,2’:5,6][l ]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenylmethyl ester;

Pyrrolo[3 ’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinoIizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methylethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, cyclopropylmethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-( 1 -piperidinyl)ethyl ester;Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(phenylmethyl)-, ethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-ijquinolizine-l-carboxylic acid, 2- ethyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester,

Pyrrolo[3’,2’:5,6][13benzopyrano[3,2-ijquinolizine-l -carboxylic acid, 2- cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester; 118 2 0 -8-

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,l0,12,13,14,14a,15-decahydro-2-propyl-, ethyl ester;

Pyrrolo[3 ’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(2-methylpropyl)-, ethyl ester; 5 Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1-dimethylethyl ester; 2,6a,7-Trimethyl-7,8,9,10,10a,ll-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester; 7-Ethyl-2,6a-dimethyl-7,8,9,10,1 Oa, 11 -hexahydro-3H,6aH-6-oxa- 10 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester; 6a-Ethyl-2,7-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester; 6a,7-Diethyl-2-methyl-7,8,9,10,1 Oa, 11 -hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester; 15 7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,l 1-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester; 2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,ll-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester;

Pyrrolo[3’,2’.-5,6][l]benzopyrano[3,2-e]indole-l-carboxylic acid, 20 8,9,1 l,12,I3,13a,14,14a-octahydro-2-methyI-, ethyl ester; 3H,7H-Pyrrolizino[r,8':5,6]pyrano[3,2-e]indole-l-acetic acid, 8,9,11,12,12a,13-hexahydro-2-methyl-, ethyl ester; 2-Methyl-8,9,10,1 Oa, 11,12,12a, 13-octahydro-3H,6aH,7H-6-oxa-3,6b- diaza-benzo[a]cyclopenta[h]anthracene-l-carboxylic acid ethyl ester; 25 3H-Pyrido[l",2":l'2']azepino[3'2':5,6]pyrano[3,2-e]indole-l-acetic acid, 7,8,9,10,12,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester or7H-Azepino[l",2":I'2']pyrido[3',2':5,6]pyrano[3,2-e]indole-l-acetic acid,3,8,9,10,ll,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester;

Pyrrolo[3’,2’:5,6][1 ]benzopyrano[3,2-i]quinolizine-l-carboxamide, 30 8,9,1 l,12,13,13a,14,14a-octahydro-2-methyl-N-(phenylmethyl)-;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxamide, N- ethyl-8,9,11,12,13,13 a, 14,14a-octahydro-2-methyl-; 118 2 0 -9-

Pymolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxaldehyde, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxamide,8,9,11,12,13,13a, 14,14a-octahydro-N,2-dimethyl-;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 8,9,11,12,13,13a,14,14a-octahydro-2-methyI-, (4-fluorophenyI)-methyl ester;

Indazolo[4',5':5,6]pyrano[3,2-zjquinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyI-, ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12,12-trimethyl-, phenylmethy 1 ester,

Pyrrolo^'^'^.ôjtljbenzopyranop^-ijquinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10,10-trimethyl-, phenyl methy I ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5-fIuoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester;

Pyrrolop'^'^ôJpjbenzopyranol^-iJquinoIizÎne-l-carboxylic acid,5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenylmethyl ester; 12H-Furo[3',2':5,63[l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5-fiuoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester,

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4.5- difluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenylmethyl ester;

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4.5- dichloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenylmethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyI-, phenylmethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, phenylmethyl ester;

Pyrrolo[3 ',2' : 5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4-dimethyl-, phenylmethyl ester; 118 2 0 -10-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4-dimethyl-, 1 -(4-fluorophenyl)ethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-(methoxycarbonyl)phenyl]ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(3-carboxyphenyl)ethyl ester; 1-Propanaminium, Ν,Ν,Ν-trimethyl-, sait with l-(3-carboxyphenyl)ethyl3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-pyrrolo[3',2':5,6] [ 1 ]-benzopyrano[3,2-i]quinolizine-l-carboxylate (1:1);

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl)methyI ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(3-cyanophenyl)ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)carbonyl]phenyl]ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-Î]quinoIizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)methyl]-phenyljethyl ester;

Pyrrolo[3 ’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-,2-phenylethyl ester;

Pyrrolo[3 ’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl)phenyl]-methyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,-methyl-, (4-carboxyphenyl)methyl ester; l-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-lH-indol-4-ylmethyl]-l,2,3,4,6,7,8,9-octahydro-quinolizinylium; chloride;

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]-methyl ester; 118 2 0 -11-

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthalenyîmethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]-methyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]-methyl ester;

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-carboxyphenyl)methyl ester);

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (3-carboxypheny)-methyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3’,2’:5,6][l]-benzopyrano[3,2-i]quinolizine-l -carboxylate (1:1);

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, [3-[(dimethylamino)methyl]-phenyljnrethyl ester;

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]-phenyl]methyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl)ethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[ 1,1 ’-biphenyl]-4-ylethylester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (2,6-difluorophenyl)methylester;

Pyrrolo[3’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 -phenyl-2,2,2-trifluoro)ethy 1ester;

Pyrrolo[3 ’,2’ :5,6][1 ]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-[3-(trifluoromethyl)phenyl]-ethyl ester; 11820 -12-

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-( 1 -pyrrolidinyl)ethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -( 1 -naphthalenyl)ethyl ester;

Pyrrolo[3 ’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcyclobutyl ester;

Pyrrolo[3’,2’ :5,6][ 1 ]benzopyrano[3,2-i] quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcylopropyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -pyrazinylethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-quinolinyl)ethyl ester;

Pyrrolo[3’,2’:5,6] [l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-pyrimidinyl)ethyl ester;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5-chloro-3,7,8,9,10,12,13,l4,14a,15-decahydro-2-methyî-, phenylmethyl ester;

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, 1 -(4-fluorophenyl)ethylester;

Quinolizinium, l-[[(4-fluorophenyl)methoxy]carbonyI]-5-hydroxy- 2- methyl-lH-indol-4-yl]methyl]-l,2,3,4,6,7,8,9-octahydro-, chloride;

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-1,2-dimethyl-, (4-fluorophenyl)methylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]qumolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylpropyl ester;

Quinolizinium, 1,2,3,4,6,7,8,9-octahydro-l -[[5-hydroxy-2-methyl- 3- [(phenylmethoxy)carbonyl]-lH-indol-4-yl]methyl]-, chloride;

PynOlo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-nitrophenyl)methyI ester; 118 2 0 -13-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,! 5-decahydro-2-methyl-, ( 1 R)-1 -phenylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)ethyl ester; 5 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester;

Pyrrolo[3',2':5,63[l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro-1 -phenyl-1 -(trifluoromethyl)ethyl ester; 10 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, bicyclo[2.2.1 ]hept-2-yl ester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fl uorophenyl)- 1- methylethyl ester; 15 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2rmethyl-, 1 -pbenylcyclopentyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcyclohexyl ester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-hydroxyphenyI)methyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -(4-pyridinyl)ethyl ester; 25 Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [ô-(methoxycarbonyl)- 2- pyridinyl]methyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-pyridinylmethyl ester; 30 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (6-carboxy-2-pyridinyl)methyl ester; 118 2 0 -14-

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (6-carboxy- 2- pyridinyI)methyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2- methylpyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylate (1:1);

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [5-(methoxycarbonyl)- 3- pyridinyl]methyl ester;

Pyrrolo[3',2':5,6][l ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-carboxy-3-pyridinyl)methylester;

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (5-carboxy- 3-pyridinyl)methyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylate (1:1);

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4'-methyl[ 1,1 ’-biphenyl]- 3-yl)ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-dimethylphenyl)ethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S,2R)-2-(dimethylamino)-1 -phenylpropyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR,2S)-2-(dimethylamino)-1 -phenylpropyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -naphthalenyl ester;

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, diphenylmethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-2,3-dihydro-lH-inden-l-yl ester; -15-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-dihydro-l -acenaphthylenylester;.

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxyIÎc acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclohexyl(phenyl)methyl ester;

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxyIic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 9H-fluoren-9-yl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydro- 10 1-naphthalenyI ester;

Pyrrolo[3',2':5,6][i]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [(2R,3R)- 3-phenyloxiranyl]methyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-oxo-l,2-diphenylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-methylphenyî)phenylmethyl ester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxyîic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,cyclopropyl(4-fluorophenyl)methyl ester; 25 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i3quinoiizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3,4-dihydro-2H- 1 -benzothiopyran-4-yl ester;

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15 -decahydro-2-methyI-, ( 1 S)-1 -(2-bromophenyl)ethyl 30 ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoroethyl ester, 11820 -16-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2S,3S)- 3-phenyloxiranyl]methyI ester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro-1 -methyl- l-(trifluoromethyl)ethyl ester;

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro-1 -(4-fluorophenyl)-l -(trifluoromethyl)ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-cyclopentyl-l-phenylethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[ 1,1 '-biphenyl]-4-yl-1 -methylethyl ester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methyl-1 -phenyl-2-propynylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -diphenylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methyl-1,2-diphenylethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclohexylester;

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-diphenylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-phenyl-2-propynyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [l,l'-biphenyl]-4-ylmethyl ester; 118 2 0 -17-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester;

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydro- 7,8-dimethoxy-2-methyl-4-isoquinolinyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-(dimethylamino)phenyl]-ethyl ester;

Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -dimethyl-2-pyrazinylethylester;

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-(dipropylamino)- l,l-dimethyl-2-butynyl ester;

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-2,3-dihydro-1 H-inden-1 -ylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S,2S)-2^(dimethylamino)- l-phenylpropyl ester;

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]-methyl ester;

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyî-, (4-chIorophenyl)methyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-, phenylmethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,l0,12,13,14,14a,15-decahydro-, ethyl ester,

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-hydroxyethyl ester;

Pyrrolo[3 ',2': 5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-methylphenyl)methyl ester; 118 2 0 -18-

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lS)-l-phenylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylethyl ester;

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carbothioic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, S-(phenylmethyl) ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[4-(trifluoromethyl)phenyl]-ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(pentafluorophenyl)ethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-difluorophenyl)ethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -(2-furanyl)ethyl este;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)- 1-phenylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinoIizine-I-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1 -(2-furanyî)ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxy-2-oxo-1 -phenylethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(3-pyridinyl)ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizme-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,l 5-decahydro-2-methyl-, (S)-carboxy(phenyl)methylester; 118 2 0 -19-

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (S)-carboxy(phenyl)methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylate (1:1);

Pyrrolo[3',2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 R)-2-methoxy-2-oxo-1 -phenylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (R)-carboxy(phenyl)methylester;

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (R)-carboxy(phenyl)methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro- 2-methylpyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylate(l:l);

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(4-pyridinyl)ethyl ester;

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-pyridinyl)ethyl ester,

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-thienylmethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -(4-fluorophenyl)ethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 R)-1 -(4-fluorophenyl)ethylester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-pyridinylmethyl ester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyI-, 3-furanylmethyl ester; 118 2 0 -20-

Pyrrolo[3',2';5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-nitrophenyl)methyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-furanylmethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-chlorophenyl)ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, carboxymethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-dichlorophenyl)ethylester;

Pyrrolo[3',2':5,6][l]benzopyfano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-methoxyphenyl)ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(5-carboxy-3-pyridinyl)ethylester; 1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin- l-yl)carbonyl]oxy]methyl]-, diethyl ester; 1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrroIo[3',2':5,6][I]benzopyrano[3,2-i]quinoIizin- 1- yl)carbonyl]oxy]methyl]-;

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl)methylester;

PyrrololB'^'iS.ôjfljbenzopyranolB^-ijquinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl)methylester;

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-amino- 2- chlorophenyI)methyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-acetic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-.alpha.-oxo-, ethyl ester; 118 2 0 -21-

PynOlo[3',2':5,6][l]benzopyrano[3,2-iJquinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2,4,5-trimethyl-, phenylmethyl ester;

PynOlo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -dimethyl-2-propynyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trichloro- 1,1 -dimethylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, tricyclo[3.3.1.1^,^]dec-l-ylester;

PynOlo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methyl-1 -phenylethyl ester;

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-z]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methylcyclohexyl ester;

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-z]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1,2-trimethylpropyl ester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methylcyclopentyl ester;

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-f]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 1 -cyclohexyl-1 -methylethylester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidinyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-fluorophenyl ester;

Pyrrolo[3',2':5,6](l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 3-methylphenyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester,

Pyrrolo[3,,2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl)phenylester; 118 2 0

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-pyridinyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-[(dimethylamino)methyl]- 2-furanyl]methyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,3 4a, 15-decahydro-2-methyl-, 2-carboxy-2-methylpropyl ester;

PynOlotS'^'rSjôltljbenzopyrano^^-zjquinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(dimethylamino)- 2,2-dimethylpropyl ester;

Propanedioic acid, monoanhydride with 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]-benzopyrano[3,2-z]quinolizine- 1- carboxylic acid, 1,1-dimethylethyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)- 2- methylpropyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-( 177-imidazol-1 -yl)ethy 1 ester; P.yrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 2-benzofuranylmethyl ester;

Pyrroîo[3',2':5,6][I]benzopyrano[3,2-z]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 Æ,2S)-2-(dimethylamino)-1 -phenylpropyl ester;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-m ethyl-, ( 1 S,27?)-2-(dimethylamino)-1 -phenylpropyl ester;

Pyrrolo[3 ’ ,2 ’ : 5,6] [ 1 ]benzopyrano[3,2-i]quinoIizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclopropylester; 118 2 0 -23-

Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin-l-yl)carbonyl]oxy]methyl]-l-methyl-, methanesulfonate;

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizinium, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,11 -dimethyl-1 -[(S)-( 1 -phenylethoxy)carbonyl]-, methanesulfonate; and

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1 S)-l -phenylethyl ester, 11-oxide.

The instant invention includes pharmaceutical compositions of compoundsof Formula 1 and methods of using the compounds for modulating chemokinereceptor activity, for preventing or treating infection by HIV, delaying the onset ofAIDS, treating AIDS, and treating inflammatory disease.

DETAILED DESCRIPTION OF THE INVENTION

In this présent invention, compounds of Formula I can exist in two forms(close and open form) at the bicyclic aminal moiety. The equilibrium betweenthese two forms is pH dépendent. At a neutral or basic pH (pH >7.0), thesecompounds predominantly exist in the closed form. However, at an acidic pHrange (pH <7.0), these molécules may exist as a mixture of both close and openform. The ratio of closed and open form may dépend on pH and solvent, as well asthe nature of substituents R, R2-R6, and n.

In the compounds of Formula I, the term alkyl means a straight orbranched hydrocarbon radical having from 1 to 8 carbon atoms and includes, forexample, methyl, ethyl, zz-propyl, isopropyl, /z-butyl, sec-butyl, isobutyl,tert-butyl, w-pentyl, n-hexyl, π-heptyl, n-octyl, and the like. The alkyl can besubstituted with fluorine, for example, additionally the alkyls can be substitutedwith from 1 to 3 substituents selected from alkoxy, carboxy, hydroxy, nitro,haîogen, amino, and substituted amino to provide other active compounds. Alkylincludes cycloalkyl of from 3 to 7 carbons which can be substituted with, for 11820 -24- example, 1 to 3 substituents selected from alkyl, alkoxy, carboxy, hydroxy, nitro,halogen, and amino and substituted amino. Cycloalkyl can be fused to an aryl ringsuch as phenyl, pyridyl, and the like.

Alkoxy is O-alkyl of from 1 to 6 carbon atoms as defined above for alkyl.O

II

Acyl is -C-alkyl, wherein alkyl is as defined above.

The term aryl means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined for alkyl, nitro, cyano, carboxy, O 0 0

Il - 8 II

SO3H, CHO, -C-alkyl as defined above for alkyl, -C-NH2» -C-NH-alkyl asO

II defined above for alkyl, -C-N(alkyl)2 as defined above for alkyl, -(CH2)n2-NH2wherein n^ is an integer of 1 to 5, -(CH2)n2-NH-alkyl as defined above for alkyl and n-, -(CH2)n2-N(alkyl)2 as defined above for alkyl and n^. The term furtherincludes heteroaryl which is a mono or bicyclic heteroaromatic radical having 5 to10 atoms which may contain one or more of heteroatom such as N, O, S,including, for example, 2- or 3-thienyl, 2- or 3-furanyI, 2- or 3-pyrrolyl, 2-, 3-, or 4- pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, or 2-, 3-, 4-, 5- , 6-, or 7-indolyl. The heteroaryls can be unsubstituted or substituted as abovefor aryl.

The term aralkyl or arylalkyl means an aryl radical attached to an alkylradical wherein aryl and alkyl are as defined above, for example, benzyl,fluorenylmethyl, and the like.

Halogen is fluorine, chlorine, bromine, or iodine.

Some of the compounds of ring close Formula I are capable of furtherforming N-oxides and N-quatemary alkyl salts with the ring nitrogen atom atN-l 1. Further, some of the compounds of ring close Formula I are capable offurther forming N-oxides and N-quatemary alkyl salts with nitrogen atoms 11820 -25- optionally présent in Rjq. These structural forms are within the scope of theprésent invention.

Some of the compounds of Formula I are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. Ail of these forms arewithin the scope of the présent invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric,phôsphorous, and the like, as well as the salts derived from nontoxic organicacids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoicacids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic andaromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide,acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate,succinate, suberate, sebacate, fumarate, .maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate,toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate,methanesulfonate, and the like. Also contemplated are salts of amino acids such asarginate and the like and gluconate, galacturonate (see, for example, Berge S.M.et al., “Pharmaceutical Salts,” J ofPharma. Sci., 1977;66:1):

The acid addition salts of said basic compounds are prepared by contactingthe free base form with a sufficient amount of the desired acid to produce the saitin the conventional manner. The free base form may be regenerated by contactingthe sait form with a base and isolating the free base in the conventional manner.

The free base forms differ from their respective sait forms somewhat in certainphysical properties such as solubility in polar solvents, but otherwise the salts areéquivalent to their respective free base for purposes of the présent invention.

Pharmaceutically acceptable base addition salts are formed with metals oramines, such as alkali and alkaline earth metals or organic amines. Examples ofmetals used as cations are sodium, potassium, magnésium, calcium, and the like.Examples of suitable amines are Ν,Ν'-dibenzylethylenediamine, chloroprocaine, 118 2 0 -26- choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge supra., 1977).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desired base toproduce the sait in the conventional manner. The free acid form may beregenerated by contacting the sait form with an acid and isolating the free acid inthe conventional manner. The free acid forms differ from their respective saitforms somewhat in certain physical properties such as solubility in polar solvents,but otherwise the salts are équivalent to their respective free acid for purposes ofthe présent invention.

Certain of the compounds of the présent invention can exist in unsolvatedforms as well as solvated forms, ineluding hydrated forms. In general, the solvatedforms, ineluding hydrated forms, are équivalent to unsolvated forms and areintended to be encompassed within the scope of the présent invention.

Certain of the compounds of the présent invention possess one or morechiral centers and each center may exist in the R or S configuration. The présentinvention includes ail diastereomeric, enantiomeric, and epimeric forms as well asthe appropriate mixtures thereof. Additionally, the compounds of the présentinvention may exist as géométrie isomers. The présent invention includes ail cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as theappropriate mixtures thereof.

The compounds of the présent invention can be prepared and administeredin a wide variety of oral and parentéral dosage forms. Thus, the compounds of theprésent invention can be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compounds of the présent invention can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the présent invention can be administered transdermally. It will beobvious to those skilled in the art that the following dosage forms may compriseas the active component, either a compound of Formula I or a correspondingpharmaceutically acceptable sait of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of theprésent invention, pharmaceutically acceptable carriers can be either solid or 118 2 0 liquid. Solid form préparations include powders, tablets, pills, capsules, cachets,suppositories, and dispersible granules. A solid carrier can be one or moresubstances which may also act as diluents, flavoring agents, solubilizers,lubricants, suspending agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture withthe finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted in the shapeand size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnésiumcarbonate, magnésium stéarate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax,cocoa butter, and the like. The term “préparation” is intended to include theformulation of the active compound with encapsulating material as a carrierproviding a capsule in which the active component, with or without other Carriers,is surrounded by a carrier, which is thus in association with it. Similarly, cachetsand lozenges are included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fattyacid glycerides or cocoa butter, is first melted and the active component isdispersed homogeneously therein, as by stirring. The molten homogenous mixtureis then poured into convenient sized molds, allowed to cool, and thereby tosolidify.

Liquid form préparations include solutions, suspensions, and émulsions,for example, water or water propylene glycol solutions. For parentéral injection,liquid préparations can be formulated in solution in aqueous polyethylene glycolsolution.

Aqueous solutions suitable for oral use can be prepared by dissolving theactive component in water and adding suitable colorants, flavors, stabilizing, andthickening agents as desired. 118 2 0 -28-

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, andother well-known suspending agents. AIso included are solid form préparations which are intended to beconverted, shortly before use, to liquid form préparations for oral administration.Such liquid forms include solutions, suspensions, and émulsions. Thesepréparations may contain, in addition to the active component, colorants, flavors,stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners,solubilizing agents, and the like.

The pharmaceutical préparation is preferably in unit dosage form. In suchform, the préparation is subdivided.into unit doses containing appropriatequantities of the active component. The unit dosage form can be a packagedpréparation, the package containing discrète quantities of préparation, such aspacketed tablets, capsules, and powders in vials or ampoules. Also, the unitdosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be theappropriate number of any of these in packaged form.

The quantity of active component in a unit dose préparation may be variedor adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to theparticular application and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

In therapeutic use as agents for the treatment of HIV infection, thecompounds utilized in the pharmaceutical method of this invention can beadministered at the initial dosage of about 1 mg to about 100 mg per kiîogramdaily. A daily dose range of about 25 mg to about 75 mg per kiîogram is preferred.The dosages, however, may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the compound beingemployed. Détermination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smaller dosages which areless than the optimum dose of the compound. Thereafter, the dosage is increasedby small incréments until the optimum effect under the circumstance is reached.For convenience, the total daily dosage may be divided and administered inportions during the day if desired. 118 2 0 -29-

The compounds of Formula I are valuable antagonists of the CCR-5chemokine receptor. Compounds which are antagonists of the CCR-5 chemokinereceptor are expected to hâve efficacy in inhibiting HIV infection and are thususeful in the treatment of AIDS. The compounds of the présent invention wereevaluated in a CCR-5 receptor binding assay. CCR-5 Receptor Binding Assay

The 125i_gpi20/sCD4/CCR-5 binding assay was carried out similarly asdescribed in Wu et al., Nature, 1996;384:179-183. Briefly, the envelope gpl20protein derived from HIV-1 JR-FL (Trkola et al., Nature, 1996;384:184-186), aM-tropic strain, was iodinated using solid phase lactoperoxidase to a spécifieactivity of 20 pCi/pg. For each binding reaction (in a final volume of 100 pLbinding buffer [50 mM HEPES, pH 7.5, 1 mM CaCb, 5 mM MgCl2, and 0.5%BSA]), 25 pL (2.5 pg) of membranes prepared from CCR-5/L 1.2 cells weremixed with 25 pL (3 nM) sCD4.i followed by 25 pL (0.1 nM) radio-labeled gpl20in the presence or absence of 25 pL compound dissolved in DMSO (finalconcentration of DMSO 0.5%). The reactions were incubated at room températurefor 45 to 60 minutes and stopped by transferring the mixture to GFB filter plates,which were then washed 3 to 4 times with binding buffer containing 0.5 M NaCl.The plates were dried and MicroScint scintillation fluid was added beforecounting.

The compounds of présent invention, represented by Formula I, block thesCD-4/GP-120 binding to CCR-5 receptor with affinity less than or equal to200 pM.

Synthesis of CCR-5 Analogs

Synthesis of the final target compounds is shown in Scheme 1.

Compound Π in a protic solvent, preferably éthanol, was treated with aqueousformaldéhyde and dimethylamine at températures which ranged from 0-90°C,preferably at 25-60°C, to give the Mannich base III. Condensation of III with aenamine at températures which ranged from 50-110°C, preferably at 80-100°C,under nitrogen atmosphère in an aprotic solvent, preferably dioxane, gives 118 2 0 -30- compound IV. Alkylation of IV with NaH and alkylhalides in an aprotic solvent,preferably DMF, under nitrogen atmosphère at températures which ranged from-10 to 25°C, preferably at 0-25°C, provides compound I (where Rj H).

The préparation of indole intermediates is shown in Scheme II. Reaction ofbromoacetate with nitriles in an aprotic solvent, preferably THF, in the presenceof activated Zn at reflux under nitrogen atmosphère gives amino crotonates V.Altematively, amino crotonates V can be obtained by reacting the correspondingβ-ketoester with ammonia in EtOH. The β-ketoesters can be derived from 2,2,6-trimethyl~4H-l,3-dioxin-4-one and the corresponding alcohols. Condensation ofamino crotonates V with substituted benzoquinone in a solvent, preferably aceticacid, éthanol, or nitromethane at températures which ranged from 25°C to refluxaffords substituted 5-hydroxyindoles Vl. The indole ester VI is hydrolyzed to thecorresponding acid VII using aqueous NaOH at températures which ranged from50-100°C, preferably at reflux, under nitrogen. To suppress the décarboxylationreaction, it is important that after the reaction is done the reaction mixture wascooled to 0°C in an ice-water bath and acidifïed with a concentrated acid,preferably HCl, at 0°C to generate the acid. Esters or amides IX can be made fromacid VIII following several standard estérification procedures or a standardprocedure for amide synthesis using HBTU as the coupling reagent. For the estersynthesis, Mitsunobu procedure is preferred where appropriate alcohols, DEAD,and PI13P are used, and the reaction is carried out at ambient température. Anotherpreferred procedure to make esters is treating the acid with a base, preferablyDBU, and alkylhalides or arylalkylhalides in a polar solvent, preferably DMF oracetonitrile at ambient température.

The following schemes are illustrative of the procedures useful in thepréparation of final compounds. Variations known to skilled chemists areconsidered part of the invention. 118 20 -31-

Scheme 1

Préparation of Final Target Compounds

-32- 118 2 0

Scheme 2

Préparation of Substituted Indole Dérivatives

xylenes+ R'OH -

150°C

activated Zn + R7—CN ->- THF, reflux h

VUI

IX 118 2 0 -33-

Scheme 3

Substituted 5-hydroxybenzofurans (C). 5 The substituted 5-hydroxybenzofurans (C) were prepared by condensing the appropriate 1,4-benzoquinone (A) with the appropriate 3-aminocrotonate (B)in acetic acid. The solvent was removed in vacuo, and the product was purified byrecrystalîization or flash chromatography on silica gel.

Mannich Bases (E). 10 The 5-hydroxybenzofuran (C, D) was treated with aqueous dimethylamine and aqueous formaldéhyde in éthanol at 50°C or, altematively, with Ν,Ν,Ν',Ν'-tetramethyldiaminomethane in refluxing dioxane until the reaction was complété. 11820 -34-

The solution was concentrated under reduced pressure, and the product waspurified by recrystallization.

Benzofurans (G).

The mannich base (E) was added to a dioxane solution of enamine (F), 5 which was freshly prepared by treating its perchlorate sait with aqueous sodium hydroxide, extracting the enamine into ether, drying and concentrating the extractsin vacuo. The resulting solution was heated between 80-100°C until the reactionwas complété. The mixture was concentrated in vacuo and the product purified by k recrystallization or flash chromatography on silica gel. -35- 11820

Scheme 4

Synthesis of 7-Azaindoles Analogs

113 2 0 -36-

Procedures:

Starting with commercially available 3-hydroxy-2-phenylazopyridine (1) thecorresponding aminopyridine is synthesized by reducing 1 in the presence ofH2 (57 bar) and Pd/C in acetic acid at 65°C (Synthesis, 1990: 681) to afïord 5 amine 2. Amine 2 is then transformed into 2-amino-5-hydroxy-3-iodopyridinethrough reaction with iodine and acetic acid (Synthesis, 1990:681) at roomtempérature. The iodopyridine 3 is then converted to the azaindole 4 via palladiumcatalyzed cyclization with the appropriately substituted alkyne (Tetrahedron Lett., 1998;39:5355; Tetrahedron Lett., 1993;34:2823). Conversion of3 to 4 is followed 10 by oxidation of the hydroxymethylene to the corresponding acid 5 usingKMnO4 in the presence of K2CO3 (Gazz. Chim. Ital., 1932;62:844).

Altematively, direct conversion of'3 to 5 is accomplished by using the carboxysubstituted alkyne. Estérification of 5 to the desired ester is effected using diimidecoupling reagents and the desired alcohol (J. Org. Chem., 1995;60:5214). 15 Substitution of the pyridine ring using formaldéhyde and dimethyl amine (Tetrahedron Lett., 1966:4459) afforded 7. Intermediate 7 is then converted to thefinal azaindole analog 8 by reacting 7 and the quinolizidine imine shown inrefluxing éthanol (J. Het. Chem., 1970;7:131). 118 2 0 -37-

Scheme 5

Préparation of Final Target Compounds From Novel Intermediate

118 2 0 -38-

Compound I in an aprotic solvent, preferably Et20, CH2CI2, or THF, was treatedwith a solution of oxalyl chloride in the same aprotic solvent at températuresranged from -10°C to 30°C, preferably at 0°C to 25°C, followed by treatment ofan amine of choice in an aprotic solvent to give the desired product IL The desired5 product III can be obtained by reacting compound I with oxalyl chloride in an aprotic solvent, preferably Et2O, CH2CI2, or THF, at températures ranged from-10°C to 30°C, preferably at 0°C to 25°C, followed by treatment of an alcohol ofchoice in an aprotic solvent. Altematively, the desired product III can be made byreacting compound I with compound IV in an aprotic solvent such as Et2O,CH2Cl2, or THF. 10 118 2 0

Préparation of the Mixed Anhydride -39-

Scheme 6

III

General Description 5 The benzylester I is subjected to hydrogenolysis reaction conditions in aprotic polar solvents, preferably THF, at ambient température to give acid Π. Theacid II is treated subsequently with benzoyl chloride in presence of an organicbase, such as ΕΐβΝ, to afford the mixed anhydride III. 118 2 0

Synthesis of Esters From the Mixed Anhydride -40-

Scheme 7

General Description 5 The mixed anhydride I is mixed with the desired alcohol, the résultant reaction mixture was heated to 100°C to 180°C until the mixed anhydride isconsumed affording the corresponding ester. 118 2 0 -41-

The présent invention is further directed to combinations of the présentcompounds with one or more agents useful in the prévention or treatment ofAIDS. For example, the compounds of this invention may be effectivelyadministered, whether at periods of pre-exposure and/or post-exposure, in 5 combination with effective amounts of the anti-HIV compounds, immunomodulators, anti-infectives, or prophactic or therapeutic vaccines knownto those of ordinary ski U in the art. -42-

ANTIVIRALS 118 2 0

Drug Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase(RT) inhibitor) GW141 W94/ VX478 Glaxo Wellcome HIV infection, AIDS, ARC(protease inhibitor) Amprenavir GW1592U89 Abacavir Glaxo Wellcome HIV infection, AIDS, ARC(RT inhibitor) Acem annan Carrington Labs(Irving, TX) ARC Acyclovir Burcoughs Wellcome HIV infection, AIDS, ARC, in Combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen (Los Angeles, CA) ARC, PGL HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi’s sarcoma, HIV in combination Alferon Interferon Interferon Sciences Kaposi’s sarcoma, HIV in combination Ansamycin LM 427 Adria Laboratories (Dublin, OH) Erbamont (Stamford, CT) ARC Antibody whichneutralizes pHlabile alpha Advanced BiotherapyConcepts(Rockville, MD) AIDS, ARC · aberrant Interferon AR177 Aronex Pharm HIV infections, AIDS, ARC beta-fluoro-ddA Nat’l Cancer Institute AIDS-associated diseases 118 2 -43- ANTIVIRALS (cont’d)

Drug Name Manufacturer Indication BMS-232623 Bristol-Myers HIV infection, AIDS, ARC (CGP-73547) Squibb/Novartis (protease inhibitor) BMS-234475 Bristol-Myers HIV infection, AIDS, ARC (CGP-61755) Squibb/Novartis (protease inhibitor) (-)6-Chloro-4(S)-c yc lopropylethyny 1-4(S)-trifIuoro- Merck HIV infection, AIDS, ARC(non-nucleoside reversetranscriptase inhibitor) methyl-1,4-dihydro-2H-3,l-benzoxazin- 2-one CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes,papillomavirus Combivir AZT+3TC Glaxo Wellcome HIV infection, AIDS, ARC Curdlan sulfate AJI Pharma USA HIV infection Cytomégalovirus Medlmmune CMV retinitis immune globin Cytovene Ganciclovir Syntex/Roche Sight threatening CMV,peripheral CMV, retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC(RT inhibitor) Dextran Sulfate Ueno Fine Chem. Ind.Ltd. (Osaka, Japan) AIDS, ARC, HIV positiveasymptomatic HIVID (ddc) Hoffman-La Roche HIV infection, AIDS, ARC Dideoxycytidine ddl Dideoxyinosine Bristol-Myers Squibb HIV infection, AIDS, ARC;combination with AZT/d4T DMP-450 Triangle Pharmaceutical HIV infection, AIDS, ARC(protease inhibitor) Efavirenz (DMP 266) DuPont Merck HIV infection, AIDS, ARC(non-nucleoside RT inhibitor) EL10 Elan Corp, PLC(Gainesville, GA) HIV infection Famciclovir Smith Kline Herpes zoster, herpes simplex Foscavir/Foscamet Astra CMV, HSV 1-2 118 2 0 -44- ANTIVIRALS (cont’d)

Drug Name Manufacturer Indication FTC Triangle Pharmaceutical HIV infection, AIDS, ARC(reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC(reverse transcriptase inhibitor) HBY097 Hoechst Marion Roussel HIV infection, AIDS, ARC(non-nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human Interferon Beta Triton Biosciences(Almeda, CA) AIDS, Kaposi’s sarcoma, ARC Interferon alpha-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC,asymptomatic HIV positive,also in combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis JE 2147 (KNI-764) Japan Energy/ HIV infection, AIDS, ARC Protease inhibitor Agouron PI (reverse transcriptase inhibitor);also with AZT KNI-272 Nat’l Cancer Institute HIV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC(reverse transcriptase inhibitor);also with AZT Lobucavir Bristol-Myers Squibb CMV infection - HBV infection Nelfinavir Agouron Pharmaceuticals HIV infection, AIDS, ARC(protease inhibitor) Nevi rapine Boeheringer Ingleheim HIV infection, AIDS, ARC(RT inhibitor) Novapren Novaferon Labs, Inc.(Akron, OH) HIV inhibitor Peptide T Octapeptide Peninsula Labs(Belmont, CA) AIDS

Sequence 118 2 0 -45- ANTIVIRALS (cont’d)

Drug Name Manufacturer Indication P NU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC Probucol Vyrex (protease inhibitor) HIV infection, AIDS RBD-CD4 Sheffield Med. Tech HIV infection, AIDS, ARC Ritonavir (Houston, TX) Abbott HIV infection, AIDS, ARC S-1153 Agouron/Shionogi (protease inhibitor) NnRTI Saquinavir Hoffmann-La Roche HIV infection, AIDS, ARC Stavudine; d4T Bristol-Myers Squibb (protease inhibitor) HIV infection, AIDS, ARC Didehydrodeoxy- thymidine Valaciclovir Glaxo Wellcome Génital HSV &amp; CMV infections Virazole Ribavirin Viratek/ICN Asymptomatic HIV positive, Zidovudine; AZT (Costa Mesa, CA)Glaxo Wellcome LAS, ARC HIV infection, AIDS, ARC,

Kaposi’s sarcoma, incombination with otherthérapies

IMMUNO-MODULATORS

Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc.(Irving, TX) AIDS, ARC CL246,738 American CyanamidLederle Labs AIDS, Kaposi’s sarcoma EL10 Elan Corp, PLC(Gainesville, GA) HIV infection FP-2I399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, in combination w/TNF(tumor necrosis factor) 118 2 -46- IMMUNO-MODULATORS (cont’d)

Drug Name Manufacturer Indication Granulocyte Macrophage Colony StimulatingFactor Genetics Institute Sandôz AIDS Granulocyte Macrophage Colony Stimulating Factor Hoeschst-Roussel Immunex AIDS Granulocyte Macrophage Colony StimulatingFactor Schering-Plough AIDS, combination w/AZT HIV core Particle Immunostimulant Rorer Séropositive HIV IL-2 Interleukin-2 Cetus AIDS, in combination w/AZT IL-2 Interleukin-2 Hoffman-La roche Immunex AIDS, ARC, HIV, in combination w/AZT IL-2 Interleukin-2(aldeslukin) Chiron AIDS, increase in CD4 cell counts Immune Globulin Cutter Biological Pédiatrie AIDS, in combination Intravenous (human) (Berkeley, CA) w/AZT IMREG-1 Imreg (New Orléans, LA) AIDS, Kaposi’s sarcoma, ARC,PGL IMREG-2 Imreg (New Orléans, LA) AIDS, Kaposi’s sarcoma, ARC,PGL Imuthiol Diethyl Dithio Carbamate Merieux Institute AIDS, ARC Alpha-2 Interferon Schering Plough Kaposi’s sarcoma ή/ΑΖΊ,AIDS Methionine- Enkephalin TNI Pharmaceutical(Chicago, IL) AIDS, ARC MTP-PE Muramyl-Tripeptide Ciba-Geigy Corp. Kaposi’s sarcoma Granulocyte ColonyStimulating Factor Amgen AIDS, in combination w/AZT 118 2 0 -47- IMMUNO-MODULATORS (cont’d)

Drug Name Manufacturer Indication Remune Immune Response Immunotherapeutic rCD4 Recombinant Corp. Genentech AIDS, ARC Soluble Human CD4 rCD4-IgG hybrids AIDS, ARC Recombinant Soluble Biogen AIDS, ARC Human CD4 Interferon Alfa 2a Hoffman-La Roche Kaposi’s sarcoma AIDS, ARC, SK&amp;F106528 Smith Kline in combination w/AZT HIV infection Soluble T4 - Thymopentin Immunobiology HIV infection Turnor Necrosis Research Institute(Annandale, NJ)Genentech ARC, in combination w/gamma Factor; TNF Interferon ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycen with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcal meningitis,candidiasis Pastille Nystatin Squibb Corp. Prévention of oral candidiasis Pastille Omidyl Eflomithine Merrell Dow PCP Pentamidine LyphoMed PCP treatment Isethionate (IM &amp; (Rosemont, IL) IV) Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate forinhalation 11820 -48- ANTI-INFECTIVES (cont’d)

Drug Name Manufacturer Indication Spiramycin Rhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen Pharm. Histoplasmosis; cryptococcal R51211 meningitis Trimetrexate Warner-Lambert PCP

OTHER Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi’s sarcoma Recombinant Human Ortho Pharm. Corp. Severe anémia associated with Erythropoietin AZT therapy Recombinant Human Growth Hormone Serono AIDS-related wasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment of anorexia associated w/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enterai Norwich Eaton Diarrhea and malabsorption Nutrition Phanmaceuticals related to AIDS

It will be understood that the scope of combinations of the compounds ofthis invention with AIDS antivirals, immunomodulators, anti-infectives orvaccines is not limited to the list in the above table, but includes in principle anycombination with any pharmaceutical composition useful for the treatment of 5 AIDS.

The following examples are illustrative of the intermediate and finalcompounds and methods for their préparation. They are not intended to limit thescope of the invention.

I ! 11820 -49-

EXPERIMENTALS

Synthesis of Intermediate Indole dérivatives 5-Acetoxy-2-methyI-lH-indole-3-carboxylic acid (A) 5-Hydroxy-2-methyl-l-H-indole-carboxylic acid (8.54 g, 44.7 mmol) was dissolved in aqueous sodium hydroxide (2N, 45 mL). l-acetyl-lH-2,3-triazolo(4,5-b-)-pyridine (7.24 g, 44.7 mmol) was dissolved in THF (30 mL), andthe solution was added to the solution of 5-hydroxy-2-methyl-l-H-indole-carboxylic acid. The mixture was stirred untiî little or no starting materialremained, ~30 minutes; a white precipitate formed. The mixture was cooled to0°C and concentrated HCl was added dropwise until the pH was ~1. The resultingwhite solid was filtered, washed with water (2 x 50 mL), recrystallized frométhanol, and dried under vacuum, yield 6.95 g (67%); mp 233-235°C (dec); IR:3331, 1740,1642,1234,1207 cm-1. *H NMR (DMSO-d6) δ: 2.21 (s, 3HCH3CO2), 2.59 (s, 1H, ArCH3), 6.79 (d, 7= 6.84 Hz, 1H, ArH), 7.27 (d, 7= 8.55 Hz, 1H, ArH), 7.53 (s, 1H, ArH), 11.77 (s, 1H, NH) 11.93 (s, 1H,COOH). MS(APCI+): m/z 234.1 (MH+). Analysis calculated for C12Hi 1N1O4:C, 61.80; H, 4.75; N, 6.01. Found: C, 61.48; H, 4.66; N, 5.86.

Procedure A. General procedure for the préparation of esters 5-Hydroxy-2-methyl-l-H-indole-carboxylic acid or 5-acetoxy-2-methyl- lH-indole-3-carboxylic acid (4-28 g) was combined with enough THF to effectdissolution. Triphenylphosphine (1 eq) and the alcohol of interest (2.5-4.0 eq,depending on solubility) were added to the THF solution. Diethylazodicarboxylate(DEAD, 1 eq) was added dropwise to the mixture over the course of 1 -1.5 hour.The mixture was stirred ovemight at ambient température. The solution wasconcentrated in vacuo to give an oily mixture; a solution of 1:1 hexane/ethylacetate was used to redissolve the oil. The desired product was purified by flashchromatography. Residual diethylhydrazinedicarboxylate remaining in the productwas removed by trituration with hot water; the resulting solid was dried undervacuum at 40°C. For compounds made with 5-acetoxy-2-methyI-lH-indole- 118 2 0 -50- 3-carboxylic acid, the 5-acetyl group was removed in the following manner: theprotected ester (1 eq) was dissolved in a small amount of MeOH. NaOMe (4 eq)was added and the mixture stirred until no starting material remained(~45 minutes). The pH of the solution was adjusted to 1 with the addition of 5 aqueous HCl, and a copious white precipitate occurred. The solid was filtered, washed with water (2 x 20 mL), and dried under vacuum at 40°C. Altematively,the pH of the solution was adjusted to 1 with the addition of aqueous HCl, and thesolution was extracted with ethyl acetate (2 x 25 mL). The organic layer was driedover Na2SC>4 and evaporated to give a solid. The solid may be further purified by 10 recrystallization from appropriate solvents. According to the Procedure A,

Intermediates B-G were synthesized. 5-Acetoxy-2-methylindole-3-carboxylic acid benzyl ester (B) Yield: 8.32 g(21.6%); mp 152-154°C; IR: 3310,1752, 1662,1226, 1094 cm’1; NMR(DMSO-dg) δ 2.21 (s, 3H, CH3CO2), 2.60 (s, 3H, ArCH3), 5.28 (s, 2H, CH2Ph), 15 6.82 (dd, J= 8.55, 2.44 Hz, 1H, ArH), 7.26-7.41 (m, 6H, ArH), 7.53 (d, 7= 2.44 Hz, 1H, ArH), 11.9 (s, 1H, NH). MS(APCI+): 324.1 (MH+). Analysiscalculated for C19H17N1O4: C, 70.58; H, 5.30; N, 4.33. Found: C, 70.47; H, 5.43; N, 4.24. 5-Hydroxy-2-methylindole-3-carboxylic acid benzyl ester (C) Yield: 5.03 g

20 (76%); mp 191-193°C; IR: 3227, 1654,1472, 1429, 1094 cm-1. ]H NMR (DMSO-dg) δ 2.54 (s, 3H, alkyl CH3 ), 5.26 (s, 2H, PhCH2), 6.55 (d, J= 6.10 Hz,1H, ArH), 7.08 (d, J= 8.8 Hz, 1H, ArH), 7.24-7.42 (m, 6H, ArH), 8.82 (s, 1H,aromatic OH), 11.55 (s, 1H, NH). MS(APCI+): m/z 282.0 (MH+). Analysiscalculated for C17H15N1O3: C, 71.71; H, 5.44; N, 4.92. Found: C, 71.72; H, 25 5.49; N, 4.85.

Altematively, Intermediate C can be synthesized from Intermediate B accordingto the procedure described in Example 9, Step A. -51- il 1 8 2 0 5-Acetoxy-2-methylindole-3-carboxylic acid propyl ester (D) Yield: 2.16 g(37%); mp 134-136°C; IR: 3263, 2966, 1758,1677, 1657,1215 cm-1. *H NMR(DMSO-d6) δ 0.99 (t, J = 7.51 Hz, 3H, CH2CH2Œ3), 1.71 (sextet, 7= 7.33 Hz, 3H, CH2CH2CH3), 2.26 (s, 3H, CH3CO), 2.63 (s, 3H, ArCH3), 4.17 (t, 7= 6.41 Hz, 2H, Ctf2CH2CH3), 6.86 (dd, 7= 8.61,2.20 Hz, 1H, ArH), 7.34 (d, J =8.61 Hz, ΙΗ,ΑτΗ), 7.55 (d, 7 = 2.20 Hz, 1H, ArH), 11.9 (s, 1H, NH).MS(APCI+): m/z 276.0 (MH+). Analysis calculated for C15H17N1O4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.13; H, 6.28; N, 5.10. 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2-isopropyl ester (E) Yield: 0.720 g (12%); mp 188-189°C; ER: 3409, 3391, 1663, 1467, 1181,1095 (cm-1). ÎH NMR (DMSO-d0) δ 1.27 (d, 7= 6.35 Hz, 6H, CH(Ctf3)2), 2.52 (s, 3H, CH3), 5.04 (septet, 7= 6.35 Hz, 1H, Ctf(CH3)2), 6.53 (dd, 7= 8.55, 2.44 Hz, 1H, ArH), 7.06 (d, 7= 8.55 Hz, ΙΗ,ΑτΗ), 7.25 (d, 7= 2.44 Hz, 1H, ArH), 8.77 (s, ΙΗ,ΟΗ) 11.4 (s, 1H, NH). MS(APCI+): m/z 234.1 (MH+). Analysis calculated forC13H15N1O3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.79; H, 6.53; N, 5.88. 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid cyclopropylmethyl ester (F)

Yield: 0.532 g (8.3%); mp 187-188°C; IR: 3388, 3297, 1663, 1466,1179, 1094 cm'1. ÎH NMR (DMSO-d6) δ 0.00-0.04 (m, 2H, cyclopropyl CH2CH2),0.22-0.26 (m, 2H, cyclopropyl CH2CH2), 0.86-0.93 (m, 1H, CH2CH), 2.27 (s, 3H, ArCH3), 3.72 (d, 7= 7.32 Hz, 2H, Ctf2CH), 6.27 (dd, 7= 8.55,2.44 Hz, 1H,ArH), 6.79 (d,7= 8.55, 1H, ArH), 6.99 (d, 7= 2.20,1H, ArH), 8.51 (s, 1H, OH), 11.2 (s, 1H, NH). MS(APCI+): m/z 246.1 (MH+). Analysis calculated forC14H15N1O3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.50; H, 6.19; N, 5.67. 5-Acetoxy-2-methylindole-3-carboxyIic acid 1-phenyl-propyl ester (G) Yield: I. 36 g (23%); mp 144-145.5°C; IR: 3289, 1755,1661, 1459,1216,1204, 1089 cm-1. lH NMR (DMSO-d6) δ 0.863 (t,7= 7.32 Hz, 3H, CH2CH3), 1.82-1.98 (m, 2H, CHCH2CH3), 2.22 (s, 3H, CH3CO), 2.63 (s, 3H, ArCH3), -52- 11820 ’ 5.80 (t, 7=6.84 Hz, 1H, benzylic CH), 6.83 (dd,7=8.79,2.20 Hz, ΙΗ,ΑτΗ), 7.21-7.36 (m, 6H, ArH), 7.60 (d, J =2.20 Hz, ΙΗ,ΑτΗ), 11.9 (s, 1H, NH). MS(APCI-): m/z 350.1 (M-l). Analysis calculated for C21H21N1O4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.53; H, 6.02; N, 3.81. 5-Hydroxy-2-methyl-lH-indole-3-carboxyIic acid isobutyl ester (H) 5-Hydroxy- 2-methyl-lH-indole-3-carboxylic acid isobutyl ester was synthesized according tothe general procedure A and was recrystaliized from hexane/CH2Cl2 to give I. 39 g (26.2%) of white solid: mp 188-190°C; IR (KBr) 3385, 3272,2963, 1655, 1630, 1464, 1174, 1094 cm-1; 1H NMR (400 MHz, DMSO-d0) δ 0.95 (d, J = 6.84 Hz, 6H, CH(C773)2), 1.94 (n, J= 6.84 Hz, 1H, CH(Ctf3)2), 2.54 (s, 3H, CCtf3), 3.95 (d, J = 1.95 Hz, 2H, 0CH2), 6.54 (dd, 7= 8.55,2.44 Hz, 1H, Arfl), 7.07 (d, 7=8, 1 H, ArH), 7.25 (s, ΙΗ,ΑτΗ), 8.81 (s, 1H, OH), 11.49 (s, 1H,N#);MS(APCI+): m/z 248.1(MH+). Analysis calculated for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.92; H, 6.87; N, 5.54. 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2,2-dimethyl-propyl ester (I)5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2,2-dimethyl-propyl ester wassynthesized according to the general procedure A and was recrystaliized fromCH2Cl2 to give 2.31 g (33.8%) of white solid: mp 195-196°C; IR (KBr) 3262, 2960, 1652,1464, 1170, 1094 cm’1; ÏH NMR (400 MHz, DMSO-d6) δ 0.97 (s, 9H, C(CH3)3), 2.55 (s, 3H, ArCH3), 3.87 (s, 2H, OCH2), 6.55 (dd, 7= 8.55, 2.44 Hz, 1H, ArCH), 7.07 (d, 7= 8.55 Hz, 1H, ArCH), 7.29 (s, 1H, ArH), 8.82 (s, 1H, OH), 11.50 (s, 1H, NH); MS(APCI+): m/z 262.1(MH+). Analysis calculated . for Ci5H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C, 68.55; H, 7.23; N, 5.41.

Procedure B: An Alternative General Procedure for the Préparation of Esters A solution of 5-acetoxy-2-methyl-lH-indole-3-carboxylic acid (Aldrich, 5.00 g, 21.4 mmol) and diethyl azodicarboxylate (Aldrich, 3.73 g, 21.4 mmol) in7 mL of THF was added dropwise to a mixture of triphenyl phosphine (Aldrich, 5.62 g, 21.4 mmol) and an alcohol of choice (Aldrich, 2.00-4.00 g, 32.2 mmol) in 118 2 0 -53- 32 mL of THF over an hour. After stirring at room température for 24 hours, themixture was concentrâtes The product was purified by flash columnchromatography on silica gel (10% MeOH,CHCl3) to give the correspondingester. 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2-piperdin-l-yl-ethyl ester (J)5-Hydroxy-2-methyl-lH-indoIe-3-carboxylic acid 2-piperdin-lyl-ethyl ester wassynthesized according to the procedure B and was recrystallized fromhexane/ethyl acetate to give 0.350 g (26.9%) of white solid: mp 210-212°C; IR(KBr) 3203, 2934, 1690,1455,1175,1067 cm'1; ÎHNMR (400 MHz,DMSO-d<5) δ 1.31 (m, 2H, NCH2CH2C//2), 1-42 (m, 4H, NCH2C/Î2)> 2.38 (m,4H, NŒ/2CH2CH2), 2.53 (s, 3H, ÂrCH3), 2.59 (t,J= 6.10 Hz, 2H, QCtiï&amp;h), 4.22 (t, J= 6.10 Hz, 2H, OCH2CH2N), 6.54 (dd, J= 8.66, 2.32 Hz, 1H, ArH),7.06 (d, J- 8.55 Hz, 1H, ArH), 7.27 (s, 1H, ArH), 8.77 (s, 1H, OH), 11.48 (s, 1H,NH); MS(APCI+): m/z 303.1(MH+). Analysis calculated for C17H22N2O3: C,67.05; H, 7.28; N, 9.20. Found: C, 66.93; H, 7.28; N, 9.00.

Procedure C: A General Procedure for the Synthesis of ethyl 3-alkyl- 3-aminocrotonates (K-O)

Activation of Zn: To a stirred 3N HCl solution (50 mL) was added Zn(20 g) and stirred at room température for 15 minutes. The HCI solution wasdecanted, and this was repeated two times. The activated Zn was washed withdistilled H2O (2x, 100 mL), éthanol (2x, 50 mL), and ether (2x, 50 mL). The

activated Zn was then placed under reduced pressure for 12 hours at 40°C. To astirred solution of dry THF (30 mL) and activated Zn (3.27 g, 50 mmol) in a flamedried 100 mL round bottom fîask under an inert atmosphère was added 0.2 mL ofethylbromoacetate (1) at room température. The reaction was then heated toreflux. After the solution tumed green (15-30 min), the alkyl cyanide (10 mmol)was added at once, and ethylbromoacetate (4.44 mL, 40 mmol) was addeddropwise over 30 minutes and refluxed for an additional 30 minutes and thenallowed to cool to room température. To the stirred solution was added THF 118 2 0 -54- (30 mL) and K2CO3 (13 mL, 50% w/w) and stirred vigorously for 30 minutes.

The solution was then placed in a centrifuge tube and centrifuged. The supematantwas decanted, and the pellet was resuspended in THF (30 mL), shaken vigorouslyand centrifuged (procedure repeated twice). The combined supematant were dried 5 over MgSC>4, filtered, and concentrated under reduced pressure to yield of ethyl 3-alkyl-3-aminocrotonate as a crude product which was used directly in the nextstep.

Ethyl 3-amino-3-benzylcrotonate (K) NMR (250 MHz, CDCI3) δ 1.26 (t, J= 7.1 Hz, 3H), 3.46 (s, 2H), 4.12 (q, J = 7.15 Hz, 2H), 4.64 (s, 1H), 7.27 (m, 10 5H).

Ethyl 3-amino-3-ethylcrotonate (L) ^H NMR (250 MHz, CDCI3) δ 1.47 (t, 7= 7.5 Hz, 3H), 1.26 (t,7=7.1 Hz, 3H), 2.16 (q, 5.7 Hz, 2H), 4.11 (q, 7= 5.4 Hz, • 2H), 4.55 (s, 1H). 13C NMR (62.5 MHz, CDCI3) δ 12.0,14.5, 29.3, 30.3, 58.5, 82.6, 164.9, 170.5. 15 Ethyl 3-amino-3-cyclopropylcrotonate (M) ^H NMR (250 MHz, CDCI3) δ 0.74 (m, 2H), 0.86 (m, 2H), 1.25 (t,7= 7 Hz, 3H), 2.27 (s, 1H), 4.10 (q,7= 7 Hz,2H), 4.45 (s, 1H). 13C NMR (62.5 MHz, CDCI3) δ 7.1,14.6, 15.8, 58.5, 80.7, 165.1,170.4. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t = 7.24 min, m/z = 156 (M+l). 20 Ethyl 3-amino-3-propylcrotonate (N) ^H NMR (250 MHz, CDCI3) δ 0.95 (t, 7=7.3 Hz, 3H), 1.26 (t,7= 7.1 Hz, 3H), 1.56 (s, 7= 7.3 Hz, 2H), 2.10 (d, 7= 7.3 Hz, 2H), 4.1 (q, 7= 7.2 Hz, 2H), 4.53 (s, 1H). 13C NMR (62.5 MHz, CDCI3) δ 13.5, 14.5, 21.1,38.4, 58.30, 84 LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t = 8.02 min, m/z = 158.4 (M+l). 118 2 0 -55-

Ethyl 3-amino-3-isobutylcrotonate (O) NMR (250 MHz, CDCI3) δ 0.95 (d,7=6.4 Hz, 6H), 1.26 (t, 7 = 7.1 Hz, 3H), 1.9 (m, 1H), 1.96 (d,7=7.0 Hz, 2H), 4.11 (q,7= 7.1 Hz, 2H), 4.51 (s, 1H). LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t = 8.69 min, m/z = 172.4 (M+î).

Procedure D: General procedure for the synthesis of ethyl 2-alkyl-5-hydroxy- 3-indolecarboxylates (P-T)

To a stirred solution of ethyl 3-alkyl-3-aminocrotonate (15.3 mmol) inacetic acid (50 mL) was added 1,4-benzoquinone (3.3 g, 30.5 mmol). The solutionwas stirred ovemight at room température and then filtered through a frit. Thesolid was washed with cold distilled water and dried in an Abderhalden overP2O5 to afford the ethyl 2-alkyl-5-hydroxy-3-indolecarboxylate.

Ethyl 2-benzyl-5-hydroxy-3-indolecarboxylate (P) 70% yield (from startingnitrile) of a white powder. ’H NMR (250 MHz, DMSO) δ 1.32 (t, 7= 7.08 Hz,3H), 4.26 (q, 7= 7.05 Hz, 2H), 4.41 (s, 2H), 6.63 (dd, 7= 8.5, 2.2 Hz, 1H), 7.25 (m, 7H), 8.88 (s, 1H), 11.64 (s, 1H). 13c NMR (62.5 MHz, DMSO) δ 14.5,17.3,32.8,58.7,102.1,105.4,111.8, 126.2, 127.8,128.4, 129.3, 139.0, 146.1,152.3, 165.1. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mMNH4OAC/CH3CN, APCI+) t = 7.83, m/z = 296.3 (M+l).

Ethyl 2-ethyl-5-hydroxy-3-indolecarboxylate (Q) 54% yield (from starting nitrile)as a white powder. NMR (250 MHz, DMSO) δ 1.23 (t, 7= 7.6 Hz, 3H), 1.33 (t,7 = 7.1 Hz, 3H), 3.04 (q, 7= 7.5 Hz, 2H), 4.24 (q, 7= 7.1 Hz, 2H), 6.5 (dd,7= 8.7,2.4 Hz, 1H), 7.14 (d, 7= 8.5 Hz, 1H), 7.33 (d, 7= 2.4 Hz, 1H), 8.82, (s,1H), 11.48 (s, 1H). Î3C NMR (62.5 MHz, DMSO) δ 13.6, 14.4, 20.7, 58.4, 105.3, 111.3,111.6,127.9,128.9,150.0, 152.2, 165.0. LC/MS (150 mm x 4.6 mm, C-18,5 micron, 10 mM NH4OAc/CH3CN, APCI+) î = 7.60 min, m/z = 234.3 (M+l).

Ethyl 2-cyclopropyl-5-hydroxy-3-indoIecarboxylate (R) 83% yield (from startingnitrile) as a white powder. !h NMR (250 MHz, DMSO) δ 0.97 (m, 2H), 1.10 (m,2H), 1.35 (t, 7= 7.1 Hz, 3H), 3.00 (m 1H), 4.26 (q, 7= 7.0 Hz, 2H), 6.59 (dd, 8.7, -56- 11820 2.4 Hz, 1H), 7.8 (d, 7 = 8.7 Hz, 1H), 7.30 (d, 7 = 2.4 Hz, 1H), 8.81 (s, 1H), 10.93 (s, 1H). 13C NMR (62.5 MHz, DMSO) δ 8.8, 9.2, 14.5, 17.2, 21.0, 58.5, 102.9.105.1, 111.1, 111.4, 127.9,128.8,150.1, 152.1,165.4,171.9. LC/MS(150 mm x 4.6mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) î = 7.03 min, m/z = 246.3 (M+l).

Ethyl 5-hydroxy-2-propyl-3-indolecarboxylate (S) 62% yield (from startingnitrile) as a white powder. ^H NMR (250 MHz, DMSO) 5 0.93 (t, 7 = 7.3 Hz, 3H), 1.35 (t,7=7.1 Hz, 3H), 1.67 (m, 2H)3.01 (t,7=9.0 Hz, 2H), 4.26(q, 7= 7.1 Hz, 2H), 6.77 (dd, 7= 8.7, 2.2 Hz, 1H), 7.16 (d,7 = 8.6 Hz, 1H), 7.35 (d, 7=2.2 Hz, 1H), 8.86 (s, 1H), 11.51 (s, 1H). 13C NMR (62.5 MHz, DMSO) δ 13.7, 14.4, 17.2,22.3,29.2,58.4, 105.2, 111.3, 115.5, 127.9, 128.9, 148.4, 149.6, 152.1, LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t = 7.21 min, m/z = 248.4 (M+l).

Ethyl 2-isobutyl-5-hydroxy-3-indolecarboxylate (T) 68% yield (from startingnitrile) the as a white powder. ^H NMR (250 MHz, DMSO) δ 0.91 (d, 7= 6.6 Hz, 6H), 1.35 (t, 7= 7.1 Hz, 3H), 2.06 (m, 1H), 2.91 (d, 7= 7.2 Hz, 2H), 4.25 (q, 7=7.1 Hz, 2H), 6.62 (dd, 7= 8.6, 2.4 Hz, 1H), 7.16 (d, 7= 8.5 Hz, 1H), 7.35 (d, 7=2.4 Hz, 1H), 8.85 (s, 1H), 11.5 (s, 1H). 13C NMR (62.5 MHz, DMSO) δ 14.4, 17.2, 22.3,28.6,36.2,58.4, 102.0, 105,2,111.2, 111.4,127.9, 128.8, 147.6, 152.1,165.0. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t = 7.69 min, m/z = 262.4 (M+l).

Procedure E: General procedure for the préparation of indole amides 5-Acetoxy-2-methyl-lH-indole-3-carboxylic acid (1.0 g, 4.3 mmol) was dissolved in 10 mL of DMF, and Et3N (0.6 mL, 1 eq) was added. The solution was stirred for 5 minutes. The solution was cooled to 0°C and HBTU (1.63 g, 4.3 mmol) was added, then stirred for 15 minutes. The amine (2 N in THF, 4 eq)was added, and the solution stiired until the starting material was consumed, ~1 hour water was added. The pH of the resulting mixture was adjusted to 5 withHCl (IN), and extracted with ethyl acetate. The organic layer was dried and -57- 11820 evaporated to give the crude product which can be further purified by flashchromatography or recrystallization.

Intermediates U-V were synthesized according to Procedure E. Acetic acid 2-methyI-3-methylcarbamoyl-lH-indoI-5-yl ester (U) Yield: 0.093 g (18%);mp 201-203°C; IR: 3402,1748,1609,1218, 1170 cm'1. *H NMR (DMSO-d6) δ 2.21 (s, 3H, CH3CO), 2.45 (s, 3H, ArCH3), 2.72 (d, 7= 4.39 Hz, 3H, NHC//3),6.76 (dd, 7= 8.79,1.46 Hz, 1H, ArH), 7.24 (d, 7 = 8.79 Hz, 1H, ArH), 7.25 (bs,1H, CONHCH3), 7.41 (s, 1H, ArH), 11.5 (s, 1H, indoleNH). MS(APCI+): m/z 247.1 (MH+); Analysis calculated for C13H14N2O3O.9 H2O; C, 59.49; H, 6.07; N, 10.67. Found: C, 59.51; H, 6.1¾ N, 10.55.

Acetic acid 3-benzylcarbamoyl-2-methyl-lH-indol-5-yl ester (V) Yield: 0.454 g(33%); mp 182-184°C; IR: 3413, 3319, 3222, 3191, 1750, 1609,1228, 1216, 1170 cm'1. JH NMR (DMSO-d6) δ 2.20 (s, 3H, CH3CO), 2.54 (s, 3H, ArCH3), 4.42 (d, 7 = 6.1 Hz, 2H, NHCH2Ph), 6.77 (dd, 7= 8.55, 1.95 Hz, 1H, ArH), 7.15-7.19 (m, 1H, ArH), 7.25-7.34 (m, 5H, ArH), 7.45 (d, 7= 1.71 Hz, 1H, ArH), 7.89 (t, 7= 6.10 Hz, 1H, CONtfCH2Ph), 11.5 (s, 1H, indole NH). MS(APCI+): m/z 323.2 (MH+); Analysis calculated for Ci9H]gN2O3: C, 70.79, H, 5.63, N,8.69. Found: C, 70.62, H, 5.78, N, 8.60.

Procedure F: General procedure for déacylation of the amides

The amide of interest (1 eq) was dissolved in a small amount of MeOH.

MeONa (4 eq) was added and the mixture stirred until no starting materialremained, ~45 minutes. The pH of the solution was adjusted to 1 with the additionof aqueous HCl, and the solution extracted with 2 x 25 mL of ethyl acetate. Theorganic layer was dried and evaporated to give a solid. Recrystallization fromethyl acetate yields a white solid.

Intermediates W-X were synthesized according to Procedure F. 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid methyl amide (W) Yield:

O. 201 g (70%); mp 226-227°C; IR: 3366, 1602, 1558, 1552, 1215, 1198 cm'1. 1H 118 2 0 -58- NMR (DMSO-dg) δ 2.45 (s, 3H, ArCH3} obscured by DMSO peak), 2.70 (d, J = 4.40 Hz, 3H, CONHC//3), 6.51 (d,7= 8.55 Hz, 1H, ArH), 7.02 (d, 7 = 8.55 Hz, 1H, ArH), 7.07 (s, 1H, ArH), 7.13-7.14 (m, 1H, CON//CH3), 8.65 (s, 1H, OH), 11.0 (s, 1H, indole NH). MS(APCI+): m/z 205.1 (MH+); Analysis5 calculated for Cj 1H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.53; H, 5.91; N, 13.44. 5-Hydroxy-2-methyl-lH-indoIe-3-carboxylic acid benzyl amide (X) Yield: 0.228 g (65.7%); mp: 194-196°C; IR: 3392, 3246, 1610,1528, 1465, 1214, 1188 cm-1. NMR (DMSO-dg) δ: 2.48 (s, 3H, ArCH3), 4.41 (d, 7= 5.86 Hz, 10 2H, NHCÆ2Ph), 6.52 (d, 7= 8.06, 1H, ArH), 7.04 (d, 7= 8.55, 1H, ArH), 7.12 (s, 1H, ArH) 7.17-7.31 (m, 5H, ArH), 7.71-7.78 (m, 1H, CON//CH2Ph), 8.68 (s, 1H, OH), 11.1 (s, 1 H, indole NH). MS(APCI+): m/z 281.1 (MH+); Analysis calculatedfor Ci7H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.78; H, 5.70; N, 9.87.

Example 1 15 Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester

Synthesized according to procedures published in 7. Het. Chem.,1970;7:1311-1319. 20 Example 2

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 8,9,1 l,12,13,13a,14,14a-octahydro-2-methyl-, (4-fluorophenyl)methyl ester 11320 -59-

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-fluoro-benzyl ester

To a solution of 5-hydroxy-2-methyl-l-H-indole-carboxylic acid (4.6 g, 24.1 mmol) in DMF (100 mL) was added DBU (3.67 g, 24.1 mmol) followed by 4-fluorobenzyl bromide (5.0 g, 26.5 mmol). The resulting mixture was stirred atroom température under nitrogen for 3 days and then partitioned between ethylacetate (200 mL) and water (200 mL). The organic phase was separated, washedwith water (2 x 100 mL) and then dried over Na2SO4 and concentrated in vacuoto give a white solid. Recrystallization from ethyl acetate gave 3.4 g (47%) of puretitled compound as a white solid: mp 209-210°C; IR 3412, 3377, 3305,1667, 1512, 1466, 1221,1176, 1094 cm’1; ]H NMR (DMSO-d6) δ 2.53 (s, 3H, CH3), 5.23 (s, 2H, CH2), 6.55 (dd, J = 8.79, 2.20 Hz, 1H, ArH), 7.08 (d, /= 8.79 Hz, 1H, ArH), 7.14-7.17 (m, 2H, ArH), 7.19 (d, J = 2.20 Hz, ÎH, ArH), 7.44-7.48 (m,2H, ArH), 8.81 (s, 1H, OH), 11.55 (s, 1H, NH); MS(APCI+): m/z 300.1 (MH+).Analysis calculated for C17H14F N O3: C, 68.22; H, 4.71; N, 4.68. Found: C, 67.91; H, 4.65; N, 4.59.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid 4-fluoro-benzyl ester 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-fluoro-benzyl ester(2.90 g, 9.69 mmol) and aqueous Me2NH (40%, 2.67 mL, 21.3 mmol) weremixed with 22 mL of EtOH, aqueous HCHO (37%, 0.940 g, 11.6 mmol) was thenadded. The resulting reaction mixture was heated with a heatgun until a clearsolution was obtained. The reaction mixture was stirred at 50°C for 16 hours. Thereaction mixture was allowed to stand at 4°C for 15 hours, white precipitateformed. Filtration and drying under vacuum gave 1.56 g (45%) of pure titledcompound as a white solid: mp 131-133°C (dec.); IR 3376,3214, 1693,1686, -60- 118 2 0 1513, 1424, 1259, 1227, 1085, 806 cm’1; !H NMR (DMSO-d6) δ 2.12 (s, 6H,N(C//3)2), 2.45 (s, 3H, ArCH3), 3.97 (s, 2H, ArCH2NMe2), 5.23 (s, 2H,CO2CH2Ar), 6.56 (d, J= 8.61 Hz, 1H, ArH), 7.06 (d, J= 8.61 Hz, 1H, ArH),7.18-7.24 (m, 2H, ArH), 7.49-7.54 (m, 2H, ArH), 11.5 (bs, 1H, exchangeableproton); MS(APCI+): m/z 357.2 (MH+). Analysis Calculated forC20H21N2O3F1O.IH2O: C, 67.06; H, 5.97; N, 7.82; F, 5.30; H2O, 0.50. Found: C, 66.90; H, 5.81; N, 7.53; F, 5.33; H2O, 0.20.

Step C: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, (4-fluorophenyl)methylester

To a mixture of perchlorate sait (1.27 g, 5.36 mmol, Example 3, Step B)and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solid had dissolved. Two layerswere separated, and the aqueous layer was extracted with ether (2x50 mL).Combined ether layer was dried over Na2SO4 and concentrated in vacuo. Theresidual oil was dissolved in 15 mL of dioxane, then indole mannich base (1.47 g, 4.12 mmol) was added; the resulting reaction mixture was refluxed under nitrogenfor 5.5 hours. The reaction mixture was cooled to ambient température andconcentrated in vacuo affording a brown solid. Recrystallization from CH3CNgave 1.63 g (88%) of pure titled compound as a brown solid: mp 209-214°C(decomposed); IR 2934, 1704, 1152, 1431, 1235, 1148, 1078, 827 cm’1; *HNMR(DMSO-dg) δ 1.06-1.67 (m, 10H, aliphatic CH2 and CH), 1.81-1.86 (m, 1H, aliphatic CH), 2.30-2.46 (m, 2H, obscured by DMSO peak, aliphatic CH), 2.46 (s,3H, ArCH3), 2.60-2.70 (m, 2H, aliphatic CH), 2.84-2.91 (m, 1H, aliphatic CH), 3.17 (dd, J= 18.3, 6.78 Hz, 1H, aliphatic CH), 5.21 (ABq, Jab = 11.9 Hz,yab = 19.0 Hz, 2H, CO2CH2Ar), 6.59 (d, J= 8.61 Hz, 1H, ArH), 7.03 (d, J= 8.61 Hz, 1H, ArH), 7.17-7.25 (m, 2H, ArH), 7.48-7.52 (m, 2H, ArH), 11.5 (bs,1H, NH); MS(APCI+): m/z 449.3 (MH+). Analysis calculated for -61- 118 2 0 C27H29n2°3f1'°-08CH3CN: C, 72.20; H, 6.52; N, 6.45; F, 4.20. Found: C, 71.88; H, 6.35; N, 6.42; F, 4.15.

Example 3 (Intermediate)

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a, 15-5 decahydro-

Step A: 4-Dimethylaminomethyl-lH-indol-5-ol 5-HydroxyindoIe (Aldrich, Milwaukee, WI, 5.09 g, 38.2 mmol) was dissolved in 25 mL of EtOH, aqueous Me2NH (40%, 5.28 mL, 42.1 mmol) was 10 added followed by aqueous HCHO (37%, 3.65 g, 45.9 mmol). The resulting reaction mixture was stirred at ambient température for 1.5 hours during whichtime a precipitate formed. Filtration and drying under vacuum gave 4.13 g (57%)ofpuretitled compound as a beige solid: mp 137-139°C; IR 3316, 1625, 1592,1523,1450,1239, 1198,724 οηΛ NMR (DMSO-d6) δ 2.25 (s, 6H, 15 Ctf2N(CH3)2, 3.76 (s, 2H, Ctf2N(CH3)2), 6.29-6.30 (m, 1H, ArH), 6.54 (d, J= 8.61 Hz, 1H, ArH), 7.10 (d, J= 8.60 Hz, 1H, ArH), 7.18-7.20 (m, 1H, ArH), 10.8 (bs, 1H, exchangeable proton); MS(APCI+): m/z 191.1 (MH+). Analysiscalculated for Ci ιΗι4Ν2Ο: C, 69.45; H, 7.42; N, 14.72. Found: C, 69.36; H,7.38; N, 14.71. 20 StepB: 1,2,3,4,6,7,8,9-Octahydro-quinolizinylium perchlorate

1 1 8 2 0 1

The synthesis is found in David A. Evans, A new endocyclic enamine synthesis. JACS, 1970;92:7593-7595 and Leonard N.J., Hay A.S., FulmerR.W.,

Gash V.W., Unsaturated amines. III. Introduction of α,β-unsaturation by means of mercuric acetate: AK^)-dehydroquinolizidine, J. Am. Chem. Suc., 1955;77:439-444.

Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a, 15-decahydro-

To a mixture of perchlorate sait (406 mg, 1.71 mmol, Example 3, Step B)and 20 mL of ether was added 30 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail. solid had dissolved. Two layerswere separated, and the aqueous layer was extracted with ether (2 x 30 mL). Thecombined ether layer was dried over Na2SC>4 and concentrated in vacuo. Theresidual oil was dissolved in 5 mL of dioxane, then 4-dimethylaminomethyl-lH-indoI-5-ol (250 mg, 1.31 mmol) was added, the resulting reaction mixture wasrefluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambienttempérature and a precipitate formed. Filtration and recrystallization from EtOAcgave 0.17 g (46%) of pure titled compound as a beige solid: mp >250°C; ER 3414, 3148, 1454, 1242, 1148, 888 cm'1; ’HNMR (DMSO-dô) δ 1.13-1.65 (m, 9H,aliphatic CIL· and CH), 1.76-1.91 (m, 2H, aliphatic CH), 2.36-2.52 (m, obscuredby DMSO peak, 3H, aliphatic CH), 2.68-2.77 (m, 1H, aliphatic CH), 2.88-2.96 (m, 1H, aliphatic CH), 3.06 (dd,J = 17.6, 6.78 Hz, 1H, aliphatic CH), 6.22-6.23 (m, 1H, ArH), 6.56 (d, J= 8.61 Hz, 1H, ArH), 7.07 (d, J= 8.61 Hz, 1H,

ArH), 7.19-7.21 (m, 1H, ArH), 10.8 (bs, 1H, NH); MS(APCI+): m/z 383.1 (MH+).Analysis calculated for Ci8H22N2O-0.1H2O: C, 76.08; H, 7.87; N, 9.86; H2O, 0.63. Found: C, 76.09; H, 7.81; N, 9.83; H2O, 0.74.

Example 4 (Intermediate)

Pyrrolo[3',2' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl- -63- 11820

Step A: 2-Methyl-lH-indol-5-ol 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (Aldrich,Milwaukee, WI, 20.0 g, 91.2 mmol) was mixed with aqueous NaOH (2N, 365 mL,730 mmol), the resulting reaction mixture was refluxed under nitrogen for 1 hour.After cooling to 70àC, the reaction solution was treated with concentrated aqueousHCl until pH = 1. The resulting dark brown solution was extracted with ether (3 x300 mL). Combined ether solution was dried over Na2SC>4 and concentratedin vacuo affording a brown solid. Recrystallization from EtOAc/CH2Cl2 gave 11.7 g (87%) of pure titled compound as a Iight brown solid: mp 129-130°C; IR3387, 3333, 1588,1453,1368,1173,783 cm"1; NMR (DMSO-dg) δ 2.29 (s,3H, ArCH3), 5.88-5.89 (m, 1H, ArH), 6.45 (dd,J= 8.42,2.38 Hz, 1H, ArH), 6.68 (d, 7 = 2.38 Hz, 1H, ArH), 7.00 (d, 7= 8.42 Hz, 1H, ArH), 8.44 (s, 1H, NH), 10.5 (bs, 1H, OH); MS(APCI+): m/z 148.1 (MH+). Analysis calculated forC9H9NO: C, 73.45; H, 6.16; N, 9.52. Found: C, 7.13; H, 6.18; N, 9.41.

Step B: 4-Dimethylaminomethyl-2-methyl-lH-indol-5-ol 2-MethyI-lH-indol-5-ol (5.00 g, 34.0 mmol) was dissolved in 20 mL ofEtOH, aqueous Me2NH (40%, 9.40 mL, 74.7 mmol) was added followed by aqueous HCHO (37%, 3.30 g, 40.8 mmol). The resulting reaction mixture wasstirred at ambient température for 2 hours, then mixed with 50 mL of water,precipitate formed. Filtration and recrystallization from éthanol (<50°C) gave3.0 g (43%) of pure titled compound as a white solid: mp 133-135°C; IR 3404,3385,1598,1515, 1428, 1271,1204, 798, 778 cm-1; ÎHNMR (DMSO-d6) δ 2.23 (s, 6H, N(CH3)2), 2.30 (s, 3H, ArCH3), 3.68 (s, 2H, CH2N), 5.98 (s, 1H,ArH), 6.42 (d, J= 8.42 Hz, 1H, ArH), 6.95 (d, 7= 8.79 Hz, 1H, ArH), 10.6 (bs, 11820 1H, exchangeable proton); MS(APCI+): m/z 205.2 (MH+). Analysis calculated for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.39; H, 7.87; N, 13.75. -64-

Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl- 5 To a mixture of perchlorate sait (973 mg, 4.10 mmol, Example 3, Step B) and 30 mL of ether was added 40 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solid had dissolved. Two layerswere separated, and the aqueous layer was extracted with ether (2 x 40 mL).Combined ether layer was dried over Na2SC>4 and concentrated in vacuo. The 10 residual oil was dissolved in 7 mL of dioxane, then 4-dimethylaminomethyl- 2-methyl-lH-indol-5-ol (697 mg, 3.41 mmol) was added, the resulting reactionmixture was refluxed under nitrogen for 16 hours. The reaction mixture wascooled to ambient température and concentrated in vacuo affording a brown solid.Trituration with EtOAc gave 1.01 g (59%) of pure titled compound as a beige 15 solid: mp 267-270°C (dec.); IR 3407, 3189, 2926,1435, 1212, 1197,774 cm-1; ÎH NMR (DMSO-dg) δ 1.13-1.64 (m, 9H, aliphatic CH2 and CH), 1.74-1.89 (m,2H, aliphatic CH), 2.31 (s, 3H, CH3), 2.35-2.50 (m, obscured by DMSO peak, 3H,aliphatic CH), 2.67-2.75 (m, 1H, aliphatic CH), 2.87-3.31 (m, 2H, aliphatic CH), 5.92 (m, 1H, ArH), 6.45 (d, 7=8.61 Hz, 1H, ArH), 6.94 (d, J= 8.79 Hz, 1H, 20 ArH), 10.6 (bs, 1H, exchangeable proton); MS(APCI+): m/z 297.1 (MH+).

Analysis calculated for C19H24N2O: C, 76.99; H, 8.16; N, 9.45. Found: C, 76.79;H, 8.19; N, 9.35. 11820 ’ -65-Example 5

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-bromo-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester

•CH, 5 Step A: 6-Bromo-4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester 6-Bromo-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester,prepared according to the literature procedure [Bell M.R.; Oesterlin R.; Beyler A.L.; Harding H.R.; Potts G.O., J. Med. Chem., 1967;10:264-266], (3.01 g, 10 10.1 mmol) and aqueous Me2NH (40%, 2.79 mL, 22.2 mmol) were mixed with 30 mL of EtOH, the mixture was heated with a heatgun until a clear solution wasobtained. After cooled to ambient température, aqueous HCHO (37%, 0.982 g, 12.1 mmol) was added. The resulting reaction mixture was stirred at ambienttempérature for 48 hours during which time white precipitate formed. Filtration 15 and drying under vacuum gave 1.91 g (53%) of pure titled compound as a whitesolid: mp 179-180°C (dec.); IR 3339, 1700,1688, 1426,1092, 833 cm-1; NMR (DMSO-d6) δ 1.30 (t, J= 7.14 Hz, 3H, CH2Ctf3), 2.26 (s, 6H, N(CH3)2),2.49 (s, 3H, obscured by DMSO peak, ArCH3), 4.16 (s, 2H, ArCH2NMe2), 4.23 (q, J =6.96 Hz, 2H, C//2CH3), 7.38 (s, 1H, ArH), 11.6 (bs, 1H, 20 exchangeable proton); MS(APCI+): m/z 355.0 (MH+). Analysis calculated for

Ci5Hi9N2O3Br: C, 50.72; H, 5.39; N, 7.89; Br, 22.49. Found: C, 50.71; H, 5.31;N, 7.75; Br, 22.67. 25

Step B:

To a mixture of perchlorate sait (1.40 g, 5.90 mmol, Example 3, Step B)and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solid had dissolved. Two layers 113 2 0 -66- were separated, and the aqueous layer was extracted with ether (2 x 50 mL).Combined ether layer was dried over Na2SC>4 and concentrated in vacuo. Theresidual oil was dissolved in 20 mL of dioxane, then bromoindole mannich base(1.61 g, 4.54 mmol) was added, the resulting réaction mixture was refluxed undernitrogen for 4 hours. The reaction mixture was cooled to ambient température andconcentrated in vacuo affording a thick oil. The crude product was further purifiedby chromatography (50% EtOAc in hexanes) to give a white foam, trituration withEtOAc/hexanes gave 1.42 g (54%) of pure titled compound as a white solid: mp1S4-185°C;IR 3295,2930, 1662, 1426,1185,1110,1081,869 cm'1; }H NMR(CDC13) δ 1.15-2.08 (m, 11H, aliphatic CH2 and CH), 1.39 (t, J= 7.14 Hz, 3H,CH2C//3), 2.45-2.65 (m, 2H, aliphatic CH), 2.60 (s, 3H, ArCH3), 2.85-3.00 (m, 2H, aliphatic CH), 3.17-3.30 (m, 1H, aliphatic CH), 3.50 (dd, 7= 18.0, 6.96 Hz,1H, aliphatic CH), 4.34 (q, J= 7.14 Hz, CÆ2CH3), 7.35 (s, 1H, ArH), 8.10 (bs, 1H, NH); MS(APCI+): m/z 447.1 (MH+). Analysis calculated for c22H27N3°3Br: c> 59.06; H, 6.08; N, 6.26; Br, 17.86. Found: C, 59.11; H, 6.07;N, 6.07; Br, 17.97.

Example 6

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,I3,14,14a,15-decahydro-2-methyl-, propyl ester

CH3

Step A: 5-Hydroxy-2-methyl-lH-indoIe-3-carboxylic acid propyl ester5-Acetoxy-2-methyl-lH-indole-3-carboxylic acid propyl ester (intermediate D, 2.04 g, 7.42 mmol) was mixed with 20 mL of methanol,NaOCH3 (1.60 g, 29.6 mmol) was then added. The resulting reaction mixture wasstirred at ambient température for 1.5 hour. The reaction mixture was then mixedwith 20 mL of water, the resulting reaction mixture was treated with 5% HCl until 118 2 0 -67- pH = 1 affording a white precipitate. The solid was isolated by filtration andrecrystallized from EtOAc/hexanes to give 1.39 g (80%) pure titled compound asa beige solid, mp 188-189°C (dec.); IR 3381,3297, 1661,1457,1178, 1090, 794,783 cm'1; ^HNMR (DMSO-dg) δ 0.989 (t, 7=7.51 Hz, 3H, CH2CH2C//3), 1.72 (sextet, 7= 7.14 Hz, 2H, CH2C//2CH3), 2.57 (s, 3H, ArCH3), 4.14 (t, 7= 6.41 Hz, 2H, C//2CH2CH3), 6.58 (dd, 7= 8.42,2.20 Hz, 1H, ArH), 7.11 (d,7=8.61 Hz, 1H, ArH), 7.29 (d,7= 2.20 Hz, 1H, ArH), 8.83 (s, 1H, OH), 11.5 (bs,1H, NH); MS(APCI+): m/z 234.1 (MH+). Analysis calculated for

Ci3Hi5N03-0.06H20: C, 66.63; H, 6.50; N, 5.98. Found: C, 66.27; H, 6.38; N,5.84.

Step B: 4-DimethylaminomethyI-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid propyl ester 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid propyl ester (1.27 g, 5.43 mrnol) and aqueous Me2NH (40%, 1.50 mL, 12.0 mmol) were mixed with10 mL of EtOH, the mixture was heated with a heat gun until a clear solution wasobtained. After cooled to ambient température, aqueous HCHO (37%, 0.528 g, 6.52 mmol) was added. The resulting reaction mixture was stirred at ambienttempérature for 3 days. The reaction mixture was then concentrated in vacuo toreduce the volume by half. Precipitate formed. Filtration and drying under vacuumgave 0.86 g (54%) ofpure titled compound as a white solid: mp 135-137°C (dec.);IR 3217, 2969, 1684, 1420, 1141, 1075 cm-h *H NMR (DMSO-d6) δ 0.953 (t, 7= 7.32 Hz, 3H, CH2CH2C//3), 1.70 (sextet,7= 7.33 Hz, 2H, CH2C//2CH3), 2.19 (s, 6H, N(C7/3)2), 2.49 (s, 3H, obscured by DMSO peak, ArCH3), 4.06 (s,2H, ArCH2NMe2), 4.13 (t, 7= 6.78 Hz, 2H, Œ2CH2CH3), 6.56 (d, 7= 8.61 Hz,1H, ArH), 7.07 (d, 7= 8.42 Hz, 1H, ArH), 11.5 (bs, 1H, exchangeable proton);MS(APCI+): m/z 291.1 (MH+). Analysis calculated for C16H22N2O3: C, 66.19;H, 7.64; N, 9.65. Found: C, 65.94; H, 7.67; N, 9.31. -68- 118 2 0

Step C: Το a mixture ofperchlorate sait (0.763 g, 3.21 mmol, Example 3, Step B)and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solid had dissolved. Two layerswere separated, and the aqueous layer was extracted with ether (2 x 30 mL).Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole Mannich base(0.717 g, 2.47 mmol) was added; the resulting reaction mixture was refluxedunder nitrogen for 3 hours. The reaction mixture was cooled to ambienttempérature and concentrated in vacuo affording a thick oil. The crude productwas further purified by chromatography (50% EtOAc in hexanes) to give a whitesolid. Recrystallization from CH3ÇN gave 0.67 g (70%) of pure titled compoundas a white solid: mp 162-164°C; IR 3329, 2931, 1702,1665, 1434, 1235, 1200,1149, 1079, 948, 781 cnr1; !HNMR (CDCI3) δ 0.992 (t, 7=7.32 Hz, 3H,CH2CH2C//3), 1.76 (sextet, 7 = 7.08 Hz, 2H, CH2C//2CH3), 1.29-1.86 (m, 10H,aliphatic CH2 and CH), 2.11 (d, 7= 13.43 Hz, 1H, aliphatic CH), 2.27-2.58 (m, 2H, aliphatic CH), 2.58 (s, 3H, ArCH3), 2.82-2.86 (m, 2H, aliphatic CH), 3.00-3.10 (m, 1H, aliphatic CH), 3.46 (dd, 7= 18.1, 6.84 Hz, 1H, aliphatic CH), 4.21 (t, 7 =6.84 Hz, C//2CH2CH3), 6.73 (d, 7= 8.79 Hz, 1H, ArH), 7.01 (d, 7= 8.79 Hz, 1H, ArH), 8.06 (bs, 1H, NH); MS(APCI+): m/z 383.1 (MH+).

Analysis calculated for C23H3QN2O3: C, 72.22; H, 7.91; N, 7.32. Found: C, 72.19; H, 7.88; N, 7.36.

Example 7

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methylpropyl ester 1 1 R 2 0

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxyIic acid isobutyl ester(intermediate H, 1.03 g, 4.17 mmol) and aqueous Me2NH (40%, 1.15 mL, 9.17 mmol) were mixed with 4 mL of EtOH, aqueous HCHO (37%, 0.406 g, 5.01 mmol) was then added. The resuîting reaction mixture was heated with a heatgun until a clear solution was obtained. The reaction mixture was stirred at 50°Cfor 4.5 hours. The reaction mixture was then allowed to stand for 16 hours at 4°C.Cotton-like white crystals formed. Filtration and drying under vacuum gave 0.62 g(49%) of pure titled compound as a white solid: mp 122-124°C (dec.); IR 3229,2957, 1686, 1424, 1242, 1085, 1000 cm’h NMR (DMSO-d6) Ô 0.951 (d, J= 6.59 Hz, 6H, CH2CH(C773)2), 1.98 (m, J= 6.59 Hz, 1H, CH2C77(GH3)2), 2.18 (s, 6H, N(Ctf3)2), 2.50 (s, 3H, obscured by DMSO peak, ArCH3), 3.97 (d, J = 6.59 Hz, 2H, C7/2CH(CH3)2), 4.07 (s, 2H, ArC^NMeg), 6.56 (d, 7=8.61 Hz, ΙΗ,ΑτΗ), 7.06 (d, 7= 8.42 Hz, 1H, ArH), 11.5 (bs, 1H,exchangeable proton); MS(APCI+): m/z 305.2 (MH+). Analysis calculated forCi7H24N2O3-I.03H2O: C, 63.23; H, 8.13; N, 8.67. Found: C, 62.84; H, 7.30; N,8.44.

Step B:

To a mixture of perchlorate sait (0.458 g, 1.93 mmol, Example 3, Step B)and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resuîtingmixture was shaken in a separatory funnel until ail solid had dissolved. Two layerswere separated, and the aqueous layer was extracted with ether (2 x 30 mL).Combined ether layer was dried over Na2SO4 an<^ concentrated in vacuo. Theresidual oil was dissolved in 5.0 mL ofdioxane, then indole mannich base(0.451 g, 1.48 mmol) was added, the resuîting reaction mixture was refluxed 11 s 2 0 -70- under nitrogen for 3 hours. The reaction mixture was cooled to ambienttempérature and concentrated in vacuo affording a thick oil. The crude productwas further purified by chromatography (50% EtOAc in hexanes) to give 0.40 g(52%) of pure titled compound as a white solid: mp 203-204.5°C; IR 3341, 2933,1700, 1673, 1434, 1236, 1082, 886, 781 cnr*; *H NMR (CDC13) δ 0.984 (d, 7= 6.84 Hz, 6H, CH2CH(C7f3)2), 1.32-1.90 (m, 10H, aliphatic CH2 and CH),2.04 (m,J = 6.59 Hz, 1H, CH2C//(CH3)2), 2.08-2.18 (m, 1H, aliphatic CH), 2.40-2.60 (m, 2H, aliphatic CH), 2.59 (s, 3H, ArCH3), 2.84-2.88 (m, 2H, aliphaticCH), 2.97-3.10 (m, 1H, aliphatic CH), 3.46 (dd, J= 18.1, 6.84 Hz, 1H, aliphaticCH), 4.00-4.09 (m, 2H, Ctf2CH(CH3)2), 6.73 (d, J= 8.79 Hz, 1H, ArH), 7.02 (d, J= 8.79 Hz, 1H, ArH), 8.05 (bs, 1H, NH); MS(APCI+): m/z 397.2 (MH+).Analysis calculated for C24H32N2C>3: C, 72.70; H, 8.13; N, 7.06. Found: C, 72.85; H, 8.19; N, 7.00.

Example 8

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,S,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2-dimethylpropyl ester

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2,2-dimethyl propylester (intermediate I, 1.55 g, 5.93 mmol) and aqueous Me2NH (40%, 1.64 mL, 13.1 mmol) were mixed with 4 mL of EtOH, aqueous HCHO (37%, 0.406 g, 5.01 mmol) was then added. The resulting reaction mixture was heated with a heatgun until a clear solution was obtained. The reaction mixture was stirred at 50°Cfor 4.5 hours. The reaction mixture was mixed with 50 mL of EtOAc, the mixturewas washed with water (2 x 50 mL), the organic phase was dried overNa2SÛ4 and concentrated in vacuo affording a thick oil. The crude product was -71- 118 2 0 further purified by flash chromatography (10%-20% methanol in CHCI3 to give0.90 g (48%) ofpure titled compound as a white solid: mp 150-151°C (dec.); IR3251, 2953, 1690, 1424, 1238, 1081, 801 cm"!; *H NMR (DMSO-d6) δ 0.970 (s,9H, CH2C(C//3)3), 2.18 (s, 6H, N(CH3)2), 2.52 (s, 3H, ArCH3), 3.91 (s, 2H,Œ2C(CH3)3), 4.08 (s, 2H, ArCH2NMe2), 6.57 (d, 7= 8.42 Hz, 1H, ArH), 7.07 (d, J~ 8.61 Hz, 1H, ArH), 11.5 (bs, 1H, exchangeable proton); MS(APC1+):m/z 319.2 (MH+). Analysis calculated for CigH2bN2O3: C, 67.90; H, 8.23; N, 8.80. Found: C, 67.53; H, 8.04; N, 8.57.

Step B:

To a mixture of perchlorate sait (0.710 g, 2.23 mmol, Example 3, Step B)and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solid had dissolved. Two layerswere separated, and the aqueous layer was extracted with ether (2 x 30 mL).Combined ether layer was dried over Na2SC>4 and concentrated in vaciio. Theresidual oil was dissolved in 5.0 mL of dioxane, then indole Mannich base(0.690 g, 2.90 mmol) was added, the resulting reaction mixture was refluxedunder nitrogen for 4 hours. The reaction mixture was cooled to ambienttempérature and concentrated in vacuo affording a thick oil. The crude productwas further purified by chromatography (50% EtOAc in hexanes) to afford awhite solid. Recrystallization from CH3CN gave 0.92 g (44%) of pure titledcompound as a white solid: mp 240-243°C; IR 3187, 2934, 1700, 1433, 1235,1077, 883, 780 cm'1; ]H NMR (DMSO-d6) δ 0.96 (d, 9H, CH2C(Ctf3)3),1.19-1.57 (m, 9H, aliphatic CH2 and CH), 1.70-1.80 (m, 1H, aliphatic CH),1.76-1.85 (m, 1H, aliphatic CH), 2.34-2.45 (m, 2H, obscured by DMSO peakaliphatic CH), 2.53 (s, 3H, ArCH3), 2.63-2.79 (m, 2H, aliphatic CH), 2.85-2.95 (m, 1H, aliphatic CH), 3.25-3.35 (m, 1H, obscured by water peakaliphatic CH), 3.94 (ABq, 7ab = 10.62 Hz, rab = 24.1 Hz, 2H, Ctf2C(CH3)3), 6.61 (d, 7=8.42 Hz, 1H, ArH), 7.04 (d, 7= 8.61 Hz, 1H, ArH), 11.51 (bs, 1H, -72- 118 2 0 NH); MS(APCI+): m/z 411.3 (MH+). Analysis calculated for C24H32N2O3: C, 73.14; H, 8.35; N, 6.82. Found: C, 73.16; H, 8.52; N, 6.77.

Procedure G: General procedure for the Mannich reaction

The 5-hydroxy indole ester of choice, (2.2-17.9 mmol, 1 eq) was dissolved 5 in EtOH by stirring while warming the solution; the solution was cooled. AqueousHCHO (37%, 1.2 eq) and Me2NH (40%, 2.2 eq) were added, and the reaction wasstirred at 50°C until the ratio of starting material to product was constant. Theéthanol was removed in vacuo, the brown oil was purified by flash chromatography (using MeOH/CHCl3 as the eluent) to afford the desired product. 10 Example 9

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenylmethyl ester

Step A: 15 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester was synthesized from intermediate C according to Procedure GYield: 3.36 g (55%); ^H NMR (DMSO-d0) δ 2.10 (s, 6H, CH2N(Ctf3)2), 2.45 (s,3H, ArCH3), 3.97 (s, 2H, CH2NMe2), 5.21 (s, 2H, ZZ^ZH^, 6.53 (d, J= 8.30 Hz, 1H, ArH), 7.04 (d, J= 8.55 Hz, 1H, ArH), 7.29-7.43 (m, 5H, ArH), 20 11.5 (s, 1H, NH). MS(APCI+): m/z 339.1 (MH+).

Step B:

By a procedure similar to that described in Example 7, Step CYield: 3.30 g (77%); mp 162-164°C; IR: 2930,2855,1700, 1432, 1077 cm-LJH NMR (DMSO-dg) δ 1.11-1.67 (m, 10H, aliphatic CH2 and CH), 1.82-1.86 (m, 11 A 2 Ο -73- 1H, aliphatic CH), 2.30-2.48 (m, 2H, obscured by DMSO peak, aliphatic CH), 2.4S (s, 3H, ArCH3), 2.62-2.70 (m, 2H, aliphatic CH), 2.86-2.92 (m, 1H, aliphaticCH), 3.19 (dd, 7= 18.3, 6.78 Hz, 1H, aliphatic CH), 5.23 (ABq, 7ab = 12.1 Hz,?ab = 16.4 Hz, 2H, CO2C//2Ph), 6.59 (d, 7= 8.61 Hz, 1H, ArH), 7.03 (d, 5 J= 8.61 Hz, IH, ArH), 7.30-7.46 (m, 5H, ArH), 11.5 (bs, 1H, NH); MS(APCI+): 431.2 (MH+). Analysis calculated for C27H3oN203: C, 75.35; H, 7.02; N, 6.51.Found: C, 75.16; H, 6.97; N, 6.47. 10

Example 10

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methylethyl ester

15

Step A: 4-DimethyIaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acidisopropyl ester was synthesized from intermediate E according to Procedure G.Yield: 0.490 g (61%); !H NMR δ 1.26 (d, J= 6.35 Hz, 6H, CH(CH3)2), 2.17 (s,6H, CH2N(CH3)2), 2.45 (s, 3H, ArCH3), 4.03 (s, 2H, CH2NMe2), 5.04 (sextet, J = 6.35, 1H, CO2Ctf(CH3)2), 6.52 (d,7= 8.55 Hz, 1H, ArH), 7.02 (d, 7 = 8.55 Hz, 1H, ArH), 11.4 (s, 1H, NH). MS(APCI+): m/z 291.1 (MH+).

Step B: 20 By a procedure similar to that described in Example 7, Step C.

Yield: 0.390 g (60.4%); mp 186-188°C; IR: 2976,2930,2856,1703,1433, 1079 cm’1. !H NMR (DMSO-d6) δ 1.10-1.57 (m, 9H, aliphatic CH2 and CH), 1.23 (d, J= 5.62 Hz, 3H, CH3), 1.25 (d,7= 5.86 Hz, 3H, CH3), 1.71-1.74 (m, 1H,aliphatic CH), 1.85-1.88 (m, 1H, aliphatic CH), 2.32-2.44 (m, 2H, obscured by 118201 -74- DMSO peak, aliphatic CH), 2.44 (s, 3H, ΑιΟΗβ), 2.63-2.74 (m, 2H, aliphaticCH), 2.83-2.89 (m, 1H, aliphatic CH), 3.21-3.28 (m, 1H, aliphatic CH, obscuredby water peak), 5.01 (septet, 1H, CO2C//(CH3)2), 6.56 (d, 7 = 8.79 Hz, 1H, ArH), 6.99 (d, 7= 8.80 Hz, 1H, ArH), 11.4 (bs, 1H,NH); MS(APCI+): 383.1 (MH+).Analysis calculated for C23H30N2O3: C, 72.22; H, 7.91; N, 7.32. Found: C, 71.98; H, 7.85; N, 7.29.

Example 11

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,S,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclopropylmethyl ester

Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acidcyclopropyl methyl ester was synthesized front intermediate F according toProcedure G. Yield: 0.406 g (62.1%); ^H NMR (DMSO-d6) δ 0.309-0.346 (m, 2H, cyclopropyl CH2CH2), 0.538-0.584 (m, 2H, cyclopropyl CH2CH2), 1.16-1.24 (m, 1H, cyclopropyl CH), 2.23 (s, 6H, CH2N(C#3)2), 2.52 (s, 3H,ArCH3), 4.02 (d, J = 7.32, 2H, CO2C//2CH), 4.10 (s, 2H, CH2NMe2), 6.58 (d,7= 8.55 Hz, 1H, ArH), 7.09 (d,7= 8.55 Hz, 1H, ArH), 11.5 (s, ΙΗ,ΝΗ).MS(APCI+): m/z 303.1 (MH+).

Step B:

By a procedure similar to that described in Example 7, Step C. Yield: 0.269 g (50.7%); mp 199-200°C; IR: 3376, 3337, 2932,2857, 1698, 1669,1433,1081 cm'l. NMR (CDCI3) δ 0.337-0.373 (m, 2H, cyclopropyl CH2CH2),0.596-0.641 (m, 2H, cyclopropyl CH2CH2), 1.21-1.89 (m, 10H, aliphaticCH2 and CH), 2.15-2.18 (m, 1H, aliphatic CH), 2.48-2.64 (m, 2H, obscured by 11820 -75- ΑτΟΗβ peak, aliphatic CH), 2.64 (s, 3H, ΑίΟΗβ), 2.86-2.96 (m, 2H, aliphaticCH), 3.00-3.10 (m, 1H, aliphatic CH), 3.52 (dd, 7= 18.1, 6.84 Hz, 1H, aliphaticCH), 4.07-4.17 (m, 1H, CO2CH2), 6.77 (d, J= 8.55 Hz, 1H, ArH), 7.06 (d, 7= 8.79 Hz, 1H, ArH), 8.10 (bs, 1H, NH); MS(APC1+): 395.1 (MH+). Analysis5 calculated for C24H3qN2Û3 : C, 73.07; H, 7.66; N, 7.10. Found: C, 72.96; H, 7.70; N, 6.97.

Example 12

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(l -pi péri d i nyl)ethy 1 ester

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2-piperdin-l-yl-ethylester (intermediate J, 0.770 g, 2.55 mmol) and aqueous Me2NH (40%, 0.704 mL, 5.60 mmol) were mixed with 2 mL of EtOH, aqueous HCHO (37%, 0.248 g, 15 3.06 mmol) was then added. The resulting reaction mixture was heated with a heatgun until a clear solution was obtained. The reaction mixture was stirred at50°C for 2 days. The reaction mixture was then diluted with EtOAc, then washedwith water and dried over Na2SO4- The solution was concentrated in vacuoaffording an oil. The crude product was further purified by flash chromatography 20 (10%-20% MeOH in CHCI3) to give an oil (402 mg, 44% crude yield) which was the desired product with minor impurities: 1 H NMR (DMSO-dg) δ 1.31 -1.33 (m,2H, piperidine CH2), 1.40-1.45 (m, 4H, 2 x piperidine CH2), 2.16 (s, 6H,CH2N(CH2N(C#3)2), 2.30-2.40 (m, 4H, 2 x piperidine CH2), 2.47 (s, 3H,ArCH3), 2.52-2.55 (m, 2H, OCH2CÆ2N), 4.01 (s, 2H, Ctf2N(CH3)2), 4.22 (t, 7= 118 2 0 -76- 5.86 Hz, 2H, OCtf2CH2N), 6.52 (d, J = 8.55 Hz, 1H, ArH), 7.02 (d, J= 8.55 Hz, IH, ArH), 11.4 (bs, 1H, exchangeable proton); MS (APCI+): m/z 360.2 (MH+).

Step B:'

By a procedure similar to that described in Example 7, Step C. Yield:0.137 g (37%); mp 169-171 °C; IR: 2928,1696,1434,1094, 1081 cm*1. !H NMR(DMSO-dg) δ 1.11-1.54 (m, 15H, aliphatic CH2 and CH), 1.71-1.74 (m, 1H, aliphatic CH), 1.86-1.90 (m, 1H, aliphatic CH), 2.34-2.47 (m, 6H, obscured byDMSO peak, aliphatic CH), 2.47 (s, 3H, ArCH3), 2.52 (t, J= 5.62 Hz, 2H,OCH2Ctf2N), 2.62-2.71 (m, 2H, aliphatic CH), 2.84-2.89 (m, 1H, aliphatic CH), 3.24-3.33 (m, 1H, aliphatic CH, obscured by water peak), 4.14-4.26 (m, 2H,OCH2CH2N), 6.56 (d, J = 8.79 Hz, 1H, ArH), 7.00 (d, 8.55 Hz, 1H, ArH), II. 5 (bs, 1H, NH); MS(APCI+): m/z 452.3 (MH+). Analysis calculated forC27H37N3O3O.I5H2O: C, 71.38; H, 8.28; N, 9.25; H2O, 0.59. Found: C, 71.08;H, S.25; N, 9.02; H2O,0.21.

Procedure H: General Procedure for the Synthesis of Ethyl 2-alkyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylate. To a stirred solutionof ethyl 2-alkyI-5-hydroxy-3-indolecarboxylate (2.63 mmol) in éthanol (8 mL)was added formaldéhyde (0.24 mL, 3.16 mmol) and dimethylamine (0.73 mL, 5.80 mmol). The solution was stirred at 45°C for 3 hours, cooled and concentratedunder reduced pressure. The residue was subjected to flash columnchromatography (SiO2, 1:1 ethyl acetate/hexane then 10:1 ethyl acetate/ethanol)to afford the desired product.

Procedure I: General Procedure for the Synthesis of Ethyl 2-alkyl- [(pyrano[2,3-b]quinolizidine)[5,6-e]]indoIe-3-carboxylate. To a stirred solution ofNaOH (50% w/w, 100 mL) and ether (20 mL) was added iminium perchlorate sait(0.42 g, 1.78 mmol, Example 3, Step B). The solution was extracted with ether(10 x 100 mL), dried over MgSC>4 an^ concentrated under reduced pressure toafford the enamine as a white solid. To a stirred solution of dioxane 118 2 0 -77- (2.5 mL/mmol) was added the enamine (0.197 g, 1.43 mmol) and indole(1.43 mmol). The solution was refluxed ovemight, cooled to room température,concentrated under reduced pressure and subjected to flash columnchromatography (SiO2, 99:1 dichloromethane/methanol) to afford the desired 5 product.

Example 13

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(phenyImethyl)-, ethyl ester

10 StepA:

Ethyl 2-benzyl-4-(dimethylamino)methylene-5-hydroxy- 3-indolecarboxylate 84% yield as a white solid was synthesized fromintcrmediate P according to Procedure H. NMR (250 MHz, CD3OD) δ 1.38 (t,J = 7.2 Hz, 3H), 4.32 (q, J = 8.5 Hz, 2H), 4.46 (s, 2H), 6.68 (dd, J= 6.8, 2.5 Hz, 15 1H), 7.17 (m, 5H) 7.47 (d, J = 2.25 Hz, 1H). LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t = 7.86 min, m/z = 353.2 (M+l).

Step B:

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(phenylmethyl)-, ethyl ester was 20 synthesized according to Procedure I. 68% yield as a white solid. NMR(250 MHz, CDCI3) δ 1.36 (t, J= 7.2 Hz, 3H), 1.42 (m, 3H), 1.68 (m, 5H), 1.92 (m, 2H), 2.15 (d, J= 13.3 Hz, 1H), 2.53 (m, 2H), 2.85 (m, 2H), 3.09 (m, 1H), 3.48 (dd, J= 20.0, 7.5 Hz, 1H), 4.35 (q, J= 7.1 Hz, 2H), 4.40 (s, 2H), 6.75 (d,

J= 8.6 Hz, 1H), 6.96 (d, J» 8.7 Hz, 1H), 7.29 (m, 5H), 7.90 (s, 1H). 13C NMR -78- 118 2 0 (62.5 MHz, CDCI3) δ 34.5, 19.7, 25.0, 25.5, 27.0, 30.2, 31.2, 34.5, 36.7, 49.6, 59.9,67,87.2, 107, 109.6, 111.4, 114.1, 126, 127.0, 128.9, 129.1, 138, 144, 149,167. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t = 10.73, m/z = 445.6 (M+l) Elemental Analysis Calculated: C, 75.64; H,7.25; N, 6.30. Found: C, 75.71; H, 7.34; N, 6.23.

Example 14

Pyrrolo(3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 2-ethyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester

Step A:

Ethyl 4-(dimethylamino)methylène-2-ethyl-5-hydroxy- 3-indolecarboxylate was synthesized from intermediate Q according toProcedure H 55% yield as a white solid. 1H NMR (250 MHz, DMSO) δ 1.23 (t,J = 7.4 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H), 2.46 (s, 6H), 2.91 (q, 7 = 7.6 Hz, 2H), 4.30 (q, 7=7.1 Hz, 2H), 4.44 (s, 2H), 6.61 (d, 7= 8.6 Hz, 1H), 7.11 (d,7= 8.4 Hz, 1H), 9.70 (bs, 1H). 13CNMR (62.5 MHz, DMSO) δ 14.1, 14.3, 17.3, 21.1,58.2, 59.1, 103.2, 110.8, 111.6, 112.1, 125.3, 129.4, 148.1, 153.0, 165.6.LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+)t = 6.25 min, m/z = 291.3 (M+l).

Step B:

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 2-ethyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester was synthesizedaccording to Procedure 143% yield as a white solid. ^H NMR (250 MHz, CDCI3) δ 1.34 (t,7= 7.6 Hz, 3H), 1.36 (t,7= 7.2 Hz, 3H), 1.63 (m, 5H), 1.88 (m, 3H), 2.15 (d, 7= 13.3 Hz, 1H), 2.47 (m, 2H), 2.82 (m, 2H), 3.02 (q, 7= 7.5 Hz, 2H), 118 2 0 -79- 3.48 (dd, J= 17.9, 6.8 Hz, 1H), 4.35 (q, J= 7.2 Hz, 2H), 6.77 (d, 8.7 Hz, 1H), 7.06 (d, J= 8.7 Hz, 1H), 7.26 (s, 1H), 8.19 (s, 1H). 13C NMR (62.5 MHz, CDCI3)δ 13.7,14.4, 19.7,21.8,25.0, 25.5,27.0, 30.1, 31.1, 36.7, 49.6, 59.8, 67.0, 87.1,106, 109.4, 113.8,126,130,148,149, 167. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) î = 10.75, m/z - 383.5 (M+l)

Elemental Analysis: Calculated C, 72.22; H, 7.90; N 7.32. Found C, 72.03; H, 7.96; N, 7.19.

Example 15

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14a, 15-decahydro-, ethyl ester

Step A:

Ethyl 2-cyclopropyl-4-(dimethylamino)methylene-5-hydroxy- 3-indolecarboxylate was synthesized from intermediate R according toProcedure H. 64% yield as a white solid. ]H NMR (250 MHz, DMSO) δ 0.92 (m,2H), 1.04 (m, 2H), 1.33 (t, J= 7.1 Hz, 3H), 2.22 (s, 6H), 3.98 (s, 2H), 4.27 (q, J= 7.1 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 10.88 (s, 1H). 13CNMR (62.5 MHz, DMSO) δ 8.4, 8.9,14.3, 1703, 43.9,58.3, 59.2, 110.6, 111.3,112.0, 129.1, 147.3, 152.8, 165.9.

Step B:

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 2-cycIopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester was synthesizedaccording to Procedure I. 60% yield as a white solid. lH NMR (250 MHz, CDCI3) δ 0.79 (m, 2H), 1.07 (d, 8.54,2H), 1.37 (m, 3H), 1.40 (t, J = 7.2 Hz, 3H), 1.61 (m, 9H), 1.92 (m, 1H), 2.17 (d,7= 15.0 Hz, 2H), 2.60 (m, 3H), 2.83 (m, 11820 « -80- 2H), 3.48 (dd,7 = 17.9, 6.8 Hz, 1H), 4.37 (q,7= 7.1 Hz, 2H), 6.75 (d, 7= 8.6 Hz,1H), 7.03 (d, J= 8.7 Hz, 1H), 7.84 (s, 1H). *3C NMR (62.5 MHz, CDC13) δ 4.8,6.0, 7.5, 7.7, 9.5, 14.5,19.7, 25.0, 25.5, 27.0, 30.0 ,36.7,49.6, 59.8, 71.1, 74.8,75.3,75.8, 76.0, 77.5, 87.1, 109.4, 111.1, 113.8. LC/MS (150 mm x 4.6 mm, Ο-Ι 8, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t ~ 10.70 min, m/z = 395.5 (M+l). Elemental Analysis: Calculated (as hydrate) C, 69.88; H,7.82; N, 6.79. Found C, 69.92; H, 7.87; N, 6.67.

Example 16

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-propyl-, ethyl ester

Step A:

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-propyl-, ethyl ester was synthesized fromintermediate S according to Procedure H. 24% yield as a white solid. LC/MS(150 mm x 4.6mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+)t = 7.45 min, m/z = 305.3 (M+l).

Step B:

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-propyl-, ethyl ester was synthesizedaccording to Procedure I. 28% yield as a white solid. ^H NMR (250 MHz,CDCI3) δ 0.99 (t, J= 7.3 Hz, 3H), 1.40 (m, 4H), 1.44 (t, J= 7.1 Hz, 3H), 1.68 (m, 7H), 1.92 (m, 1H), 2.12 (d, J= 12.0 Hz, 1H), 2.55 (m, 2H), 2.92 (m, 5H), 3.47 (dd, 7= 16.7, 6.6 Hz, 1H), 4.35 (q, 7= 7.1 Hz, 2H), 6.77 (d, 7= 8.7 Hz, 1H),7.05 (d, 7=8.7 Hz, lH),8.12(s, 1H). 13C NMR (62.5 MHz, CDC13)Ô 13.9, 14.4, 118 2 0 -81- 19.8, 23.0, 25, 26, 27.0, 30.1, 30.5, 36.7, 49.6, 59.7, 87.1, 110, 111, 113.8, 127,129, 146, 149, 167. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mMNH4OAC/CH3CN, APCI+) t = 11.56 min, m/z = 397.5 (M+l). ElementalAnalysis: Calculated C, 72.69; H, 8.13; N, 7.06. Found C, 72.30; H, 8.18; N, 6.79.

Example 17

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(2-methyIpropyl)-, ethyl ester

10

Step A:

Ethyl 2-isobutyl-4-(dimethylamino)methylene-5-hydroxy- 3-indolecarboxylate was synthesized from intermediate T according toProcedure H. 39% yield as a white solid. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 7.S6 min, m/z = 319.3 (M+l).

Step B: 15 Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-(2-methylpropyl)-, ethyl ester wassynthesized according to Procedure I. 27% yield as a white solid. NMR(250 MHz, CDCI3) δ 0.95 (d, 7= 4.3 Hz, 3H), 0.98 (d, 7= 4.3 Hz, 3H) 1.23 (m, 1H), 1.39 (t,7= 7.1 Hz, 3H), 1.42 (m, 6H), 1.63 (m, 6H), 1.88 (m, 1H), 2.00 (m, 20 1H), 2.16 (d,7= 13.3 Hz, 1H), 2.53 (m, 2H), 2.86 (m, 4H), 3.01 (m, 1H), 3.47 (dd,7= 17.4, 7.2 Hz, 1H), 4.34 (q, 7= 7.1,2H), 6.77 (d,7= 8.6 Hz, 1H), 7.06 (d, 7= 8.7 Hz, 1H), 8.04 (s, 1H). 13C NMR (62.5 MHz, CDCI3) δ 14.5,19.8,22.5,22.6, 25.0, 25.5,27.0, 29.4, 30.1, 31.2, 36.7,37.5,49.5,59.7, 87.1,109.3,

111.4,113.8, 166.1. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM 118 2 0 -82- NH4OAC/CH3CN, APCI+) / = 6.43 min, «2/2 = 411.4 (M+l). Elemental Analysis:Calculated C, 73.14; H, 8.35; N, 6.82. Found C, 73.04; H, 8.55; N, 6.60.

Example 18

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1-dimethylethyl ester

Step A: /e/-/-Butyl 3-amino-3-methÿIcrotonate Activation of Zn: To a stirred 3NHCl solution (50 mL) was added Zn (20 g) and stirred at room température for 10 15 minutes. The HCl solution was decanted, and this was repeated two times. The activated Zn was washed with distilled H2O (2x, 100 mL), éthanol (2x, 50 mL), and ether (2x, 50 mL). The activated Zn was then placed under reduced pressurefor 12 hours at room température. To a stirred suspension of anhydrous THF(10 mL) and activated Zn (0.83 g, 13 mmol) in a flame dried 100 mL round 15 bottom flask was added 5 drops of tert-butyl bromoacetate at room température.

The mixture was then heated to reflux for 15 minutes. 0.60 mL (6 mmol)Acetonitrile was added at once and tert-butyl bromoacetate (1.50 mL, 10 mmol)was added dropwise over 30 minutes. The reaction mixture tumed to green whenabout 2/3 of tert-butyl bromoacetate was added. The mixture was refluxed for an 20 additional 30 minutes and then allowed to cool to room température. To the stirredsolution was added THF (30 mL) and K2CO3 (2 g dissolved in 3 mL water) andstirred vigorously for 30 minutes. The solution was then placed in a centrifugetube and centrifuged. The supematant was decanted and the pellet wasresuspended in THF (30 mL), shaken vigorously and centrifuged (2x). The 25 combined supematant was dried over MgSC>4, filtered, and concentrated under

reduced pressure to yield 0.78 g (83%) of tert-butyl 3-amino-3-methylcrotonate aslight yellow liquid which solidifies at 0°C to a light yellow solid. ^H NMR 11820 -83- (250 MHz, CDCI3) δ 1.45 (s, 9H), 1.84 (s, 3H), 4.43 (s, 2H). 13c NMR(62.5 MHz, CDCI3) δ 22.3, 28.6, 78.1,86.0, 158.9, 171.1.

Step B: /er/-Butyl 5-hydroxy-2-methyl-3-indolecarboxylate. 1,4-Benzoquinone 5 (3.30 g, 30 mmol) in éthanol (15 mL) was heated up until ail solid was dissolved. tert-Butyl 3-amino-3-methylcrotonate (5.50 g, 35 mmol) in éthanol (15 mL) wasadded to the hot solution, and the reaction mixture was refluxed for 6 hours,cooled, and concentrated under reduced pressure. The residue was subjected toflash column chromatography (AI2O3, ethyl acetate) to afford 3.57 g of title 10 compound (14.4 mmol, 48%) as abrown crystal. mp 114.0-116.0°C. ^H NMR(250 MHz, DMSO) δ 1.57 (s, 9H ), 2.55 (s, 3H), 6.57 (dd, 7 = 8.6,2.3 Hz, 1H),7.09 (d, 7=8.6 Hz, 1H,), 7.28 (d, 7= 2.3 Hz, 1H),8.78 (s, 1H), 11.41 (s, 1H). 13CNMR (62.5 MHz, d6-MeOH) δ 14.4, 29.1,80.6,105.3, 106.8, 112.2, 129.9, 131.1, 145.9.153.1, 161.7, 167.9. 15 StepC: /<?r/-Butyl 4-(dimethylamino)methylene-5-hydroxy-2-methyl- 3-indolecarboxylate. To a stirred solution of tert-butyl 5-hydroxy-2-methyl- 3-indolecarboxylate (1.48 g, 6.0 mmol) in éthanol (4.5 mL) was addedformaldéhyde (0.55 mL, 7.2 mmol) and dimethylamine (1.66 mL, 13.2 mmol). 20 The solution was stirred at 60°C for 10 hours, cooled and concentrated under reduced pressure. The residue was extracted with ether (30 mL), filter, evaporatedsolvent under reduced pressure again to afford 1.54 g of title compound(5.05 mmol, 84%) as a brown crystal. mp 151.0°C (décomposé). ^H NMR(250 MHz, d0-MeOH) δ 1.63 (s, 9H), 1.88 (s, 3H), 2.61 (s, 3H), 2.90 (s, 6H),

25 4.76 (s, 2H), 6.81 (d, 7= 8.7 Hz, 1 H), 7.27 (d, 7= 8.6 Hz, 1 H). 13CNMR (62.5 MHz, dg-MeOH) δ 16.1,24.2,29.0,43.1, 55.4, 82.0,107.7, 112.4,115.4, 131.6.146.5.154.1, 161.7. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mMNH4OAC/CH3CN, APCI+) t - 7.75 min, m/z - 305.4 (M+l). -84- 11320 <

Step D:

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1-dimethylethyl ester To astired solution of NaOH (50% w/w, 100 mL) and ether (20 mL) was added0.082 g (0.20 mmol) of iminium sait (Example 3, Step B). The solution wasextracted with ether (3 x 30 mL), dried over MgSÛ4 and concentrated under reduced pressure to afford the enamine as a white solid. 1.0 mL dioxane wasadded to the enamine and then ter/-butyl 4-(dimethylamino)methylene-5-hydroxy- 2-methyl-3-indole carboxylate (0.061 g, 0.20 mmol) followed by 0.5 mL dioxane.The solution was refluxed ovemight, cooled to room température, concentratedunder reduced pressure and subjected to flash column chromatography (S1O2, 1:1 hexane/ethyl acetate) to afford 0.031 g desired product (0.08 mmol, 40%) as awhite solid; mp 214.0°C (décomposé). !H NMR (250 MHz, CDCI3) δ 1.45 (m, 4H), 1.61 (s, 9H), 1.69 (m, 5H), 1.89 (m, 1H), 2.14 (d, J= 15 Hz, 1H), 2.49 (m,2H), 2.56 (s, 3H), 2.84 (d, J = 6 Hz, 2H), 3.06 (m, 1H), 3.48 (dd, J= 18, 7 Hz, 1H), 6.74 (d, 7= 8.6 Hz, 1H), 7.01(d, 7=8.6 Hz, 1H), 8.07 (s, 1H). ^CNMR(62.5 MHz, CDCI3) δ 14.8, 19.8, 25.0, 25.5, 27.1, 28.6, 30.2, 31.2, 36.7, 49.6,66.4, 80.0,87.2, 108.0, 109.2, 111.3, 113.6, 126.0, 129.2, 140.6, 148.7, 165.6.LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t =7.98 min, m/z = 397.4 (M+l). Elemental Analysis: Calculated C, 72.70; H, 8.13;N, 7.06. Found C, 72.28; H, 8.23; N, 6.72.

Example 19 2,6a,7-Trimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester

-85- 118 2 0

Step A: l,6-Dimethyl-l,2,3,4-tetrahydro-pyridine l,6-Dimethyl-l,2,3,4-tetrahydro-pyridine was synthesized according to the procedure published in Lipp A., Liebigs Ann. Chem., 1 S9S;289:216.

Step B: 2,6a,7-Trimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester A solution of l,6-dimethyl-l,2,3,4-tetrahydropyridine (0.100 g, 0.899 mmol, Example 19, Step A) and 4-dimethyIaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.200 g, 0.724 mmol) indioxane (0.800 mL) under N2 was heated at 100°C for 4 hours. An additional 1.0 mL of dioxane was added, and heating was continued for 24 hours. Thesolution was cooled to room température, concentrated, and the residue waspurified by flash column chromatography on silica gel using 50%-75% ethylacetate:hexane and recrystallized with ethyl acetate to give 12 mg (4.8%) of2,6a,7-trimethyl-7,8,9,10,10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester as a white powder: mp169-173°C; ÏHNMR (400 MHz, CDCI3) δ 1.34 (m, 2H), 1.36 (t, J = 7.08 Hz, 3H, CH2C//3), 1.45 (s, 3H, Ctf3C(O)N), 1.56 (m, 2H), 1.66 (m, 1H), 1.93 (m, 1H), 2.56 (s, 3H, C//3), 2.58 (s, 3H, CÆ3), 2.87 (bd, J= 17.58 Hz, 2H), 3.50 (dd,J= 18.19, 6.72 Hz, IH,),4.31 (q, J= 7.08 Hz, 2H, CH2CH3), 6.68 (d, J= 8.79 Hz, 1H, Ar/7), 7.01 (d, J= 8.30 Hz, 1 H, Artf), 8.03 (bs, 1H, Ntf); MS(APCI+) m/z 343.2 (MH+). Analysis calculated for θ2θΗ26Ν2°3·θ·17 Η2θ; C, 69.53; H, 7.68; N, 8.11. Found: C, 69.52; H, 7.33; N, 7.84.

Example 20 7-Ethyl-2,6a-dimethyl-7,8,9,10,10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester

118 2 0 -86-

Step A: 1-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate l-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate was synthesized according to the procedure published in Ladenburg A., Liebigs Ann.Chem., 1899;304:54.

Step B: 7-Ethyl-2,6a-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester l-Ethyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.245 g, 1.08 mmol, Example 20, Step A) was dissolved in a minimum amount of waterand treated with 50% aqueous NaOH until strongly basic. The aqueous solutionwas extracted with 4x10 mL of Et20, and the combined extracts were washedwith 1x10 mL of saturated aqueous NaCl, dried with MgSO4, filtered, andconcentrated into the reaction flask to give 90 mg (0.724 mmol) of 1-ethyl- 6-methyI-l,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane(0.750 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid ethyl ester (0.200 g, 0.724 mmol) was added. The resultingsolution was heated at reflux under N2 for 4 hours, cooled to room température,and concentrated. The crude residue was purified by flash columnchromatography on silica gel using 100% ethyl acetate and recrystallized withethyl acetate to give 98 mg (38%) of 7-ethyl-2,6a-dimethyl-7,8,9,I0,10a,l 1-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acidethyl ester as a white powder: mp 173-174°C; IR (KBr) 3298, 2930, 2856, 1669,1433, 1238, 1094 cm'1; *H NMR (300 MHz, CDCI3) δ 1.16 (m, 3H, C//3CH2N), 1.37 (m, 1H), 1.40 (m, 1H), 1.48 (s, 2H), 1.56 (s, 2H), 1.64 (m, 2H), 1.97 (m, 1H), 2.61 (s, 3H, CÆ3), 2.72 (m, 1H), 2.84 (m, 1H), 2.90 (bd, J= 19.04 Hz, 2H), 3.16 (m, 1H), 3.54 (dd, J= 18.31, 6.78 Hz, 1H), 4.35 (qd, J = 7.14, 1.65 Hz, 2H,OCH2CH3), 6.70 (d, 7= 8.61 Hz, 1H, ArÆ), 7.03 (d, 7= 8.61 Hz, AxH), 8.06 (bs, 1H, N77); MS (APCI+) m/z 357.1 (MH+). Analysis calculated for 02ΐΗ2δΝ2θ3:C, 70.76; H, 7.92; N, 7.86. Found: C, 70.49; H, 7.80; N, 7.66. 11820 -87-

Example 21

Isomer A: 6a-Ethyl-2,7-dimethyI-7,8,9,10,10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester

Step A: 6-Ethyl-l-methyl-2,3,4,5-tetrahydropyridinium perchlorate 6-Ethyl-l -methyl-2,3,4,5-tëtrahydro-pyridinium perchlorate wassynthesized according to the procedure published in Leonard N.J.; Hauck, Jr., F.P., J. Am. Chem. Soc., 1957;79:5279.

Step B: 6a-Ethyl-2,7-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester 6-Ethyl-l-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.712 g, 3.16 mmol, Example 21, Step A) was dissolved in a minimum amount of waterand treated with 50% aqueous NaOH until strongly basic. The aqueous solutionwas extracted with 4x15 mL of Et20, and the combined extracts were washedwith 1x15 mL of saturated aqueous NaCl, dried with MgSC>4, filtered, andconcentrated into the reaction flask to 6-ethyl-l-methyl-1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (2.1 mL) and

4-dimethyIaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylester (0.581 g, 2.10 mmol) was added. The resulting solution was monitored by ticand MS as it was stirred at room température under N2 for 2 hours, heated at 50°C for 24 hours, at 60°C for 3 hours, at 70°C for 17 hours, and between 89-90°C for 4.5 hours. The darkening solution was cooled to room température, andconcentrated. The crude residue was purified by flash column chromatography onsilica gel using 20-60% ethyl acetate:hexanes to give 56 mg (7.5 %) of a singleisomer A of 6a-ethyl-2,7-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 118 2 0 -88- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester with a largerRfvalue as a white powder: mp 144-147°C; IR (KBr) 3375, 2975, 2937, 2858, 1671,1470, 1432, 1245,1202 cm-1; JHNMR (400 MHz, CDCl3)ÔO.91 (m, 3H,C//3CH2C(O)N), 1.34 (m, 2H), 1.36 (m, 3H, OCH2C//3), 1.54 (bs, 1H), 1.63 (m,1H), 1.76 (m, 1H), 1.84 (m, 1H), 2.06 (m, 1H), 2.46 (s, 3H, C//3), 2.52 (m, 1H), 2.57 (2, 3H, C//3), 2.79 (d,7= 18.07 Hz, 1H), 2.88 (m, 1H), 3.37 (dd, J= 18.07,6.59 Hz, 1H), 4.31 (m, 2H, OC//2CH3), 6.67 (d, J= 8.79 Hz, 1H, Artf), 6.99 (d, J= 8.55 Hz, 1H, Ar/7), 8.03 (bs, 1H, N//); MS (APCI+) m/z 357.2 (MH+).Analysis calculated for C21H28N2O3O.O4 H2O: C, 70.61; H, 7.92; N, 7.84;water, 0.22. Found: C, 70.27; H, 7.92; N, 7.58; water, 0.22.

Isomer B: 6a-Ethyl-2,7-dimethyl-7,8,9,10,10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester 6-EthyI-l-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.712 g, 3.16 mmol, Example 21, Step A) was dissolved in a minimum amount of waterand treated with 50% aqueous NaOH until strongly basic. The aqueous solutionwas extracted with 4x15 mL of Εί2Ο, and the combined extracts were washedwith 1x15 mL of saturated aqueous NaCl, dried with MgSC>4, filtered, and concentrated into the reaction flask to give 6-ethyl-l-methyl-l,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (2.1 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyI-l H-indole-3-carboxylic acid ethylester (0.581 g, 2.10 mmol) was added. The resulting solution was monitored by ticand MS as it was stirred at room température under N2 for 2 hours, heated at 50°Cfor 24 hours, at 60°C for 3 hours, at 70°C for 17 hours, and between 89-90°C for 118 2 0 -89- 4.5 hours. The darkening solution was cooled to room température, andconcentrated. The crude residue was purified by flash column chromatography onsilica gel using 20-60% ethyl acetate:hexanes to give 37 mg (4.9 %) of a singleisomer B of 6a-ethyl-2,7-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cycIopenta[a]anthracene-l-carboxylic acid ethyl ester with a smaller Rfvalue as a fine off-white powder: mp 158-161°C; IR (KBr) 3310,2957,2928,2862, 1654, 1436, 1419, 1204 cm-1; 1H NMR (400 MHz) δ 1.08 (m, 3H,Ctf3CH2C(O)N), 1.20 (m, 1H), 1.37 (m, 3H, OCH2Œ3), 1.41 (m, 1H), 1.52 (s,3H, Ctf3), 1.59 (m, 2H), 1.85 (bd, J= 13.18 Hz, 1H), 2.30 (m, 1H), 2.35 (m, 2H),

2.58 (s, 3H, Ctf3), 2.91 (m, 1H), 3.11 (m, 2H), 4.32 (m, 2H, OCH2CH3), 6.72 (d,J = S.55 Hz, 1H, Ar//), 7.00 (d, 8.79 Hz, 1H, Artf), 8.03 (bs, 1H, Ntf); MS (APCI+) m/z 357.2 (MH+). Analysis calculated for C21H28N2O3: C, 70.76; H,7.92; N, 7.86. Found: C, 71.45; H, 8.44; N, 6.65. HPLC (ALLTECH/ALLTIMAC-18 1:1 H2O/CH3CN + 0.05% TFA): rétention time = 4.940 min, 99.40% purity.

Example 23 6a,7-Diethyl-2-methyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester

Step A: l,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate l,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Leonard N.J., Hauck, Jr., F.P., J. Am.Chem. Soc., 1957;79:5279.

Step B: 6a,7-Diethyl-2-methyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester l,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.485 g, 2.02 mmol, Example 23, Step A) was dissolved in a minimum amount of water 118 2 0 -90- and treated with 50% aqueous NaOH until strongly basic. The aqueous solutionwas extracted with 4x15 mL of Et20, and the combined extracts were washedwith 1x15 mL of saturated aqueous NaCl, dried with MgSC>4, filtered, and concentrated into the reaction flask to give 207 mg (1.49 mmol) of 1,6-diethyl-5 1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (1.3 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylester (0.373 g, 1.35 mmol) was added. The resulting solution was heated at 100°Cunder N2 for 7 hours, cooled to room température, and concentrated. The cruderesidue was purified by flash column chromatography on silica gel using 20-100% 10 ethyl acetate:hexanes and recrystallized with ethyl acetate to give 123 mg (25%)of 6a,7-diethyI-2-methyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester as a white crystalline solid:mp 162-163°C; IR (KBr) 3390, 2972, 2929, 2859, 1654, 1432, 1201, 1097 cm'1;lH NMR (400 MHz, CDCI3) δ 0.900 (m, 2H, C//3CH2C(O)N), 1.11 (m, 2H, 15 CÆ3CH2N), 1.34 (m, 2H), 1.36 (m, SH.C/^ttbO), 1.57 (m, 2H), 1.85 (m, 2H),2.06 (m, 1H), 2.57 (s, 3H, C//3), 2.70 (m, 2H), 2.79 (bd, J= 18.31 Hz, 1H), 2.84 (m, 1H), 3.00 (m, 1H), 3.37 (m, 1H), 4.31 (m, 2H, CH3Œ2O), 6.64 (d, J = 8.55 Hz, 1 H, Ar/7), 6.98 (d, J = 8.55 Hz, 1 H, Ar/7), 8.00 (bs, 1 H, N/7); MS(APCI+) m/z 371.1 (MH+). Analysis calculated for θ22Η3θΝ2θ3: C> 71.32; 20 H, 8.16; N, 7.56. Found: C, 71.28; H, 7.77; N, 7.32.

Example 24 7-Benzyl-2,6a-dimethyl-7,8,9,10,10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester

118 2 0 -91-

Step A: l-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate l-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Môhrle H.; Dwuletzki H.Z.,Naturforsch., B: Anorg. Chem., Org. Chem., 1986;41b:l323.

Step B: 7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester

An excess of l-benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate(Example 24, Step A) was dissolved in a minimum amount of water and treatedwith 50% aqueous NaOH until strongly basic. The aqueous solution was extractedwith 4x20 mL of Et20, and the combined extracts were washed with 1 x 20 mLof saturated aqueous NaCl, dried with MgSC>4, filtered, and concentrated to givethe enamine. l-Benzyl-2-methyl-l,2,3,4-tetrahydro-pyridine (0.447 g, 2.39 mmol)was dissolved in dioxane (2.4 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.330 g, 1.20 mmol) was added.The resulting solution was heated at 80-90°C under N2 for 20 hours, cooled to room température, and concentrated. The crude residue was purified by flashcolumn chromatography on silica gel using 10-20% ethyl acetatethexanes andrecrystallized with ethyl acetate to give 208 mg (42%) of 7-benzyl-2,6a-dimethyl-7,8,9,10,10a, 1 l-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene- 1-carboxylic acid ethyl ester of an off-white powder: mp 196-198°C; IR (KBr)3397, 2983,2923, 2897, 2854, 1668, 1432, 1200,1097 ατΗ; NMR(400 MHz, CDCI3) δ 1.36 (m, 1H), 1.37 (m, 3H, OCH2Ctf3), 1.50 (s, 3H,CH3C(O)N), 1.53 (m, 3H), 2.03 (m, ÎH), 2.56 (m, 1H), 2.58 (s, 3H, Ctf3), 2.71 (m, 1H), 2.94 (d, J = 18.07 Hz, 1H), 3.53 (dd, J= 18.07, 6.84 Hz, 1H), 3.58 (d, J = 15.14 Hz, 1H, NC£f(H)Ph), 4.32 (m, 2H, OC//2CH3), 4.47 (d, J= 14.89 Hz, 1H, NCH(fl)Ph), 6.71 (d, J= 8.55 Hz, 1H, AxH), 7.01 (d, J= 8.55 Hz, 1H, ArJT), 7.18 (t,7= 7.08 Hz, 1H, Phfl), 7.28 (m, 2H, Phtf), 7.35 (d, J= 7.33 Hz, 2H, Phtf), 8.06 (bs, 1H, N//); MS (APCI+) m/z 419.2 (MH+). Analysis calculated for C26H3oN203 H20: C, 74.39; H, 7.24; N, 6.67; water, 0.30. Found: C, 74.27; H, 7.25; N, 6.54; water, 0.31. 11 82 0 -92-

Isomer A: 2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,ll-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracenc-l-carboxylic acid ethyl ester

Step A: l-Methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate A procedure for the synthesis of l-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate is published in Leonard N.J.; Hauck Jr. F.P., J. Am. Chem.Soc., 1957;79:5279.

Step B: 2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester

An excess of l-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate(Example 25, Step A) was dissolved in a minimum amount of water and treatedwith 50% aqueous NaOH until strongly basic. The aqueous solution was extractedwith 4x20 mL of Et20, and the combined extracîs were washed with 1 x 20 rnLof saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated to givethe enamine. l-Methyl-6-phenyl-l,2,3,4,-tetrahydro-pyridine(0.428 g, 2.47 mmol)was dissolved in dioxane (1.8 mL) and 4-dimethylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol) wasadded. The reaction mixture was heated at 75-80°C under N2 for 16 hours, 1.0 mLof dioxane was added and heating was continued at 90°C for 5 hours. Driedtoluene (1.0 mL) was added to the mixture and it was heated at 100°C for26 hours, cooled to room température, and concentrated. The crude residue waspurified by flash column chromatography on silica gel using 10-50% ethylacetate:hexanes to give a single isomer A with a smaller Rf value, which wasrecrystallized with ether:hexanes to give 73 mg (15%) of2,7-dimethyl-6a-phenyl- 118 2 0 -93- 7,8,9,10,10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza-cycIopenta[a]anthracene- 1-carboxylic acid ethyl ester as an off-white powder; mp 176-177°C; IR (KBr)3400,2942, 2930,2859,1647, 1434,1206, 1099, 1079 cm*1; ]H NMR(400 MHz, CDC13) δ 1.20 (m, 3H, OCH2CH3), 1.48 (m, 2H), 1.67 (d, J= 13.18 Hz, 1 H), 1.84 (m, 1H), 2.13 (s, 3H, Ctf3), 2.35 (m, 1H), 2.52 (s, 3H,C//3), 2.58 (m, 1H), 2.68 (m, 1H), 2.81 (d,7= 17.33 Hz, 1H), 2.90 (m, 1H), 4.17 (q, J = 7.08 Hz, 2H, OCH2CH3), 6.89 (d, 7= 8.79 Hz, 1H, Artf), 7.06 (d, 7= 8.79 Hz, 1H, Ar/7), 7.15 (m, 3H, Phtf), 7.35 (m, 2H, Plift), 8.07 (bs, 1H, N/f);MS (APCI+) m/z 405.2 (MH+). Analysis calculated for C25H2sN2O3: C, 74.23;H, 6.98; N, 6.93. Found: C, 73.93; H, 7.11 ; N, 6.66.

Example 26

H

Isomer B: 2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester

An excess of l-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate(Example 25, Step A) was dissolved in a minimum amount of water and treatedwith 50% aqueous NaOH until strongly basic. The aqueous solution was extractedwith 4 x 20 mL of Εΐ2Ο, and the combined extracts were washed with 1 x 20 mLof saturated aqueous NaCl, dried with MgSC>4, filtered, and concentrated to givethe enamine. l-Methyl-6-phenyl-l,2,3,4,-tetrahydro-pyridine(0.428 g, 2.47 mmol)was dissolved in dioxane (1.8 mL) and 4-dimethylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol) wasadded. The reaction mixture was heated at 75-80°C under N2 for 16 hours, 1.0 mLof dioxane was added and heating was continued at 90°C for 5 hours. Driedtoluene (1.0 mL) was added to the mixture and it was heated at 100°C for 118 2 0 -94- 26 hours, cooled to room température, and concentrated. The crude residue waspurified by flash colunrn chromatography on silica gel using 10-50% ethylacetate:hexanes, recrystallized with ether:hexanes and the filtrate further purifiedby silica gel chromatography using 1-10% ethyl acetate-.hexanes to give 70 mg(14%) of a single isomer B of2,7-dimethyl-6a-phenyl-7,8,9,10,10a,ll-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl esterwith a larger Rf value as a course peach powder: mp 184-186°C; IR (KBr) 3380,2926,1698, 1684, 1436, 1073 cm’1; ^HNMR(400MHz, CDC13) δ 1.37(t, J= 7.08 Hz, 3H, OCH2CH3), 1.49 (m, 2H), 1.64 (m, 1H), 1.76 (m, 1H), 2.29 (m,1H), 2.31 (s, 3H, Ctf3), 2.59 (s, 3H, CH3), 2.97 (d, J= 17.58 Hz, 1H), 3.52 (m,1H), 3.77 (m, 1H), 4.32 (m, 2H, OC//2CH3), 4.89 (bs, 1H), 6.74 (d, J= 8.55 Hz,1H, AiH), 7.02 (d, J= 8.55 Hz, 1H, ArH), 7.33 (m, 5H, PhH), 8.06 (bs, 1H, NH);MS (APCI+) m/z 405.2 (MH+). Analysis calculated for C25H28N2O3: C, 74.23;H, 6.98; N, 6.93. Found: C, 74.18; H, 6.90; N, 6.72

Example 27. lH,7H-Indolizino[8',8a':5,6]pyrano[3,2-e]indole-l-carboxylic acid, 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, ethyl ester

Step A: 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate was synthesized according to the procedure published in Reinecke M.G.; Kray L.R., J. Org.Chem., 1964;29:1736.

Step B: lH,7H-Indolizino[8',8a':5,6]pyrano[3,2-e]indole-l-carboxylic acid,8,9,11,12,13,13a,14,14a-octahydro-2-methyl-, ethyl ester 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate (0.330 g, 1.48 mmol, Example 27, Step A) was dissolved in a minimum amount of water 118 2 0 -95- and treated with 50% aqueous NaOH until strongly basic. The aqueous solutionwas extracted with 4x15 mL of Et2O, and the combined extracts were washedwith 1x15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 143 mg (1.16 mmol) of enamine. 5 1,2,3,5,6,7-Hexahydro-indolizine was dissolved in dioxane (1.5 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-l H-indole-3-carboxylic acid ethylester (0.321 g, 1.16 mmol) was added. The resulting solution was heated at refluxunder N2 for 5 hours, cooled to room température, and concentrated. The cruderesidue was purified by flash column chromatography on silica gel using 100% 10 acetone and recrystallized with ethyl acetate to give 129 mg (31 %) of 1 H,7H-

Indolizino[8',8a':5,6]pyrano[3,2-e]-iridole-l-carboxylic acid, 8,9,11,12,13,13a,14,14a-octahydro-2-methyI-, ethyl ester as an off-white powder:mp 170-172°C; IR (KBr) 3396, 3353, 2929, 2853,1668, 1434, 1156, 1096, 1075 cm’1; ÎHNMR (300 MHz, CDCI3) δ 1.38 (m, 2H), 1.40 (t,J= 7.14 Hz, 3H, 15 OCH2C#3), 1.68 (m, 3H), 1.90 (m, 3H), 2.05 (m, 1H), 2.61 (s, 3H, C//3), 2.74 (m, 1H), 2.84 (m, 1H), 2.97 (d, J= 17.40 Hz, 1H), 3.09 (m, 2H), 3.47 (dd, J= 17.76, 6.78 Hz, 1H), 4.36 (m, 2H, OC//2CH3), 6.67 (d, 8.61 Hz, 1H,

Artf), 7.03 (d, J= S.61 Hz, 1H, ArH), 8.06 (bs, 1H, Ntf); MS (APCI+) m/z 355.2 (MH+). Analysis calculated for C21H26N2O3-0.23H2O: C, 70.34; H, 7.44; 20 N, 7.81. Found: C, 70.35; H, 7.48; N, 7.61. 118 2 0 -96-

Example 28 3H,7H-Pyrrolizino[l',8':5,6]pyrano[3,2-e]indole-l-acetic acid, 8,9,11,12,12a,13-hexahydro-2-methyl-, ethyl ester

Step A: 1,2,3,5,6,7-Hexahydro-pyrrolizinylium perchlorate 1,2,3,5,6,7-Hexahydro-pyrrolizinylium perchlorate was synthesizedaccording to the procedure published in Miyano S. et al., Synthesis, 1978;9:701.

Step B: 3H,7H-Pyrrolizino[T,8':5,6]pyrano[3,2-e]indole-l-acetic acid, 8,9,11,12,12a, 13-hexahydro-2-methyl-, ethyl ester 1,2,3,5,6,7-Hexahydro-pyrrolizinylium perchlorate (0.904 g, 4.31 mmol,Example 28, Step A) was dissolved in a minimum amount ofwater and treatedwith 50% aqueous NaOH until strongly basic. The aqueous solution was extractedwith 4x15 mL of Et20, and the combined extracts were washed with 3x15 mLof saturated aqueous NaCl, dried with MgSC>4, filtered, and concentrated into thereaction flask to give 325 mg (2.98 mmol) of enamine, 2,3,5,6-tetrahydro-lH-pyrrolizine. The residue was dissolved in dioxane (2.8 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylester (0.794 g, 2.88 mmol) was added. The resulting solution was heated at 80°Cunder N2 for 17 hours, cooled to room température, and concentrated. The cruderesidue was purified by flash column chromatography on silica gel using 15%MeOH:CH2Cl2 and recrystallized with ether to give 105 mg (11%) of 3H,7H-pyrrolizino[ 1 ',8':5,6]pyrano[3,2-e]indole-1 -acetic acid, 8,9,11,12,12a, 13-hexahydro-2-methyl-, ethyl ester as a white powder; mp 206-207°C; IR (KBr)2972,2901,2864,2828, 1694,1429, 1196, 1087 cm'1; NMR (400 MHz,CDCI3) δ 1.37 (t, 7= 7.08 Hz, 3H, OCH2Ctf3), 1.60 (m, 2H), 1.91 (m, 1H), 1.99 (m, 2H), 2.10 (m, 1H), 2.27 (m, 2H), 2.46 (m, 1H), 2.55 (m, 1H), 2.60 (s, 3H,CH3), 3.22 (m, 1H), 3.35 (m, 1H), 3.36 (d, J= 4.88 Hz, 1H), 4.34 (m, 2H, 118 2 0 -97- OC/y2CH3), 6.76 (d,7= 8.55 Hz, 1H, Artf), 7.00 (d, J= 8.55 Hz, 1H, ArH), 8.26 (m, 1H, N77); MS (APCI+) m/z 341.1 (MH+). Analysis calculated forC20h24n2°3: c> 70·57; H, 7.11; N, 8.23. Found: C, 70.40; H, 7.27; N, 7.94.

Example 29 2-Methyl-8,9,10,10a, 11,12,12a, 13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopenta[h]anthracene-l-carboxylic acid ethyl ester

Step A: l,3,4,8,9,9a-Hexahydro-2H-quinolizine l,3,4,8,9,9a-Hexahydro-2H-quinolizine was synthesized according to the procedure published in Bohlmann F. et al., Chem. Ber., 1973; 106:3026.

Step B: 2-Methyl-8,9,10,10a,l l,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopenta[h]anthracene-l-carboxylic acid ethyl ester l,3,4,8,9,9a-Hexahydro-2H-quinolizine (0.372 g, 2.71 mmol, Example 29,Step A) was dissolved in dioxane (2.7 rnL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.374 g, 1.36 mmol)was added. The resulting solution was heated at 80°C under N2 for 17 hours, at reflux for 24 hours, cooled to room température, and concentrated. The cruderesidue was purified by flash column chromatography on silicâ gel using 10-20%ethyl acetate:CH2CI2 and recrystallized with cyclohexane to give 71 mg (14%) of 2-methyl-8,9,10,10a, 11,12,12a, 13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopenta[h]anthracene-l-carboxylic acid ethyl ester as an off-whitepowder: mp 178-180°C; IR (KBr) 3372,2929, 2859, 1669,1654, 1435,1198,1095, 1079 cm-1; ^H NMR (400 MHz, CDC13) δ 1.15 (m, 1H), 1.35 (t, J= 7.08 Hz, 3H, OCH0CH3), 1.36 (m, 4H), 1.49 (m, 2H), 1.65 (m, 3H), 2.20 (m,1H), 2.58 (s, 3H, C//3), 2.68 (m, 1H), 2.82 (m, 1H), 2.89 (d, J= 17.58 Hz, 1H), 11820 -98- 3.05 (m, 1H), 3.45 (m, 1H), 4.31 (m, 2H, OC//2CH3), 4.68 (s, 1H, C//(O)N),6.68 (d, 7=8.79 Hz, lH,Artf), 6.99 (d, J= 8.55 Hz, 1H, Artf), 8.03 (bs, 1H,N/7); minor diastereomer diagnostic peaks ^H NMR (400 MHz, CDCI3) δ 6.75 (d, J= 8.55 Hz, 1H, Artf); MS (APCI+) m/z 369.1 (MH+). Analysiscalculated for 022^28^2031 O, 71.71; H, 7.66; N, 7.60. Found: C, 71.96; H,7.92; N, 7.09. HPLC (ALLTECH/ALLTIMA C-18 150 mm x 4.6 mm column, 1:1 H2O/CH3CN + 0.5% TFA): rétention time = 3.526 min (11.26%), 3.882 min(85.82 %) (diastereomers), 97.08 % purity. HPLC (Àlltima Silica 5 micron, 150 mm x 4.5 mm column, 95:5 hexane + 0.05 % Et2NH,éthanol + 0.05%Et2NH): rétention time = 5.19 min (84.08 %), 5.87 min (8.63 %) (diastereomers), 92.71 % purity.

Example 30 3H-pyrido[ 1 ",2": 1 '2']azepino[3'2':5,6]pyrano[3,2-e]indole-1 -acetic acid,7,8,9,10,12,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester, or7H-Azepino[I'',2'': 1 "2']pyrido[3',2':5,6]pyrano[3,2-e]indole-l -acetic acid,3,8,9,10,11,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester

Step A: 2,3,4,6,7,8,9,10-Octahydro-pyrido[ 1,2-a]azepine perchlorate A synthesis of 2,3,4,6,7,8,9,10-octahydro-pyrido[l,2-a]azepine perchlorateis published in Mclntosh J.M. et al., Can. J. Chem., 1983;61:2016.

Step B:

An excess of 2,3,4,6,7,8,9,10-octahydro-pyrido[l,2-a]azepine perchlorate(Example 30, Step A) was dissolved in a minimum amount of water and treatedwith 50% aqueous NaOH until strongly basic. The aqueous solution was extractedwith 4 x 20 mL of Ει2Ο, and the combined extracts were washed with 1 x 20 mL 11820 -99- of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated to give 5S2 mg (3.85 mmol) of the crude enamine. The residue was dissolved in dioxane (3.8 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole- 3-carboxyIic acid ethyl ester (0.797 g, 2.88 mmol) was added. The reaction mixture was heated at 80°C under N2 for 6 hours, cooled to room température, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10% ethyl acetate:CH2Cl2-100% ethyl acetateand recrystallization with iso-octane to give 18 mg (2%) of a single compound,either 3H-pyrido[l",2":l'2']azepino[3'2':5,6]pyrano[3,2-e]indole-l-acetic acid,7,8,9,l0,12,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester or 7H-azepino[l",2":T2']pyrido[3',2':5,6]pyrano[3,2-e]indole-l-acetic acid, 3,8,9,10,11,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester as a finewhitepowder: mp 118-121°C; IR (KBr) 3379, 3306, 2926, 2853, 1671,1435,1151,1094, 1073 cm’1; !H NMR (400 MHz, CDCI3) δ 0.86 (m, 1H), 1.35 (m, 3H), 1.36 (m, 3H, OCH2Ctf3), 1.45 (m, 3H), 1.60 (m, 3H), 1.69 (dd, J= 14.65, 10.01 Hz, 1H), 1.95 (m, lH),2.19(m, 1H), 2.41 (m, 1H),2.54 (m, 1H), 2.57 (s,3H, CHÿ, 2.80 (d,J= 18.56 Hz, 1H), 3.11 (m, 1H), 3.34 (m, 1H), 3.48 (m, 1H), 4.31 (m, 2H, OC//2CH3), 6.70 (d,7= 8.55 Hz, 1H, ArH), 6.98 (d, 8.55 Hz, 1H, Ar/7), 8.01 (bs, 1H, Ntf); MS (APCI+) m/z 383.1 (MH+). Analysis calculatedfor C23H30N2O3: C, 72.22; H, 7.91; N, 7.32. Found: C, 72.14; H, 7.95; N, 6.97.

Procedure J: General procedure for the Mannich reaction: The amide (1.1 mmol), 1 eq) was dissolved in EtOH by stirring while warming the solution: the solutionwas cooled. Aqueous HCHO (37%, 1.32 mmol, 1.2 eq) and Me2NH (40%, 2.42 mmol, 2.2 eq) were added, and the reaction was allowed to stir. After severalhours, a white precipitate begins to form in the solution; the reaction may beheated to 5°C to speed the reaction. Upon completion, there is little or no startingmaterial présent. Water was added to the solution, and the mixture was thencooled in an ice bath. The resulting white solid was collected by filtration anddried under vacuum. 118 2 0 -100-

Procedure K: General procedure for the condensation reaction: 1,2,3,4,6,7,8,9-octahydro-quinolizinylium perchlorate (17.8 mmol, 1.2 eq) was converted to theenamine in the following manner: the imine was dissolved in IN NaOH (10 mL)and the solution extracted with 2 x 20 mL of diethyl ether. The extracts werecombined dried, and evaporated under vacuum to yield a white solid. The solidwas dissolved in dioxane (10 mL). A solution of the 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid methyl orbenzyl amide(14.8 mmol, 1 eq) was dissolved in dioxane (10 mL) and added to the enamine.The solution was refluxed for 19 hours, resulting in the formation of a whiteprecipitate. The mixture was cooled in an ice bath, and the resulting solid wascollccted by filtration. The solid was washed sparingly with CH3CN and driedunder vacuum at 50 degrees for 24 hours.

Example 31 8,9,1 l,12,13,13a,14,I4a-Octahydro-N,2-dimethyl-pyrrolo[3’,2’:5,6][l]-benzopyrano[3,2-i]quinolizine-l-carboxamide

Step A: 4-Dimelhyîaminomethyl-5-hydroxy-2-methyI-lH-indole-3-carboxylic acidmethyl amide was synthesized from Intermediate W according to Procedure J.Yield: 0.186 g (63.2%); mp: décomposition at >210°C; IR: 3319, 1615, 1515,1433, 1218, 801 cm’1. NMR (DMSO-d0) Ô: 2.14 (s, 6H, CH2N(Ctf3)2), 2.28 (s, 3H, ArCH3), 2.70 (d, J= 3.91 Hz, 3H, CONHŒ/3), 3.69 (s, 2H,C//2N(CH3)2), 6.48 (d, J= 8.55 Hz, 1H, ArH), 6.97 (d, J= 8.55 Hz, 1H, ArH),8.06 (s, 1H, CON//CH3), 10.88 (s, 1H, indole NH). MS(APCI+): m/z 262.1 (MH+); Analysis calculated for Ci4Hi9N3O2: C, 64.35, H, 7.33, N, 16.08.Found: C, 64.26, H, 7.44, N, 15.87. 11820 -101-

Step B: 8,9,11,12,13,13a, 14,14a-Octahydro-N,2-dimethyl-pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxamide wassynthesized according to Procedure K. Yield: 0.057 g (9.8%); mp: décompositionat >210°C; IR: 3392,3057,2935, 2857, 1625, 1429, 1215 cm-1; Ή NMR(DMSO-dg) δ 1.08-1.54 (m, 9H, aliphatic CH2 and CH), 1.63-1.69 (m, 1H,aliphatic CH), 1.81-1.93 (m, 1H, aliphatic CH), 2.27 (s, 3H, ArCH3), 2.31-2.45 (m, 3H, obscured by DMSO peak, aliphatic CH), 2.63-2.69 (m, 1H,aliphatic CH), 2.68 (d, J= 3.91 Hz, 3H, CONHC//3), 2.87-2.95 (m, 1H, aliphatic CH), 3.05 (dd, J= 18.3, 5.37 Hz, 1H, aliphatic CH), 6.49 (d, J = 8.79 Hz, IH,ArH), 6.94 (d, J= 8.79 Hz, 1H, ArH), 7.70-7.75 (m, 1H, CON//CH3), 10.9 (s, 1H, NH); MS(APCI+): m/z 354.2 (MH+); Analysis calculated for C2lH27N3O2-0.5C4H8O2(CH3CO2Et): C, 69.49, H, 7.86, N, 10.57. Found: C, 69.64, H, 7.75, N, 10.54.

Example 32 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-N-(phenylmethyl)- pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxamide

Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acidbenzyl amide was synthesized from Intermediate X according to Procedure J.Yield: 0.582 g (69.2%); mp: 208-210 °C; IR: 3312, 1610,1510, 1437,1207, 747,697 (cm-1). !H NMR (DMSO-d6) δ: 2.05 (s, 6H, CH2N(C//3)2), 2.31 (s, 3H,ArCH3), 3.67 (s, 2H, C//2N(CH3)2), 4.40 (d, J= 5.86 Hz, 2H, CONHC//2). 6.46 (d, J= 8.55, 1H, ArH), 6.98 (d, 8.55, 1H, ArH), 7.18-7.34 (m, 5H, ArH), 8.63 (t, J= 5.86, 1H, CON77CH2), 10.76 (s, 1H, aromatic OH), 10.91 (s, 1H, -102- 118 2 0 indole NH). MS(APCI+): m/z 338.2 (MH+); Analysis calculated for C20H23N3o2i C> 71-19> H’ 6·87’ N> 12·45· Found: c> 70-82, H> 6.86, N, 12.24.

Step B:

Example 32 was synthesized according to Procedure K. Yield: 0.228 g(35.9%); mp: 235-237°C; IR: 3177,2929, 1627, 1429, 1089 cm’l. NMR(DMSO-dg) δ 1.08-1.17 (m, 3H, aliphatic CH2 and CH), 1.35-1.61 (m, 7H,aliphatic CH2 and CH), 1.85-1.88 (m, 1H, aliphatic CH), 2.26-2.45 (m, 3H,obscured by DMSO peak, aliphatic CH), 2.29 (s, 3H, ArCH3), 2.61-2.67 (m, 1H,aliphatic CH), 2.82-2.88 (m, 1H, aliphatic CH), 2.97 (dd, J= 17.6, 6.59 Hz, 1H,aliphatic CH), 4.33-4.43 (m, 2H, CONHCtf2Ph), 6.49 (d, J = 8.55 Hz, 1H, ArH), 6.94 (d, J = 8.55 Hz, 1H, ArH), 7.17-7.31 (m, 5H, ArH), 8.36 (t, J = 6.10 Hz, 1H,CONtfCH2Ph), 10.9 (s, 1H, indole NH); MS(APCI+): m/z 430.2 (MH+); Analysiscalculated for C^^j^OrO.lC^gO^ C, 75.07, H, 7.31, N, 9.59. Found: C, 74.99, H, 7.33, N, 9.54.

Example 33

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxamide, N-ethyl- 8,9,1 l,12,13,13a,14,14a-octahydro-2-methyl-

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxyIic acid ethylamide 5-Hydroxy-2-methyl-l-H-indole carboxylic acid (3.28 g, 17.2 mmol) was dissolved in dry DMF (20 mL) under nitrogen atmosphère and cooled to 0°C in anice-water bath. To this solution were added in succession triethylamine (2.39 mL, 17.2 mmol) and solid O-benzotriazol-l-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate (6.51 g, 17.2 mmol). The resulting reaction mixture wasstirred at that température for 15 minutes, gaseous ethylamine was bubbled in for 11820 -103- 10 minutes. After sequentially 15 minutes stirring at 0°C and 15 minutes atambient température, reaction mixture was mixed with 60 mL of EtOAc, theresulting mixture was successively washed with IN HCl aqueous solution(2 x 60 mL), brine (2 x 60 mL), and was dried over Na2SÛ4. The solution wasconcentrated in vacuo affording a solid. The crude product was further purified byflash chromatography (100% EtOAc) followed by recrystallization from EtOAc toprovide 0.81 g (18%) of pure titled compound as a white solid: mp 199-201°C(dec.); IR 3372, 1609, 1523, 1464,1246, 1216, 1193 cm'1; !H NMR (DMSO-d6)δ 1.11 (t, J= 7.14 Hz, 3H, CH2C#3), 2.48 (s, 3H, ArCH3), 3.25 (quintet, J = 6.96 Hz, 2H, NHC//2CH3), 6.54 (dd, J= 8.61, 2.20 Hz, 1H, ArH), 7.06 (d,7=8.42Hz, 1H, ArH), 7.09 (d,7=2.01 Hz, 1H, ArH), 7.23 (t,7=5.68 Hz, 1H,NHEt), 8.70 (s, 1H, NH), 11.1 (bs, 1H, OH); MS(APCI+): m/z 219.1 (MH+).

Analysis calculated for C12H14N2O2O.I3H2O: C, 65.34; H, 6.52; N, 12.70.

Found: C, 65.00; H, 6.38; N, 12.64.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid ethylamide 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide (0.708 g, 3.24 mmol) was mixed with 7 mL of EtOH, aqueous Me2NH (40%, 0.895 mL, 7.13 mmol) was added followed by aqueous HCHO (37%, 0.315 g, 3.89 mmol). Aclear reaction solution was obtained. The resulting reaction mixture was stirred atambient température for 2 hours during which time precipitate formed. Filtrationand drying under vacuum gave 0.298 g (33%) of pure titled compound as a whitesolid: mp 198-200°C (dec.); IR 3346, 3189, 2986, 1615, 1436, 1215, 801 cnH; ]H NMR (DMSO-d^) δ 1.11 (t, 7= 7.14 Hz, 3H, CH2CZ/3), 2.18 (s, 6H, N(Ctf3)2), 2.32 (s, 3H, ArCH3), 3.24 (quintet, 7= 6.78 Hz, 2H, Œ2CH3), 3.78(s, 2H, ArCH2NMe2), 6.50 (d,7= 8.42 Hz, 1H, ArH), 7.01 (d, 7= 8.61 Hz, 1H,

ArH), 10.6 (bs, 1H, exchangeable proton), 10.9 (bs, 1H, exchangeable proton);MS(APCI+): m/z 276.1 (MH+). Analysis calculated for C15H21N3O2: C, 65.43; H, 7.69; N, 15.26. Found: C, 65.24; H, 7.73; N, 14.92. -104- 118 2 0

Step C: PynOlo[3’,2’.-5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxamide, N- ethyl-8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-

To a mixture of perchlorate sait (263 mg, 1.11 mmol, Example 3, Step B)and 30 mL of ether was added 40 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solid had dissolved. Two layerswere separated, and the aqueous layer was extracted with ether (2 x 40 mL).

Combined ether layer was dried over Na2SC>4 and concentrated in vacuo. The,residual oil was dissolved in 20 mL of dioxane, then 4-dimethylaminomethyl- 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide (234 mg, 0.851 mmol) was added, the resulting reaction mixture was refluxed undernîtrogen for 16 hours. The reaction mixture was cooled to ambient températureand concentrated in vacuo affording a brown solid. The crude product wasrecrystallized from CH3CN, and then further purified by chromatography (10%

MeOH in HCCI3) to give 0.070 g (17%) of pure titled compound as a yellowsolid: mp 264-266°C (dec.); IR 3313, 2930, 1623, 1604, 1435, 1216, 872 cm*1; !H NMR (DMSO-dg) δ 1.08 (t, J= 7.14 Hz, 3H, CH7C//3), 1.18-1.58 (m, 9H,aliphatic CH2 and CH), 1.71-1.75 (m, 1H, aliphatic CH), 1.92-1.96 (m, 1H,aliphatic CH) 2.32 (s, 3H, ArCH3), 2.38-2.49 (m, obscured by DMSO peak, 3H,aliphatic CH), 2.66-2.73 (m, 1H, aliphatic CH and CH2), 2.90-2.94 (m, 1H,aliphatic CH), 3.10 (dd, J= 18.3, 6.78 Hz, 1H, aliphatic CH), 3.23 (quintet, J= 6.78 Hz, NHC//2CH3), 6.53 (d, 8.79 Hz, 1H, ArH), 6.98 (d, J= 8.61 Hz, 1H, ArH), 7.87 (t, J= 5.68 Hz, 1H, NHEt), 10.9 (bs, 1H, exchangeable proton);MS(APCI+): m/z 368.2 (MH+). Analysis calculated for C22H29N3O2: C, 71.90; H, 7.95; N, 11.43. Found: C, 71.52; H, 7.97; N, 11.25.

Example 34

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxaldehyde, 8,9,11,12,13,13 a, 14,14a-octahydro-2-methyl- 118 2 0 -105-

Το a solution of DMF (642 pL, 8.29 mmol) in CH2CI2 was added POCI3(736 pL, 7.89 mmol) dropwise under nitrogen atmosphère. After stirring atambient température for 10 minutes, pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]- 5 quinolizine, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl- (Example 4, 1.17 g, 3.95 mmol) was added. When reaction was done as shown by TLC, the reactionmixture was poured into 300 mL of saturated aqueous NaHCC>3 solution andstirred vigorously for 10 minutes. The resulting mixture was extracted withCHCI3 (4 x 100 mL), the combined organic phase was washed with water (1 x 10 200 mL) and brine (1 x 200 mL), dried over Na2SC>4, and concentrated in vacuo affording a golden solid. The crude product was further purified by flashchromatography (25% acetone in EtOAc). Recrystallization from EtOH/Et2Ogave 0.63 g (49%) of pure titled compound as a white solid: mp 262°C (dec.); IR3178, 2931, 1633, 1617, 1484, 1474, 1436, 1391, 1130, 1085, 868, 772 cnrb 15 NMR (DMSO-dô) δ 1.14-1.59 (m, 9H, aliphatic CH2 and CH), 1.75-1.87 (m, 2H, aliphatic CH), 2.34-2.54 (m, obscured by DMSO peak, 2H, aliphatic CH), 2.56 (s,3H, ArCH3), 2.63-2.70 (m, 1H, aliphatic CH), 2.83-2.90 (m, 2H, aliphatic CH), 3.22-3.29 (m, 1H, obscured by water peak, aliphatic CH), 6.60 (d, 7= 8.55 Hz, 1H, ArH), 7.04 (d,7= 8.55 Hz, 1H, ArH), 10.0 (s, 1H, ArCHO), 11.9 (bs, 1H, 20 exchangeable proton); MS(APCI+): m/z 325.2 (MH+). Analysis calculated forC20H24N2O2: C, 74.05; H, 7.46; N, 8.63. Found: C, 73.97; H, 7.48; N, 8.58. 118 2 0 -106-

Example 35

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, methyl ester

Step A: 5-Hydroxy-2-methyI-lH-indole-3-carboxylic acid methyl ester

Synthetic procedure is available in: Studies on the Nenitzescu synthesis of 5-hydroxyindoles. Patrick, James B.; Saunders, Elizabeth K., Tetrahedron Lett.,1979;42:4009-4012.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid methyl ester 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid methyl ester (10.0 g,49.0 mmol) and aqueous Me2NH (40%, 12.0 mL, 107 mmol) were mixed with32 mL of EtOH, aqueous HCHO (37%, 4.75 mL, 58 mmol) was then added. Afterstirring at ambient température for 16 hours, the reaction mixture was mixed with100 mL of water. The resulting mixture was extracted with EtOAc (3 x 100), thecombined organic phase was washed with water (1 x 100 mL) and brine (1 x100 mL), dried over NaQSO4 and filtered. The filtrate was treated with HCl gas,precipitate formed and was isolated by filtration. Trituration in hot acetone(150 mL) gave 3.88 g ofwhite solid. The white solid was suspended in 150 mL ofEtOAc and mixed with 100 mL of 10% aqueous K2CO3 solution, the mixture wasstirred until a clear solution is obtained, two layers were separated, the aqueouslayer was extracted with EtOAc (50 mL). The combined organic phase was overNa2SO4 and concentrated in vacuo to give 3.22 g (25%) of light tan crystals.Recrystallization of small portion of the crude product from acetone/water gavepure titled compound as white crystals: mp 145-146°C; NMR (CDCI3) δ 2.33 (s, 6H, N(Ctf3)2), 2.55 (s, 3H, ArCH3), 3.84 (s, 3H, CO2CH3), 4.19 (s, 2H,ArCH2NMe2), 6.72 (d, J= 8.55 Hz, 1H, ArH), 7.04 (d, J= 8.55 Hz, 1H, ArH); 118 2 0 -107- MS(APCI+): m/z 263,1 (MH+). Analysis calculated for C14H18N2O3: C, 64.11;H, 6.92; N, 10.68. Found: C, 63.77; H, 6.85; N, 10.54.

Step C:

To a mixture of perchlorate sait (2.17 g, 9.10 mmol, Example 3, Step B)and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solid had dissolved. Two layerswere separated, and the aqueous layer was extracted with ether (2 x 50 mL).Combined ether layer was dried over Na2SO4 an^ concentrated in vacuo. Theresidual oil was dissolved in 8 mL of dioxane, then indole mannich base (2.00 g,7.60 mmol) was added, the resulting reaction mixture was refluxed under nitrogenfor 2.5 hours followed by stirring.at ambient température for 16 hours. Thereaction mixture was concentrated in vacuo affording a thick oil. Crystallizationfrom CH3CN gave 1.75 g (63%) of pure titled compound as a white solid: mp 205-205.5°C; IR 3242,2938, 1696, 1441,1236,1079, 884 cm*1; ]H NMR(CDCI3) δ 1.21-1.80 (m, 9H, aliphatic CH2 and CH), 1.82-1.95 (m, 1H, aliphaticCH), 2.09-2.13 (m, 1H, aliphatic CH), 2.41-2.77 (m, 2H, obscured by ArCH3peak, aliphatic CH), 2.77 (s, 3H, ArCH3), 2.82-2.86 (m, 2H, aliphatic CH),3.00-3.07 (m, 1H, aliphatic CH), 3.44 (dd,J = 18.1, 6.59 Hz, 1H, aliphatic CH), 3.83 (s, 3H, CO2CH3), 6.73 (d, J= 8.55 Hz, 1H, ArH), 7.01 (d, J = 8.79 Hz, 1H,

ArH), 8.12 (bs, 1H, NH); MS(APCI+): m/z 355.2 (MH+). Analysis calculated forC2iH26N2O3: C, 71.16; H, 7.39; N, 7.90. Found: C, 71.17; H, 7.32; N, 8.00.

Example 36

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,l2,12-trimethyl-, phenylmethyl esterand/or

Pyrrolo[3 ',2': 5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10,10-trimethyl-, phenylmethyl ester -108- 118 2 0

Step A: 4,4-Dimethyl-l,2,3,4,6,7,8,9-octahydro-quinolizinylium perchlorate

The synthesis of 4,4-dimethyl-l)2,3,4,6,7,8,9-octahydro-quinolizinylium 5 perchlorate from l-chloro-3-iodopropane and 2,3,4,5-tetrahydro-2,2,6- trimethylpyridine was adapted from the procedure described in Evans, D.A.;Domeier, L.A. Org Synth Coll Vol VI, p 819. !H NMR (400 MHz, CDCI3)

Ô 1.52 (s, 6H, C(C//3)2), 1.75-1.86 (m, 4H, aliphatic CH), 1.88-2.00 (m, 4H,aliphatic CH), 2.80-2.87 (m, 4H, aliphatic CH), 2.65-2.75 (m, 2H, NC//2); MS 10 (APC1+) m/z 166.0 (parent MH+).

Step B: PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12,12-trimethyl-, phenylmethylester and/or 15 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10,10-trimethyl-, phenylmethylester

One équivalent of 4,4-dimethyl-l,2,3,4,6,7,8,9-octahydro-quinolizinyliumperchlorate (1.45 mmol, 0.385 g) was dissolved in a minimum amount of water 20 and treated with 50% aqueous NaOH until strongly basic. The aqueous solutionwas extracted with 4 x 20 mL of Et20 and the combined extracts were washedwith 1 x 20 mL of saturated aqueous NaCl, dried with MgSO4, fïltered, and 118 2 0 -109- concentrated to give the enamine. The residue was dissolved in dioxane (14 mL)and 4-dimethylaminomethyî-5-hydroxy-2-methyl-17f-indole-3-carboxylic acidbenzyl ester (1.45 mmol, 0.490 g) was added. The reaction mixture was heated at90°C under N2 for 18 hours, cooled to room température, and concentrated. The 5 crude residue was purified by flash column chromatography on silica gel using100% ethyl acetate and trituration with ether to give 90 mg (14%) ofpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12,12-trimethyl-, phenylmethyl esterand/or pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2,10,10-trimethyl-, phenylmethyl esteras a yellow foam: ER. (KBr) 3383, 2932, 2857, 1675, 1432, 1090, 1072 cm-1; NMR(400 MHz, DMSO-dg) δ 1.07 (s, 3H, CH3), 1.23 (s, 3H, C//3), 1.09-1.26 (m, 5H, aliphatic CH), 1.42-1.61 (m, 6H, aliphatic CH), 1.90 (d, 7=12.70 Hz, ÎH, aliphaticCH), 2.58 (d, 7=18.56 Hz, 1H, aliphatic CH), 2.64-2.75 (m, 3H, aliphatic CH), 15 3.11-3.19 (m, 2H, aliphatic CH), 3.24-3.30 (m, 1H, aliphatic CH), 5.15-5.25 (m, 2H, OCtf2Ar), 6.52 (d, 7=8.79 Hz, 1H, AxH), 6.99 (d, 7=8.55 Hz, 1H, Artf), 7.30-7.42 (m, 5H, ArÆ), 11.50 (s, 1H, N//); MS (APCI+) m/z 459.3 (MH+). Anal.Calcd forC29H34N2O3-0.19 H2O: C, 75.39; H, 7.50; N, 6.06; H2O, 0.74. Found:C, 75.00; H, 7.73; N, 5.79; H2O, 0.36. 20 Example 37

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester

118 2 0 -110-

Step A: 6-Fluoro-5-hydroxy-2-methyl-17f-indole-3-carboxylic acid ethyl ester

6-Fluoro-5-hydroxy-2-methyl-177-indole-3-carboxylic acid ethyl ester wassynthesized according to the procedure published in Littell, R.; Allen, G.R., Jr. 5 J. Org. Chem. 1968;33:2064.

Step B: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-17/-indole- 3-carboxylic acid ethyl ester

4-DimethyIaminomethyl-6-fluoro-5-hydroxy-2-methyl-17f-indole- 10 3-carboxylic acid ethyl ester was prepared according to Procedure G from 6-fluoro-5-hydroxy-2-methyl-l//-indole-3-carboxylic acid ethyl ester (4.51 mmol, I. 07 g). The product precipitated out of the reaction solution upon reducing thevolume by one-third and was recrystallized from acetonitrile to give a yellow-orange solid (0.510 g, 38%): mp 174-176°C (dec); IR (KBr) 3278, 2975, 1692, 15 1443, 1124, 1078 cnrh 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 7=7.08 Hz, 3H, OCH2C//3), 2.26 (s, 6H, N(Ctf3)2), 2.50 (s, 3H, ArCtf3), 4.17 (s, 2H,NCtf2Ar), 4.24 (q, 7=7.08 Hz, 2H, OCÆ2CH3), 7.05 (d, 7=10.50 Hz, 1H, Artf),

II. 56 (bs, 1 H, NT/); 19F NMR (DMSO-d6) δ -141.69 (d, 7=10.68 Hz); MS (APCI+) m/z 295.1 (MH+). Anal. Calcd for Ci5H19FiN2O3: C, 61.21; H, 6.51; 20 N, 9.52; F, 6.45. Found: C, 61.32; H, 6.55; N, 9.51; F, 6.61. 118 2 0 -111-

Step C: PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester was 5 synthesized according to Procedure I from 4-dimethylaminomethyl-6-fluoro- 5-hydroxy-2-methyl-l/f-indole-3-carboxylic acid ethyl ester (1.66 mmol, 0.488 g). The compound was purified by silica gel flash column chromatography(50:50 ethyl acetate:hexanes) and recrystallized from ethyl acetate to give a whitesolid (32%): mp 184-186°C; IR (KBr) 3367, 2932,2858,1670, 1456, 1437, 10 1135 cm’1; !H NMR (400 MHz, CDC13) δ 1.37 (t, 7=7.08 Hz, 3H, OCH2C//3), 1.25-1.47 (m, 4H, aliphatic CH), 1.60-1.78 (m, 5H, aliphatic CH), 1.85-1.95 (m,1H, aliphatic CH), 2.09 (bd, 7=13*43 Hz, 1H, aliphatic CH), 2.43-2.49 (m, 2H,aliphatic CH), 2.57 (s, 3H, AtCH$), 2.87-2.92 (m, 2H, aliphatic CH), 3.05-3.18 (m, 1H, aliphatic CH), 3.43-3.50 (m, 1H, aliphatic CH), 4.32 (q, 15 7=7.08 Hz, 2H, OC//2CH3), 6.86 (d, 7=10.01 Hz, 1H, ArH), 8.09 (bs, 1H, NÂ); 19F NMR (CDCI3) δ -140.62 (d, 7=10.68 Hz); MS (APCI+) m/z 387.1 (MH+).Anal. Calcd for C22H27F1N2O3: C, 68.37; H, 7.04; N, 7.25; F, 4.92. Found: C,68.30; H, 7.11; N, 7.09; F, 4.97.

Example 38 20 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenylmethyl ester

118 2 0 -112-

Step A: 6-Fluoro-5-hydroxy-2-methyl-l//-indole-3-carboxylic acid

6-Fluoro-5-hydroxy-2-methyl-17Y-indole-3-carboxylic acid ethyl ester(Example 37, Step A, 9.02 mmol, 2.14g) was dissolved in 40 mL of 2N sodium 5 hydroxide and heated at reflux for 1 hour. The solution was cooled to 0°C andcarefully acidified to pH 9 with concentrated HCl. The solution was extractedwith CH2CI2, the extracts were discarded and the aqueous layer was further acidified at 0°C to pH 4 with concentrated HCl. The precipitate was filtered offand dried in vacuo for 18 hours to.afford a tannish pink solid (1.16 g, 62%); mp

10 202-204°C (dec); IR (KBr) 3584, 3358, 1649, 1471,1109 cm'1; ^NMR (400 MHz, DMSO-dg) δ 2.53 (s, 3H, AtCH3), 7.04 (d, 7=11.23 Hz, 1H, Artf), 7.46 (d, 7=9.03 Hz, 1H, ArH), 9.17 (s, 1H, ArOtf), 11.46 (s, 1H, NTYor COOH),11.76(s, 1H, COOHorW); 19F NMR (DMSO-dg) δ-141.60 (t, 7=10.68 Hz);MS (APCI-) m/z 208.0 (M-l). 15 Step B: 6-Fluoro-5-hydroxy-2-methyl-17/-indole-3-carboxylic acid benzyl ester

To a suspension of 6-fluoro-5-hydroxy-2-methyl-l//-indole-3-carboxylicacid (4.92 mmol, 1.03 g) in 10.0 mL of DMF at room température under N2 wasadded dropwise via syringe l,8-diazabicyclo[5.4.0]undec-7-ene (4.92 mmol, 20 0.736 mL) followed by benzyl bromide (5.42 mmol, 0.644 mL). After 48 hours,

water (10 mL) was added, and the precipitate was filtered off, dried, andrecrystallized from chloroform to give a white, cottony solid (0.677 g, 46%): mp191-193°C; IR (KBr) 3384, 3254, 1662, 1475,1327, 1129,1098 cm'1; ÎH NMR 118 20 -113- (400 MHz, DMSO-dg) δ 2.59 (s, 3H, ArC//3), 5.32 (s, 2H, OCT/2C6H5), 7.12 (d, 7=10.99 Hz, 1H, ArT/), 7.31-7.49 (m, 6H, Ar//), 9.29 (s, 1H, ArOT/), 11.67 (s, 1H, NT/); 19p NMR (DMSO-d6) δ -140.96-141.01 (m); MS (APCI-) m/z 298.1 (M-l).

Anal. Calcd for C17H14F1N1O3O.O4 H2O: C, 68.06; H, 4.73; N, 4.67; F, 6.33; 5 H2O, 0.24. Found: C, 67.69; H, 4.63; N, 4.57; F, 6.61; H2O, 0.10.

Step C: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-lT/-indole- 3-carboxylic acid benzyl ester

H A solution of 6-fluoro-5-hydroxy-2-methyl-l//-indole-3-carboxylic acid 10 benzyl ester (2.26 mmol, 0.677 g) and jy./V.AC/V’-tetramethyldiaminomethane(2.49 mmol, 0.34 mL) in 5 mL of dioxane under N2 was heated at reflux for21 hours. An additional aliquot of N,N, N’, 77-tetramethyldiaminomethane(2.49 mmol, 0.34 mL) was added, and the reaction was continued at reflux for24 hours, cooled to room température, and concentrated. The residue was 15 recrystaîlized from ethyl acetate to afford a light yellow solid (0.260 g, 32%): mp167-169°C; IR (KBr) 3280, 2951, 1692, 1443, 1123,1081 cm'1; !H NMR(400 MHz, DMSO-dg) δ 2.12 (s, 6H, N(Œ/3)2), 2.44 (s, 3H, ArC//3), 4.04 (s,2H, NC//2Ar), 5.23 (s, 2H, OCtf2C6H5), 7.01 (d, 7=10.50 Hz, 1H, AxH), 7.31-7.44 (m, 5H, ArT/), 11.57 (s, ΙΗ,ΝΤ/); 19F NMR (DMSO-d6) δ-141.55 (d, 20 7=10.68 Hz); MS (APCI+) m/z 357.1 (MH+). Anal. Calcd for C20H2lFlN203-0.07 C4H8O2: C, 67.18; H, 5.99; N, 7.73; F, 5.24. Found: C,66.81; H, 6.20; N, 7.74; F, 5.49. 11820 -114-

Step D: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]qtnnolizine-l-carboxylic acid, ' 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, phenylmethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5 5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester was synthesized according to Procedure I from 4-dimethylaminomethyl-6-fluôro-5-hydroxy-2-methyl-l#-indole-3-carboxylic acidbenzyl ester (0.601 mmol, 0.214 g), heating at 80°C for 40 hours. The product was purified by silica gel flashcolumn chromatography (30-50% ethyl acetate/hexanes) and recrystallized from 10 ether to give a white solid (0.169 g, 63%): mp 179-181°C; IR (KBr) 2932,2857,1699, 1453, 1131, 1075 cnr*; 1H NMR (400 MHz, CDCI3) δ 1.17-1.38 (m, 3H, aliphatic CH), 1.41-1.48 (m, 1H, aliphatic CH), 1.55-1.85 (m, 6H, aliphatic CH),2.03 (bd, 7=12.94 Hz, 1H, aliphatic CH), 2.42-2.48 (m, 2H, aliphatic CH), 2.55 (s,3H, ArCH3), 2.79 (d, 7=17.58 Hz, 1H, aliphatic CH), 2.85-2.92 (m, 1H, aliphatic 15 CH), 3.04-3.17 (m, 1H, aliphatic CH), 3.35 (dd, 7=18.31, 6.51 Hz, 1H, aliphaticCH), 5.25-5.37 (m, 2H, OŒ2C6H5), 6.86 (d, 7=10.25 Hz, 1H, ArH), 7.28-7.38 (m, 3H, Ar#), 7.40-7.44 (m,2H, Ar#), 8.07 (bs, 1H, N#); 19F NMR(CDCI3) δ -142.0 (m); MS (APCI+) m/z 449.1 (MH+). Anal. Calcd forC27H29F1N2O3: C, 72.30; H, 6.52; N, 6.25; F, 4.24. Found: C, 72.28; H, 6.45; 20 N, 6.09; F, 4.50.

Example 39 12H-Furo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester

11820 -115-

Step A: 6-Fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester

To a solution of 2-fluoro-[l,4]benzoquinone (38.3 mmol, 4.82 g) in300 mL of glacial acetic acid was added 3-amino-but-2-enoic acid ethyl ester 5 (31.9 mmol, 4.12 g). The solution was heated at reflux for 1.5 hours, cooled to room température, and concentrated. The product was isolated by silica gel flashcolumn chromatography (30-50% ethyl acetate/hexanes) to afford a yellow solid(0.456 g, 6%): mp 138-139°C; IR (KBr) 3284, 2991, 1680, 1469, 1422, 1326, 1110 cm"1;1H NMR (400 MHz, DMSO-d6) δ 1.36 (t, 7=7.08 Hz, 3H, 10 OCH2CH3), 2.68 (s, 3H, ArCJ/3), 4.32 (q, 7=7.08 Hz, 2H, OC//2CH3), 7.43 (d, 7=8.79 Hz, 1H, Artf), 7.55 (d, 7=10.74 Hz, 1H, Artf), 9.82 (s, 1H, ArOH); 19pNMR (DMSO-dg) δ -137.42 (t, 7=9.16 Hz); MS (APCI-) m/z 237.1 (M-l). Anal.Calcd for Ci2Hi jFiO4: C, 60.50; H, 4.65; F, 7.98. Found: C, 60.50; H, 4.46; F,8.20. 15 Step B: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyî-benzofuran- 3-carboxylic acid ethyl ester

A solution of 6-fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acidethyl ester (1.90 mmol, 0.452 g) and -tetramethyldiaminomethane 20 (2.09 mmol, 0.285 mL) in 4 mL of dioxane under N2 was heated at reflux for

4.5 hours, cooled to room température, and concentrated. Water (10 mL) wasadded to the residue, and the résultant precipitate was filtered off, dried, andrecrystallized from /-butyl methyl ether to give a light yellow solid (0.225 g,40%); mp 120-122°C; IR (KBr) 2989,1706, 1446, 1384,1322,1120 cm-1; ÎH 118 2 0 -116- NMR (400 MHz, DMSO-d6) δ 1.34 (t, 7=7.08 Hz, 3H, OCH2C//3), 2.21 (s, 6H,N(C//3)2), 2.57 (s, 3H, A1CH3), 4.03 (s, 2H, NCH2Ar), 4.32 (q, 7=7.08 Hz, 2H,OCH2CH3), 7.48 (d, 7=10.25 Hz, 1H, Ar/7); 19F NMR (DMSO-dô) δ-137.69 (d, 7=10.68 Hz); MS (APCI+) m/z 296.1 (MH+). Anal. Calcd for CisHigFjNiOzf. C, 61.01; H, 6.14; N, 4.74; F, 6.43. Found: C, 61.06; H, 6.07; N, 4.61; F, 6.47.

Step C: 12H-Furo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5-fîuoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester 12H-Furo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester was synthesizedaccording to Procedure I (90°C, 21 hours) from 4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester (0.603 mmol, 0.178 g). The product was purified by silica gel flash column chromatography(30% ethyl acetate/hexanes) and recrystallized from ether to afford a white solid(0.210 g, 90%): mp 147-149°C; IR (KBr) 2936, 2848, 1717, 1453, 1242, 1125 cm’1; *H NMR (400 MHz, CDCI3) δ 1.25-1.37 (m, 2H, aliphatic CH), 1.38 (t, 7=7.08 Hz, 3H, OCH9CH3), 1.40-1.52 (m, 2H, aliphatic CH), 1.57-1.80 (m, 5H, aliphatic CH), 1.84-1.96 (m, 1H, aliphatic CH), 2.02 (d, 7=13.43 Hz, 1H, aliphatic CH), 2.42-2.58 (m, 2H, aliphatic CH), 2.61 (s, 3H,ArCH3), 2.83-2.91 (m, 1H, aliphatic CH), 2.90 (d, 7=17.82 Hz, 1H, aliphatic CH),3.06-3.16 (m, 1H, aliphatic CH), 3.34-3.40 (m, 1H, aliphatic CH), 4.34 (q, 7=7.08 Hz, 2H, OCH2CH3), 7.03 (d, 7=9.77 Hz, 1H, Artf); 19F NMR (CDCI3) δ -137.90 (d, 7=9.16 Hz); MS (APCI+) m/z 388.2 (MH+). Anal. Calcd forC22H26FIN1Û4: C, 68.20; H, 6.76; N, 3.62; F, 4.90. Found: C, 68.12; H, 6.84; N, 3.56; F, 4.96.

Example 40

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4,5-difluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester -117- 118 20

Step A: 2,3-Difluoro-benzene-l,4-diolOH

OH 2,3-Difluorophenol (Aldrich, 183.2 mmol, 24.32 g) was oxidized using 5 potassium persulfate nitrate following the procedure of Feiring, A.E.; Sheppard,W.A. J. Org. Chem. 1975;40:2543. The crude material was purifîed by silica gelflash column chromatography (10% acetonitrile/chloroform) and recrystallizedfrom chîoroform to give a light yellow solid (7.32 g, 27%); mp 156-158°C; IR(KBr) 3343 (br), 1514,1505, 1259,1199,1041 cnrb ^H NMR (400 MHz,

10 DMSO-d6) δ 6.52 (d, 7=5.37 Hz, 2H, ArH), 9.45 (s, 2H, AxOH)·, 15 * * * l9F NMR (DMSO-dô) δ -159.78 (d, 7=4.58 Hz); MS (APCI-) m/z 145.0 (M-l). Anal. Calcdfor C6H4F2O2: C, 49.33; H, 2.76; F, 26.01. Found: C, 49.09; H, 2.73; F, 26.37.

Step B: 2,3-Difluoro-[l,4]benzoquinone

O

O 15 2,3-Difluoro-benzene-l,4-diol (49.1 mmol, 7.17 g) was oxidized using ammonium cerium(IV) nitrate following the procedure of Feiring, A.E.; Sheppard, W.A. J. Org. Chem. 1975;40:2543 to afford a bright yellow solid (6.63 g, 94%); mp 97.0-98.5°C; IR (KBr) 3352,1684, 1333 cnr*; JH NMR (400 MHz, DMSO- d6) δ 6.98 (s, 2H, AtH); î9f NMR (DMSO-d6) δ -144.85 (s); MS (APCI-) m/z -118- 118 2 0 144.0 (M'). Anal. Calcd for Q5H2F2O2: C, 50.02; H, 1.40; F, 26.37. Found: C, 49.89; H, 1.31; F, 26.19.

Step C: 6,7-Difluoro-5-hydroxy-2-methyl-l//-indole-3-carboxylic acid benzylester

To a solution of 2,3-diiluoro-[l,43benzoquinone (1.26 mmol, 0.180 g) in 3.4 mL of glacial acetic acid was added 3-amino-but-2-enoic acid benzyl ester(1.05 mmol, 0.200 g). The mixture was heated at 50°C for 18 hours, cooled toroom température, and the precipitate was filtered off. The beige solid was washed 10 with glacial acetic acid and dried in vacuo to give clean product. The filtrate was neutralized, water (20 mL) was added, and the solution was extracted with ethylacetate (4 x 20 mL). The extracts were dried over MgSC>4, filtered, concentrated and the residue purified by silica gel flash column chromatography (20% ethylacetate/hexanes). The pure portions were combined to give 0.174 mg (52%) of 15 off-white solid, which was recrystallized from acetonitrile: mp 215-217°C; IR(KBr) 3457, 3243, 1658, 1480, 1338,1150 cm-1; 1HNMR(400 MHz, DMSO-d6) δ 2.58 (s, 3H, ArC//3), 5.31 (s, 2H, OŒ2C6H5), 7.29-7.45 (m, 6H, Artf), 9.75 (s, 1H, AïOH), 12.13 (s, 1H, Ntf); MS (APCI+) m/z 318.0 (MH+). Anal.Calcd for CpH^N^-O^ C2H4O2: C, 64.17; H, 4.15; N, 4.38; F, 11.89. 20 Found: C, 63.80; H, 4.15; N, 4.05; F, 12.18. 11820 -119-

Step D: 4-Dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-l//-indole- 3-carboxylic acid benzyl ester

F 4-DimethylaminomethyI-6,7-difluoro-5-hydroxy-2-methyl-lJ7-indole- 3- carboxylic acid benzyl ester was prepared according to Procedure G from 6,7-difluoro-5-hydroxy-2-methyl-177-indole-3-carboxylic acid benzyl ester(8.08 mmol, 2.56 g). The reaction was heated at 50°C for 21 hours, the precipitatewas ftltered off, washed with éthanol, and dried to give a light yellow solid(1.49 g, 49%): mp 159-160°C (dec); IR (KBr) 3235,1688, 1438, 1365,1301,1123, 1083 cm'1 ; NMR (400 MHz, DMSO-d6) δ 2.13 (s, 6H, N(C?/3)2), 2.46 (s, 3H, ArCtf3), 4.00 (s, 2H, ArCH2N), 5.24 (s, 2H, OCtf2C6H5), 7.27-7.38 (m, 3H, Artf), 7.41-7.44 (m, 2H, Artf), 12.08 (s, 1H, Ntf); ^F NMR(DMSO-d<5) δ -168.26 (d, 7=21.4 Hz), -159.68 (d, 7=21.4 Hz); MS (APCI+) m/z 375.0 (MH+). Anal. Calcd for C2oH2oF2N203: C, 64.16; H, 5.38; N, 7.48; F,10.15. Found: C, 64.00; H, 5.44; N, 7.36; F, 10.15.

Step E: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxyîic acid, 4,5-difluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,phenyîmethyl ester

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxyîic acid, 4,5-difluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyîmethyl esterwas synthesized according to Procedure I (90°C, 18 hours) from 4- dimethylaminomethyî-6,7-difluoro-5-hydroxy-2-methyl-l//-indoIe-3-carboxylicacid benzyl ester (3.82 mmol, 1.43 g). The product was purified by silica gel flashcolumn chromatography (5-10% ethyl acetate/dichloromethane) to give 1.37 g(77%) of cream colored solid. A portion was recrystallized from z-butyl methylether/hexanes to afford a white solid: mp 159-160°C; IR (KBr) 3297, 2933, 2857, 118 2 0 -120- 1704, 1455,1141, 1124 cm'l; ^NMR(400 MHz, CDC13) δ 1.17-1.36 (m, 3H, aliphatic CH), 1.43-1.49 (m, 1H, aliphatic CH), 1.57-1.78 (m, 6H, aliphatic CH),2.00 (d, 7=13.7 Hz, 1H, aliphatic CH), 2.46 (d, 7=9.77 Hz, 1H, aliphatic CH),2.53-2.57 (m, 1H, aliphatic CH), 2.57 (s, 3H, \xCH^), 2.71 (d, 7=18.31 Hz, 1H, 5 aliphatic CH), 2.83-2.88 (m, 1H, aliphatic CH), 3.06-3.16 (m, 1H, aliphatic CH), 3.24-3.30 (m, 1H, aliphatic CH), 5.24-5.36 (m, 2H, OŒ2C6H5), 7.32-7.38 (m,3H, kxH), 7.42 (d, 7=6.84 Hz, 2H, Artf), 8.21 (s, 1H, Ntf); 19F NMR (CDCI3) δ -166.80 (d, 7=19.84 Hz), -162.52 (d, 7=21.36 Hz); MS (APCI+) m/z 467.1 (MH+)Anal. Calcd for C27H28F2N2O3: C, 69.51; H, 6.05; N, 6.00; F, 8.14. Found: C, 10 69.36; H, 5.99; N, 5.88; F, 8.37.

Example 41 P>Trolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4,5-dichloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenylmethyl ester

15 Step A: 6,7-Dichloro-5-hydroxy-2-methyl-l//-indole-3-carboxylic acid benzyl ester

Cl 6,7-Dichloro-5-hydroxy-2-methyl-17f-indole-3-carboxylic acid benzylester was prepared from 2,3-dichloro-[l,4]benzoquinone (16.8 mmol, 2.98 g) and 20 3-amino-but-2-enoic acid benzyl ester (25.3 mmol, 4.83 g) following the procedure for the corresponding ethyl ester reported by Grinev, A.N.; Zaitsev, 11820 -121- I.A.; Shvedov, V.I.; Terent’ev, A.P. J. Org. Chem. USSR (English) ;28:439. Yield

0.649 g (11%): mp 235-236°C; IR (KBr) 3421, 3281, 1651,1098 cm'1; NMR (400 MHz, DMSO-dg) δ 2.59 (s, 3H, ArCH3), 5.29 (s, 2H, OCH2C6H5), 7.30 (t, 7=7.08 Hz, 1H, ArH), 7.34-7.38 (m, 2H, ArH), 7.42 (d, 7=7.32 Hz, 2H, ArH),

5 7.51 (s, 1H, ArH); MS (APCI-) m/z 348.0 (M-l). HPLC (ALLTECH/ALLTIMA C-18, 1:1-2:98 H2O/CH3CN + 0.05% TFA): rétention time=6.573 min, 98.41%purity.

Step B: 4-Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester 10 15

Me2N. h%A, O Λ -O cPp Cl "y -Me ""N H 4-Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester was prepared according to Procedure G from 6,7-dichloro-5-hydroxy-2-methyl-lH-indole-3-carboxyIic acid benzyl ester(3.06 mmol, 1.07 g). The reaction was heated at 50°C for 22.5 hours, concentratedand purified by silica gel flash column chromatography (30-50% acetone/hexanes)to afford a golden yellow solid (0.830 g, 67%): mp 167-170°C; IR (KBr) 3328,1695,1438, 1409, 1330,1281,1107 cm'b 1H NMR (400 MHz, DMSO-d6) δ 2.18 (s, 6H, N(Ctf3)2), 2.52 (s, 3H, ArCH3), 4.06 (s, 2H, ArCH2N), 5.27 (s, 2H,OCA2C6H5), 7.30-7.39 (m, 3H, Ar//), 7.41-7.47 (m, 2H, ArH), Π.84 (s, 1H, NH); MS (APCI+) m/z 407.1 (M+). Anal. Calcd for C2QH20CÎ2N2O3: C, 58.98;H, 4.95; N, 6.88; Cl, 17.41. Found: C, 58.87; H, 4.96; N, 6.68; Cl, 17.23. 20 118 2 0 -122-

Step C: Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4,5-dichloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,phenylmethyl ester

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 5 4,5-dichloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester was synthesized according to Procedure I (80°C, 18 hours) from 4-dimethyIaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-l/7-indole- 3-carboxylic acid benzyl ester (1.82 mmol, 0.742 g). The product was purified bysilica gel flash column chromatography (10% acetone/hexanes) to give 0.684 g 10 (75%) peach colored foam: mp 100-105°C; IR (KBr) 3424, 2932, 2853, 1685, 1430, 1125, 1076 cm’1; ^HNMR (400 MHz, DMSO-dg) δ 1.00-1.30 (m, 3H, aliphatic CH), 1.37-1.76 (m, 8H, aliphatic CH), 2.37-2.40 (m, 1H, aliphatic CH),2.46-2.49 (m, 1H, aliphatic CH), 2.50 (s, 3H, ArC/Tj), 2.63-2.69 (m, 2H, aliphatic CH), 2.95-2.99 (m, 1H, aliphatic CH), 3.17 (dd, 7=18.31, 6.74 Hz, 1H, aliphatic15 CH), 5.23 (dd, 7=28.08, 12.21 Hz, 2H, OC//2C6H5), 7.31-7.39 (m, 3H, ΑτΗ), 7.42-7.44 (m, 2H, ΑτΗ), 11.85 (s, 1H, Ntf); MS (APCI+) m/z 499.1 (MH+). Anal.Calcd for C27H2SCI2N2O3O.O7 H2O: C, 64.77; H, 5.66; N, 5.59; Cl, 14.16; H2O, 0.25. Found: C, 64.37; H, 5.64; N, 5.51; Cl, 13.96; H2O, 0.32.

Example 42 20 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethylester

O

Me OMe 118 2 0 -123-

Step A: 6,7-Dimethoxy-5-hydroxy-2-methyl-î//-indole-3-carboxylic acid benzyl ester

OMe 2,3-Dimethoxy-[l,4]benzoquinone (10.4 mmol, 1.74 g) was added to a 5 solution of 3-amino-but-2-enoic acid benzyl ester (8.62 mmol, 1.65 g) in éthanol (25 mL) at 0°C. The reaction was warmed to room température and then heated atreflux for 18 hours. The solvent was removed and the product was purified bysilica gel flash column chromatography (30-50% ethyl acetate/hexanes) andrecrystallized from toluene to give a peach colored solid (0.621 g, 2î%): mp

10 I54-156°C; IR (KBr) 3336, 3267, 1660, 1468, 1327, 1146, 1081 cm'1; *HNMR (400 MHz, DMSO-dô) δ 2.56 (s, 3H, ArC//3), 3.73 (s, 3H, OC/Z3), 3.89 (s, 3H,OC//3), 5.29 (s, 2H, OC//2C6H5), 7.11 (s, 1H, Artf), 7.29-7.43 (m, 5H, Artf),8.79 (s, 1H, ArO/7), 11.59 (s, 1H, N//); MS (APCI-) m/z 340.0 (M-l). Anal. Calcdfor C19H19N1O5: C, 66.85; H, 5.61 ; N, 4.10. Found: C, 66.69; H, 5.55; N, 3.79. 15 Step B: 4-DimethyIaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-17/-indole- 3-carboxylic acid benzyl ester

OMe 4-Dimethylaminomethyl-6,7-methoxy-5-hydroxy-2-methyl-l//-indole-3-carboxylic acid benzyl ester was prepared according to procedure G from 20 6,7-dimethoxy-5-hydroxy-2-methyI-l#-indole-3-carboxylic acid benzyl ester (1.69 mmol, 0.577 g). The reaction was heated at 50°C for 18 hours, concentratedand purified by silica gel flash column chromatography (0-3% triethylamine/ethyl 118 20 -124- acetate) and recrystallized from cyclohexane to afford a lemon yellow solid(0.274 g, 41 %): mp 132-134°C; IR (KBr) 3312, 1698, 1440, 1415, 1290, 1129 cm'1; ]H NMR (400 MHz, DMSO-d6) δ 2.10 (s, 6H, N(C#3)2), 2.44 (s,3H, ArC#3), 3.73 (s, 3H, ArOC#3), 3.86 (s, 3H, ArOC#3), 3.94 (s, 2H,ArCH2N), 5.21 (s, 2H, OC//2C6H5), 7.29-7.38 (m, 3H, Ar#), 7.41-7.43 (m, 2H,

Ar#), 11.48 (s, 1H, N#); MS (APCI+) m/z 399.0 (MH+). Anal. Calcd forC22h26n2°5; c’ 66.32; H>6·58;N»7·03·Found; c>66.47; H>6.58; N>6·73·

Step C: PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quÎnoIizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-,phenylmethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethylester was synthesized according to Procedure I (90°C, 21 hours) from 4-dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-l#-indole-3-carboxylic acid benzyl ester (0.595 mmol, 0.237 g). The product was purified bysilica gel flash column chromatography (50% ethyl acetate/hexanes) andrecrystallized from 2,2,4-trimethylpentane to give 0.089 g (30%) white solid: mp130-136°C; IR (KBr) 3307, 2931, 2856, 1833, 1700,1684, 1448, 1418, 1282,1137, 1123 cm-1; 1HNMR(400 MHz, CDC13) δ 1.24-1.38 (m, 4H, aliphatic C//), 1.44-1.55 (m, 1H, aliphatic C//)» 1-59-1.80 (m, 6H, aliphatic C#), 2.09 (d,7=13.98 Hz, 1H, aliphatic C#), 2.51 (d, 7=10.37 Hz, 1H, aliphatic CH), 2.58 (s,3H, ArC#3), 2.78 (d, 7=18.08 Hz, 1H, aliphatic CH), 2.85-2.91 (m, 1H, aliphaticCH), 3.08-3.14 (m, 1H, aliphatic CH), 3.29-3.36 (m, 1H, aliphatic CH), 3.96 (s,3H, OC#3), 4.05 (s, 3H, OC#3), 5.26-5.37 (m, 2H, OC^QHs), 7.31-7.40 (m, .3H, MH), 7.44 (d, 7=6.99 Hz, 2H, Ai#), 8.29 (s, 1H, N#); MS (APCI+) m/z 491.1 (MH+). HPLC (ALLTECH/ALLTIMA C-18,1:1-2:98 H2O/CH3CN + 0.05 % TFA): rétention time=4.527 min, 100.00% purity. 1182ο -125-

Example 43

Pyrrolo[3',2':5,6][l]bcn2opyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2,5-dimethyl-, phenylmethyl ester

5 Step A: 6-Methyl-5-hydroxy-2-methyl-l//-indoîe-3-carboxylic acid benzyl ester

6-Methyl-5-hydroxy-2-methyl-l//-indole-3-carboxylic acid benzyl ester(2.42 g, 10%) was obtained from methyl-[l,4]benzoquinone (Aldrich, 81.9 mmol,10.0 g) and 3-amino-but-2-enoic acid benzyl ester (79.5 mmol, 15.2 g) following 10 the procedure for the corresponding ethyl ester reported by Allen, G.R., Jr.;

Pidacks, C.; Weiss, M.J. J. Am. Chem. Soc. 1966;88:2536. The crude reactionproduct consisted of a mixture of the desired 6-methyl-5-hydroxy-2-methyl-l/7-indole-3-carboxylic acid benzyl ester and the regioisomer, 7-methyl-5-hydroxy- 2-methyl-l/7-indole-3-carboxylic acid benzyl ester. The regioisomers were 15 separated following the procedure for the corresponding ethyl esters reported byPoletto, J.F.; Allen, G.R., Jr.; Sloboda, A.E.; Weiss, M.J. J. Med. Chem. 1973; 16:757. Each isomer was separately recrystallized from acetone to giveX-ray quality crystals. Single crystal X-ray analysis indicated that the higher Rfisomer (silica gel, 50% ethyl acetate/hexanes) was 6-methyl-5-hydroxy-2-methyl- 20 l//-indole-3-carboxylic acid benzyl ester: mp 196-197°C; IR (KBr) 3399, 3314,1655, 1469,1438, 1086 cm’1; 1HNMR(400MHz,DMSO-d6) δ 2.14 (s, 3H,ArCtf3), 2.53 (s, 3H, ArC/f3), 5.28 (s, 2H, OC//2C6H5), 6.99 (s, 1 H, Arfl), 7.28-7.42 (m, 6H, Arfl), 8.81 (s, 1H, ArOtf), 11.42 (s, 1H, Nfl); MS (APCI+) m/z 11820 -126- 296.0 (MH+). Anal. Calcd for CigHnNjOyO.25 H2O: C, 72.10; H, 5.88; N,4.67. Found: C, 71.72; H, 5.54; N, 4.74.

Step B: 4-Dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-l//-indole- 3-carboxylic acid benzyl ester

4-DimethylaminomethyI-6-methyl-5-hydroxy-2-methyl-l//-indole- 3- carboxylic acid benzyl ester was prepared according to Procedure G from6-methyl-5-hydroxy-2-methyl-17/-indole-3-carboxylic acid benzyl ester(7.48 mmol, 2.21 g) with the addition of 49.4 mmol of dimethylamine and 26.9 mmol of formaldéhyde. The reaction was heated at 50°C for 70 hours,concentrated and purified by silica gel flash column chromatography (0-5%triethylamine/ethyl acetate) to afford a tan solid (1.67 g, 63%). A portion wasrecrystallized from ethyl acetate to give a light yellow solid: mp 162-164°C; IR(KBr)3313, 1688, 1432, 1227,1119, 1075 cnr1; ’HNMR (400 MHz, DMSO-d6) δ 2.13 (s, 9H, N(CH3)2 and ArCtf3), 2.44 (s, 3H, ArC//3), 4.01 (s, 2H,ArCÆ2N), 5.22 (s, 2H, OCtf2C6H5), 6.95 (s, 1H, AiH), 7.29-7.44 (m, 5H, ArH), 11.40 (s, 1H, N/7); MS (APCI+) m/z 353.1 (MH+). Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.30; H, 6.92; N, 7.87.

Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, phenylmethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, phenylmethyl ester wassynthesized according to Procedure I (90°C, 24 hours) from 4- dimethyIaminomethyl-6-methyl-5-hydroxy-2-methyl-l//-indole-3-carboxylicacid benzyl ester (4.45 mmol, 1.57 g). The product was purified by silica gel flashcolumn chromatography (20-50% acetone/hexanes then 20-40% ethyl 118 2 0 -127- acetate/dichloromeîhane) to give 0.953 g (48%) yellow solid: mp 110-115°C; IR(KBr) 3379, 2931,2857,1673, 1425, 1123, 1071 cm'1; 1H NMR (400 MHz,DMSO-dô) δ 1.05-1.16 (m, 2H, aliphatic C77), 1.21-1.25 (m, 1H, aliphatic C//), 1.33-1.42 (m, 2H, aliphatic CH), 1.45-1.66 (m, 5H, aliphatic CH), 1.78 (d, 5 7=13.67 Hz, 1H, aliphatic CH), 2.18 (s, 3H, ArCtf3), 2.34 (d, 7=9.28 Hz, 1H, aliphatic CH), 2.44 (s, 3H, ArCZ/3), 2.41-2.46 (m, 1H, aliphatic CH), 2.62-2.70 (m, 2H, aliphatic CH), 2.87-2.95 (m, 1H, aliphatic CH), 3.16 (dd,7=18.07, 6.59 Hz, 1H, aliphatic CH), 5.19 (dd, 7=25.15, 12.21 Hz, 2H,OCH2C6H5), 6.90 (s, 1H, Artf), 7.28-7.37 (m, 3H, Arff), 7.41 (d, 7=6.84 Hz, 2H, 10 ArH), 11.37 (s, 1H, NH); MS (APCI+) m/- 445.3 (MH+). Anal. Calcd for C28H32N2O3O.16 H2O: C, 75.16; H, 7.28; N, 6.26; H2O, 0.64. Found: C, 74.76;H, 7.35; N, 6.07; H20,0.34.

Example 44

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, phenylmethyl ester

Me

Step A: 7-Methyl-5-hydroxy-2-methyI-l//-indole-3-carboxylic acid benzyl ester

7-Methyl-5-hydroxy-2-methyl-l#-indoIe-3-carboxylic acid benzyl ester20 (2.04 g, 8.7% yield) was obtained as an off-white powder from methyl- [l,4]benzoquinone (81.9 mmol, 10.0 g) and 3-amino-but-2-enoic acid benzyl ester -128- 118 2 0 (79.5 mmol, 15.2 g) as in Example 43, Step A. Single crystal X-ray analysisindicated that the lower Rf isomer (silica gel, 50% ethyl acetate/hexanes) was

7-methyl-5-hydroxy-2-methyl-lT/-indole-3-carboxylic acid benzyl ester: mp188-189°C; IR (KBr) 3430, 3286, 1641, 1446, 1294, 1153, 1098 cm"1; *HNMR 5 (400 MHz, DMSO-d6) δ 2.32 (s, 3H, ArCT/3), 2.58 (s, 3H, ArCT/3), 5.27 (s, 2H, OC//2C6H5), 6.39 (d, 7=1.22 Hz, 1H, AiH), 7.10 (d, 7=1.71 Hz, 1H, ArH), 7.26-7.31 (m, 1H, AxH), 7.34-7.38 (m, 2H, ArT/), 7.42 (d, 7=7.81 Hz, 1H, ArT/), 8.71 (s, 1H, ArOH), 11.42 (s, 1H, NT/); MS (APCI+) m/z 296.0 (MH+). Anal.Calcd for CigHjyN^: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.02; H, 5.70; N, 10 4.40.

Step B: 4-DimethyIaminomethyl-7-methyl-5-hydroxy-2-methyl-17/-indole- 3-carboxylic acid benzyl ester

Me 4-Dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-lT/-indole- 15 3-carboxylic acid benzyl ester was prepared according to procedure G from 7-methyl-5-hydroxy-2-methyl-lT/-indole-3-carboxylic acid benzyl ester(6.62 mmol, 1.85 g), 41.3 mmol of dimethylamine, and 22.5 mmol offormaldéhyde. The reaction was heated at 50°C for 46 hours, concentrated,purified by silica gel flash column chromatography (0-5% tri ethylamine/ethyl 20 acetate) and recrystallized from ethyl acetate to give a Iight tan solid (0.900 g,41%); mp 161-164°C; IR (KBr) 3307,1684, 1292,1220,1070 cm'1 ; ]H NMR(400 MHz, DMSO-d0) δ 2.08 (s, 6H, N(CT/3)2), 2.30 (s, 3H, ArCT/3), 2.47 (s, 3H, ArCT/3), 3.89 (s, 2H, ArCT/2N), 5.22 (s, 2H, OCT/2C6H5), 6.37 (s, 1H, ArT/),

7.28-7.38 (m, 3H, ArT/), 7.43 (d, 7=7.08 Hz, 2H, ArT/), Π.28 (s, 1H, NT/); MS 1 1 8.2 0 -129- (APCI+) m/z 353.2 (MH+). Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N,7.95. Found: C, 71.20; H, 6.82; N, 7.79.

Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, phenylmethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4-dimethyI-, phenylmethyl ester wassynthesized according to Procedure I (80°C, 39 hours) from 4-dimethylaminomethyl-7-methyl-5-hydroxy-2-methyI-l//-indole-3-carboxylicacid benzyl ester (2.55 mmol, 0.900 g). The product was purified by silica gelflash column chromatography (30% ethyl acetate/hexanes then 20-50% ethylacetate/dichloromethane) to give 0.569 g (50%) off-white solid: mp 183-187°C; IR (KBr) 3325, 2929,1664, 1431, 1279, 1221,1107, 1075 cm-1; ÎHNMR(400 MHz, DMSO-d6) δ 1.06-1.15 (m, 2H, aliphatic C//), 1.19-1.22 (m, 1H, aliphatic C//), 1.31-1.62 (m, 8H, aliphatic CH), 1.81 (d, 7=12.94 Hz, 1H, aliphaticCH), 2.30 (s, 3H, ArC/fj), 2.33-2.42 (m, ÎH, aliphatic CH), 2.45 (s, 3H, ArC//3), 2.55 (d, 7=17.82 Hz, 1H, aliphatic CH), 2.61-2.66 (m, 1H, aliphatic CH), 2.82-2.88 (m, 1H, aliphatic CH), 3.09-3.15 (m, 1H, aliphatic CH), 5.20 (dd,7=24.90,12.21 Hz, 2H, OC^CôHs), 6.41 (s, 1H, AiH), 7.28-7.43 (m, 5H, Artf), 11.31 (s, 1 H, N/7); MS (APCI+) m/z 445.3 (MH+). Anal. Calcd for C28H32N2O3: C, 75.65; H, 7.26; N, 6.30. Found: C, 75.62; H, 7.34; N, 6.31.

Example 45

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, 1-(4-fluorophenyl)ethyl ester

Me'

O

Me 118 2 0

Step A: Pyrrolo[3',2’:5,6][l)benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,5-dimethyl-, anhydride with -130-

To a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinoîizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,5-dimethyl-,phenylmethyl ester (1.88 mmol, 0.837 g) and triethylamine (1.88 mmol, 0.262 mL) in 18 mL of tetrahydrofuran was added 20% Pd(OH)2/C (0.200 g, 24 wt%). The mixture was stirred under a hydrogen atmosphère (balloon) at roomtempérature for 20 minutes and filtered through celite, rinsing withtetrahydrofuran, to give the carboxylic acid: MS (APCI+) m/z 355.2 (MH+). Tothe filtrate under N2 at room température was added benzoyl chloride (1.88 mmol, 0.218 mL) dropwise. After 60 hours at room température, the precipitate wasfiltered off, the filtrate was concentrated, and the residue was triturated with etherto afford a light peach solid (0.517 g, 60%): NMR (400 MHz, DMSO-d6)selected diagnostic peaks δ 2.23 (s, 3H, ArC//3), 2.48 (s, 3H, ArC/Tj), 7.00 (s, 1H, Artf), 7.57 (t, 7=7.81 Hz, 2H, Artf), 7.73 (t, 7=7.57 Hz, 1H, ArJT), 8.06 (d,7=7.32 Hz, 2H, Artf), 11.94 (s, 1H, N#); MS (APCI+) m/z 459.2 (MH+).

Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2,5-dimethyî-, 1 -(4-fluorophenyl)ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, anhydride with benzoic acid(1.13 mmol, 0.517 g) was added to 4-fluoro-a-methylbenzyI alcohol (3.38 mmol,0.427 mL) and heated with stirring at 150°C for 2 minutes. A homogeneoussolution formed, was cooled to room température, dissolved with ethyl acetate 11820 -131- (10 mL), and stirred with a saturated aqueous solution of NaHCO3. The layerswere separated, and the aqueous phase was extracted with 3 portions (10 mL) ofethyl acetate. The combined extracts were concentrated, and the product waspurified by silica gel flash column chromatography (10-15% acetone/hexanes) togive a shiny beige powder (0.256 g, 48%): mp 124-128°C; IR (KBr) 3378, 2933,1675,1425, 1228,1127, 1059 cm’l; 3H NMR (400 MHz, DMSO-d6) δ1.07-1.28 (m, 3H, alîphatic CH}, 1.42-1.65 (m, 6H, aliphatic CH}, 1.57 (d, 7=6.75 Hz, 3H, OCH(Ctf3)Ar), 1.71-1.74 (m, 1H, aliphatic CH}, 1.79-1.87 (m,1H, aliphatic CH}, 2.21 &amp; 2.22 (s, 3H, ArC/73, diastereomers), 2.38 (d, 7=11.09 Hz, 1H, aliphatic CH}, 2.46-2.49 (m, 1H, aliphatic CH}, 2.50 &amp; 2.52 (s,3H, ArCtf3, diastereomers), 2.64-2.72 (m, 2H, aliphatic CH}, 2,92-2.98 (m, 1H,aliphatic CH}, 3.10-3.29 (m, 1H, aliphatic CH}, 5.94-6.00 (m, 1H, OC//(CH3)Ar), 6.92 &amp; 6.93 (s, 1H, Artf, diastereomers), 7.16-7.22 (m, 2H, Ar/7), 7.45-7.51 (m,2H, Artf), 11.40 (s, 1H, Ntf); 39F NMR (DMSO-d6) -115.13 &amp; -114.94 (s,diastereomers); MS (APCI+) m/z 477.3 (MH+). Anal. Calcd for C2Ç)H33FiN2O3:C, 73.09; H, 6.98; N, 5.88; F, 3.99. Found: C, 72.84; H, 7.02; N, 5.78; F, 3.89.

Example 46

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4-dimethyl-, 1 -(4-fluorophenyl)ethylester

118 2 0 -132-

Step A: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4-dimethyl-, anhydride withbenzoic acid

Me

Following the procedure in Example 45, Step A,pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxyiic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4-dimethyl-, phenylmethyl ester(1.10 mmol, 0.491 g) was converted to the mixed anhydride intermediate (creamcolorcd solid, 0.512 g, 100%): MS (APCI+) m/z 459.3 (MH+).

Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4-dimethyl-, 1 -(4-fluorophenyl)ethyl ester

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxyiic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, l-(4-fluorophenyl)ethylester was synthesized following the procedure in Example 45, Step B frompyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxyiic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, anhydride with benzoic acid(1.12 mmol, 0.512 g). The product was purified by silica gel flash columnchromatography (10-20% acetone/hexanes) to give a fluffy off-white powder(0.227 g, 43%): mp 105-108°C; IR (KBr) 3325, 2931, 1674, 1512, 1433, 1222,1109,1059 cm*1; ÏH NMR (400 MHz, OMSO-d^) δ 1.12-1.26 (m, 3H, aliphaticCH), 1.39-1.72 (m, 7H, aliphatic CH), 1.57 (d, 7=6.51 Hz, 3H, OCH(C#3)Ar), 1.82-1.91 (m, 1H, aliphatic CH), 2.31-2.36 (m, 1H, aliphatic CH), 2.33 &amp; 2.34 (s,3H, ArC/ή}, diastereomers), 2.43-2.47 (m, 1H, aliphatic CH), 2.54 &amp; 2.56 (s, 3H,AxCHt,, diastereomers), 2.58-2.70 (m, 2H, aliphatic CH), 2.86-2.91 (m, 1H,aliphatic CH), 3.06-3.25 (m, 1H, aliphatic CH), 5.94-6.01 (m, 1H, OCtf(CH3)Ar), 118 2 0 -133- 6.43 &amp; 6.45 (s, 1H, ArH, diastereomers), 7.16-7.22 (m, 2H, Artf), 7.45-7.51 (m,2H, AiH), 11.31 &amp; 11.32 (s, 1H, N//, diastereomers); 19F NMR (DMSO-d6) -(115.13-115.08) &amp; -(114.92-114.91) (m, diastereomers); MS (APCI+) m/z477.3 (MH+). Anal. Calcd for ^9^^^03-0.12 H2O: C, 72.75; H, 7.00; N, 5 5.85; F, 3.97; H2O, 0.45. Found: C, 72.38; H, 7.13; N, 5.73; F, 3.61; H20,0.31.

Example 47

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-[3-(methoxycarbonyl)phenyl]ethyl ester

A 500 mL stainless Steel reactor was purged with N? and chargedsuccessively with l-(3-bromophenyl)ethanol (0.126 mol, 25.4 g), DMSO 15 (150 mL), methanol (3.70 mol, 150 mL), triethylamine (0.143 mol, 20.0 mL),

Pd(OAc)2 (2.78 mmol, 0.625 g), and l,3-bis(diphenylphosphino)propane(2.62 mmol, 1.08 g). The reactor was sealed, purged with N2 and then with CO,pressurized to 663 psi with CO, rocked and heated to 80°C for 12 hours. Thereactor was re-pressurized to 724 psi with CO, rocked and heated to 100°C for 20 70 hours. The reaction was cooled to room température, filtered through celite, concentrated, and partitioned between H2O and CH2C12. The aqueous phase wasextracted with CH2C12 (3 x 100 mL), and the extracts were washed with water(3 x 100 mL), dried over MgSOzj, and concentrated to an oil. The product was -134- 118 2 0 purified by silica gel flash column chromatography (10-25% ethyl acetate/hexanes) to give 3-(l-hydroxyethyl)benzoic acid methyl ester (15.1 g,66%): JH NMR (400 MHz, CDC13) δ 1.50 (d, 7=6.59 Hz, 3H, CH(CH3)OH), 1.86 (d, 7=3.66 Hz, 1H, CH(CH3)OH), 3.90 (s, 3H, CC>2CH3), 4.92-4.97 (m, 1H,CH(CH3)OH), 7.39-7.43 (m, 1H, ArH), 7.57 (d, 7=7.57 Hz, 1H, ArH), 7.92 (d,7=7.57 Hz, 1H, ArH), 8.02 (s, 1H, ArH).

Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-(methoxycarbonyl)phenyl]ethyl ester A 100 mL flask was charged with 3-(l-hydroxyethyl)benzoic acid methylester (18.0 mmol, 3.24 g) followedby pyrrolo[3',2':5,6][l]benzopyrano[3,2- i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,anhydride with benzoic acid (Example 86, 4.50 mmol, 2.00 g) and heated withstirring at 150°C until a homogeneous solution was obtained (4.5 min). Thesolution was cooled to room température, dissolved in ethyl acetate and stirredwith a saturated aqueous solution of NaHCO3. A white solid precipitated out andwas filtered away. The layers of the filtrate were separated, the aqueous phase wasextracted with ethyl acetate (3 x 25 mL), and the combined extracts were driedand concentrated to give a thick oil. The product was purified by silica gel flashcolumn chromatography (20% acetone/hexanes) to give a white solid (0.776 g,34%); mp 100-103, 155-156°C (diastereomers); IR (KBr) 3375, 2931, 2855,1725,1704, 1432, 1200, 1078, 1065 cnr1; 1H NMR (400 MHz, CDC13) δ 1.20-1.29 (m, 1H, aliphatic CH), 1.32-1.34 (m, 2H, aliphatic CH), 1.38-1.47 (m, 1H, aliphaticCH), 1.53-1.58 (m, 2H, aliphatic CH), 1.62-1.82 (m, 4H, aliphatic CH), 1.68 (d,7=6.59 Hz, 3H, OCH(CH3)Ar), 2.01-2.12 (m, 1 H, aliphatic CH), 2.41-2.45 (m, 1H, aliphatic CH), 2.50-2.53 (m, 1H, aliphatic CH), 2.60 &amp; 2.62 (s, 3H, ArCH3,diastereomers), 2.69-2.85 (m, 2H, aliphatic CH), 2.98-3.04 (m, 1H, aliphatic CH), 3.29-3.43 (m, 1H, aliphatic CH), 3.89 (s, 3H, CO2CH3), 6.09-6.17 (m, 1H,OCH(CH3)Ar), 6.73 &amp; 6.74 (d, 7=8.55 Hz, 1H, ArH, diastereomers), 7.01 &amp; 7.02 (d, 7=8.79 &amp; 8.55 Hz, 1H, ArH, diastereomers), 7.41 &amp; 7.42 (t, 7=7.81 &amp; 11820 7.57 Hz, 1H, AiH, diastereomers), 7.61 &amp; 7.63 (d, 7=7.57 Hz, 1H, AiH, diastereomers), 7.93-7.95 &amp; 7.95-7.97 (m, 1H, ArH, diastereomers), 8.06 (bs, 1H,

Ntf), 8.10 &amp; 8.13 (s, 1H, Ar//, diastereomers); MS (APCI+) m/z 503.1 (MH+).

Anal. Calcd for C30H34N2O5: C, 71.69; H, 6.82; N, 5.57. Found: C, 71.58; H, 6.95; N, 5.42. -135-

Example 48

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(3-carboxyphenyl)ethyl ester

A solution of pyrrolo[3',2':5,6][l ]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[3-(methoxycarbonyl)phenyl]ethyl ester (1.43 mmol, 0.717 g) in methanol (18 mL) ·and IN NaOH (5.71 mmol, 5.71 mL) was heated at 55-60°C for 1 hour. Thesolution was cooled to room température, the methanol was removed by rotaryévaporation, and the aqueous phase was neutralized with IN HCl. A precipitateformed and was filtered off and purified by silica gel flash columnchromatography (10-15% MeOH/CHCl3) to afford a cream colored powder(0.522 g, 75%): mp 244-250°C (dec); IR (KBr) 3413-3229 (b), 2931, 1685,1432,1195,1150,1078, 1063 cm*1; lHNMR(400 MHz, DMSO-d^) δ 1.03-1.22 (m,3H, aliphatic C//), 1.38-1.72 (m, 7H, aliphatic C//), 1.57 (d, 7=6.35 Hz, 3H,OCH(C//3)Ar), 1.78-1.88 (m, 1H, aliphatic C//), 2.28-2.38 (m, 1H, aliphatic CH}, 2.40-2.47 (m, 1H, aliphatic CH), 2.51 &amp; 2.55 (s, 3H, AxCHt,, diastereomers),2.56-2.69 (m, 2H, aliphatic CH), 2.81-2.92 (m, 1H, aliphatic CH}, 3.06-3.23 (m,1H, aliphatic CH}, 5.96-6.04 (m, 1H, OCtf(CH3)Ar), 6.57 &amp; 6.58 (d, 7^=8.55 &amp;8.30 Hz, 1H, AzH, diastereomers), 7.01 &amp; 7.02 (d, 7=8.30 Hz, 1H, ArH, 118 2 0 -136- diastereomers), 7.45-7.50 (m, 1H, Ar/7, diastereomers), 7.64 &amp; 7.67 (d, J=10.25 &amp; 8.55 Hz, 1H, Ar/7, diastereomers), 7.83 &amp; 7.85 (d, 7=6.10 &amp; 7.32 Hz, 1H, ArZf,diastereomers), 7.96 &amp; 7.98 (s, 1H, ArTY, diastereomers), 11.54 (s, 1H, N77), 13.00 (s, 1H, CO2H); MS (APCI+) m/z 489.1 (MH+). Anal. Calcd forC29H32N2O5-O.5OH2O-O.2O SiO2: C, 68.35; H, 6.53; N, 5.50; H2O, 1.77. Found:C, 67.96; H, 6.81; N, 5.22; H20,1.81. HPLC (ALLTECH/ALLTIMA C-18,60:40-20:80 H2O/CH3CN + 0.05% TFA): rétention time=4.843 &amp; 4.970 min(diastereomers), 95.53% purity.

Example 49 1-Propanaminium, Ν,Ν,Ν-trimethyl-, sait with 1-(3-carboxyphenyl)ethyl3,7,8,9,10,12,13,14,14a, 15-decah'ydro-2-methylpyrrolo[3',2':5,6][ 1 ]-benzopyrano[3,2-i]quinolizine-l-carboxylate (1:1)

An aqueous solution of choline bicarbonate (0.935 mmol, 0.165 mL, 5.66 M) was added to a suspension ofpyrrolo[3',2':5,6][I]benzopyrano[3,2-ijquinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(3-carboxyphenyl)ethyl ester (0.935 mmol, 0.457 g) in éthanol (23 mL), and themixture was heated at 75-80°C for 30 minutes, cooled to room température, andfiltered. The filtrate was concentrated. The residue was stirred vigorously withether and filtered to give a light yellow solid. The solid was dissolved in hotCHCI3, filtered, concentrated, and dried at 60°C in vacuo to give a yellow powder(0.233 g, 42%): mp 210-216°C; IR (KBr) 3428-3211 (b), 2930, 1684, 1566,1432,1878, 1870,1079, 1063 cm'1; *H NMR (400 MHz, DMSO-dô) δ 1.03-1.26 (m, 3H, aliphatic CH), 1.36-1.72 (m, 6H, aliphatic CH), 1.55 (d, 7=6.35 Hz, 3H,OCH(C//3)Ar), 1.80-1.88 (m, 1H, aliphatic CH), 2.30-2.42 (m, 2H, aliphatic CH), 118 2 0 -137- 2.51 &amp; 2.52 (s, 3H, ArCH3, diastereomers), 2.61-2.70 (m, 2H, aliphatic CH), 2.S1-2.92 (m, 1H, aliphatic CH), 3.07 (s, 9H, ^(CH3)3), 3.11-3.23 (m, 1H,aliphatic CH), 3.26-3.35 (m, 2H, CH2Otf &amp; aliphatic CH), 3.36 (t, 7=4.88 Hz, 2H,OCH2C//2N(CH3)3), 3.77-3.83 (m, 2H, OCtf2CH2N(CH3)3), 5.91-5.99 (m, 1H,OC//(CH3)Ar), 6.54-6.58 (m, 1H, AxH), 7.01-7.04 (m, 1H, Artf), 7.21-7.28 (m,1H, AxH), 7.32-7.38 (m, 1H, ArH), 7.71-7.79 (m, 1H, Ar/7), 7.91 &amp; 7.93 (s, 1H,ArH, diastereomers), 11.70 (s, 1H, NTT); MS (APCI-) m/z 487.1 (parent M-l).Anal. Calcd for C29H3^^Ο.δδ CsH^NO OJO H20-0.50 CHC13: C, 62.84;H, 6.97; N, 6.23; H2O, 1.39. Found: C, 62.92; H, 6.17; N, 6.93; H20,1.72.

Example 50

Pyrrolo[3',2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl)methyl ester

Following the procedure from Example 47, Step B, 3-nitrobenzyl alcohol(18.0 mmol, 2.81 g) and pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydridewith benzoic acid (Example 86, 4.50 mmol, 2.00 g) were converted topyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl)methyl ester. Theproduct was purifîed by silica gel flash column chromatography (25-50% ethylacetate/hexanes) and recrystallized from ethyl acetate to afford a light yellowpowder (1.10 g, 51%): mp 203-205°C; IR (KBr) 3383, 3181, 2929,2855,1709,1532,1430, 1351, 1236, 1075, 886 cm’l; NMR (400 MHz, DMSO-d6)5 1.02-1.16 (m, 2H, aliphatic CH), 1.19-1.24 (m, 1H, aliphatic CH), 1.32-1.62 (m,7H, aliphatic CH), 1.82 (d, 7=13.18 Hz, 1H, aliphatic CH), 2.33 (d, 7=9.76 Hz, 11820 -138- 1H, aliphatic CH}, 2.41 (d, 7=11.23 Hz, 1H, aliphatic CH}, 2.48 (s, 3H, AtCHt,},2.60-2.67 (m, 2H, aliphatic CH}, 2.84-2.89 (m, 1H, aliphatic CH}, 3.15-3.21 (m,1H, aliphatic CH}, 5.32-5.40 (m, 2H, OCtf2Ar), 6.59 (d, 7=8.79 Hz, 1H, ArH),7.03 (d, 7=8.55 Hz, 1H, AiH}, 7.65-7.69 (m, 1H, Arfl), 7.89 (d, 7=7.57 Hz, 1H, 5 AiH}, 8.18 (d, 7=8.06 Hz, 1H, AiH), 8.29 (s, 1H, AiH}, 11.58 (s, 1H, Ntf); MS(APCI+) m/z 476.1 (MH+). Anal. Calcd for C27H29N3O5: C, 68.20; H, 6.15; N,8.84. Found: C, 67.89; H, 6.20; N, 8.74.

Example 51

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(3-cyanophenyl)ethyl ester

Step A: 3-(l-Hydroxyethyl)benzonitrile

To a solution of 3-acetylbenzonitrile (68.9 mmol, 10.0 g) in MeOH 15 (230 mL) at 0°C under N2 was added NaBH4 (68.9 mmol, 2.61 g) in portions.

After 2 hours of graduai warming to room température, IN HCl was added andthe solvent removed under reduced pressure. Dichloromethane (50 mL) wasadded, the layers were separated, and the aqueous phase was extracted with3 portions of CH2CI2 (50 mL). The combined extracts were washed with 20 NaHCC>3 (1 x 50 mL), saturated NaCl (1 x 50 mL), dried over MgSC>4, and concentrated under vacuum to give pure product as a yellow oil (10.0 g, 98%):!H NMR (400 MHz, CDCI3) 5 1.47 (d, 7=6.35 Hz, 3H, ArCH(Ctf3)OH), 1.99 (bs, 1H, OH}, 4.92 (q, 7=6.35 Hz, 1H, ArCH(CH3)OH), 7.43 (t, 7=7.81 Hz, 118 2 0 -139- 1H, Artf), 7.53 (d, 7=7.57 Hz, 1H, AtH), 7.59 (d, 7=7.81 Hz, 1H, Artf), 7.66 (s, lH.Artf).

Step B: Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(3-cyanophenyl)ethyl ester

Following the procedure from Example 47, Step B, 3-(l -hydroxyethyl)-benzonitrile (13.5 mmol, 1.98 g) and pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]-quinolizine-î-carboxylic acid, 3,7,S,9,10,12,13,14,14a,15-decahydro-2-methyI-,anhydride with bcnzoic acid (Example 86,3.37 mmol, 1.50 g) were convertedpyrrolo[3',2':5,6][l]-benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(3-cyanophenyl)ethyl ester.The product was purified by silica gel flash column chromatography (20-30%acetone/hexanes) to afford a cream colored powder (0.614 g, 39%): mp131-134 and 171-173°C (diastereomers); IR (KBr) 3377, 2931, 2856,2230, 1702,1432, 1148, 1077,1066 cnr1; iHNMR (400 MHz, DMSO-d6) δ 1.02-1.25 (m,3H, aliphatic CH), 1.31-1.72 (m, 7H, aliphatic CH), 1.57 (d, 7=6.35 Hz, 3H,OCH(C//3)Ar), 1.79-1.88 (m, ÎH, aliphatic CH), 2.32-2.44 (m, 2H, aliphatic CH), 2.46 (s, 3H, ArC/Tj), 2.56-2.69 (m, 2H, aliphatic CH), 2.80-2.91 (m, 1H, aliphaticCH), 3.02-3.28 (m, 1H, aliphatic CH), 5.93-6.01 (m, IH, OCtf(CH3)Ar), 6.56-6.60 (m, 1H, Artf), 7.00-7.04 (m, 1H, AxH), 7.51-7.59 (m, 1H, AtH),7.71-7.80 (m, 2H, AxH), 7.86 &amp; 7.90 (s, 1H, AxH, diastereomers), 11.56 (s, 1H,Ntf); MS (APCI+) m/z 470.1 (MH+). Anal. Calcd for C29H31N3O3 O.25 H2O: C, 73.47; H, 6.70; N, 8.86; H2O, 0.95. Found: C, 73.18; H, 6.73; N, 8.56, H2O,0.58.

Example 52

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)carbonyl]phenyl]ethyl ester 118 2ο

A mixture of 3-(l-hydroxyethyl)benzonitrile (Example 51, Step A, 5 6.79 mmol, 1.00 g) in 10% aqueous NaOH (68 mL) was heated at reflux for 4.5 hours, cooled lo room température, and extracted with ether (2 x 50 mL). Theextracts were discarded. The aqueous phase was acidified with concentrated HCl,extracted with ether (3 x 50 mL), and the combined extracts were washed withbrine, dried over MgSOzj, and concentrated to give a white solid (0.98 g, 87%): 10 mp 107-110°C; 5H NMR (400 MHz, DMSO-d0) δ 1.29 (d, 7=6.35 Hz, 3H,

ArCH(C//3)OH), 4.71-4.78 (m, 1H, ArC77(CH3)OH), 5.25 (d, 7=4.40 Hz, 1H,OH), 7.39 (t, 7=7.57 Hz, 1H, Ar//), 7.53 (d, 7=7.57 Hz, 1H, Ar//), 7.76 (d, 7=7.57 Hz, 1H, Ar//), 7.91 (s, 1H, AxH), 12.87 (s, 1H, COOH); MS (APCI-) m/z 165.1 (M-l).

15 Step B: 3-(l-HydroxyethyI)-MA-dimethylbenzamideOH O

To a solution of 3-(l-hydroxyethyl)benzoic acid (54.8 mmol, 9.10 g),dimethylamine (54.8 mmol, 27.4 mL of 2.0 M THF solution), and zPrçNEt(109 mmol, 19.1 mL) in 55 mL of DMF at 0°C under N2 was added HBTU 20 (54.8 mmol, 20.8 g) in two portions. After 45 minutes, IN HCl (50 mL) and ether (50 mL) were added, and the layers were separated. The aqueous phase was 118 2 0 -141- further acidified with IN HCl and extracted with ether (4 x 50 mL). The extracts were combined and concentrated. The aqueous phase was concentrated also. The concentrâtes were combined, dissolved in CH2CI2, washed with 10% HCl (1 x 20 mL), saturated NaHCC>3 (1 x 20 mL), brine (1 x 20 mL), dried over

MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (50-100% ethyl acetate/hexanes) to give a mixture of 3-(l-hydroxyethyl)-N,7V-dimethylbenzamide, z'P^NEt, and Ν,Ν,Ν’,Ν’-tetramethylurea. The yield based on JH NMR was 6.56 g (62%). A small portionwas rechromatographed to give pure product as a clear, colorless oil: ^H NMR(400 MHz, DMSO-dg) δ 1.28 (d, 7=6.59 Hz, 3H, ArCH(C//3)OH), 2.86 (s, 3H,NC//3), 2.93 (s, 3H, NC/fj), 4.67-4.73 (m, 1H, ArC//(CH3)OH), 5.20 (d, 7=4.15 Hz, 1H, OH), 7.18-7.20 (m, 1H, ArH), 7.31-7.37 (m, 3H, Artf); MS(APCI+) ni/z 194.0 (MH+).

Step C: Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-meîhyI-, 1 -[3-[(dimethylamino)carbonyl]phenyl]ethyî ester

Following the procedure from Example 47, Step B, 3-(l-hydroxyethyl)- /V.A-dimethylbenzamide (14.9 mmol, 2.88 g) and pyrrolo[3',2':5,6][ 1]-benzopyrano(3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 3.73 mmol, 1.66 g) were combined with xylenes (10 mL) and heated at 150°C for 5 minutes toform pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizirie-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)-carbonyljphenyl] ethyl ester. The product was purified by silica gel flash columnchromatography (0-5% Et3N/ethyl acetate), dissolved in ether/ethyl acetate and washed with water (15 x 20 mL) to remove unreacted 3-(l-hydroxyethyl)-MA-dimethylbenzamide. The organic phase was concentrated and the residue wasrecrystallized from acetonitrile to give a white powder (1.65 g, 86%); mp199-2Q2°C; IR (KBr) 3416 (br), 3219 (br), 2930, 2855,1684,1622, 1432, 1188,1146, 1091, 1062 cnrb ÎH NMR (400 MHz, DMSO-d6) 5 1.02-1.28 (m, 3H, 118 2 0 -142- aliphatic CH), 1.32-1.70 (m, 7H, aliphatic CH), 1.57 (d, 7=6.84 Hz, 3H,OCH(C7Ï3)Ar), 1.76-1.88 (m, 1H, aliphatic CH), 2.32-2.43 (m, 2H, aliphatic CH),2.50 &amp; 2.51 (s, 3H, ArCH3, diastereomers), 2.52-2.689 (m, 2H, aliphatic CH), 2.84 (s, 3H, NCH3), 2.84-2.89 (m, 1H, aliphatic CH), 2.92 (s, 3H, NCH3), 5 3.06-3.30 (m, 1H, aliphatic CH), 5.94-6.01 (m, 1H, OCH(CH3)Ar), 6.57 &amp; 6.58 (d, 7=8.55 Hz, 1H, ArH, diastereomers), 7.01 &amp; 7.02 (d, 7=8.55 Hz, 1H,

ArH, diastereomers), 7.29 (t, 7=7.33 Hz, 1H, ArH)> 7.37-7.50 (m, 3H, AxH), 11.53 (s, 1H, NH); MS (APCI+) m/z 516.3 (MH+). Anal. Calcd forC31H37N3O4: C, 72.21; H, 7.23; N, 8.15. Found: C, 71.96; H, 7.25; N, 8.22. 10 Example 53

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethyiamino)methyl]phenyl]ethyl ester

15 Step A: l-(3-Dimethylaminomethylphenyl)ethanol

OH

To a suspension of L1AIH4 (23.3 mmol, 0.931 g/95 %) in THF (40 mL) at0°C under N2 was added a solution of 3-(l-hydroxyethyl)-HH- dimethylbenzamide (Example 52, Step B, 15.5 mmol, 3.00 g) in 10 mL of THF.20 After the évolution of H2 had ceased, the reaction was warmed to room température. After 4 hours at room température, the mixture was cooled to 0°Cand ethyl acetate (0.74 mL) and 10% aqueous NaOH were sequentially added.The mixture was warmed to room température for 30 minutes, MgSC>4 and celite 11β 2 0 -143- were added with stirring, and the mixture was filtered through celite, washing with20 mL of THF. The filtrate was concentrated to afford 2.73 g (99%) of pure l-(3-dimethylaminomethylphenyl)ethanol: NMR (400 MHz, DMSO-dg) δ 1.26 (d, 7=6.59 Hz, 3H, ArCH(C//3)OH), 2.09 (s, 6H, N(Ctf3)2), 3.31 (s, 2H,ArCtf2N), 4.64-4.67 (m, 1H, ArCtf(CH3)OH), 5.08 (d, 7=4.15 Hz, 1H, OH), 7.07 (d, 7=7.08 Hz, 1H, AiH), 7.15-7.25 (m, 3H, AtH); MS (APCI+) m/z180.0 (MH+).

Step B: Pyrrolo[3',2':5,6][l]benzopyrano(3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[3-[(dimethylamino)methyl]phenyl]ethyl ester

Following the procedure from Example 47, Step B l-(3-dimethylaminomethylphenyl)ethanol (15.2 mmol, 2.73 g) andpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride with benzôic acid(Example 86, 3.81 mmol, 1.69 g) were combined with xylenes (10 mL) andheated at 150°C for 5 minutes to form pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-[3-[(dimethylamino)methyl]phenyl]ethyl ester. The usual extractive work-up(ethyl acetate) was followed. The aqueous phase was diluted with 100 mL ofacetone and the inorganic salts filtered off. The filtrate was concentrated. Theorganic and aqueous residues were combined, mixed with 15 mL of CH2C12 atroom température under N2 and treated with pyridine (68.5 mmol, 5.54 mL) andacetic anhydride (34.3 mmol, 3.23 mL) sequentially. After 48 hours, the whiteprecipitate was filtered off, and the filtrate was washed with water (3 x 20 mL).The aqueous washes were concentrated and the product was purified by siîica gelflash column chromatography (0-5% Et3N/ethyl acetate) to give a yellow solid(0.160 g, 8.4%); mp 95-100°C; IR (KBr) 2931,2857, 1678,1430, 1237, 1195,1147,1062 cm-1. *H NMR (400 MHz, DMSO-d6) δ 1.09-1.27 (m, 3H, aliphaticCtf), 1.32-1.68 (m, 7H, aliphatic CH), 1.54 (d, 7=6.35 Hz, 3H, OCH(Ctf3)Ar),1.79-1.84 (m, 1H, aliphatic CH), 2.07 &amp; 2.08 (s, 6H, N(CH3)2, diastereomers), 118 2 0 -144- 2.29-2.43 (m, 2H, aliphatic CH), 2.49 &amp; 2.50 (s, 3H, MCH^, diastereomers),2.59-2.69 (m, 2H, aliphatic CH), 2.81-2.92 (m, 1H, aliphatic CH), 3.02-3.17 (m,1H, aliphatic CH), 3.33 &amp; 3.34 (s, 2H, ArC//2N, diastereomers), 5.90-5.98 (m,1H, OCtf(CH3)Ar), 6.56-6.59 (m, 1H, MH), 7.00-7.03 (m, 1H, MH), 5 7.12-7.21 (m, lH,Artf), 7.26-7.33 (m,3H,Arfl), 11.50 &amp; 11.51 (s, 1H, NT/, diastereomers); MS (APCI+) m/z 502.2 (MH+). Anal. Calcd forC31H39N3O3O.27 C4H8O2: C, 73.33; H, 7.90; N, 8.00. Found: C, 72.94; H,7.90; N, 8.10.

General Procedure J. 10 Diethyl azodicarboxylate (Aldrich, 1 eq.) was a*dded dropwise to a mixture of 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (1 eq.), triphenylphosphine(1 eq.), and an alcohol of choice (1.5 eq.) in THF over an hour period. Afterstirring at room température for 24 hours, the mixture was concentrated. Theproduct was purified by recrystallization or flash column chromatography on 15 silica gel (45% ethyl acetate:hexanes) to give the corresponding ester.

General Procedure KL

Under a nitrogen atmosphère, DBU (Aldrich, 1 eq.) was added to a solution of 5-acetoxy-2-methyl-lH-indole-3-carboxyIic acid (1 eq.) in DMF by the syringetechnique. To this reaction mixture, a solution of an alkyl halide of choice 20 (Aldrich, 1.1 eq.) in DMF was added. After stirring at room température for24 hours, the reaction mixture was diluted with CH2C12 which inducedprécipitation of the desired product. The solid product was filtered off and washedwith H2O.

General Procedure L. 25 Dimethylamine (2.2 eq.) and formaldéhyde (1.2 eq.) were added to a solution ofthe ester of choice (1.0 eq.) in 10 mL of denatured éthanol. The mixture wasstirred under a nitrogen atmosphère at reflux for 24 hours. After the reaction wascomplété according to MS and TLC, the mixture was concentrated. The product 118 2 0 -145- was purified by flash column chromatography on silica gel (30%

MeOH:CH2Cl2).

General Procedure M. 1,2,3,4,6,7,8,9-Octahydroquinolizinylium perchlorate (1.7 eq.) was dissolved in2N NaOH (excess). The solution was extracted with diethyl ether. The combinedorganic layers were concentrated to give a clear oil. This oil was dissolved indioxane and added to a solution of the desired Mannich base (1 eq.) dioxane. Afterheating at 110°C for 24 hours, the reaction was cooled to room température anddioxane was removed to afford a brown oil. The product was purified by flashcolumn chromatography on silica gel (40% hexanes:ethyl acetate).

General Procedure N. A mixture of the mixed anhydride (4 eq.) and an alcohol of choice (4 eq.) washeated at 150°C for 5 minutes or until the reaction was homogeneous. After beingcooled to room température, the oil was diluted with ethyl acetate and washedwith saturated NaHCÛ3. The organic Iayer was separated and concentrated toafford a brown oil. The product was purified by flash column chromatography onsilica gel.

General Procedure O.

To a solution of a ester (1 eq.) in methanol was added 2N NaOH (4 eq.). Afterheating at 55°C for 1 hour, the reaction became clear. The reaction mixture wascooled to 0°C and neutralized with concentrated HCl. The product precipitated outof solution as a white solid and was filtered off. The mother liquor was extractedwith ethyl acetate and the solvent removed to afford additional product.

General Procedure P.

To a suspension of Mannich base of choice (1 eq.) in anhydrous THF was addedslowly solid LiBH4 (5 eq.). MeOH (5 eq.) was immediately added dropwise viasyringe. The resulting mixture was heated at reflux for 1 hour. After cooling to0°C, IN HCl was added to neutraiize the reaction. The product precipitated out ofsolution as a white solid. The mother liquor was extracted with CH2C12. The 118 2 0 combined organic layers were dried with MgSC>4, and solvent was removed to yicld more product. -146-

Example 54

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-,2-phenylethyl ester

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid phenylethyl ester

5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid phenylethyl ester was 10 synthesized according to Procedure J from 2-phenyl-ethanol (6.39 g, 52.3 mmol)and recrystallized from hexane/ethyl acetate to give 2.40 g (31.1%) of fine whitepowder.mp 186-188°C; IR (KBr) 3231,2978, 1644, 1463,1173, 1101 cm'l; ÏH NMR (400 MHz, DMSO-dg) δ 2.49 (s, 3H, CCity, 3.03 (t, >6.99 Hz, 2H,OCH2C//2)’ 4·4θ (t, >6.75 Hz, 2H, OCH2CH2), 6.57 (dd, >8.60, 2.29 Hz, 1H, 15 ArH), 7.09 (d, >8.68 Hz, 1H, ArH), 7.20 (d, >6.99 Hz, 1H, ArH), 7.26-7.33 (m,5H, ArH), 8.81 (s, 1H, OH), 11.49 (s, 1H, NH); MS(APCI+): m/z 326.1 (MH+).Anal. Calcd for CigHnN^: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.23; H,5.74; N, 4.67. 118 2 0

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid phenylethyl ester

4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 5 phenethyl ester was synthesized according to Procedure L from 5-hydroxy- 2-methyl-lH-indole-3-carboxylicacid phenylethyl ester (2.89 g, 9.78 mmol) andrecrystallized from ethyî acetate to give 0.250 g (15.0%) of a white solid: mp200-201°C; IR (KBr) 3138,2971,1673, 1585,1437,1279, 1099 cnr1; *H NMR(400 MHz, DMSO-dg) δ 2.34 (s, 3H, CCtf3) 2.68 (s, 6H, N(C/73)2), 3.00 (t, 10 7=6.59 Hz, 2H, OCH2C//2)> 4.43 (t, 7=6.59 Hz, 2H, OCÆ2CH2), 4.67 (s, 2H, NC#2Ar), 6.81 (d, 7=8.79 Hz, 1H, AiH), 7.17-7.20 (m, 1H, Ar//), 7.23-7.28 (m, 5H, Ar//), 11.93 (s, 1H, N//); MS(APCI+): m/z 353.2 (MH+). Anal. Calcd forC21H24N2O3: C, 61.35; H, 7.48; N, 6.81. Found: C, 60.96; H, 6.66; N, 6.42.

Step C: Pyrrolo[3’,2’:5,6](l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 15 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyI-,2-phenylethyl ester

Pyrrolo[3 ’,2 ’ : 5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-,2-phenylethyl ester wassynthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid phenethyl ester (0.250 g, 0.709 mmol) and 20 recrystallized from ethyl acetate/hexanes to give 0.170 g (54.0%) of a white solid:mp 185-186°C; IR (KBr) 3297, 2931,2856, 1673,1432,1199, 1080 cm'1; NMR (400 MHz, CDCI3) δ 1.20-1.81 (m, 10H, aliphatic CH), 2.07 (d, 7=13.92 Hz, 1H, aliphatic CH), 2.41 (s, 3H, CC//3), 2.44-2.53 (m, 2H, aliphaticCH), 2.73-2.84 (m, 2H, aliphatic CH), 2.98-3.04 (m, 1H, aliphatic CH), 118 2 0 -148- 3.05-3.08 (m, 2H, OCH2CH2), 3.38 (dd, >17.95, 6.71 Hz, 1H, aliphatic CH), 4.50-4.53 (m, 2H, OŒ2CH2), 6.72 (d, >8.79 Hz, 1H, Artf), 6.99 (d, >8.79 Hz, 1H, AxH), 7.17-7.29 (m, 5H, AiH), 7.99 (s, 1H, Ntf); MS(APCI+): m/z 445.3 (MH+). Anal. Calcd for C28H32N2O3: C, 75.56; H, 7.26; N, 6.30. Found: 5 C, 75.36; H, 7.28; N, 6.13.

Example 55

PyrroÎo[3’,2’:5,6][l]benzopyrano[3,2-i]quinoIizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[4-(methoxycarbonyl)phenyl]methyl ester

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester

20 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-methoxycarbonyl-15 benzyl ester was synthesized according to Procedure K from 4-bromomethyl- benzoic acid methyl ester (6.64 g, 29.0 mmol) and precipitated out of dietliyl etherto give 4.88 g (55.0%) of light lavender powder: mp 232-234°C; IR (KBr) 3322,2950, 1696, 1654, 1465, 1288, 1093 cnr1; *H NMR (400 MHz, DMSO-d6) δ2.57 (s, 3H, CC#3), 3.80 (s, 3H, OCtf3), 5.34 (s, 2H, OCÆ2Ar), 6.55 (dd, >8.67, 2.32 Hz, 1H, Ar/7), 7.09 (d, >8.55 Hz, 1H, Artf), 7.24 (d, >2.20 Hz, 1 H, ArH),7.54 (d, >8.06 Hz, 2H, AxH), 7.94 (d, >8.30 Hz, 2H, Artf), 8.83 (s, 1H, QH), -149- 11820 11.59 (s, 1H, NH); MS(APCI+): m/z 340.1 (MH+). Anal. Calcd forC19H17N1O5: C, 67.25; H, 5.05; N, 4.13. Found: C, 66.88; H, 5.06; N, 4.05.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid 4-methoxycarbonyl-benzyl ester

4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4- methoxycarbonyl-benzyl ester was synlhesized according to Procedure L from 5- hydroxy-2-methyl-lH-indole-3-carboxyIic acid 4-methoxycarbonyl-benzyl ester(17.2 g, 50.7 mmol) and triturated with ethyl acetate to give 8.50 g (43.0%) ofwhite solids: mp 125-126°C; IR (KBr) 3142, 2959, 1672, 1585, 1434,1285, 1095 cm'1 ; JH NMR (400 MHz, DMSO-dç) δ 2.12 (s, 6H, N(Ctf3)2), 2.49 (s, 3H, CCH3), 3.84 (s, 3H, OC//3), 4.02 (s, 2H, NCtf2Ar), 5.34 (s, 2H, OCH2Ar), 6.58 (d, >8.44 Hz, 1H, Artf), 7.09 (d, >8.44 Hz, 1H, ArH), 7.60 (d, >8.20 Hz,2H, Ar/7), 7.98 (d, >8.20 Hz, 2H, ArH), 11.56 (s, 1H, N#); MS(APCI+): m/z 397.2 (MH+). Anal. Calcd for C22H24N2O5: C, 66.41; H, 6.12; N, 7.04. Found:C, 66.41; H, 6.01; N, 6.97.

Step C: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[4-(methoxycarbonyl)phenyl]methyl ester

Pyrrolo(3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[4-(methoxycarbonyl)phenyljmethyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (0.200 g, 0.505 mmol) and recrystallized fromt-butyl methyl ether to give 0.090 g (23.0%) of granular off-white solids: mp 118 2 0 -150- 179-180°C; IR (KBr) 3173, 2930, 2856, 1725, 1615, 1433, 1275, 1079 cm'1; 1H NMR (400 MHz, CDC13) δ 1.21-1.81 (m, 10H, aliphatic CH), 2.06 (d, 7=8.79 Hz, 1H, aliphatic CH), 2.43 (d, 7=12.70 Hz, 1H, aliphatic CH), 2.50-2.53(m, 1H, aliphatic CH), 2.55 (s, 3H, CCZZ3), 2.73-2.84 (m, 2H, aliphatic CH),2.96-3.05 (m, 1H, aliphatic CH), 3.38 (dd, >17.70, 7.20 Hz, 1H, aliphatic CH), 3.89 (s, 3H, OCZZ3), 5.34 (dd, >16.36, 12.70 Hz, 2H, OCZZ2Ar), 6.73 (d, 7=8.79 Hz, 1H, ArZZ), 7.01 (d, 7= 8.79 Hz, 1H, ArZ/), 7.47 (d, >8.06 Hz, 2H,ArZZ), 8.01 (d, >8.30 Hz, 2H, ArH), 8.06 (s, 1H, NZZ); MS(APCI+): m/z 489.3 (MH+). Anal. Calcd for C29H32N2O5: C, 71.29; H, 6.60; N, 5.73. Found:C, 70.94; H, 6.26; N, 5.57.

Example 56

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,-methyl-, (4-carboxyphenyl)methyl ester

Pyrrolo[3 ’ ,2 ’ :5,6] [ 1 ]benzopyrano[3,2-i]quinoIizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-carboxyphenyl)methyl esterwas synthesized according to Procedure O and triturated with methanol to give0.030 g (11.0%) of fine off-white powder : mp 243-244°C; IR (KBr) 2932,2863,1698, 1592,1432, 1077 cm'1; 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.26 (m,3H, aliphatic CH) 1.39-1.66 (m, 6H, aliphatic CH), 1.85 (d, 7=13.67 Hz, 1H,aliphatic CH), 2.44 (d, 7=11.23 Hz, 1H, aliphatic CH), 2.47-2.48 (m, 1H, aliphaticCH), 2.48 (s, 3H, CCZZ3), 2.63-2.69 (m, 2H, aliphatic CH), 2.85-2.91 (m, 1H,aliphatic CH), 3.19 (dd, 7=18.07, 6.84 Hz, 1H, aliphatic CH), 3.41-3.43 (m, 1H,aliphatic CH), 5.31 (dd, 7=20.02, 12.94 Hz, 2H, OCZZ2Ar), 6.60 (d, 7=8.55 Hz,1H, ArZZ), 7.04 (d, 7=8.55 Hz, 1H, ArZZ), 7.54 (d, 7=8.30 Hz, 2H, ArZZ), 7.94 (d, 11320 5 -151- J= 8.30 Hz, 2H, Artf), 11.57 (s, 1H, Ntf), 12.98 (s, 1H, CO2//); MS(APCI+): tn/z 475.3 (MH+). Anal. Calcd for C28H30N2O5: C, 70.17; H, 6.42; N, 5.85. Found:C, 69.78; H, 6.50; N, 5.62.

Example 57 l-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-lH-indol-4-ylmethyl]-1,2,3,4,6,7,8,9-octahydro-quinolizinyIium; chloride

To a solution ofpyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,[4-(methoxycarbonyl) phenyljmethyl ester (Example 56, Step C, 1.00 g, 2.05 mmoî) in 25.6 mL of methanol was added 2N NaOH (4.09 mL, 8.19 mmol).After heating at 55°C for 1 hour, the mixture tumed to a clear solution. Thereaction mixture was cooled to 0°C and concentrated HCl was added slowly untilpH 3. The aqueous layer was extracted with ethyl acetate (5 x 50 mL), and thecombined organic layers were dried with MgSC>4, and solvent was removed. Theresidue was triturated with dichloromethane to give 0.967 g (92.0%) of fine whitepowder: mp 230-231°C; IR (KBr) 3361,2941,2360, 1709, 1589, 1428,1227, 1083 cm’1; ]H NMR (400 MHz, DMSO-dg) δ 1.20-1.30 (m, 1H, aliphatic CH) I. 43-1.51 (m, 4H, aliphatic CH), 1.69-2.30 (m, 5H, aliphatic CH), 2.48 &amp; 2.49 (s,3H, CC//3, opened and closed forms), 2.48-2.55 (m, 2H, aliphatic CH), 2.85-3.30(m, 2H, aliphatic CH), 3.40-3.80 (m, 3H, aliphatic CH), 5.33-5.36 (m, 2H,OCffyAi), 6.79 &amp; 6.82 (d, 7=8.55 &amp; 8.06 Hz, 1H, Ar/7, opened &amp; closed forms),7.11 &amp; 7.20 (d, 7=8.55 &amp; 8.55 Hz, 1H, Ar/7, opened &amp; closed forms), 7.54-7.56(m, 2H, Ar/7), 7.94-7.96 (m, 2H, Ar/7), 9.19 (s, 1H, OH, opened), 11.79 &amp; II. 85 (s, 1H, N/7, opened &amp; closed forms), 13.00 (s, 1H, CO2H); MS(APCI+): 11820 -152- m/z 475.3 (MH+). Anal. Calcd for C28H31N2O5CI1: C, 65.35; H, 6.12; N, 5.44.Found.-C, 65.06; H, 6.17; N, 5.15.

Ex amp le 58

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl ester

Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid 4-hydroxymethyl-benzyl ester

4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester was synthesized according to Procedure P from4-dimethyIaminomethyl-5-hydroxy-2-methyl-lH-indoIe-3-carboxyîic acid4-methoxycarbonyl-benzyI ester (Example 56, Step B, 2.32 g, 5.84 mmol) and 15 triturated with acetone to give 0.993 g (47.0%) of a white solid: mp 140-143°C; IR (KBr) 3140, 2777, 1686,1583, 1435, 1092 cm'1; TH NMR (400 MHz, DMSO-d6) δ 2.51 (s, 3H, Ctf3), 2.71 (s, 6H, N(CH3)2), 4.47 (d, 7=5.13 Hz, 2H,ArCH2OH), 4.73 (s, 2H, NCH2Ar), 5.18 (t, 7=5.62 Hz, 1H, ArCH2OH), 5.25 (s,2H, OCH2At), 6.84 (d, 7=8.55 Hz, 1H, ArH), 7.28 (d, 7=8.55 Hz, 1H, ArH), 20 7.31 (d, 7=7.81 Hz, 2H, AiH ), 7.40 (d, 7=7.81 Hz, 2H, ArH), 8.60 (s, 1H, OH),

11.97 (s, 1H, NH); MS(APCI+): m/z 369.2 (MH+). HPLC (ALLTCH/ALLTIMA 11820 -153- C-18 1:1-2:98 H2O/CH3CN + 0.05% TFA): rentention time=4.57 min, 95.23%purity.

Step B: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl esterPyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl)-phenyljmethyl ester was synthesized according to Procedure M front4-dimethylaminomethyl-5-hydroxy-2-methyl-IH-indole-3-carboxylic acid4-hydroxymethyl-benzyl ester (0.969 g, 2.63 mmol) and triturated with acetone togive 0.890 g (49.0%) of a white solid: mp 19S-200°C; IR (KBr) 3405, 3237, 2931,1660, 1424, 1237,1 OS 1 cm-5 ; 1H NMR (400 MHz, DMSO-d6) δ 1.11 -1.27 (m,3H, aliphatic CH),1.39-1.70 (m, 7H, aliphatic CH), 1.85 (d, 7=13.50 Hz, 1H,aiiphatic CH), 2.36 (d, 7=10.37 Hz, 1H, aliphatic CH), 2.41-2.43 (m, 1H, aliphaticCH), 2.47 (s, 3H, CCH3), 2.65-2.69 (m, 2H, aliphatic CH), 2.86-2.92 (m, 1H,aliphatic CH), 3.23 (dd, 7=16.64, 9.64 Hz, 1H, aliphatic CH), 4.48 (d, 7=5.78 Hz,2H, ArCtfoOH), 5.17 (t, 7=5.55 Hz, 1H, ArCH2Otf), 5.21 (dd, 7=22.42, 12.06,Hz, 2H, OCH2Ar), 6.59 (d, 7=8.44 Hz, 1H, AtH), 7.03 (d, 7=8.68 Hz, 1H, Artf), 7.31 (d,7= 7.72 Hz, 2H, ArfÎ), 7.39 (d, 7=7.96 Hz, 2H, Artf), 11.52 (s, IH, Ntf);MS(APCI+): m/z 461.2 (MH+). Anal. Calcd for C2SH32N2O4: C, 73.02; H, 7.00;N, 6.08. Found: C, 72.62; H, 6.84; N, 5.83.

Example 59

Pyrrolo[3’,2’:5,6][l]benzopyrâno[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthalenylmethyl ester

K 0, 11820 -154-

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid naphthalen- 2-ylmethyl ester

10 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid naphthalen-2-ylmethylester was synthesized according to Procedure K from 2-bromomethyl-naphthalene(7.63 g, 34.5 mmol) and precipitated out of CH2CI2 to give 5.01 g (48.1%) of palelavender powder: mp 243-245°C; IR (KBr) 3408, 3306, 3058, 1665, 1596, 1465, 1172,1093 cm'1 ; 1H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3H, CCtf3), 5.46 (s,2H, OCtf2Ar), 6.59 (dd, 7=8.44,2.41 Hz, 1H, ArH), 7.12 (d, 7=8.44 Hz, 1H,

ArH), 7.30 (d, 7=2.41 Hz, 1H, ArH), 7.51 (dd, 7=6.03, 3.38 Hz, 1H, ArH), 7.59 (d, 7=1.69 Hz, ΙΗ,ΑτΗ), 7.61 (d, 7=1.69 Hz, 1H, ArH), 7.90-7.96 (m, 4H,

ArH), 8.83 (s, 1H, OH), 11.58 (s, 1H, NH); MS(APCI+): m/z 332.2 (MH+). HPLC(ALLTCH/ALLTIMA C-l8 35:65-2:98 H2O/CH3CN + 0.05% TFA): rententiontime=3.70 min, 95.81% purity. 15

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid naphthalen-2-ylmethyl ester

20 4-Dimethylaminomethyl-5-hydroxy-2-methyI-lH-indole-3-carboxylic acidnaphthalen-2-ylmethyl ester synthesized according to the Procedure L from 5-hydroxy-2-methyî-lH-indole-3-carboxylic acid naphthaIen-2-ylmethyl ester(Example 57, Step A, 3.38 g, 10.2 mmol) and recrystallized from CH2C12 to give 11820 -155- 0.750 g (19.0%) of a white soïid: mp 170-171°C; IR (KBr) 3120, 2964,2853,1675, 1592, 1431, 1257,1088 cm'1; *HNMR (400 MHz, DMSO-d6) δ 2.11 (s,6H, N(C#3)2), 2.49 (s, 3H, CC//3), 4.03 (s, 2H, NCtf2Ar), 5.43 (s, 2H,OCtf2Ar), 6.57 (d, 7=8.68 Hz, 1H, AiH), 7.08 (d, 7=8.44 Hz, 1H, Artf), 7.51-7.53 (m, 2H, AiH), 7.60 (d, 7=8.44 Hz, 1H, ArH), 7.9Ϊ-Ί.99 (m, 4H, AiH), 11.55 (s, 1H, NÆ); MS(APCI+): m/z 389.2 (MH+). HPLC (ALLTCH/ALLTIMAC-18 55:45-15:85 H2O/CH3CN + 0.05% TFA): rentention time=4.80 min,94.36% purity.

Step C: Pyrrolo[3’,2’:5,6][l]bçnzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthalenylmethylester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,I3,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmethyl ester wassynthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxyIic acid naphthalen-2-ylmethyl ester (0.620 g, 1.62 mmol) and recrystallized from ethyl acetate/hexanes to give 0.690 g (59.0%)of granular a white solid: mp 141-143’C; IR (KBr) 3177, 3056, 2929, 1702, 1430,1146,1079 cm'1 ; 1H NMR (400 MHz, CDCI3) δ 1.19-1.45 (m, 4H, aliphatic CH) 1.55-1.78 (m, 6H, aliphatic CH), 2.07 (d, 7=13.99 Hz, 1H, aliphatic CH), 2.43-2.46 (m, 1H, aliphatic CH), 2.52-2.55 (m, 1H, aliphatic CH), 2.58 (s, 3H,CC//3), 2.77-2.86 (m, 2H, aliphatic CH), 3.01-3.07 (m, 1H, aliphatic CH), 3.41 (dd, 7=18.08, 6.75 Hz, 1H, aliphatic CH), 5.48 (dd, 7=19.53, 10.61 Hz, 2H,OCtf2Ar), 6.75 (d, 7=8.68 Hz, 1H, Arfl), 7.03 (d, 7=8.68 Hz, 1H, Ar#), 7.48-7.50 (m, 2H, Artf), 7.55-7.57 (m, 1H, AxH), 7.82-7.86 (m, 3H, Artf), 8.11 (s,1H, NH)î MS(APCI+): m/z 481.3 (MH+). Anal. Calcd for C31H32N2O3: C,77.47; H, 6.71; N, 5.83. Found: C, 77.13; H, 6.84; N, 5.51. 118 2 0 -156-

Ex ample 60

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester

5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxycarbonyl- 10 benzyl ester was synthesized according to Procedure K from 3-bromomethyl- benzoic acid methyl ester (5.49 g, 24.0 mmol) and triturated with ethyl acetate togive 2.01 g (27.0%) of light gray powder: mp 160-162°C; IR (KBr) 3383, 3310,1721,1666, 1465, 1289, 1095 cm’1; 1H NMR (400 MHz, DMSO-dô) δ 2.56 (s,3H, CCH3), 3.81 (s, 3H, OCtf3), 5.35 (s, 2H, OCH2Ar), 6.57 (dd, 7=8.55, 15 2.20 Hz, 1H, AiH), 7.10 (d, 7=8.55 Hz, 1H, Artf), 7.25 (d, 7=2.20 Hz, 1 H, Artf), 7.53 (t, 7=7.81 Hz, 1H, ArH), 7.70 (d, 7=7.81 Hz , 1H, ArZ/), 7.89 (d, 7=7.57 Hz,1H, ArH), 8.01 (s, 1H, ArH), 8.82 (s, 1H, OH), 11.58 (s, 1H, Ntf); MS(APCI+):m/z 340.1 (MH+). Anal. Calcd for C19H17N1O5: C, 67.25; H, 5.05; N, 4.13.Found: C, 67.22; H, 4.75; N, 4.05. 11820 -157-

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indoîe-3-carboxylic acid 3-methoxycarbonyl-benzyl ester

4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3- methoxycarbonyl-benzyl ester was synthesized according to Procedure L from 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester(7.26 g, 21.4 mmol) and triturated with ethyl acetate to give 4.80 g (56.6%) of finewhitepowder: mp 164-167°C; IR (KBr) 3031, 2951,1725,16S3, 1432, 1285, 1077 cm'1; NMR (400 MHz, DMSO-d6) δ 2.10 (s, 6H, N(Ctf3)2), 2.49 (s, 3H, CCtf3), 3.81 (s, 3H, OCtf3), 3.96 (s, 2H, NC//2Ar), 5.31 (s, 2H, OC/^Ar), 6.55 (d, 7=8.55 Hz, 1H, Artf ), 7.06 (d, 7=8.55 Hz, 1H, Artf), 7.52 (t, 7=7.81 Hz,1H, ArH), 7.72 (d, 7=7.57 Hz, 1H, ArH), T.9Q (d, 7=7.81 Hz, 1H, ArH), 8.03 (s, 1 H, ArH), 11.54 (s, 1 H, NH); MS(APCI+): m/z 397.0 (MH+). HPLC(ALLTCH/ALLTIMA C-18 65:35-15:85 H2O/CH3CN + 0.05% TFA): rententiontime=4.91 min, 92.97% purity.

Step C: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[3-(methoxycarbonyl)phenyl]methyl ester

Pyrrolo[3’,2’:5,6][l jbenzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl)-phenyljmethyl ester was synthesized according to Procedure M from 4- dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (2.09 g, 5.27 mmol) and recrystallized fromt-butyl methyl ether to give 1.21 g (47.1%) of fine white powder: mp 169-170°C;IR (KBr) 3380, 2931,2855,1721,1433, 1289,1076 cm-1; !H NMR (400 MHz,DMSO-dô) δ 1.03-1.21 (m, 3H, aliphatic CH) 1.36-1.63 (m, 7H, aliphatic CH), 118 2 0 -158- 1.81 (d, /=13.43 Hz, 1H, aliphatic CH), 2.33 (d, /=10.50 Hz, 1H, aliphatic CH), 2.40-2.42 (m, 1H, aliphatic CH), 2.46 (s, 3H, CC//3), 2.56-2.67 (m, 2H, aliphaticCH), 2.82-2.88 (m, 1H, aliphatic CH), 3.14 (dd, /=18.07, 6.84 Hz, 1H, aliphaticCH), 3.81 (s, 3H, OC//3), 5.29 (dd,/=25.15, 12.45 Hz, 2H, OCtf2Ar), 6.57 (d, 5 /=8.79 Hz, 1H, AiH), 7.02 (d, /= 8.79 Hz, 1H, Artf), 7.52 (t, /=7.57 Hz, 1H,

ArH), 7.71 (d, /=7.57 Hz, 1H, Arfl), 7.90 (d, /=7.81 Hz, 1H, Artf), 8.02 (s, 1H, ΑχΗ), 11.55 (s, 1H, Ntf); MS(APCI+): m/z 489.2 (MH+). Anal. Calcd forC29H32N2O5: C, 71.29; H, 6.60; N, 5.73. Found: C, 71.22; H, 6.91; N, 5.43. 10

Example 61

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[3-(hydroxymethyl)phenyl]methyl ester

15 20

Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3-carboxylicacid 3-hydroxymethyl-benzyl ester

4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3- hydroxymethyl-benzyl ester was synthesized according to procedure P ffom 4- dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (Example 60, Step B, 2.21 g, 5.58 mmol) andtriturated with CH2CI2 to give 1.11g (54.0%) of white powder: mp 199-201°C; IR (KBr) 3065,2884, 1681,1586, 1432, 1090 cm’1; ]H NMR (400 MHz, DMSO- 1192 0 -159- d6) δ 2.25 (s, 3H, CC//3) 2.72 (s, 6H, N(CZ/3)2), 4.48 (d, 7=5.37 Hz, 2H,ArC//2OH), 4.75 (s, 2H, NC//2Ar), 5.22 (t, 7=5.62 Hz, 1H, ArCH2O//), 5.28 (s,2H, OC//2Ar), 6.87 (d, 7=8.55 Hz, 1H, Ar//), 7.25-7.34 (m, 4H, Ar//), 7-40 (s,1H, Ar//), 8.59 (s, 1H, ArO/7), 12.06 (s, 1H, N//); MS(APCI+): m/z 369.2 (MH+). HPLC (ALLTCH/ALLTIMA C-18 98:2-75:25 H2O/CH3CN +0.05% TFA): rétention time=2.11 min, 98.74% purity.

Step B: Pyrrolo[3’,2’:5,6][13benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[3-(hydroxymethyl)phenyl]methyl ester

Pyrroîo[3 ’ ,2’:5,6][1 ]benzopyrano[3,2-i]quinolizine-1 -carboxyîic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl)-phenyl]methyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyI-1 H-indole-3-carboxylic acid3-hydroxymethyl-benzyl ester (0.980 g, 2.66 mmol) and triturated with t-butylmethyl ether to give 0.420 g (44.2%) of a light yellow green crystal: mp183-185°C; IR (KBr) 3381, 3197, 2931,1682, 1430,1249,1076 cnr1; *H NMR(400 MHz, DMSO-dô) δ 1.06-1.37 (m, 3H, aliphatic CH) 1.40-1.65 (m, 6H,aliphatic CH), 1.82 (d, 7=13.43 Hz, 1H, aliphatic CH), 2.33 (d, 7=10.01 Hz, 1H,aliphatic CH), 2.40-2.43 (m, 1H, aliphatic CH), 2.46 (s, 3H, CC//3), 2.61-2.68 (m,2H, aliphatic CH), 2.83-2.89 (m, 1H, aliphatic CH), 3.12-3.16 (m, 1H, aliphaticCH), 3.18 (dd,7=18.31, 6.84 Hz, 1H, aliphatic CH), 4.46 (d, 7=5.62 Hz, 2H,ArC//2OH), 5.18 (t, 7=6.10 Hz, 1H, ArCH2O//), 5.21 (dd, 7=20.27, 12.21 Hz, 2H, OC//2Ar), 6.58 (d, 7=8.79 Hz, 1H, Ar//), 7.01 (d, 7=8.55 Hz, 1H, Ar//), 7.23-7.32 (m, 3H, Ar//), 7.36 (s, 1H, Ar//), 11.51 (s, 1H, N//); MS(APCI+): m/z461.1 (MH+). Anal. Calcd for C28H32N2O4: C, 73.02; H, 7.00; N, 6.08. Found:C, 72.84; H, 7.07; N, 5.91. 118 2 0 -160-

Example 62

Pyrroîo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-carboxyphenyl)methyl ester)

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-carboxyphenyl)methylester was synthesized according to Procedure O from pyrrolo[3’,2’:5,6][l]-benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester (Exampîe 60,Step C, 0.923 g, 1.89 mmol) and triturated with ethyl acetate to give 0.456 g(50.7%) of white powder: mp 205-208°C; IR (KBr) 2932,2859, 1693, 1563, 1432, 1076 cm'1; ]H NMR (400 MHz, DMSO-d6) δ 1.08-1.36 (m, 3H, aliphatic CH) 1.39-1.63 (m, 7H, aliphatic CH), 1.81 (d, 7=13.18 Hz, 1H, aliphatic CH), 2.33 (d, 7=11.23 Hz, 1H, aliphatic CH), 2.40-2.43 (m, 1H, aliphatic CH), 2.47 (s,3H, CC//3), 2.56-2.67 (m, 2H, aliphatic CH), 2.84-2.88 (m, 1H, aliphatic CH), 3.15 (dd, 7=17.82, 6.35 Hz, 1H, aliphatic CH), 5.28 (dd, 7=24.17, 12.45 Hz, 2H,OCH2Ar), 6.57 (d, 7=8.79 Hz, 1H, AxH), 7.02 (d, 7=8.55 Hz, 1H, Artf), 7.48 (t,7=7.57 Hz, 1H, AxH), 7.65 (d, 7=7.57 Hz, 1H, Artf), 7.87 (d, 7=7.81 Hz, 1H,ArH), 8.00 (s, 1H, ArH), 11.55 (s, 1H, N#); MS(APCI+): m/z 475.1 (MH+). Anal.Calcd for C28H30N2O5: C, 69.18; H, 6.50; N, 5.75. Found: C, 68.83; H, 6.40; N,5.63.

Ex ample 63

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (3-carboxypheny)methyl3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyIpyrrolo[3 ’,2’ :5,6] [ 1 ]-benzopyrano[3,2-i]quinolizine-l-carboxylate (1:1) ί 7 8 2 0

Το a suspension ofpyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,l3,14,14a,15-decahydro-2-methyl-,(3-carboxyphenyl)methyl ester (Example 62, 0.100 g, 0.211 mmol) in 5 mL ofEtOH was added choline carbonate (0.037 mL, 0.211 mmol, 5.66 M). Thereaction mixture was heated at reflux for 1 hour resulting in a clear solution. Aftercooling to room température, the mixture was concentrated to give a yellow oil.Triturating this oil with diethyl ether yielded 0.097 g (88.0%) of beige solid: mp165-170°C; IR (KBr) 2930, 2855, 1685, 1566, 1436, 1077 cm-1; ^NMR 10 15 (400 MHz, DMSO-dô) δ 1.09-1.28 (m, 3H, aliphatic CH) 1.39-1.70 (m, 7H, aliphatic CH), 1.86 (d, 7=13.50 Hz, 1H, aliphatic CH), 2.35 (d, 7=10.37 Hz, 1H,aliphatic CH), 2.42-2.45 (m, 1H, aliphatic CH), 2.47 (s, 3H, CCffy, 2.65-2.72 (m,2H, aliphatic CH), 2.87-2.91 (m, 1H, aliphatic CH), 3.09 (s, 9H, N(CH3)3), 3.23 (dd, 7=15.19, 8.44 Hz, 1H, aliphatic CH), 3.35-3.40 (m, 2H, NCH2CH2OH),3.81-3.85 (m, 2H, NCH2CH2OH), 5.20 (dd, 7=23.63,12.30 Hz, 2H, OCH2Ar), 6.55 (d, 7=8.44 Hz, 1H, ArH), 7.03 (d, 7= 8.44 Hz, 1H, ArH), 7.22 (t, 7=7.47 Hz,1H, Ar//), 7.29 (d, 7=7.23 Hz, 1H, ArH), 7.75 (d, 7=7.48 Hz, 1H, ArH), 7.89 (s,1H, ΑτΗ), 11.55 (s, 1H, NH); MS(APCI+): m/z 475.1 (MH+). Anal. Calcd forC33H43N3O6: C, 65.23; H, 7.68; N, 6.92. Found: C, 64.95; H, 7.68; N, 6.92. 20 Example 64

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-[(dimethyIamino)methyl]phenyl]methyl ester 11 8 2 0 -162- !

Το a stirred solution of PI13P (0.161 g, 0.616 mmol) and pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]-methyl ester (Example 61, Step B, 0.284 g, 0.616 mmol) in 2.93 mL of anhydrousTHF at -18°C was added dropwise a solution of N-bromosuccinimide (0.110 g,0.616 mmol) in 2 mL of THF. Aftef 10 minutes, the cold bath was removed, anddimethylamine was introduced in one portion. The reaction was heated at 80°C for1 hour in a stainless Steel vessel. The THF was removed, and the product was ·purified by flash column chromatography on silica gel (20% MeOH:CH2Cl2) andrecrystallized from CH2CI2 to give 1.21 g (40.3%) of coarse off-white powder: mp 87-90°C; IR (KBr) 2930, 2854,1700, 1589, 1432,1077 cm'1; !H NMR(400 MHz, DMSO-d6) δ 1.06-1.36 (m, 3H, aliphatic CH) 1.39-1.63 (m, 7H,aliphatic CH), 1.82 (d, >13.18 Hz, 1H, aliphatic CH), 2.11 (s, 6H, N(C#3)2) 2.34 (d, >10.74 Hz, ÎH, aliphatic CH), 2.40-2.46 (m, 1H, aliphatic CH), 2.45 (s,3H, CCH3), 2.59-2.67 (m, 2H, aliphatic CH), 2.83-2.89 (m, 1H, aliphatic CH), 3.15 (dd,>18.31,6.84 Hz, 1H, aliphatic CH), 3.37 (s, 2H, ArCfl2N(CH3)2), 5.20 (dd, >23.93,12.21 Hz, 2H, OCH2Ar), 6.57 (d, >8.79 Hz, 1H, AiH), 7.02 (d, >8.79 Hz, 1H, ArJT), 7.22-7.31 (m, 3H, Artf), 7.34 (s, 1H, AxH), 11.53 (s, IH, Ntf); MS(APCI+): m/z 488.1 (MH+). Anal. Calcd for C30H37N3O3: C, 71.89; H, 7.65; N, 8.62. Found: C, 71.89; H, 7.65; N, 8.20.

Example 65

Pyrrolo[3 ’ ,2 ’ :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[3-[(dimethyIamino)carbonyl]phenyl]methyl ester -163- 11«20 o.

Μ

Step A: 3-HydroxymethyI-N,N-dimethyl-benzamideo HO'

To a mixture of 3-(hydroxymethyl)benzoic acid (9.87 g, 64.9 mmol), 5 dimethylamine (2 M in THF, 32.4 mL, 64.9 mmol), Ν,Ν-diisopropyl ethylamine (22.6 mL, 130 mmol) in 20 mL of DMF was added a solution of HBTU (24.6 g, 64.9 mmol) in 55 mL of DMF at 0°C. After 5 minutes, the yellow solution tumedorange. After stim'ng at 0°C for 1 hour, the reaction mixture was diluted withdiethyl ether, washed with 10% HCl, saturated NaHCO3, brine, dried with 10 MgSC>4, and concentrated to give a brown oil. The product was purified by flashcolumn chromatography on silica gel (3% MeOH:CH2Cl2) to afford 7.5 g(64.5%) of a yellow oil: ^H NMR (400 MHz, DMSO-d0) δ 2.88 (s, 3H, NC//3), 2.96 (s, 3H, NC//3), 4.51 (d, 7=5.55 Hz, 2H, OC//2Ar), 5.25 (t, 7=5.79 Hz, 1H,OH}, 7.21-7.25 (m, 1H, Artf), 7.31-7.47 (m, 3H, ΛχΗ}; MS(APCI+): m/z 15 180.1 (MH+).

Step B: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[3-[(dimethylamino)carbonyI]phenyl]methyl ester

PynOÎo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]- phenyljmethyl ester was synthesized according to Procedure N from 3-hydroxymethyl-N,N-dimethyl-benzamide (1.04 g, 5.81 mmol) and trituratedwith acetone to give 0.250 g (25.7%) of fluffy white powder: mp 112-116°C; IR(KBr) 2929,2854,1698,1624,1432,1077 cnr1; ^H NMR (400 MHz, DMSO- -164- 11820 dg) δ 1.09-1.62 (m, 10H, aliphatic CH), 1.82 (d, 7=14.16 Hz, 1H, aliphatic CH), 2.33 (d, 7=10.25 Ηζ,ΙΗ, aliphatic CH), 2.40-2.43 (m, 1H, aliphatic CH), 2.45 (s,3H, CCZ/3), 2.46 (s, 6H, N(Ctf3)2), 2.59-2.67 (m, 2H, aliphatic CH), 2.86-2.93 (m, 1H, aliphatic CH), 3.16 (dd, 7=18.80, 7.81 Hz, 1H, aliphatic CH), 5 5.24 (dd, 7=20.75, 12.45 Hz, 2H, OCZ72Ar), 6.57 (d, 7=8.55 Hz, 1H, Artf), 7.02 (d, 7=8.55 Hz, 1H, ArH), 7.33 (d, J=1.51 Hz, 1H, Artf), 7.40-7.44 (m, 2H,Ar//), 7.49 (d, 7=7.57 Hz, 1H, Ar//), 11.54 (s, 1H, N//); MS(APCI+): m/z 502.2 (MH+). Anal. Calcd for C30H35N3O4: C, 71:83; H, 7.03; N, 8.38. Found:C, 71.44; H, 7.05; N, 8.21. 10 Example 66

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl)ethyI ester

PynOlo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [2-(4-morphoîinyl)ethyl ester was synthesized according to Procedure N from 2-morpholin-4-yl-ethanol(0.300 mL, 2.64 mmol) and triturated with CH2C12 to give 0.122 g (41.0%) of awhitesolid: mp 188-190°C; IR (KBr) 2931,2854,1696,1588, 1432, 1148 cm'1;ÏH NMR (400 MHz, DMSO-dô) δ 1.14-1.75 (m, 10H, aliphatic CH), 1.90 (d, 20 7=13.18 Hz, 1H, aliphatic CH), 2.34-2.46 (m, 2H, aliphatic CH), 2.46 (s, 4H, N(CH2C//2)2O), 2.49 (s, 3H, CC//3), 2.59 (t, 7=5.62 Hz, 2H, CO2CH2CZ/2),2.64-2.73 (m, 2H, aliphatic CH), 2.86-2.91 (m, 1H, aliphatic CH), 3.29 (dd,7=19.29,10.25 Hz, 1H, aliphatic CH), 3.52 (s, 4H, N(C//2CH2)2O), 4.18-4.30(m, 2H, CO2C//2CH2), 6.58 (d, 7= 8.55 Hz, 1H, AiH), 7.02 (d, 7=8.55 Hz, 1H, 118 2 0 -165-

Ar/7), 11.48 (s, 1H, NH); MS(APCI+): m/z 454.1 (MH+). Anal. Calcd forC26h35n3°4: C, 68.60; H, 7.79; N, 9.23. Found: C, 68.23; H, 7.80; N, 9.02.

Example 67

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-[1,1 ’-biphenyl]-4-yIethyl ester

Pyrrolo[3’,2’:5,6][l]benzo'pyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(1,1 ’-biphenyl]-4-ylethyl esterwas synthesized according to Procedure N from l-biphenyl-4-yl-ethanol (2.68 g, 10 13.5 mmol) and triturated with diethyl ether to give 0.619 g (35.4%) of white powder: mp 132-135°C; IR (KBr) 2929,2855,1677, 1432,1078 cm’1; NMR(400 MHz, DMSO-dg) δ 1.11-1.67 (m, 10H, aliphatic CH), 1.59 (d, 7=6.59 Hz,2H, OCHCT/j), 1.79-1.89 (m, 2H, aliphatic CH), 2.33-2.47 (m, 1H, aliphatic CH), 2.53 &amp;. 2.54 (s, 3H, CC/Tj, diastereomers), 2.60-2.67 (m, 2H, aliphatic CH), 15 2.79-2.95 (m, 1H, aliphatic CH), 3.14 (dd, 7=28.08, 10.12 Hz, 1H, aliphatic CH), 5.96-6.03 (m, 1H, OC//CH3), 6.55-6.59 (m, 1H, Ar//), 7.00-7.03 (m, 1H, Ar//), 7.31-7.34 (m, 1H, AiH), 7.40-7.51 (m, 4H, Ar//), 7.60-7.64 (m, 4H, krH), 11.53 (s, ÎH, NT/); MS(APCI+): m/z 521.1 (MH+). Anal. Calcd forc34H36N2O3.· C, 78.25; H, 7.36; N, 5.14. Found: C, 78.20; H, 7.76; N, 4.85. 20 Example 68

Pyrrolo(3 ’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2,6-difluorophenyl)methyl ester 11820 -166-

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,(2,6-difluorophenyl)methyl esterwas synthesized according to Procedure N from (2,6-difluoro-phenyl)-methanol 5 (1.50 mL, 13.5 mmol) and triturated with diethyl ether to give 1.07 g (68.0%) of fluffy white powder: mp 219-220°C; IR (KBr) 3330, 2928, 1664, 1473, 1059 cm-1; ^NMR (400 MHz, DMSO-d6) δ 1.03-1.35 (m, 3H, aliphatic CH), I. 38-1.56 (m, 7H, cylic CH), 1.78 (d, 7=13.18 Hz, 2H, aliphatic CH), 2.32-2.34(m, 2H, aliphatic CH), 2.41 (s, 3H, CC//3), 2.55-2.66 (m, 2H, aliphatic CH), 10 2.83-2.88 (m, 1H, aliphatic CH), 3.08 (dd, 7=18.31, 7.08 Hz, 1H, aliphatic CH), 5.20 (d, 7=11.96 Hz, 1H, OCH2At), 6.57 (d, 7=8.55 Hz, 1H, Ar/7), 7.01 (d,7=8.55 Hz, 1H, ArH), 7Λ6 (t,J=1.81 Hz, 2H, AiH), 7.48-7.53 (m, 1H, ArH), II. 57 (s, 1H, NT/); MS(APCI+): m/z 467.1 (MH+). Anal. Calcd forC27H28N2O3F2: C, 69.32; H, 6.19; N, 5.80. Found: C, 69.51; H, 6.05; N, 6.00. 15 Example 69

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 -phenyl-2,2,2-trifluoro)ethylester

20 Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 -phenyl-2,2,2-trifluoro)ethylester was synthesized according to Procedure N from 2,2,2-trifluoro-l-phenyl-ethanol (1.58 g, 9.00 mmol) and triturated with t-butyl methyl ether to give 118 2 0 -167- 0.356 g (31.8%) of fluffy white powder: mp 115-117°C; IR (KBr) 3382, 2931,1718, 1432, 1067 cm"1; 1H NMR (400 MHz, DMSO-d6) δ 1.07-1.68 (m, 10H, aliphatic CH), 1.87-1.90 (m, 2H, aliphatic CH), 2.35-2.46 (m, 2H, aliphatic CH),2.58-2.62 (m, 1H, aliphatic CH), 2.61 &amp; 2.62 (s, 3H, CCHj, diastereomers), 2.62-2.90 (m, 1H, aliphatic CH), 3.18 (dd, 7=17.82,6.84 Hz, 1H, aliphatic CH), 6.52-6.57 (m, 1H, OCHCF3), 6.61-6.63 (m, 1H, AxH), 7.05-7.07 (m, 1H, AiH), 7.43-7.44 (m, 3H, AiH), 7.55-7.57 (m, 2H, Artf), 11.83 (s, 1H, N//); MS(APCI+)m/z 499.1 (MH+). Anal. Calcd for C2SH29N2O3F3: C, 67.46; H, 5.86; N, 5.62.Found: C, 67.40; H, 6.03; N, 5.44.

Ex ample 70

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-(trifiuoromethyl)phenyl]ethyl ester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[3-(trifluoromethyl)phenyl]-ethyl ester was synthesized according to Procedure N from l-(3-trifluoromethyl-phenyl)-ethanol (2.06 mL, 13.5 mmol) and triturated with diethyl ether to give

J 0.793 g (45.8%) of white solid: mp 102-105°C; IR (KBr) 3380, 2931, 1680,1432,1075 cm-1; NMR (400 MHz, DMSO-d6) δ 1.05-1.59 (m, 10H, aliphatic CH), 1.59 (d, 7=6.59 Hz, 3H, OCHCH3), 1.77-1.88 (m, 1H, aliphatic CH), 2.33 (d,7=9.03 Hz, 1H, aliphatic CH), 2.41 (d, 7=8.55 Hz, 1H, aliphatic CH), 2.51 &amp; 2.52 (s, 3H, CC//3, diastereomers), 2.51-2.67 (m, 2H, aliphatic CH), 2.83-2.86(m, 1H, aliphatic CH), 3.06 (dd, 7=18.07,6.84 Hz, 1H, aliphatic CH), 6.01-6.05(m, 1H, OŒCH3), 6.58-6.60 (m, 1H, Arfl), 7.01-7.04 (m, 1H, Ar//), 7.57-7.67 11820 -168- (m, 2H, ArTY), 7.71-7.75 (m, 2H, AiH), 11.56 (s, 1H, N//); MS(APCI+): m/z 513.1 (MH+). Anal. Calcd for C29H31N2O3F3: C, 67.69; H, 6.08; N, 5.44.Found: C, 67.34; H, 6.35; N, 5.24.

Example 71 5 Pyrrolo[3 ’ ,2 ’ : 5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester 10 was synthesized according to Procedure N front 2-dimethylamino-ethanol (1.36 mL, 13.5 mmol) and triturated with diethyl ether to give 0.489 g (34.9%) ofgranular off-white solid: mp 190-191°C; ER. (KBr) 3274, 2950, 1653, 1518, 1248 cm-1; ]H NMR (400 MHz, DMSO-d6) δ 1.13-1.59 (m, 10H, aliphatic CH), I. 71-1.76 (m, 1H, aliphatic CH), 1.90 (d, 7=13.43 Hz, 1H, aliphatic CH), 2.05 (s, 15 6H, N(Ctf3)2), 2.35 (d, 7=10.25 Hz, 1H, aliphatic CH), 2.48 (s, 3H, CC//3), 2.52 (t, 7=5.86 Hz, 2H, OCH2C//2). 2.64-2.74 (m, 2H, aliphatic CH), 2.85-2.89 (m, 1H, aliphatic CH), 3.31 (dd, 7=18.56, 7.08 Hz, 1H, aliphatic CH), 4.14-4.27 (m,2H, OC7/2CH2), 6.58 (d, 7=8.55 Hz, 1H, AiH), 7.02 (d, 7=8.79 Hz, 1H, Artf), II. 56 (s, 1H, NT/); MS(APCI+): m/z 412.2 (MH+). Anal. Calcd for 20 C24H33N3O3: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.01; H, 8.20; N, 9.98.

Example 72

Pyrrolo[3’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(l-pyrrolidinyl)ethyl ester 11820 -169-

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-( 1 -pyrrolidinyl)ethy 1 ester wassynthesized according to Procedure N from 2-pyrrolidin-l-yl-ethanol (1.02 g, 8.85 mmol) and triturated with t-butyl methyl ether to give 0.253 g (26.0%) ofwhite solid: mp 195-196°C; ER (KBr) 3377,2930, 1700,1432, 1081 cm"!;lH NMR (400 MHz, DMSO-d6) δ .1.12-1.78 (m, 10H, aliphatic CH), 1.61-1.69(m, 8H, cyclic CH2), 1.92 (d, 7=13.26 Hz, 1H, aliphatic CH), 2.37 (d, 7=10.61 Hz,1H, aliphatic CH), 2.47-2.49 (m, 1H, aliphatic CH), 2.50 (s, 3H, C//3), 2.66-2.76(m, 2H, aliphatic CH), 2.72 (t, 7=6.51 Hz, 2H, OCH2Ctf2), 2.87-2.93 (m, 1H,aliphatic CH), 3.32 (dd, 7=19.05,13.02 Hz, 1H, aliphatic CH), 4.19-4.30 (m, 2H,OC//2CH2), 6.60 (d, 7=8.68 Hz, 1H, AiH), 7.04 (d, 7=8.68 Hz, 1H, Artf), 11.49 (s, 1H, Ntf); MS(APCI+): m/z 438.2 (MH+). Anal. Calcd for C26H35N3O3.· C,71.37; H, 8.06; N, 9.60. Found: C, 70.99; H, 8.13; N, 9.49.

Example 73

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -( 1 -naphthalenyl)ethyl ester

Pyrrolo[3 ’ ,2 ’ :5,6][1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 1 -( 1 -naphthalenyl)ethyl esterwas synthesized according to Procedure N from 1-naphthalen-l-yl-ethanol -170- 118 2 0 (2.32 g, 13.5 mmol) and triturated with diethyl ether to give 0.707 g (40.9%) offine white powder: mp 140-145°C; IR (KBr) 3387, 2929,1682, 1432,1078 cm'1;1h NMR (400 MHz, DMSO-d6) δ 0.94-1.72 (m, 10H, aliphatic CH), 1.72 (d,>2.69 Hz, 3H, OCHC773), 1.83 (d, >12.94 Hz, 1H, aliphatic CH), 2.30-2.63 (m, 5 3H, aliphatic CH), 2.50 &amp; 2.52 (s, 3H, CC//3, diastereomers), 2.83-2.88 (m, 2H, aliphatic CH), 3.21 (dd, >32.72, 26.12 Hz, 1H, aliphatic CH), 6.52-6.58 (m, 1H,AiH), 6.74-6.75 (m, 1H, OC//CH3), 6.98-7.03 (m, 1H, ArH), 7.46-7.65 (m, 4H,ArH), 7.84-7.89 (m, 1H, ΑτΗ), Ί.93-1.96 (m, 1H, Artf), 8.12-8.14 (m, 1H, ArH), 11.54 (s, 1H, Ntf); MS(APCI+): m/z 513.1 (MH+). Anal. Calcd for 10 C32H34N2O3: C, 76.66; H, 6.92; N, 5.58. Found: C, 76.29; H, 6.96; N, 5.40.

Example 74

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcyclobutyl ester

To a solution of phenylmagnesium bromide (1 M in THF, 148 mL, 148 mmol) in 87 mL of anhydrous diethyl ether was added cyclobutanone (10.0 g,143 mmol) in 15 mL of ether at 0°C. The reaction mixture was stirred in an ice 20 bath for 1 hour. Saturated ammonium chloride was added and stirred for 10 minutes. The reaction mixture was washed with H2O (2 x 250 mL), dried withMgSC>4, and concentrated to give a yellow oil. The product was purified by flashcolumn chromatography on silica gel (10% acetone:hexanes) to give 10.1 g 11820 -171- (47.7%) of a yellow oil: NMR (400 MHz, CDCI3) δ 1.62-1.73 (m, 1H,CCH9C//2), 1-94-2.09 (m, 1H, CCH2C//2). 2.29-2.38 (m, 2H, CC//2), 2.50-2.57

Ar//), 7.38-7.50 (m, 2H, Ar#); MS(APCI+): m/z 171.5 (MH+). 5 Step B: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcyclobutylester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 1 -phenylcyclobutyl ester was 10 synthesized according to Procedure N from î-phenyl-cyclobutanol (1.33 g, 9.00 mmol) and triturated with diethyl ether to give 0.201 g (19.0%) of whitepowder: mp 218-220°C; IR (KBr) 3328,2930,1674, 1434, 1080 cm-1; iHNMR(400 MHz, DMSO-d6) δ 1.09-1.84 (m, 10H, aliphatic CH), 1.94-2.00 (m, 1H, aliphatic CH), 2.33 (d, 7=9.03 Hz, 1H, aliphatic CH), 2.40-2.46 (m, 1H, aliphatic 15 CH), 2.46 (s, 3H, CCH3), 2.56 (s, 6H, cyclic C(Ctf2)3Ar), 2.52-2.64 (m, 2H,aliphatic CH), 2.83-2.88 (m, 1H, aliphatic CH), 3.15 (dd, 7=18.80, 7.08 Hz, 1H,aliphatic CH), 6.56 (d, 7=8.55 Hz, 1H, Artf), 7.00 (d, 7=8.55 Hz, 1 H, Artf), 7.22 (t, 7=7.08 Hz, 1H, ArTf), 7.33 (t, 7=7.57 Hz, 2H, Artf), 7.47 (d, 7=7.32 Hz,2H, Ar/f),11.48 (s, 1H, NT/); MS(APC1+): m/z 671.1 (MH+). Anal. Calcd for 20 C30H35N2O3: C, 74.72; H, 7.56; N, 5.81. Found: C, 74.43; H, 7.26; N, 5.41.

Example 75

Pyrrolo[3’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcylopropyl ester 0

H -172- ’182o

StepA: 1-PhenyI-cyclopropanol 1-Phenyl-cyclopropanol was synthesized according to the procedurepublished in Kulinkovich, O.G.; Sviridov, S.V.; Vasilevskii, D.A.; Savchenko,A.I.; Pritytskaya, T.S. J. Org. Chem. USSR (Engl.) 1991;27:250-253.

Step B: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcylopropylester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydror2-methyl-, 1-phenylcylopropyl ester wassynthesized according to Procedure N from 1-phenyl-cyclopropanol (1.22 g,9.00 mmol) and triturated with diethyl ethcr to give 0.078 g (7.57%) of shinyyellow powder: mp 130-135°C; ER (KBr) 3384, 2929,1690,1431, 1069 cm^;NMR (400 MHz, DMSO-d6) δ 1.06-1.69 (m, 10H, aliphatic CH), 1.86 (d, 7=13.43 Hz, 1H, aliphatic CH), 2.34 (d, 7=10.01 Hz, 1H, aliphatic CH), 2.41-2.44 (m, 1H, aliphatic CH), 2.46 (s, 3H, CCtf3), 2.52 (s, 4H, cyclicC(C7/2)2Ar). 2.63-2.70 (m, 2H, aliphatic CH), 2.81-2.89 (m, 1H, aliphatic CH), 3.20 (dd, 7=18.56, 7.33 Hz, 1H, aliphatic CH), 6.59 (d, 7=8.55 Hz, 1H, Ar//),7.03 (d, 7=8.55 Hz, 1H, Ar//), 7.15-7.19 (m, 3H, Ar//), 7.26-7.30 (m, 2H, Ar//),11.57 (s, 1H, N//); MS(APCI+): m/z 457.1 (MH+). Anal. Calcd forC29H32N2O3: C, 76.29; H, 7.06; N, 6.14. Found: C, 76.12; H, 7.39; N, 5.83.

Example 76

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -pyrazinylethyl ester o. -173- 118 2 0

Step A: l-Pyrazin-2-yl-ethanol

Το a solution of l-pyrazin-2-yl-ethanone (5.00 g, 40.9 mmol) in 100 mL ofMeOH at 0°C was added NaBH4 (0.774 g, 20.5 mmol) in portions. Aller stirringat room température for 24 hours, the reaction mixture was quenched with IN HCland extracted with CH2CI2 (3 x 100 mL). The organic layers were dried withNa2SC>4 and concentrated to give 2.60 g (51.2%) of a yellow oil: NMR (400 MHz, CDCI3) δ 1.54 (d, 7=6.59 Hz, 3H, CHC//3), 3.54 (s, 1H, OH), 4.97 (q,7=6.59 Hz, 1H, CH3C//), 8.49 (s, 2H, NCtfCHN), 8.65 (s, 1H, CCtfN);MS(APCI+): m/z 125.1 (MH+).

Step B: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -pyrazinyîethyl ester

Pyrrolo[3’,2’:5,6][l]benzopyranô[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -pyrazinyîethyl ester wassynthesized according to Procedure N from l-pyrazin-2-yl-ethanol (1.12g, 9.00 mmol) and triturated with cold acetone to give 0.303 g (30.3%) of coarsewhite powder: mp 224-225’C; IR (KBr) 3172,2930, 1704, 1431, 1073 cm'1; ^HNMR (400 MHz, DMSO-d0) δ 1.06-1.63 (m, 10H, aliphatic CH), 1.61 (d, 7=3.17 Hz, 3H, OCHC//3), 1.77-1.98 (m, 1H, aliphatic CH), 2.34 (d, 7=10.25 Hz,IH, aliphatic CH), 2.40-2.43 (m, 1H, aliphatic CH), 2.52 &amp; 2.53 (s, 3H, CCH^,diastereomers), 2.62-2.68 (m, 1H, aliphatic CH), 2.84-2.87 (m, 1H, aliphatic CH),3.12 (dd, 7=19.04,6.84 Hz, 1H, aliphatic CH), 5.99 (q, 7=7.08 Hz, 1H, OC//CH3), 6.56-6.60 (m, 1H, ArH), 7.01-7.04 (m, 1H, ArH), 8.57 (s, 1H, ArH), 8.62 (s, 1H, ArH), 8.71 &amp; 8.73 (s, 1H, ArH, diastereomers), 11.56 (s, 1H, N#);MS(APCI+): m/z 447.1 (MH+). Anal. Calcd for C26H30N4O3: C, 69.90; H, 6.79;N, 12.50. Found: C, 69.51 ; H, 6.78; N, 12.35. 11820 -174-

Example 77

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-meîhyl-, 1 -(4-quinolinyl)ethyl ester

To a solution of quinoline-4-carbaldehyde (5.00 g, 31.8 mmol) in 127 mLof anhydrous THF at -40°C was added méthylmagnésium bromide (13.8 mL, 41.4 mmol). After stirring for 5 hours, the reaction mixture was quenched with 10 saturated NH4CI and extracted with ethyl acetate (5 x 100 mL). The organiclayers were washed with brine, dried with Na2SC>4, and concentrated to give apurple solid. The solid was triturated with acetone to yield 4.52 g (82.2%) of lightpurple solid: 1H NMR (400 MHz, CDCI3) δ 1.60 (d, 7=6.35 Hz, 3H, CHC/7}),3.70 (s, 1H, OH), 5.62 (q, 7=6.35 Hz, 1H, CZ/CH3), 7.50 (t, 7=7.57 Hz, 1H, 15 CCCÜCH), 7.56 (d, 7=4.40 Hz, 1H, NCHCtf), 7.63 (t, 7=7.32 Hz, 1H,NCCHCtf), 7.97 (d, 7=8.55 Hz, 1H, CCC77CH), 8.05 (d, 7=8.30 Hz, 1H,NCŒCH), 8.73 (d, 7=4.39 Hz, 1H, NŒCH), MS(APCI+): m/z 174.1 (MH+).

Step B: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-quinolinyl)ethyl 20 ester

Pyrrolo[3’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methy I-, 1 -(4-quinolinyl)ethyl ester wassynthesized according to Procedure N from l-quinolin-4-yl-ethanol (1.56 g, 9.00 mmol) and triturated with acetone to give 0.192 g (17.1%) of pale yellow 118 2 0 -175- powderzmp 165-168°C; IR (KBr) 2930, 2853, 1690, 1429, 1074 cm-1; ÎHNMR(400 MHz, DMSO-dg) δ 1.00-1.46 (m, 10H, aliphatic CH), 1.70 (d, 7=6.35 Hz,3H, OCHC//3), 1.85 (d,7=13.18 Hz, 1H, aliphatic CH), 2.32-2.63 (m, 3H,aliphatic CH), 2.57 &amp; 2.58 (s, 3H, CC//3, diastereomers), 2.83-2.86 (m, 2H, 5 aliphatic CH), 3.20 (dd, 7=18.31, 6.84 Hz, 1H, aliphatic CH), 6.55-6.58 (m, 1H,Artf), 6.65 (q, 7=6.59 Hz, 1H, OC//CH3), 7.01-7.05 (m, 1H, ArH), 7.50-7.54 (m, 1H, ΑτΗ), 7.63-Ί.67 (m,.lH, AtH), 7.75-7.79 (m, 1H, ArH), 8.04-8.06 (m, 1H,ArH), 8.21-8.23 (m, 1H, ArH), 8.84-8.88 (m, IH, ArH), 11.61 (s, 1H, N//);MS(APCI+): m/z 496.2 (MH+). Anal. Calcd for C31H33N3O3: C, 74.12; H, 7.00; 10 N, 7.83. Found: C, 73.73; H, 7.09; N, 7.44.

Example 78

Pyrrolo[3’,2’:5,ô](l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(2-pyrimidinyl)ethyl ester

15 StepA: J-Pyrimidin-2-yl-ethanone 0

l-Pyrimidin-2-yl-ethanone was synthesized according to the procedurepublished in Naumenko, 1.1.; Mikhaleva, M. A.; Mamaev, V. P. Chem.Hel.Cmpds. 1981;17:710-714. 20 StepB: 1-Pyrimidin-2-yl-ethanol ΌΗ 11820 -176- Το a solution of l-pyrimidin-2-yl-ethanone (2.34 g, 19.2 mmol) in 65 mLof MeOH at 0°C was added NaBH4 (0.726 g, 19.2 minol) in portions. Afterstirring at room température for 4 hours, the reaction mixture was quenched withIN HCl and extracted with CH2CI2 (3 x 100 mL). The organic layers were driedwith Na2SC>4 and concentrated to afford 0.984 g (41.3%) of a yellow oil: NMR (400 MHz, DMSO-d6) 5 1.36 (d, 7=6.59 Hz, 3H, CHCtf3), 4.73 (q, 7=6.59 Hz, 1H, CH3Ctf), 5.21 (s, 1H, OH), 7.33-7.36 (m, 1H, NCHC77),8.73-8.77 (m, 2H, NCtfCH); MS(APCI+): m/z 125.1 (MH+).

Step C: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-pyrimidinyl)ethylester P)Trolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(2-pyrimidinyl)ethyl ester wassynthesized according to Procedure N from l-pyrimidein-2-yl-ethanol (1.01 g,8.10 mmol) and triturated with acetone to give 0.360 g (29.9%) of fine off-whitepowder: mp 220-222°C; IR (KBr) 3176, 2932, 1686, 1426, 1078 cm’l; ^H NMR(400 MHz, DMSO-d6) δ 1.06-1.54 (m, 10H, aliphatic CH), 1.59 (d, 7=6.59 Hz,3H, OCHCH3), 1.84 (d, 7=13.92 Hz, 1H, aliphatic CH), 2.34-2.55 (m, 2H,aliphatic CH), 2.58 (s, 3H, CC//3), 2.64-2.69 (m, 2H, aliphatic CH), 2.81-2.86 (m,1H, aliphatic CH), 3.17 (dd, 7=18.31, 6.59 Hz, 1H, aliphatic CH), 5.84 (q, 7=6.84 Hz, 1H, OC//CH3), 6.57 (d, 7=8.79 Hz, 1H, ArH), 7.02 (d, 7=9.03 Hz, 1H,AxH), 7.37-7.38 (m, 1H, AxH), 8.76-8.77 (m, 2H, ArH), 11.53 (s, 1H, NH);MS(APCI+): m/z 447.1 (MH+). Anal. Calcd for C26H3oN403: C, 69.86; H, 7.04;N, 12.07. Found: C, 69.50; H, 6.94; N, 11.71.

Example 79

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, phenylmethyl ester 11820 -177-

Step A: 6-Chloro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester

To a solution of 3-amino-but-2-enoic acid benzyl ester (10.1 g, 52.9 mmol)

5 in 211 mL of EtOH was added 2-chloro-l,4-benzoquinone (9.04 g, 63.4 mmol).After heating at 50°C for 24 hours, the mixture was cooled to room températureand concentrated to afford a brown oil. The product was purified by flash columnchromatography on silica gel (20% ethyl acetate-.hexanes) and recrystallized fromethyl acetate to give 1.02 g (5.12%) of light yellow powder: mp 221-224°C; IR 10 (KBr) 3409, 3226, 1642, 1461,1181 cm'1; 1H NMR (400 MHz, DMSO-d0) δ 2.55 (s, 3H, CCT/3), 5.29 (s, 2H, OC/^Ar), 7.27 (s, 1H, Ar//), 7.30 (d, 7=6.84 Hz,1H, Ar//), 7.36 (t, 7=8.30 Hz, 2H, Ar//), 7.42 (d, 7=7.57 Hz, 2H, Ar//), 7.50 (s, 1 H, Ar//), 9.56 (s, 1 H, OH), 11.67 (s, 1 H, NT/); MS(APCI+): m/z 316.1 (MH+).HPLC (ALLTCH/ALLT1MA C-1S 50:50-2:98 H2O/CH3CN + 0.05% TFA): 15 rentention time=5.47 min, 95.86% purity.

Step B: 6-Chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-l H-indole- 3-carboxylic acid benzyl ester

6-Chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-20 3-carboxyIic acid benzyl ester was synthesized according to Procedure L from -178- 11820 6-chloro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (7.77 g, 24.6 mmol) and triturated with cold EtOH to give 6.77g (73.8%) of a white solid:mp 178-180°C; IR (KBr) 3298,2951,1687, 1425, 1437,1264, 1078 cm'1; ÎHNMR (400 MHz, DMSO-d6) δ 2.14 (s, 6H, N(C//3)2) 4.06 (s, 2H, NCtf2Ar), 5.23 (s, 2H, OCtf2Ar), 7.22 (s, 1H, AiH), 7.31-7.39 (m, 3H, ArH), 7.44 (d, 7=6.84 Hz, 2H, Ar/7), 11.85 (s, 1H, NÀ0; MS(APCI+): m/z 373.1 (MH+). HPLC(ALLTCH/ALLTIMA C-18 50:50-2:98 H2O/CH3CN + 0.05% TFA): rétentiontime=3.10 min, 99.09% purity.

Step C: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,I4a,15-decahydro-2-methyI-, phenylmethylester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2methyl-, phenylmethyl ester wassynthesized according to Procedure M from 6-chloro-4-dimethylaminomethyl- 5-hydroxy-2-methyl-lH-indole-3-carboxyIic acid benzyl ester (6.77 g, 18.2 mmol)and triturated with acetone to give 6.05 g (71.7%) of shiny white powder: mp90-93°C; IR (KBr) 3291, 2933, 2858, 1673, 1427, 1076 cm-1; ÎHNMR(400 MHz, DMSO-d0) δ 1.01-1.71 (m, 10H, aliphatic CH), 1.75 (d,7=13.43 Hz, 1H, aliphatic CH), 2.37 (d, 7=10.50 Hz, 1H, aliphatic CH), 2.45-2.46 (m, 1H,aliphatic CH), 2.46 (s, 3H, CC//3), 2.64-2.74 (m, 2H, aliphatic CH), 2.94-2.99 (m, IH, aliphatic CH), 3.38 (dd, 7=18.56,7.08 Hz, 1H, aliphatic CH), 5.21 (dd,7=26.12,12.21 Hz, 2H, OCH2Ar), 7.18 (s, 1H, Ar/7), 7.29-7.43 (m, 5H, Artf), II. 62 (s, 1H, Ntf); MS(APCI+): m/z 465.2 (MH+). Anal. Calcd for C27H29N2O3Cli: C, 69.74; H, 6.29; N, 6.02. Found: C, 69.45; H, 6.68; N, 5.82.

Example 80

Pyirolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, 1 -(4-fluorophenyl)ethyl ester 11820 -179-

Step A: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, anhydridewith benzoic acid

In a 250 mL, three-necked, round bottom flask was addedpyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2methyl-, phenylmethyl ester (Example 79,Step C, 5.44 g, 11.7mmol), THF (58.6mL, 0.2 M), Et3N(1.63 mL, 11.7 mmol), 10 and 10% Pd(OH)2/C (1.26 g) sequentially. The mixture was stirred under a H2 atmosphère (balloon) for 1 hour. The reaction mixture was fïltered through apad of celite, and the yellow filtrate was carried on the next step. To this yellowfiltrate was added benzoyl chloride in a dropwise fashion (1.36 mL, 11.7 mmol).The mixture was stirred at room température for 48 hours and the solvent removed 15 to give a brown oil. Trituration with acetone afforded 3.50 g (62.4%) of yellowpowder: mp 160-165°C; lH NMR (400 MHz, DMSO-d6) δ 1.10-1.58 (m, 10H, aliphatic CH), 1.83 (d, 7=12.94 Hz, 1H, aliphatic CH), 2.41-2.46 (m, 2H, aliphaticCH), 2.51 (s, 3H, CCH3), 2.66-2.71 (m, 1H, aliphatic CH), 2.98-3.01 (m, 2H, aliphatic CH), 3.38 (dd, 7=17.82,6.59 Hz, 1H, aliphatic CH), 7.29 (s, 1H, Arf/), 20 7.58 (t, 7=7.57 Hz, 2H, ArH), 7.74 (t, 7=7.57 Hz, 1H, AtH), 8.07 (d, 7=7.08 Hz, 2H, ArT/), 12.14 (s, 1H, NT/); MS(APCI+): m/z 479.1 (MH+).

Step B: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI, 1 -(4-fluorophenyl)ethyl ester 11820 -180-

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2methyl-, 1 -(4-fluorophenyl)ethylester was synthesized according to Procedure N from 1 -(4-fluoro-phenyl)-ethanol(0.900 g, 7.16 mmol) and pyrrolo[3’,2’:5,6][l]-benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl,anhydride with benzoic acid (0.857 g, 1.79 mmol). The product was recrystallizedfrom t-butyl methyl ether to give 0.210 g (23.6%) of white powder: mp102-107°C; IR (KBr) 2934, 2859, 1674, 1428, 1055 cm’1; NMR (400 MHz,DMSO-dg) δ 1.06-1.81 (m, 11H, aliphatic CH), 1.55 (d, 7=6.59 Hz, 3H,OCHCT/3), 2.37 (d, 7=10.25 Hz, 1H, aliphatic CH), 2.44-2.46 (m, 1H, aliphaticCH), 2.46 (s, 3H, CCTT3), 2.63-2.75 (m, 2H, aliphatic CH), 2.97-3.14 (m, 1H,aliphatic CH), 3.20 (dd, 7=13.18, 6.59 Hz, 1H, aliphatic CH), 5.95 (q, 7=6.59 Hz,1H, OC//CH3), 7.15-7.19 (m, 3H, ΑιΗ), 7.43-7.49 (m, 2H, ArTT), 11.62 (s, 1H,NT/); MS(APCI+): m/z 497.2 (MH+). Anal. Calcd for C28H3QN2O3F1CIJ : C,66.82; H, 6.15; N, 5.57. Found: C, 66.96; H, 6.39; N, 5.46.

Example 81

Quinolizinium, l-[[(4-fluorophenyl)methoxy]carbonyl]-5-hydroxy-2-methyl-lH-indol-4-yl]methyl]-1,2,3,4,6,7,8,9-octahydro-, chloride

To a solution ofpyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,(4-fIuorophenyI)methyI ester (0.500 g, 1.11 mmol) in 125 mL of CH2CI2 wasadded ethereal HCl in portions until the solution tumed cloudy. After the solventwas removed, the yellow residue was triturated with acetone to give 0.307 g(61.0%) of white powder: mp 179-185°C; IR (KBr) 3408,3193, 2934, 1697,1431,1152 cm-1; !H NMR (400 MHz, CDCI3) δ 1.37-1.52 (m, 1H, aliphaticCH), 1.52-1.77 (m, 8H, aliphatic CH), 2.07-2.15 (m, 1H, aliphatic CH), 2.26 (d, -181- 11820 7=14.65 Hz, 1H, aliphatic CH), 2.40-2.54 (m, 2H, aliphatic CH), 2.58 (s, 3H,CCH3), 3.10-3.18 (m, 2H, aliphatic CH), 3.34-3.48 (m, 2H, aliphatic CH), 5.28 (dd, 7=14.65, 12.45 Hz, 2H, OCtf2Ar), 6.78 (d, 7=14.65 Hz, 1H, Ar/7), 7.05 (t, 7=8.55 Hz, 1H, ArH), 7.14 (d, 7=8.79 Hz, 1H, Artf), 7.41 (t, 7=5.37 Hz,1H, ΑτΗ), 8.58 (s, 1H, OH), 12.52 (s, 1H, N//); MS(APCI+): m/z 449.3 (MH+).Anal. Calcd for C27H30N2O3F1CI1: C, 66.87; H, 6.23; N, 5.78; CI, 7.31; F, 3.92.Found: C, 66.37; H, 6.27; N, 5.69; Cl, 7.64; F, 4.02.

Example 82

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro:l,2-dimethyl-, (4-fluorophenyl)methyl ester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-fluorophenyl)methyl ester(0.500 g, 1.11 mol) in 20 mL of DMF was added to NaH (60% dispersion inminerai oil, 0.049 g, 1.23 mmol, washed with hexanes) and was stirred at roomtempérature for 1 hour. Methyl iodide (0.076 mL, 1.23 mol) was added to thereaction mixture. The reaction was stinred for 2 hours, quenched with 15 mL ofH2O and extracted with diethyl ether (5 x50 mL). The organic Iayers wereconcentrated to afford a yellow solid which was triturated with acetone to give0.274 g (52.7%) of white solid: mp 179-180°C; IR (KBr) 3466, 2932, 2854, 1673,1482, 1155 cm’1; ]H NMR (400 MHz, CDCI3) δ 1.06-1.21 (m, 3H, aliphatic CH), 1.36-1.58 (m, 7H, aliphatic CH), 1.79 (d, 7=14.20 Hz, 1H, aliphatic CH), 2.34 (d, 7=10.74 Hz, 1H, aliphatic CH), 2.42-2.49 (m, 2H, aliphatic CH), 2.49 (s,3H, CCtf3), 2.64 (t, 7=10.74 Hz, 1H, aliphatic CH), 2.86 (t, 7=11.48 Hz, 1H,aliphatic CH), 3.10 (dd, 7=18.31, 6.84 Hz, 1H, aliphatic CH), 3.59 (s, 3H, NC//3), 5.21 (dd, 7=29.05, 11.96 Hz, 2H, OCtf2Ar), 6.64 (d, 7=8.79 Hz, 1H, ArH), 118 2 0 -182- 7.16-7.22 (m, 3H, ΑχΗ), 7.48 (t, 7=7.81 Hz, 1H, Artf); MS(APCI+): m/z 463.1(MH+). Anal. Calcd for C, 72.71; H, 6.76; N, 6.06. Found: C, 72.89; H, 6.72; N, 5.92.

Example 83

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 1 -phenylpropyl ester

Step A: 5-Acetoxy-2-methyl-lH-indole-3-carboxylic acid 1-phenyl-propyl ester

H 10

This compound was made according to Procedure A. White solid, mp144-145.5°C; MS(APCI-): m/z 350.1 (M-H).

Step B: 5-Hydroxy-2-methyI-IH-indoIe-3-carboxyIic acid I-phenyl-propyl ester

5-Acetoxy-2-methyI-lH-indole-3-carboxylic acid, 1-phenyl-propyl ester(1.36 g, 3.86 mmol) was mixed with 10 mL of methanol, NaOCH3 (0.834 g, 15 118 2 0 -183- 15.4 mmol) was then added. The resulting reaction mixture was stirred at refluxfor 1 minute, then allowed lo cool to ambient température. The reaction mixturewas then mixed with 10 mL of water, the resulting reaction mixture was treatedwith 5% HCl until pH = 1 affording a white precipitate. The mixture was 5 extracted with EtOAc (2 x 60 mL). The combined organic mixture was dried overNa2SÛ4 and concentrated in vacuo to give a black thick oil which was furtherpurified by chromatography using 10% MeOH in HCCI3 as the eluant to give 1.13 g (98%) of the desired product as a brown solid: NMR (DMSO-dg) δ 0.917 (t, 7.33 Hz, 3H, CHCH2C//3), 1.84-2.03 (m, 2H, CHC//2CH3), 2.59 (s, 10 3H, ArCH3), 5.84 (t, J = 5.68 Hz, 2H, C//CH2CH3), 6.59 (dd, J= 8.61, 2.38 Hz, 1H, ArH), 7.12 (d, J = 8.61 Hz, ΙΗ,-ΑγΗ), 7.23-7.41 (m, 6H, ArH), 8.87 (s, 1H,exchangeable proton), 11.6 (bs, 1H, exchangeable proton).

Step C: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid, 1 -phenyl-propyl ester

5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid, 1-phenyl-propyl ester(1.07 g, 3.60 mmol) and aqueous Me2NH (40%, 0.99 mL, 7.92 mmol) weremixed with 2.4 mL of EtOH, the mixture was heated with a heatgun until a clearsolution was obtained. After cooled to ambient température, aqueous HCHO 20 (37%, 0.35 g, 4.3 mmol) was added. The resulting reaction mixture was stined at 50°C for 4 hours, then at ambient teperature for 12 hours. The raction mixture wasdiluted with EtOAc (30 mL), washed with water (2 x 30 mL), and dried overNa2SÛ4. Concentration in vacuo followed by chromatography using 100%

EtOAc, then 10% MeOH in HCCI3 as the eluants gave 0.50 g (38%) ofpure titled 25 compound as a yellow foam: mp 50-62°C (dec.); MS(APCI+): ni/z 367.2 (MH+). 118 2 0 -184-

Step D: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylpropyl ester

To a mixture of perchlorate sait (0.38 g, 1.6 mmol, Example 3, Step B) and30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixturewas shaken in a separatory funnel until ail solid had dissolved. Two layers wereseparated, and the aqueous layer was extracted with ether (2 x 30 mL). Combinedether layer was dried over Na2SC>4 and concentrated in vacno. The residual oil was dissolved in 10 mL of dioxane, then indole mannich base (0.45 g, 1.2 mmol)was added, the resulting reaction mixture was refluxed under nitrogen for18 hours. The reaction mixture was cooled to ambient température andconcentrated in vacuo affording a thick oil. The crude product was further purifiedby chromatography (50% EtOAc in hexanes) to 0.40 g (71%) of titled compoundas a white foam: mp 90-115°C; MS(APCI+): m/z 459.3 (MH+).

Example 84

Quinolizinium, l,2,3,4,6,7,8,9-octahydro-l-[[5-hydroxy-2-methyl- 3-[(phenyîmethoxy)carbonyl]-lH-indoI-4-yl]methyl]-, chloride

To a solution of pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethylester (0.209 g, 0.485 mmol) in CH2CI2 was added etheral HCl. After stirring at 118 2 0 -185- ambient température for 1 minute, the reaction mixture was concentrated in vacuo.

The residue was triturated with 2-butanone. Filtration followed by drying under vacuum gave 0.18 g (79%) of the desired product as a white solid: MS(APCI+): m/z 431.3 (MH+). Anal. Calcd for C27H3oN203-1.0 HCl-0.3H2O: C, 68.65; H, 5 7 6.74; N, 5.93; Cl, 7.50; H20,1.14. Found: C, 68.62; H, 6.80; N, 6.00; Cl, 7.54; H2O, 0.93.

Example 85

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-nitrophenyl)methyl ester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester (0.149 g,0.341 mmol) was dissolved in 15 mL of THF, to the solution was added N,N-dimethylacetamide dimethyl acetal (0.5 mL), and Pd(OH)2/Ç (20%, 0.125 g). The 15 resulting reaction solution was stirred at ambient température under hydrogenatmosphère until the benzyl ester was completely consumed. The catalyst wasremoved by filtration, and the filtrate was concentrated in vacuo at ambienttempérature and used in the next step without further purification.

To a solution of crude product of débenzylation reaction in DMF were 20 added para-nitrobenzylbromide and DBU. The resulting reaction solution was stirred at ambient température for 16 hours. The reaction mixture was diluted with50 mL of EtOAc and washed successively with saturated aqueous NaHCÛ3 (3 x 50 mL) and water (3 x 50 mL). After drying over Na2SO4, the solution wasconcentrated in vacuo and purified by chromatography twice using 10% MeOH in 118 2 0 -186- HCCL3 and 50% EtOAc in hexanes îo give 28 mg (17%) of desired product as ayellow solid: mp 240-242°C; MS(APCI+): m/z 476.3 (MH+).

Example 86 / PyrrolotS'^’^ôjtljbenzopyranoP^-ÎJquinoIizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester (10.15 g,23.58 mmol) was dissolved in 110 mL of THF, and the solution was transferred to 10 a round bottom flask equipped with a stir bar and a three-way stopcock connectedto a hydrogen balloon. To the solution was added triethylamine (3.287 mL, 23.58 mmol), followed by Pd(OH)2/C (20%, 2.7 g). The flask was purged withhydrogen gas several times. The resulting réaction solution was stirred at ambienttempérature under hydrogen atmosphère until the benzyl ester was completely 15 consumed (2 hours in this case). The catalyst was removed by filtration, and the filtrate was used in the next step.

To the filtrate was added benzoyl chloride (2.737 mL, 23.58 mmol). The resultingreaction solution was stirred at ambient température for 16 hours under nitrogen.White precipitate formed was removed by filtration. The filtrate was concentrated 20 in vctcuo affording thick oil; trituration with Et2Û gave 9.18g (88% over twosteps) the desired product as a white solid: mp 159-160°C; MS(APCI+): m/z 443.3 (MH+). 118 2 0 -187-

General procedure Q: ester synthesis from the mixed anhydride

The mixed anhydride (1 eq.) was mixed with the corresponding alcohol (>2 eq.), the resulting slurry was heated at 120-150°C until a clear solution wasobtained. After cooling down to ambient température, thé solution was dilutedwith EtOAC, then mixed with aqueous NaHCOj (saturated). The mixture was for5 minutes. Two layers were separated, and the organic layer was washed withbrine and water, then dried over MgSO4- Purification with flash chromatographyor recrystallization gave the desired product.

Example 87

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinoîizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 R)-1 -phenylethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 R)-1 -phenylethyl ester wassynthesized according to procedure Q from (R)-(+)-l-phenylethanol. The crudeproduct was chromatographed on a préparative silica gel plate using 100%acetonitrile as eluant to give 25 mg of the desired product as a white solid: mp100-112°C; MS(APCI+): m/z 445.3 (MH+).

Example 88

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)ethyl ester 11820 -188-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)ethyl esterwas synthesized according to procedure Q from l-(para-fluorophenyl)ethanol. Thecrude product was chromatographed first on a silica gel column (30% of EtOAc inhexanes as eluant) then on a préparative silica gel plate (100% acetonitrile aseluant) to give 54.5 mg (37%) of the desired product as a yellow foam: mp98-110°C; MS(APC1+): m/z 463.1 (MH+).

General procedure R: parallel synthesis of 6 esters from the mixed anhydride

The mixed anhydride (1 eq.) and the corresponding alcohol (2 eq.) weremixed in a VWR 60826-202 tube. The tube was loosely capped and submerged inoil-bath at 120°C for 7 minutes. After cooling to ambient température, 10 mL ofether and 10 mL of saturated aqueous Na2SC>4 were added to the tube. Themixture was stirred for 1 minute, then the ether layer was transferred into a newtube with MgSO4- After 10 minutes, the MgSC>4 was removed by filtration. Thefiltrate was blown down with a nitrogen stream and the residue was re-dissolvedin 0.2 mL of ether and transferred onto a SPE cartridge containing 1 g of silicagel. The short column was eluded with 20 mL of a 10% of EtOAc in hexanessolution. The fractions collected contained mainly the corresponding alcohol andwere dicarded. The column was then eluded with 5 mL of a 10% of EtOAc inhexanes solution. The fraction collected was concentrated down (blown downwith a nitrogen stream) to give the crude product.

Example 89

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester -189- 11820

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester was synthesizedaccording to procedure R from phénol. The crude product was not further 5 purified: white solid; MS(APCI+): m/z 417.1 (MH+).

Example 90

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro-l -phenyl- l-(trifluoromethyl)ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro-1 -phenyl- l-(trifluoromethyl)ethyi ester was synthesized according to procedure R from l,l,l,3,3,3-hexfluoro-2-phenyl-2-propanol. The crude product was not further 15 purified: white solid; MS(APCI-): m/z 565.1 (M-H).

Example 91

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, bicyclo[2.2.1 ]hept-2-yl ester -190- 118 2 0

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, bicyclo[2.2.1 ]hept-2-yl esterwas synthesized according to procedure R from exo-norbomeol. The crude 5 product was not further purified: white solid; MS(APCI-): m/z 433.2 (M-H).

Example 92

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,I5-decahydro-2-methyl-, l-(4-fluorophenyI)-

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxyIic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)- 1- methylethyl ester was synthesized according to procedure Q from 2- (4-fIuorophenyl)-2-propanol. The crude product was chromatographed on a 15 silica gel column (50-70% of ether in hexanes as eluant) to give 0.15 g (9%) of thedesired product as a white solid mp 110-112°C; MS(APCI+): m/z 477.1 (MH+).

Example 93

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcyclopentyl ester 191- 11820

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylcyclopentyl ester wassynthesized according to procedure Q from 1-phenyl-l-cyclopentanol. The cradeproduct was chromatographed on a silica gel column (50% of ether in hexanes aseluant) to give 0.15 g (6%) of the desired product as a white solid: mp 205-206°C;MS(APCI+): m/z 483.1 (MH+).

Example 94 P>,rrolo[3,,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcyclohexyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcyclohexyl ester wassynthesized according to procedure Q from 1-phenylcyclohexanol. The cradeproduct was chromatographed on a silica gel column (50-70% of ether in hexanesas eluant) to give 0.13 g (5%) of the desired product as a yellow solid: mp217-219°C; MS(APCI-): m/z 497 (M-H).

Example 95

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester 192- 118 20

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl~, 3-(hydroxymethyl)phenyl esterwas synthesized according to procedure Q from 3-hydroxybenzyl alcohol. The 5 crude product was chromatographed on a silica gel column (50-100% of ÉtOAc in hexanes as eluant) to give 0.196 g (16%) of the desired product as a white foam:mp 138-140°C; MS(APCI+): m/z 447.2 (MH+).

Example 96

Pyrrolo[3’,2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl esterwas synthesized according to procedure Q from 3-hydroxybenzyl alcohol. The 15 crude product was chromatographed on a silica gel column (50-100% of EtOAc inhexanes as eluant) to give 0.4818 g (39%) of the desired product as a white solid:mp 231-233°C; MS(APCI+): m/z 447.1 (MH+).

Example 97

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lS)-l-(4-pyridinyl)ethyl ester -193- 11820

Pyrrolo[3',2':5,6][l]ben2ûpyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -(4-pyridinyl)ethyl esterwas synthesized according to procedure Q from (S)-(-)-l-(4-pyridyl)ethanol. The 5 crude product was chromatographed on a silica gel column (100% EtOAc aseluant) to give 0.09 g of the desired product as a yellow foam: mp 105-115°C;MS(APCI+): m/z 447.2 (MH+). 10

Example 98

Pyrrolo[3',2':5,6J[l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)- 2-pyridinyl]methyl ester

15 20

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyî-, [6-(methoxycarbonyl)- 2-pyridinyl]methyl ester was synthesized according to procedure Q from 6-(hydroxymethyl)-picolinic acid ethyl ester. The EtOAc solution (40 mL) of thecrude product was mixed with 40 mL of 0.5 N HCl solution in a séparative funneland shaken well, then the aqueous phase was basifîed with 2N NaOH solution topH = 1, shaken well. The two Iayers were then separated. The organic layer wasdried over Chromatography on a silica gel column (50-100% of EtOAc in hexanes as eluant) to give 0.87 g (53%) of the desired product as a white foam:mp 90-100°C; MS(APCI+): m/z 490.1 (MH+). 118 2 0 -194-

Example 99

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-pyridinylmethyl ester

5 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-pyridinylmethyl ester wassyntbesized according to procedure Q from 2-pyridylmelhanol. The EtOAcsolution (40 mL) of the crude product was mixed with 40 mL of 0.5N HClsolution in a séparative funnel and shaken well, then the aqueous phase was 10 basified with 2N NaOH solution to pH = 1, shaken well. The two layers were thenseparated. After this process was repeated for three times, the organic layer wasseparated and dried over Na2SC>4. Chromatography on a silica gel column(60-100% of EtOAc in hexanes as eluant) to give 1.39 g (72%) ofthe desiredproduct as a white foam: mp 85-95°C; MS(APCI+): m/z 432.2 (MH+). 15 Example 100

PyiToIo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (6-carboxy-2-pyridinyl)methylester

20 To a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-

1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,[6-(methoxycarbonyl)-2-pyridinyl]methyl ester (797.4 mg, 1.629 mmol) in MeOH 11820 -195- (20 mL) was added IN NaOH (6.5 mL, 6.5 mmol). The resulting reaction mixturewas refluxed for 15 minutes, then concentrated in vacuo. The residue was purifiedby chromatography (10-30% MeOH in HCCI3 as eluant) to give 0.62 g of a mixture of free acid and the sodium sait. 0.5 g of the mixture was dissoîved in 5 MeOH/HCC13, then mixed with 0.64 mL of IN HCl. The mixture was concentrated in vacuo, the residue was purified by chromatography (10-30%MeOH in HCCI3 as eluant) followed by recrystallization from MeOH to give0.25 g of the desired product as a white solid: MS(APCI-): ni/z 474.1 (M-H).

Example 101 10 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (6-carboxy-2-pyridinyl)methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylate (1:1)

To a suspension of Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 15 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (6-carboxy- 2-pyridinyl)methyl ester (167.5 mg, 0.3522 mmol) in éthanol was added aqueouscholine bicarbonate (5.66 M, 0.056 mL, 0.32 mmol). The resulting mixture wasrefluxed until a clear solution was obtained. The reaction mixture wasconcentrated in vacuo, and the residue was dissoîved in 2 mL of éthanol and then 20 diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate wascollected by filtration to give 0.15 g (74%) of the desired product as a yellowsolid: mp 120-130°C; MS(APCI-): m/z 474.1 (M-H). Anal. Calcd for • C27H2sN3O5-1.0C5H14N1Oi-0.2C5H15NiO2T.8H2O: C, 62.38; H, 7.71;N,9.26. Found: C, 62.40; H, 7.58; N, 9.03. 11820 -196-

Example 102

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)- 3-pyridinyl]methyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)- 3-pyridinyl]methyl ester was synthesized according to procedure Q from 5-hydroxymethyl-nicotinic acid methyl ester. The EtOAc solution. (40 mL) of the 10 crudc product was mixed with 40 mL of 0.5 N HCl solution in a séparative funneland shaken well, then the aqueous phase was basified with 2N NaOH solution topH = 1, shaken well. The two layers were then separated. After this process wasrepeated twice, the organic layer was separated and dried over MgSÛ4.Chromatography on a silica gel column (50-100% of EtOAc in hexanes as eluant) 15 followed by crystallization from ether gave 0.4254 g (25%) of the desired productas a yellow solid: mp 195-197°C; MS(APCI+): m/z 490.1 (MH+).

Example 103

Pyrrolo[3',2':5,6][l]benzopyrano[3,2'i]quinolizine-1-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-carboxy-3-pyridinyl)methyl 20 ester

To a solution of Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 118 2 0 -197- [5-(methoxycarbonyl)-3-pyridinyl]methyl ester (391.6 mg, 0.7999 mmol) inMeOH (30 mL) was added IN NaOH (3.2 mL, 3.2 mmol). The resulting reactionmixture was stirred at 50°C for 60 minutes. After cooling down to ambienttempérature, 3.2 mL of IN aqueous HCl was added, then concentrated in vacuo. 5 The residue was purified by chromatography (10-30% MeOH in HCCI3 as eluant)followed by trituration with ether to give 0.25 g (67%) of the desired product as awhite solid: mp 224-227°C; MS(APCI-): m/z 474.1 (M-H).

Example 104

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (5-carboxy- 10 3-pyridinyl)methyl 3,7,8,9,10,12,13,14,14a,15-decahydro- 2-methylpyrrolo[3',2':5,6][I]benzopÿrano[3,2-i]quinolizine-l-carboxylate (1:1)

To a suspension of Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-T (5-carboxy- 15 3-pyridinyl)methyl ester (170.3 mg, 0.3580 mmol) in éthanol was added aqueouscholine bicarbonate (5.66 M, 0.0569 mL, 0.322 mmol). The resulting mixture wasrefluxed until a clear solution was obtained. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in 2 mL of éthanol and thendiluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was 20 collected by filtration to give 0.163 g (79%) of the desired product as a beigesolid: mp 147-152°C; MS(APCI-): m/z 474 (M-H). Anal. Calcd forC27H28N3O5-1.0C5H14NiOr0.28C4Hi0O-1.2Si1O2T.4H2O: C, 57.09; H,6.89; N, 8.04. Found: C, 57.09; H, 6.70; N, 7.77. 118 2 0 -198-

Example 105

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4'-methyl[ 1,1 -biphenyl]- 3-yl)ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinoli2ine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4'-methyl[ 1,1 ’-biphenyl]- 3-yl)ethyl ester was synthesized according to procedure Q from l-(4’-methyl-biphenyl-3-yl)-ethanol. The crude product was chromatographed on a silica gel 10 column (40% of EtOAc in hexanes as eluant) to give 0.67 g (36%) of the desired product as a white foam: mp 105-115°C; MS(APCI+): m/z 535 (MH+).

Example 106

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-dimethylpheny])ethyl 15 ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-dimethylphenyl)ethylester was synthesized according to procedure Q from l-(2,6-dimethyI-phenyl)- 20 éthanol. The crude product was chromatographed on a silica gel column (30-50% 118 2 0 -199- of EtOAc in hexanes as eluant) to give 1.02 g of the desired product which wasimpure as a yellow foami mp 100-105°C; MS(APCI+): m/z 473.3 (MH+).

Procedure S: procedure for the array synthesis:

The mixed anhydride (1 eq.) and the corresponding alcohol (2-4 eq.) were 5 mixed in a VWR 60826-202 tube. The tube was loosely capped and submerged inoil-bath at 120°C until a clear solution was obtained (generally 5-7 minutes). Aftercooling to ambient température, 6 mL of EtOAc and 5 mL of saturated aqueousNa2SO4 were added to the tube. The mixture was shaken and stirred for 1 minute,then the organic îayer was pipeted out and filtered through a pack of MgSÛ4 10 (packed in a syringe filter) followed by washing with 1 mL of EtOAc. The filtratewas collected in a 2-dram vial and sample was blown dry with a stream ofnitrogen. The residue was chromatagraphed on a silica gel column using ISCOsystenr to give the desired product.

The Example 107 through Example 142 were made following Procedure S 15 in a parallel fashion:

Example 107

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S,2R)-2-(dimethylamino)- 20

MS(APCI+): m/z 502 (MH+). 118 2 0 -200-

Example 108

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 R,2S)-2-(dimethylamino)-

MS(APCI+): m/z 502 (MH+).

Example 109

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -naphthalenyl ester

MS(APCI+): m/z 467 (MH+).

Example 110

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, diphenylmethyl ester -201- 11820

MS(APCI+): m/z 507 (MH+).

Example 111

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-2,3-dihydro-!H-inden-l-yl ester

MS(APCI+): m/z 457 (MH+).

Example 112 10 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15 -decahydro-2-methyl-, 1,2-dihydro-1 -acenaphthylenylester 11820 -202-

MS(APCI+): m/z 493 (MH+).

Example 113 P>TTolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5 3,7,8,9,10,12,I3,14,14a,15-decahydro-2-methyl-, cyclohexyl(phenyl)methyl ester

MS(APCI+): m/z 513 (MH+). 10

Example 114

Pyrrolo^'^'^ôKljbenzopyranoP^-ijquinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 9H-fluoren-9-yl ester

MS(APC1+): m/z 505 (MH+). 118 2 0 -203-

Example 115

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydro-1 -naphthalenyl ester

MS(APCI+): m/z 471 (MH+). - '

Example 116

PynOlo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, [(2R,3R)- 10 3-phenyloxiranyl]methyl ester

MS(APCI+): m/z 473 (MH+).

Example 117

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-metbyl-, 2-oxo-1,2-diphenylethyl ester 15 11820

MS(APCI+): m/z 535 (MH+).

Example 118

PyTrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 10,11 -dihydro-5H- dibenzo[a,d]cyclohepten-5-yl ester

MS(APCI+): m/z 533 (MH+).

Example 119 10 Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,

3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-methylphenyl)phenylmethyI ester 118 2 0 -205-

MS(APCI+): m/z 521 (MH+).

Example 120

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclopropyl(4-flnorophenyl)methyl ester

MS(APCI+): m/z 489 (MH+).

Example 121 10 P>Trolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3,4-dihydro-2H-l-benzothiopyran-4-yl ester

118 2 0 -206- MS(APCI+): m/z 489 (MH+).

Example 122

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -(2-bromophenyl)ethyl 5 ester

MS(APCI+): m/z 524 (MH+).

Example 123

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 10 3,7,8,9,I0,12,13,14,14a,15-decahydro-2-methyl-, 2,2,2-trifluoroethyl ester

MS(APCI+): m/z 423 (MH+).

Example 124

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,15 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [(2S.3S)- 3-phenyloxiranyl]methyl ester -207- 11320 *

MS(APC1+): m/z 475 (MH+).

Example 125

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 2,2,2-trifluoro-1 -methyl- 1-(trifluoromethyl)ethyl ester

MS(APCI+): m/z 505 (MH+).

Example 126 10 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro-l-(4-fluorophenyl)-l -(trifluoromethyl)ethyl ester 118 2 0 -208-

MS(APCI+): m/z 585 (MH+).

Example 127

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 1 -cyclopentyl-1 -phenylethyl ester

MS(APCI+): m/z 513 (MH+).

Example 128 10 Pyrrolo[3’,2,':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a. 15-decahydro-2-methyl-, 1 -[ 1,1 '-biphenyl]-4-yl-1 -methylethyl ester 118 2 0 -209-

MS(APCI+): m/z 535 (MH+).

Example 129

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methyl-1 -phenyl-2-propynyl ester

MS(APCI+): m/z 469 (MH+).

Example 130 10 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -diphenylethyl ester

MS(APCI+): m/z 521 (MH+). 118 2 0 -210-

Example 131

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 1 -methyl-1,2-diphenylethyl ester

MS(APCI+): m/z 535 (MH+).

Example 132

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclohexyl 10 ester

MS(APCI+): m/z 517 (MH+). 15

Example 133

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-diphenylethyl ester -211- 118 2 0

MS(APCI+): m/z 521 (MH+).

Example 134

Pyrrolo[3',2':5,6][l]benzopyrano[3',2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenyl-2-propynyl ester

MS(APCi+): m/z 455 (MH+). 10

Example 135

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [1,1 ’-biphenyl]-4-ylmethyl ester

MS(APCI+): m/z 507 (MH+). 11 8 2 Ο -212-

Example 136

PyHolo[3\2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester

5 MS(APCI+): m/z 432 (MH+).

Example 137

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydro- 7,8-dimethoxy-2-methyl-4-isoquinolinyl ester

MS(APCI+): m/z 546 (MH+).

Example 138

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 15 l-[3-(dimethylamino)phenyl]ethyl ester 118 2 0 -213-

MS(APCI+): m/z 488 (MH+).

Example 139

Pyrïolo^'^'jS.ôJfljbenzopyranofS^-ijquinolizine-l-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -dimethyl-2-pyrazinylelhyl ester

MS(APCI+): m/z 475 (MH+).

Example 140 10 Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylÎc acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-(dipropylamino)- 1,1 -dimethyl-2-butynyl ester 11820 -214-

MS(APCI+): m/z 520 (MH+).

Example 141

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-2,3-dihydro-1 H-inden-1 -ylester

MS(APCI+): m/z 457 (MH+).

Example 142 10 Pyrrolo[3',2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S,2S)-2-(dimethylamino)-

MS(APCI+): m/z 502 (MH+). 11820 ’ -215-

Example 143

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]methyl ester

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-trifluoromethylbenzyl ester

To a mixture of 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (4.5 g, 10 23.54 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.58 g, 23.54 mmol) in DMF (50 mL) was added 2’-bromo-2,2,2-trifluoro-p-xylene (6.2 g, 25.89 mmol).The mixture was stirred at room température for 2 days and then partitionedbetween ethyl acetate and water. The organic phase was washed with water andbrine, dried over Na2SC>4 and concentrated in vacno to give a residue, which was 15 recrystallized from ethyl acetate to give 4.26 g (52%) of the desired product as awhite solid: mp 224-225°C; MS(APCI+): m/z 350.1 (MH+); Anal. Calcd forC1SH14F3NJO3·· C, 61.89; H, 4.04; N, 4.01. Found: C, 61.87; H, 4.00; N, 3.98.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-l H-indole-3-carboxyIicacid 4-trifluoro-methylbenzyl ester 11820 -216-

5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-trifluoromethylbenzylester (3.0 g, 8.59 mmol) and aqueous dimethylamine (40%, 2.37 mL, 18.9 mmol)were mixed with 6.7 mL of éthanol. The mixture was heated with a heatgun until 5 a clear solution was obtained. After cooled to ambient température, aqueous HCHO (37%, 0.83 g, 10.31 mmol) was added. The resulting reaction mixture wasstirred at 50°C ovemight. The reaction mixture was concentrated in vacuo to halfvolume to give a solid, which was filtered. The solid was washed with ethanol-water and dried in vacuo to give 1.8 g (52%) of pure titled compound as an off- 10 white foam: MS(APCI+): m/z 407.2 (MH+).

Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,[4-(trifluoromethyl)phenyI]methyl ester

15 To a mixture of perchlorate sait (1.37 g, 5.75 mmol, Example 3, step B) and 100 mL of ether was added 150 mL of aqueous NaOH (2N). The resultingmixture was shaken in a sèparatory funnel until ail solids had dissolved. Twolayers were separated, and the aqueous layer was extracted with ether (2 x50 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. 20 The residual oil was dissolved in 25 mL of dioxane, then indole mannich base 11820 -217- (1.8 g, 4.42 mmol) was added, the resulting reaction mixture was refluxed undernitrogen for 6 hours. The reaction mixture was cooled to ambient température andconcentrated in vacuo affording a thick oil. The crude product was further purifiedby chromatography (10%-30% ethyl acetate in hexanes) to give 1.21 g (55%) of 5 titled compound as a white foam: mp 97-99°C; MS(APCI+): m/z 499.2 (MH+);

Anal. Calcd for C28H29F3N2O3: C, 67.46; H, 5.86; N, 5.62; F, 11.43. Found: C,67.13; H, 5.86; N, 5.45; F, 11.32.

Example 144

Pyrrolo[3',2':5,6J[l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 10 3,7,8,9,l0,12,13,14,14a,15-decahydro-2-methyl-, (4-chlorophenyl)methyl ester

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-chIorobenzyl ester

To a mixture of 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (5.0 g,15 26.15 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.98 g, 26.15 mmol) in DMF (50 mL) was added 4-chlorobenzyl bromide (5.9 g, 28.77 mmol). Themixture was stirred at room température for 2 days and then partitioned betweenethyl acetate and water. The organic phase was washed with water and brine,dried over Na2SO4 and concentrated in vacuo to give a residue, which was 20 recrystaîlized from ethyl acetate to give 5.0 g (61%) of the desired product as anoff-white solid: mp 236-237°C; MS(APCI-): m/z 314,1 (M-H). 11820 -218-

Step B: 4-DimethyIaminomethyI-5-hydroxy-2-methyl-lH-indole-3-carboxyIic acid 4-chlorobenzyl ester

5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-chlorobenzyl ester 5 (4.0 g, 12.7 mmol) and aqueous dimethylamine (40%, 3.5 mL, 27.8 mmol) were mixed with 10.4 mL of éthanol. The mixture was heated with a heatgun until aclear solution was obtained. After cooled to ambient température, aqueous HCHO(37%, 1.24 g, 15.2 mmol) was added. The resulting reaction mixture was stirred at50°C ovemight. The reaction mixture was concentrated in vacno to give a residue, 10 which was chromatographed using 100% ethyl acetate as eluant to give 2.3 g (49%) ofpure titled compound as an off-white foam: MS(APCI+): m/z 373.2 (MH+).

Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 15 (4-chlorophenyl)methyl ester

To a mixture of perchlorate sait (1.9 g, 8.02 mmol, Example 3, Step B) and150 mL of ether was added 200 mL of aqueous NaOH (2N). The resulting mixturewas shaken in a separatory funnel until ail solids had dissolved. Two layers were 20 separated and the aqueous Iayer was extracted with ether (2 x 100 mL). Combined 11820 -219- ether layer was dried over Na?SO4 and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannich base (2.3 g, 6.17 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours.

The reaction mixture was cooled to ambient température and concentrated 5 in vacuo to give a thick oil. The crude product was further purified by chromatography (20%-25% ethyl acetate in hexanes) to give 1.7 g (59%) of titledcompound as a white solid: mp 220-221 °C; MS(APCI+): m/z 465.3 (MH+).

Example 145

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,

Step A: 5-Hydroxy-lH-indole-3-carboxylic acid benzyl ester

To a mixture of 5-hydroxy-lH-indole-3-carboxylic acid (4.5 g, 25.4 mmol)15 and l,8-diazabicyclo[5.4.0]undec-7-ene (3.87 g, 25.4 mmol) in DMF (50 mL) was added benzyl bromide (4.78 g, 27.94 mmol). The mixture was stirred at roomtempérature for 2 days and then partitioned between ethyl acetate and water. Theorganic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was recrystallized from ethyl20 acetate-hexanes to give 2.4 g (36%) of the desired product as an off-white solid: mp 184-186°C; MS(APCI-): m/z 266.1 (M-H). 118 2 0 -220-

Step B: 4-Dimethylaminomethyl-5-hydroxy-lH-indole-3-carboxylic acid benzylester

5-Hydroxy-lH-indole-3-carboxylic acid benzyl ester (2.3 g, 8.6 mmol) and 5 aqueous dimethylamine (40%, 2.37 mL, 18.9 mmol) were mixed with 6.67 mL oféthanol. The mixture was heated with a heatgun until a clear solution wasobtained. After cooled to ambient température, aqueous HCHO (37%, 0.84 g,10.32 mmol) was added. The resulting reaction mixture was stirred at 50°Covemight. The reaction mixture was concentrated in vacuo to give a residue, 10 which was chromalographed using 50%-100% ethyl acetate in hexanes as eluantto give 2.16 g (77%) of pure titled compound as an off-white foam: MS(APCI+):m/z 325.3 (MH+).

Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,

To a mixture of perchlorate sait (1.91 g, 8.02 mmol, Example 3, Step B)and 150 mL of ether was added 200 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solids had dissolved. Twolayers were separated and the aqueous layer was extracted with ether (2 x 20 100 mL). Combined ether layer was dried over Na2SÛ4 and concentrated 11820 -221- in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannichbase (2.0 g, 6.17 mmol) was added, the resulting reaction mixture was refluxedunder nitrogen for 6 hours. The reaction mixture was cooled to ambienttempérature and concentrated in vacuo to give a thick oil, which was 5 recrystallized from acetonitrile to give 1.2 g (47%) of titled compound as an off-white solid: mp 255-257°C; MS(APCI+): m/z 417.3 (MH+).

Example 146

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester 10

Step A: 5-Hydroxy-lH-indole-3-carboxylic acid ethyl ester

To a mixture of 5-hydroxy-lH-indole-3-carboxylic acid (4.5 g, 25.4 mmol)and l,8-diazabicyclo[5.4.0]undec-7-ene (3.87 g, 25.4 mmol) in DMF (50mL) was 15 added iodoethane (4.36 g, 27.94 mmol). The mixture was stirred at room température ovemight and then partitioned between ethyl acetate and water. Theorganic phase was washed with water and brine, dried over Na2SÛ4 andconcentrated in vacuo to give a residue, which was recrystallized from ethylacetate-hexanes to give 2.2 g (42%) of the desired product as a light brown solid: 20 MS(APCI+): m/z 206.2 (MH+).

Step B: 4-Dimethylaminomethyl-5-hydroxy-lH-indole-3-carboxylic acid ethyl ester 118 2 0 -222-

HC

5-Hydroxy-lH-indole-3-carboxylic acid ehtyl ester (2.1 g, 10.23 mmol)and aqueous dimethylamine (40%, 2.83 mL, 22.51 mmol) were mixed with 7.7 mL of éthanol. The mixture was heated with a heatgun until a clear solutionwas obtained. After cooled to ambient température, aqueous HCHO (37%, 0.99 g, 12.28 mmol) was added. The resulting reaction mixture was stirred at 50°Covemight. The reaction mixture was concentrated in vacuo to give a residue,which was chromatographed using 50%-100% ethyl acetate in hexanes as eluantto give 2.1 g (78%) of pure titled compound as a gum: MS(APCI+): m/z 10 263.1 (MH+).

Step C: Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester

To a mixture of perchlorate sait (2.36 g, 9.9 mmol, Example 3, Step B) and 15 150 mL of ether was added 250 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until ail solids had dissolved. Two layers wereseparated and the aqueous layer was extracted with ether (2 x 100 mL). Combinedether layer was dried over Na2SC>4 and concentrated in vacuo. The residual oilwas dissolved in 30 mL of dioxane, then indole mannich base (2.0 g, 7.6 mmol) 20 was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours.The reaction mixture was cooled to ambient température and concentrated 118 2 0 -223- in vacuo to give a îhick oil, which was recrystallized from acetonitrile to give 1.7 g (63%) of titled compound as an off-white solid: mp 242-244°C;MS(APCI+): m/z 355.3 (MH+).

Example 147 5 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-hydroxyethyl ester

Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid hydroxyethyl ester

10 To a mixture of 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (5.0 g, 26.15 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.91 g, 26.15 mmol) inDMF (100 mL) was added 2-bromoethanol (3.6 g, 28.77 mmol). The mixture wasstirred at room température for 7 days and then partitioned between ethyl acetateand water. The organic phase was washed with water and brine, dried over 15 Na2SC>4 and concentrated in vacuo to give a residue, which was choromatographed using 30%-100% ethyl acetate in hexanes as eluant to give 2.4 g (39%) of the desired product as a gum: MS(APCI+): m/z 236.1 (MH+).

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3-carboxylicacid hydroxyethyl ester 118 2 0 -224-

5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid hydroxyethyl ester(2.3 g, 9.8 mmol) and aqueous dimethylamine (40%, 2.7 mL, 21.5 mmol) weremixed with 7.4 mL of éthanol. The mixture was heated with a heatgun until a 5 clear solution was obtained. After cooled to ambient température, aqueous HCHO(37%, 0.95 g, 11.7 mmol) was added. The resulting reaction mixture was stirred at50°C ovemight. The reaction mixture was concentrated in vacuo to give a residue,which was chromatographed using 100% ethyl acetate followed by 20% methanolin methylene chloride as eluant to give 2.0 g (70%) of pure titled compound as a 10 gum: MS(APCI+): m/-293.2 (MH+).

Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-hydroxyethyl ester

To a mixture of perchlorate sait (2.1 g, 8.9 mmol, Example 3, step B) and15 150 mL of ether was added 250 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until ail solids had dissolved. Two layers wereseparated and the aqueous layer was extracted with ether (2 x 100 mL). Combinedether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 6.84 mmol)20 was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours.

The reaction mixture was cooled to ambient température and concentrated 118 2 0 -225- i/t vacuo to give a residue as thick oil, which was recrystallized from acetonitrileto give 1.6 g (61%) of titled compound as a light brown solid: mp 221-223°C;MS(APCI+): m/z 385.2 (MH+).

Example 148

Pyrrolo[3',2':5,6][ljbenzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-methylphenyl)methyl ester

Step A: 5-Hydroxy-2-methyl-lH-indoIe-3-carboxylic acid 3-methylbenzyl ester

10

To a mixture of 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (4.0 g, 20.92 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.18 g, 20.92 mmol) inDMF (100 mL) was added cc-bromo-m-xylene (4.28 g, 23.1 mmol). The mixturewas stirred at room température for 7 days and then partitioned between ethylacetate and water. The organic phase was washed with water and brine, dried overNa2SC>4 and concentrated in vacuo to give a residue, which was chromatographedusing 20%-50% ethyl acetate in hexane as eluant to give 3.0 g (48%) of thedesired product as a tan solid: mp 165-167°C; MS(APCI+): m/z 296.2 (MH+).

Step B: 4-DimethylaminomethyI-5-hydroxy-2-methyl-lH-indole-3-carboxylicacid 3-methylbenzyl ester 15 11820 -226-

5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methylbenzyl ester (2.7 g, 9.14 mmol) and aqueous dimethylamine (40%, 2.52 mL, 20.1 mmol) weremixed with 7.4 mL of éthanol. The mixture was heated with a heatgun until a

5 clear solution was obtained. After cooled to ambient température, aqueous HCHO (37%, 0.89 g, 10.97 mmol) was added. The resulting reaction mixture was stirredat 50°C ovemight. The reaction mixture was concentrated in vacuo to give aresidue, which was chromatographed using 50%-100% ethyl acetate in hexanes aseluant to give 2.0 g (62%) ofpure titled compound as a gum: MS(APCI+): m/z 10 353.3 (MH+).

Step C: Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-m ethyl-,(3-methylphenyl)methyl ester

15 To a mixture of perchlorate sait (1.75 g, 7.38 mmol, Example 3, step B) and 100 mL of ether was added 150 mL of aqueous NaOH (2N). The resultingmixture was shaken in a separatory funnel until ail solids had dissolved. Twolayers were separated and the aqueous layer was extracted with ether (2 x 50 mL).Combined ether layer was dried over Na2SC>4 and concentrated in vacuo. The 20 residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 118 2 0 -227- 5.67 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The réaction mixture was cooled to ambient température and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (10%-25% ethyl acetate in hexanes) to give 1.8 g (55%) of 5 titled compound as a white solid: mp 80-82°C; MS(APCI+): m/z 445.4 (MH+).

Example 149

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -phenylethyl ester

10 Pyrrolo[3',2':5,6][l]benzopyrano(3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1 S)-1 -phenylethyl ester wassynthesized according to procedure Q from (S)-(-)-l-phenyIethanol. The crudeproduct was chromatographed using 30% ethyl acetate in hexanes as eluant togive 75 mg of the desired product as a white solid: mp 98-100°C; MS(APCI+): 15 m/z 445.2 (MH+).

Example 150

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylethyl ester

O 11820 -228-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-meîhyl-, 1 -phenylethyl ester wassynthesized according to procedure Q froml-phenylethanol. The crude productwas chromatographed using 40% ether in hexanes followed by 50% ethyl acetate 5 in hexanes as eluant to give 480 mg of the desired product as a white solid: mp 89-90°C; MS(APCI+): m/z 445.2 (MH+).

Example 151

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carbothioic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, S-(phenylmethyl) ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinoîizine-l-carbothioic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, S-(phenylmethyl) ester wassynthesized according to procedure Q from benzyl mercaptan. The crude productwas chromatographed using 50% ether in hexanes as eluant to give 150 mg of the 15 desired product as a white solid: MS(APCI+): m/z 447.1 (MH+).

Example 152

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinyhnethyl ester

11820 -229-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-pyridinylmethyl ester wassynthesized according to procedure Q from 3-pyridylcarbinol. The crude productwas chromatographed using 50% ethyl acetate in hexanes followed by 10%methanol in ethyl acetate as eluant to give 400 mg of the desired product as awhite solid: MS(APCI-): m/z 430.1 (M-H).

Example 153

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[4-(trifluoromethyI)phenyI]ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[4-(trifluoromethyl)phenyl]-ethyl ester was synthesized according to procedure Q from 4-trifluoro-a-methylbenzyl alcohol. The crude product was chromatographed using 40%-50%ether in hexanes as eluant to give 180 mg of the desired product as a white solid:mp 104-106°C; MS(APCI-): m/z 511.1 (M-H).

Example 154

Pyrroîo[3’,2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(pentafluorophenyl)ethyl ester 118 2 0 -230-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(pentafluorophenyl)ethyl esterwas synthesized according to procedure Q from pentafluoro-a-methylbenzyl 5 alcohol. The crude product was chromatographed using 40% ether in hexanes aseluant to give 160 mg of the desired product as a white solid: mp 93-95°C;MS(APCI+): m/z 535.1 (MH+).

Example 155

Pynolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-difluorophenyl)ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-difluorophenyl)ethyl 15 ester was synthesized according to procedure Q from 2,6-difluoro-a-methylbenzylalcohol. The crude product was chromatographed using 40% ether in hexanes aseluant to give 180 mg of the desired product as a white solid: mp 85-87°C;MS(APCI+): m/z 481.1 (MH+). 118 2 0 -231-

Example 156

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, ( 1 S)-l-(2-furanyl)ethyI ester

5 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i}quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -(2-furanyl)ethyl esterwas synthesized according to procedure Q from S(-)-l-(2-furyl)ethanol. The crudeproduct was chromatographed using 40%-60% ether in hexanes as eluant to give300 mg of the desired product as a white solid: mp 84-86°C; MS(APCI+): m/z 10 435.1 (MH+).

Example 157

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(4-morphol inyl)-

Pyrrolo[3',2*:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)-l-phenylethyl ester was synthesized according to procedure Q from a-phenyl- 118 2 0 -232- 4-morpholineethanol. The crude product was chromatographed using 40%-60%ether in hexanes as eluant to give 130 mg of the desired product as a white solid:mp 251-252°C; MS(APCI-): m/z 528.2 (M-H).

Example 158 5 Pyrroîo[3’,2':5,6][l ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 R)-l-(2-furanyl)ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1 R)-l~(2-furanyl)ethyl ester 10 was synthesized according to procedure Q front R(+)-l-(2-furyl)ethanol. The crude product was chromatographed using 40%-60% ether in hexanes as eluant togive 300 mg of the desired product as a white solid: mp 79-81°C; MS(APCI+):m/z 435.1 (MH+).

Example 159 15 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxy-2-oxo-l -phenylethylester

11820 -233-

Pyrrolo[3’,2': 5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxy-2-oxo-l -phenylethylester was synthesized according to procedure Q from (S)-(+)-methyl mandelate.The crude product was chromatographed using 40%-60% ether in hexanes as 5 eluant to give 309 mg of the desired product as a white solid: mp 103-105°C; MS(APCI+): m/z 489.2 (MH+).

Example 160

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(3-pyridinyl)ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-I-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(3-pyridinyl)ethyl ester wassynthesized according to procedure Q from l-(3-pyridyl)ethanol. The crudeproduct was chromatographed using 50% ether in hexanes followed by 10% 15 methanol in methyîene chloride as eluant to give 300 mg of the desired product asa white solid: mp 78-80°C; MS(APCI+): m/z 446.2 (MH+),

Example 161

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,I4a,15-decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester 118 2 0

Το a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1- carboxyîic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-methoxy- 2- oxo-1-phenylethyl ester (650 mg, 1.33 mmol) in methanol (60 mL) was added 5 IN NaOH solution (5.32 mL, 5.32 mmol). The resulting reaction mixture was stirred at 50°C for 1 hour, then concentrated in vacito. The residue was purifted bychromatography (10-30% methanol in chloroform as eluant) to give 0.58 g of amixture of free acid and the sodium sait. AU of the mixture (0.58g) was dissolvedin methanol-chloroform, then mixed with 0.53 mL of IN HCl. The mixture was 10 concentrated in vacuo, the residue was purified by chromatography (10-30% methanol in chloroform as eluant) followed by recrystallization from methanol togive 0.35 g of the desired product as a white solid: mp 250-251°C; MS(APCI-):m/z 473.1 (M-H), Anal. Calcd for C28H30N2O5 O.36H2O: C, 69.91; H, 6.44; N,5.82. Found: C, 69.96; H, 6.33; N, 5.59. 15 Example 162

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (S)-carboxy(phenyî)methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylate (1:1)

OH 11820 -235-

To a suspension of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,(S)-carboxy(phenyI)methyl ester (181 mg, 0.38 mmol) in éthanol (5 mL) wasadded aqueous choline bicarbonate (5.66 M, 0.06 mL, 0.34 mmol). The resulting 5 mixture was refluxed until a clear solution was obtained. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in 2 mL of éthanol andthen diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate wascollected by filtration to give 0.17 g (77%) of the desired product as an off-whitesolid: mp 223-225°C; MS(APCI+): m/z 475.2 (MH+). Anal. Calcd for 10 C2sH29N2O5-C5Hi4NO-1.2H2O: C, 66.13; H, 7.64; N, 7.01. Found: C, 65.96; H, 7.56; N, 6.78.

Example 163

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, ( 1 R)-2-methoxy-2-oxo-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 R)-2-methoxy-2-oxo-1 -phenylethyl ester was synthesized according to procedure Q from (R)-(-)-methyl 20 mandelate. The crude product was chromatographed using 40%-60% ether inhexanes as eluant to give 750 mg of the desired product as a white solid: mp106-108°C; MS(APCI+): m/z 489.2 (MH+). 11820 -236-

Example 164

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (R)-carboxy(phenyl)methylester

To a solution of pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine- 1- carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R)- 2- methoxy-2-oxo-l-phenylethyl ester (670 mg, 1.37 mmol) in methanol (60 mL)was added IN NaOH (5.5 mL, 5.5 mmol). The resulting reaction mixture was 10 stirred at 50°C for 1 hour and IN HCl (5.5 mL) was added. The mixture was concentrated in vacuo to give a residue, which was purified by chromatography(10-30% methanol in chloroform as eluant)'followed by recrystallization frommethanol to give 0.35 g of the desired product as a white solid: mp 248-250°C;MS(APCI-): m/z 473.1 (M-H). 15 Example 165

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, sait with (R)-carboxy(phenyl)methyl, 3,7,8,9,10,12,13,14,14a,15-decahydro- 2-methylpyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylate (1:1)

OH 118 2 0 -237-

To a suspension of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (R)-carboxy(phenyl)methyl ester (210 mg, 0.44 mmol) in éthanol (5 mL) was addedaqueous choline bicarbonate (5.66 M, 0.07 mL, 0.40 mmol). The resulting mixture 5 was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vactio, and the residue was dissolved in 2 mL of éthanol and thendiluted with 70 mL of ether. After cooling in an ice-bath, the precipitate wascollected by filtration to give 0.2 g (78%) of the desired product as an off-whitesolid: mp 215-217°C; MS(APCI+): m/z 4,152 (MH+). Anal. Calcd for 10 C2sH29N2O5-C5H14NO-1.8H2O: C, 64.96; H, 7.7.70; N, 6.89. Found: C, 65.04; H, 7.59; N, 6.55.

Example 166

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester wassynthesized according to procedure Q from 4-pyridylcarbinol. The crude productwas chromatographed using 50% ethyl acetate in hexanes followed by 100% ethyl 20 acetate as eluant to give 260 mg of the desired product as a white solid: mp199-201 °C; MS(APCI+): m/z 432.5 (MH+).

Example 167

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-pyridinyl)ethyl ester 11820

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(4-pyridinyl)ethyI ester wassynthesized according to procedure Q from l-(4-pyridyl)ethanol. The crude 5 product was chromatographed using 50% ethyl acetate in hexanes followed by100% ethyl acetate as eluant to give 210 mg of the desired product as a whitesolid: mp 219-221°C; MS(APCI+): m/z 446.2 (MH+).

Example 168

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(2-pyridinyl)ethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-pyridinyl)ethyl ester wassynthesized according to procedure Q from l-(2-pyridyl)ethanol. The crude 15 product was chromatographed using 50%-75% ethyl acetate in hexanes as eluantto give 200 mg of the desired product as a white solid: mp 87-89°C; MS(APCI+):m/z 446.2 (MH+). 11820 -239-

Example 169

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-thienylmethyl ester

5 Pyrrolo[3',2':5,6][l ]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-thienylmethyl ester wassynthesized according to procedure Q from 3-thiophenemethanol. The crudeproduct was chromatographed using 50% ether in hexanes as eluant to give330 mg of the desired product as a white solid: mp 115-116°C; MS(APCI+): m/z 10 437.5 (MH+).

Example 170

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -(4-fluorophenyl)ethylester

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -(4-fîuorophenyl)ethylester was synthesized according to procedure Q from S(-)-l-(4-florophenyl)ethanol. The crude product was chromatographed using 30%-50%ether in hexanes as eluant to give 300 mg of the desired product as a white solid:mp 108-110°C; MS(APCI+): m/z 463.3 (MH+). 20 118 2 0 -240-

Example 171

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 R)-1 -(4-iluorophenyl)ethyl ester

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinoIizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-l-(4-fluorophenyl)ethylester was synthesized according to procedure Q from R(+)-l-(4- floropbenyl)ethanol. The crude product was chromatographed using 30%-50%ether in hexanes as eluant to give 300 mg of the desired product as a white solid:MS(APCI+): m/z 463.3 (MH+).

Example 172

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,I4a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester wassynthesized according to procedure Q from 3-pyridylcarbinol. The crude productwas chromatographed (1:1 hexane/EtOAc) to give 1.43g (49.4%) of desiredproduct as a solid: mp 73-80°C; MS(APCI+): m/z 432.6 (MH+). 11820 -241-

Example 173

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decabydro-2-methyl-, 2-ethoxy-2-oxoethyl ester wassynthesized according to procedure Q front ethyl glycolate. The crude product waschromatographed (1:1 hexane/EtOAc) to give 0.5287g (36.8%) of desired productas a solid: mp 60-70°C; MS(APCI+): m/z 427.2 (MH+).

Example 174

Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin-l-.yl)carbonyl]oxy]methyl]-i-methyl-, methanesulfonate

Pyrrolo[3',2':5,6][l ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester (1 eq)and methyl methanesulfonate (4 eq) was mixed together in 1,2 dichloroethane andrefluxed at 88°C for 30 minutes. After cooling down to ambient température theprecipitate was isolated by suction filtration and washed with ether to give 86mg(41.2%) of pure desired product as crystals: mp 228-232°C; MS(APCI+): m/z 446.2 (M+). 118 2 0 -242-

Some of the compounds of ring close Formula I are capable of furtherforming N-oxides and N-quatemary alkyl salts with the ring nitrogen atom atN-l 1. Further, some of the compounds of ring close Formula I are capable offurther forming N-oxides and N-quatemary alkyl salts with nitrogen atoms 5 optionally présent in Rjo- These structural forms are within the scope of theprésent invention.

Example 175

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizinium, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,1 l-dimethyl-l-[(S)-(l-phenylethoxy)carbonyl]-, methanesulfonate

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (IS)-l-phenylethyl ester (0.6 g,1.349 mmol) and methyl methanesulfonate (1.089 g, 10.7964 mmol) were mixedtogether in 1,2 dichloroethane (8ml) and refluxed at 88°C for 18 hours. The 15 reaction mixture was concentrated in vacuo. The crude product was chromatographed (2:10 MeOH/CH2Cl2) to give 0.41 g (61.5%) of desired productas a solid: mp 160-170°C; MS(APCI+): m/z 459.3 (M+).

Some of the compounds of ring close Formula I are capable of further 20 forming N-oxides and N-quatemary alkyl salts with the ring nitrogen atom atN-l 1. Further, some of the compounds of ring close Formula I are capable offurther forming N-oxides and N-quatemary alkyl salts with nitrogen atomsoptionally présent in R^q. These structural forms are within the scope of theprésent invention. 11820 -243-

Example 176

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinoIizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-furanylmethyl ester

5 Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-furanylmethyl ester wassynthesized according to procedure Q from furan-3-yl-methanol. The crudeproduct was chromatographed (1:1 hexane/EtOAc) to give 0.40 g (42.4%) ofdesired product as a solid: mp 174-177°C; MS(APCI+): m/z 421.4 (MH+). 10 Example 177

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-nitrophenyl)methyl ester

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyI-, (2-nitrophenyl)methyl ester was synthesized according to procedure Q from 2-nitrobenzylalcohol. The crudeproduct was chromatographed (1:1 hexane/EtOAc) to give 0.39 g (35.9%) ofdesired product: mp 200-203°C; MS(APCI+): m/z 476.5 (MH+). 11820 -244-

Example 178

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-furanylmethyl ester

5 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-furanylmethyl ester was . synthesized according to procedure Q from furan-2-yl-methanol. The crudeproduct was chromatographed (1:1 hexane/EtOAc) to give 0.24 g (24.8%) ofdesircd product as a solid: mp 65-77°C; MS(APCI+): m/z 421.4 (MH+). 10 Example 179

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-chlorophenyl)ethyl ester

Pyrroîo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 15 3,7,S,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(2-chlorophenyl)ethyl ester was synthesized according to procedure Q from l-(2-chlorophenyl) éthanol. Thecrude product was chromatographed (1:1 hexane/ether) to give 80 mg (5.0%) ofdesired product as a solid: mp 95-105°C; MS(APCI+): m/z 479.2 (MH+). 11820 -245-

Example 180

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, carboxymethyl ester

5 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 2-ethoxy-2-oxoethyl ester(0.47 g, 0.96 mmol) was mixed with IN NaOH (5.73 mmol, 5.73 mL) in MeOHand kept it in a oil bath at 50°C for 3 hours. Then the reaction mixture was cooledto ambient température followed by addition of IN HCl to neutralize. The reaction 10 mixture was concentrated in vacuo, and the crude product was chromatographed(initially 1:1 hexane/ether, then 10% MeOH in CHCI3) to give 0.374g of crudesolid. The crude solid was redissolved in CHCI3 and filtered to get 78 mg (20.6%)of desired product as a solid: MS(APCI +): mp 260°C; m/z 399.1 (MH+).

Example 181 15 Pyrrolo[3',2’:5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-dichlorophenyl)ethylester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i3quinolizine-l-carboxylic acid,20 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2,6-dichîorophenyl)ethyI ester was synthesized according to procedure Q from l-(2,2-dichloro phenyl) 11820 -246- éthanol. The crude product was chromatographed (1:1 hexane/ether) to give93 mg (5.30%) of desired product as a solid: mp 130-135°C; MS(APCI+): m/z 513.1 (M+).

Example 182 5 PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-methoxyphenyl)ethyl ester /

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-methoxyphenyl)ethyl ester 10 was synthesized according to procedure Q from l-(2-methoxyphenyl) éthanol.

The crude product was chromatographed (1:1 hexane/ether) to give 0.90 g (42%)of desired product as a solid; mp 115-125°C; MS(APCI+): m/z 475.2 (MH+).

Example 183

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 15 3,7,8,9,I0,12,13,14,14a,15-decahydro-2-methyl-, (IS)-l-phenylethyl ester, 11-oxide

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (IS)-l-phenylethyl ester (0.3 g) 11820 -247- was mixed with 50% H2O2 in MeOH and the mixture was stirred at roomtempérature for 3 hours. Then excess H2O2 was destroyed using Pd/C. Thereaction solution was filtered and concentrated in vacuo. The crude product waschromatographed (10% MeOH in CH2CI2) to give 52 mg (48.2%) of pure desired 5 product as a solid: mp 180-190°C; MS(APCI+): m/z 461.2 (MH+).

Some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quatemary alkyl salts with the ring nitrogen atom atN-l 1. Further» some of the compounds of ring close Formula I are capable offurther forming N-oxides and N-quatemary alkyl salts with nitrogen atoms 10 optionally présent in Riq. These structural forms are within the scope of theprésent invention.

Example 184

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(5-carboxy-3-pyridinyl)ethyl 15 ester

Step A: l-(5-Bromo-pyridin-3-yl)-ethanone 3-(5-Bromo-pyridin-3-yl)-3-oxo-propionic acid methyl ester (8.75 g, 30 mmol) was mixed with 2N H2SO4 and the mixture was refluxed for 24 hours.20 The reaction solution was then neutralized with solid NaHCOg and extracted with

K ether. The organic phase was dried and ether was evaporated to give 6.06 g(89.5%) of the pure desired product as crystals: MS(APCI+): m/z 201 (MH+). 118 2 0 -248-

Step B: l-(5-Bromo-pyridin-3-yl)-ethanol

Compound l-(5-bromo-pyridin-3-yl)-ethanone (5.85 g, 29.2 mmol) was dissolved in MeOH (100 mL) and NaBH4 (1.104 g, 29.19 mmol) was addedslowly. The reaction was monitored by TLC. When the starting material was 5 completely consumed mixture was neutralized by NaHCC>3 solution and extractedwith ether to give the crude product. Crade product was mixed with 1:1 hexane/ethyl acetate and fïltered. The filtrate was concentrated to give the pure desiredproduct. MS(APCI+): m/z 203 (MH+).

Step C: 5-(l-Hydroxy-ethyl)-nicotinic acid methyl ester 10 l-(5-Bromo-pyridin-3-yl)-ethanol (6.0 g), Palladium acetate (0.14 g), DPPP (0.28 g), Triethylamine(6 mL), DMSO (60 mL), and MeOH (60 mL) weremixed together and the reaction mixture was stirred at 100-110°C for 18 hours.End of the reaction mixture was fïltered to remove the solids and the filtrate wasconcentrated under vacuum. The residue was triturated with EtOAc and fïltered, 15 the filtrate and the solid were collected. The solid was dissolved in NaHCÛ3 andextracted with EtOAc. The extracts and the filtrate were combined together anddried over Na2SO4- Concentration in vacuo gave the crade product which waschromatographed with 1:1 hexane/EtOAc to give 3.32 g (61.8%) of the puredesired product: MS(APCI+): m/z 182 (MH+). 20 StepD: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-[5-(methoxycarbonyl)-3-pyridinyl]ethyl ester

I 118 2 0 -249- 10 10 15 15

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i']quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -[5-(methoxycarbonyl)- 3-pyridinyl]ethyl ester was synthesized according to procedure Q from 5-(l-hydroxy-ethyl)-nicotinic acid methyl ester. The crude product waschromatographed (1:1 hexane/EtOAc) to give 0.81 g (37%) of desired product asa solid: MS(APCI+): m/z 504.3 (MH+).

Step E: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(5-carboxy- 3-pyridinyl)ethyl ester

Example 184, Step D, pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,-13,14,14a, 15-decahydro-2-methyl-, l-[5-(methoxycarbonyl)-3-pyridinyl]ethyl ester (0.2202 g, 0.4378 mmol) wasmixed with IN NaOH (1.75 mmol, 1.75 mL) in MeOH (10 mL). The reactionflask was kept in an oil bath at 50°C for 1 hour. Then the reaction mixture wascooled to ambient température followed by addition of IN HCl (2 mL) toneutralize the reaction mixture. Mixture was concentrated in vacuo to give thecrude product which was chromatographed (20:10, MeOH/CH2Cl2) to give0.2665 g (100%) of the desired product as a solid: MS(APCI+): m/z 490.2 (MH+).

Example 185 1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyTrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizin-l-yl)carbonyl]oxy]-methyl]-, diethyl ester O,

O

O ; 118 2 0 -250-

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid(Example 86) (0.502 g, 1.13 mmol) is combined with diethyl-5- (hydroxymethyl)isophthalate (0.859 g, 3.40 mmol) and placed in a 150°C oil bathfor 6 minutes. The reaction is allowed to cool to room température, diluted withEtOAc and saturated NaHCO3 and stirred until ail residue is dissolved. The layersare separated and the organic layer is washed with water and brine, dried(MgSO4) and evaporated. The product is purified by column chromatography eluting with a gradient of ether/hexanes (30% yield). NMR (CDC13, 300 MHz): δ 8.64 (s, 1H), 8.31 (s, 2H), 8.11 (s, 1H), 7.03 (d, 1H) 6.76 (d, 1H),5.40 (d, 2H), 4.44 (q, 4H), 3.38-3.44 (dd, 1H), 3.04 (m, 1H), 2.76-2.82 (m, 2H),2.61 (s, 3H), 2.44-2.56 (m, 2H), 1.40 (t, 6H), 1.23-1.78 (m, 11H). MS (APCI, m/z, M+l): 575.2 C33H3SN2O7-0.67 H2O. Calcd: C, 67.50; H, 6.70; N, 4.77. Found: C, 67.19; H6.54; N, 4.37.

Example 186 1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin-1-yl)carbonyl]oxy]methyl]-

1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin-l-yl)carbonyl]oxy]methyl]-, diethyl ester (0.4787 g, 0.83 mmol) in 10 mL THF, 2 mL MeOH and 0.83 mL (1.66 mmol) of 2 M NaOH were combined and heatedto 50-60°C. Two 0.83 mL portions of 2 M NaOH were added until reactioncomplété by MS. The reaction was cooled to room température and washed withEt2O. The aqueous layer was neutralized and concentrated. The residue was 118 2 0 -251- dissolved in hot MeOH and filtered to remove NaCl. The filtrate was concentratedand dissolved in MeOH at room température and again filtered. The filtrate wasdried over MgSO4, filtered and concentrated. The product was lyophilized to give 362.2 mg (83%). LCMS: 88.17% 5 Example 187

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl)methylester

10 Step A: 2-Chloro-5-nitrobenzyl alcohol

An oven dried 3 neck flask, fitted with 2 septa and a reflux condenser is charged with 2-chloro-5-nitrobenzoic acid (5.53 g, 27.43 mmol), 14 mL THF andBF3‘OEt2 (3.5 mL, 27.62 mmol) is added dropwise. The solution is heated to reflux for 2 hours at which point borane methyl sulfide complex (2M/THF, 15 18 mL, 36 mmol) is added dropwise over 30 minutes. The refluxing is continued for another 2 hours until the reaction is complété by TLC- The reaction is cooledto room température and 4 mL 1:1 THFZH2O is slowly added followed by 20.5 mL 5 M NaOH. The reaction is heated to reflux for 16 hours and filteredthrough a coarse sintered glass funnel while hot, washing solids with THF (2x). 20 The filtrate is dried (MgSOzt), filtered, concentrated and purified by column chromatography eluting with a EtOAc/hexane gradient. The product is trituratedwith hexanes and filtered to obtain the product in 79% yield. ^H NMR (CDCI3,300 MHz): δ 8.45 (d, 1H). 8.11 (dd, 1H), 7.52 (d, 1H), 8.86 (d, 2H), 2.18 (t, 1H)MS (APCI, AP-) 186.9 118 2 0 -252-

Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyI)methyl ester 2-Chloro-5-nitrobenzyl alcohol (1.0879 g, 5.80 mmol) andpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyI-, anhydride with benzoic acid(Example 86) (0.512 g, 1.15 mmol) are combined and placed in a 150°C oil bathfor 6 minutes. The reaction is cooled to ambient température and diluted withEtOAc. The mixture is washed with saturated NaHCC>3, water and brine, dried(MgSO4), filtered, concentrated and purified by column chromatography eluting with a gradient of EtOAc/hexanes to obtain the product in 57% yield. NMR(DMSO, 300 MHz): δ 11.65 (s, 1H), 8.39 (s, 1H), 8.24 (dd, 1H), 7.85 (d, 1H),7.07 (d, 1H), 6.63 (d, 1H), 5.42 (d, 2H), 3.23 (m, 1H), 2.8-3.0 (m, 1H), 2.60-2.70 (m, 2H), 2.30-2.60 (m, 3H), 2.37 (s, 3H), 1.82-1.87 (m, 1H), 1.0-1.75 (m, 11H) MS (APCI, AP+): 510.1 LCMS: 98.23 % rétention time: 7.627 minutes

Ex ample 188

PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-amino- 2-chlorophenyl)methyl ester

Step A: 5-Amino-2-chlorobenzoic acid

Raney-Nickel (3 gm) was added to a methanolic solution of 5-nitro- 2-chlorobenzoic acid (10 gm,150 mL), this mixture was then connected to aH2 source, after 4 hours, the reaction was completed by TLC (30% 11820 -253-

MeOH/CH2Cl2). The catalyst was removed by filtration and the filtrate wasevaporated to dryness, collected 8 g ofproduct and it was used in the next stepwithout further purification. MS (APCI, AP+): 172.0

Step B: 5-Amino-2-chlorobenzyl alcohol

An oven dried two neck flask fïtted with a septum and a reflux condenseris charged with 5-amino-2-chlorobenzoic acid (2.611 g, 15.22 mmol) and 7.5 mLTHF. BF3OEt2 is added dropwise and the reaction is heated to reflux for 2 hours.Borane methyl sulfide complex (2M/THF, 10 mL, 20 mmol) is added dropwise.The reaction is refluxed for 3 hours, and an additional 3.8 mL of borane methylsulfide complex (7.2 mmol) is added. The refluxing is continued for 1 hour,cooled to ambient température and 3 mL 1:1 THF/HoO is added slowly, followedby 11.2 mL 5 M NaOH. The reaction is heated to reflux for 16 hours and filteredhot through a coarse sintered glass funnel, rinsing the solids with THF (2x). Thefiltrate is concentrated and the residue partitioned between CH2CI2/H2O. Theproduct is extracted three times into CH2CI2. The tan solid in the organic layer is collected by filtration and dried in a 40°C vacuum oven ovemight to give 0.6374 gof product. The organic filtrate is dried (MgSOzj.), filtered, concentrated andpurified by column chromatography eluting with a MeOH/CH2Cl2 gradient to give 0.56 g ofproduct. *H NMR (DMSO, 300 MHz): δ 6.93 (d, 1H), 6.75 (d, 1H), 6.39 (dd, 1H), 5.16 (s, 2H), 4.38 (d, 2H). MS (APCI, AP+): 158.0

Step C: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-amino- 2-chlorophenyl)methyl ester 5-Amino-2-chlorobenzyl alcohol (1.055 g, 6.70 mmol) andpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid(Example 86) (0.7023 g, 1.58 mmol) are combined and placed in a 150°C oil bathfor 6 minutes. The reaction is cooled, diluted with EtOAc and saturated NaHCO3and stirred until ail residue is dissolved. The organic layer is washed with water 118 2 0 -254- and brine, dried (MgSC>4), filtered and concentrated. The product is purified bycolumn chromatography eluting with 5% MeOH/CH2Cl2- The product is placed under high vacuum for two days to yield 0.260 g (34%) of a iight pink solid.NMR(DMSO, 300 MHz): δ 11.16 (s, 1H), 10.13 (s, 1 H), 8.02 (d, 1H), 7.60 (dd, 5 1H), 7.29 (d, 1H), 7.05 (d, 1H), 6.60 (d, 1H), 5.37 (t, 1H), 4.51 (d, 2H), 3.14-3.18 (m, 1H), 2.90-3.00 (m, 1H), 2.65-2.72 (m, 1H), 2.30-3.20 (m, 3H), 2.39 (s, 3H),1.10-1.75 (m, 11H). MS (APCI, AP+): 480.1 LCMS: 91.44% rétention time: 4.623 minutes

Ex ample 189 10 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-acetic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-.alpha.-oxo-, ethyl ester

2-Methyl-pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinoIizine (0.296 gm, 1 mm) and ethyl oxylate (0.123 mL, 1.1 mm) were mixed in 20 mL of THF and 15 this mixture was stirred at ambient température for 48 hours. THF was evaporatedand residue was redissolved in EtOAc, the organic layer was washed withbicarbonate, brine, and evaporated to dryness. The pure product was isolated bycolumn chromatography eluted with hexanes/EtOAc = 1:1 (50 mg, 12.4%) MS (APCI, AP+): 397.1. ^H NMR (CDCI3, 300 MHz): δ 8.3 (s, NH), 7.05 (d, 20 1H), 6.8 (d, 1H), 4.4 (q, 2H), 2.4-3.6 (m, 6H), 2.75 (s, 3H), 1.22-2.15 (m, 11H),

1.4 (t, 3H), C23H28N2O4-l/3 H2O. Calc’d: C, 68.69; H, 7.19; N, 6.96. Found: C,68.85; H 6.98; N, 6.51. MP: 200°C 118 2 0

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4,5-trimethyl-, phenyimethyl ester -255-

Example 190

Step A: 2,3-Dimethyquinone

To a solution ofNaOAc (16.4 gm, 60 mm) in 200 mL of water was added 2,3-dimethyl-4-hydroxyphenol (5.526 gm, 20 mm) and a solution ofbenzyltrimethylammonium tribromide (17.6 gm, 22 mm). The mixture was stirreduntil the color of the solution was faded (3 hours). The organic layer wasseparated and washed with brine, dried and evaporated, total weight 5 gm, Thismaterial was used for the next step without further purification.

Step B: 5-Hydroxy-2,6,7-trimethyl-l//-indole-3-carboxylic acid ethyl ester

To a solution of 2,3-dimethylquinone (3.5 gm, 25.7 mm) in 60 mL ofEtOH, was added a solution of 3-amino-but-2-enoic acid, benzyl ester (5.41 gm, 28.3 mm) under nitrogen. White solid was filtered, and the filtrate wasconcentrated and the product was purified by column chromatography eluted withhexanes/EtOAc =1:1 (0.5 gm, 6.3%) MS (APCI, AP+): 367.1.

Step C: 4-Dimethylaminomethyl-5-hydroxy-2,6,7-trimethyl-ltf-indole-3-carboxylic acid ethyl ester 37.5% formaldéhyde solution (0.157 mL, 1.94 mm) and 40%dimethylamine solution were added to a solution of 5-hydroxy-2,6,7-trimethyl-l//-indole-3-carboxylic acid ethyl ester in 11 mL of EtOH. The reaction mixturewas stirred at 55°C for 48 hours. The solvent was removed, the pure product wasisolated by column chromatography eluted with MeOH/EtOAc = 1:4 (0.22 gm,37.3%) 118 2 0 -256- MS (APCI, AP+): 367.1.

Step D: Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4,5-trimethyl-, phenylmethyl ester 5 The perchlorate sait 1,2,3,4,6,7,8,9-octahydro-quinolizinylium perchlorate (0.204 gm, 0.855 mm) was dissolved in 10 mL IN NaOH and extracted with 3 x35 mL ether. The ether was concentrated and the residue was redissolved in 4 mLdioxane. The imine solution solution was added to the 4-dimethylaminomethyl-5-hydroxy-2,6,7-trimethyl-l//-indole-3-carboxylic acid ethyl ester in 8 mL of 10 dioxone. The reaction was refluxed at 110°C for 18 hours. The solvent was evaporated and the pure product was isolated by column chromatography elutedwith MeOH/EtOAc = 1:4 (0.117 gm, 44.5%)

MS (APCI, AP+): 459.2. MP: 75-80°C C23H2gN2O4-2/3 H2O. Calc’d: C, 74.11; H, 7.52; N, 5.966.96. Found: C, 74.12; 15 H 7.37; N, 5.77.

Example 191

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-z]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -dimethyl-2-propynyl ester

20 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -dimethyl-2-propynyl esterwas synthesized according to procedure Q from 2-methyl-but-3-yn-2-ol. MS: m/z 407.52 (MH+). 118 2 0 -257-

Example 192

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trichloro- 1,1 -dimethylethyl ester

Pyrrolo[3',2':5,6][l]benzOpyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,S,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trichloro-1,1-dimethylethyl ester was synthesized according to procedure Q from 1,1,1 -trichloro-2-methyl-propan-2-ol. MS: m/z 500.86 (MH+). 10 Example 193

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, tricyclo[3.3.1.l3>7]dec-l-ylester

15 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, tricyclo[3.3.1.1^ >7] dec-1 -ylester was synthesized according to procedure Q from adamantan-l-ol. MS: m/z 474.63 (MH+). 118 2 0 -258-

Example 194

Pyrrolo[3’,2':5,6][ 1 ]benzopyrano[3,2-z']quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methyl-1 -phenylethyl ester

5 Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methyl-1 -phenylethyl esterwas synthesized according to procedure Q from 2-phenyl-propan-2-ol. MS: m/z 459.59 (MH+). 10

Example 195

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methylcyclohexyl ester

15

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methylcyclohexyl ester wassynthesized according to procedure Q. MS: m/z 437.59 (MH+).

Example 196

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1,2-trimethylpropyl ester 11820 -259-

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-/']quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1,2-trimethylpropyl ester wassynthesized according to procedure Q. MS: m/z 425.58 (MH+). 5 , Example 197

Pyrrolo[3',2’:5,6][ 1 ]benzopyrano[3,2-/]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methylcyclopentyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l -carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methylcyclopentyl ester was synthesized according to procedure Q. MS: m/z 423.56 (MH+).

Example 198

PyrTolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 1 -cyclohexyl-1 -methylethyl 15 ester 1182 ο •260-

Ρ^ο1ο[3',2':5,6][1^εηζορ>τ3ηο[3,2-ζ^υϊηο1ΐζΐη6-1-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -cyclohexyl-1 -methylethylester was synthesized according to procedure Q. MS: m/z 465.64 (MH+). . Ex amp le 199

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l,4-dimethyl-4-piperidinyl ester

Ό 10

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidinyl esterwas synthesized according to procedure Q. MS: m/z 452.60 (MH+).

Example 200

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-z']quinolizine-l -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-fluorophenyI ester

15 11820 -261-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i']quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-fluorophenyl ester wassynthesized according to procedure Q. MS: m/z 435.50 (MH+).

Example 201 5 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-methylphenyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-methylphenyl ester was 10 synthesized according to procedure Q. MS: m/z 431.54 (MH+).

Example 202

Pyrrolo[3',2’:5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,3,7,S,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester was synthesizedaccording to procedure Q. MS: m/z 417.51 (MH+). 15 118 2 0 -262-

Example 203

PynOÎo[3’,2':5,6][l]benzopyrano[3,2-i!quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 3-(methoxycarbonyl)phenylester

10

PyiTolo[3’,2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl)phenylester was synthesized according to procedure Q. MS: m/z 475.55 (MH+).

Example 204

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, 3-pyridinyl ester

15

PynOlo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-pyridinyl ester wassynthesized according to procedure Q. MS: m/z 417.50 (MH+).

Example 205

Pyrrolo[3’,2’:5,6][ 1 ]benzopyrano[3,2-z']quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-(trifluoromethyl)-, ethyl ester 118 2 0 -263-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester wassynthesized according to procedure Q. MS: m/z 423.44 (MH+).

Example 206

Pyrrolo[3’,2':5,6](l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-[(dimethylamino)methyl]- 2-furanyl]melhyl ester

10

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-[(dimethylamino)methyl]- 2-furanyl]methyl ester was synthesized according to procedure Q. MS: m/z 478.60 (MH+).

Example 207 15 PyrTOÎo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-carboxy-2-methyîpropyl ester 264- 11820

Pyrroio[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl·, 2-carboxy-2-methylpropyl esterwas synthesized according to procedure Q. MS: m/z 441.53 (MH+). 5 Example 208

Pyrrolo[3',2':5,6][l]benzopyranô[3,2-z]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(dimethylamino)- 2,2-dimethylpropyl ester

10 Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-z']quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(dimethylamino)- 2,2-dimethylpropyI ester was synthesized according to procedure Q. MS: m/z 454.62 (MH+).

Example 209 15 Propanedioic acid, monoanhydride with 3,7,8,9,10,12,13,14,14a,15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid, 1,1-dimethylethyl ester 11820 -265-

Propanedioic acid, monoanhydride with 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano(3,2-i]quinolizine-l-carboxylic acid, 1,1-dimethylethyl ester was synthesized according to procedure Q. MS: m/z 5 483.57 (MH+). , Example 210

Pyrrolo[3',2’:5,63[l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethyîamino)-2-methylpropyl ester

Pyrrolo[3’,2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)-2-methylpropyl ester was synthesized according to procedure Q. MS: m/z440.59 (MH+). 15 Example 211

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i']quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(177-imidazol-l-yl)ethyl ester

H 11820 -266-

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-( 1 //-imidazol-1 -yl)ethy 1 esterwas synthesized according to procedure Q. MS: m/z 435.53 (MH+).

Example 212

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-benzofuranylmethyl ester

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z']quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-benzofuranylmethyl ester wassynthesized according to procedure Q from benzofuran-2-yl-methanol.MS(APCI+): m/z 471.2 (MH+).

Example 213

Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( lÆ,25)-2-(dimethylamino)-l -phenylpropyl ester

H

PynOlo[3',2':5,6][l]benzopyrano[3,2-z]qumoIizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (17?,25)-2-(dimethylamino)-l-phenylpropyl ester was synthesized according to procedure Q from (IR, 2S)~dimethylamino-phenyl-propan-l-ol. MS(APCI+): m/z 502.1 (MH+). 11820 -267-

Example 214

Pyrrolo[3’,2':5,6][ 1 ]benzopyrano[3,2-z]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 15,27?)-2-(dimethylamino)-1 -phenylpropyl ester

Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-z']quinolizine-1 -carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyI-, (1 £,2Æ)-2-(dimethylamino)-1 -phenylpropyl ester was synthesized according to procedure Q from ( 1 S, 2/?)-2-(dimethylamino-phenyl-propan-l-ol. MS(APCI+): m/z 502.1 (MH+).

Exampîe 215

Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclopropylester

Step A: l-(4-Fluorophenyl)cyclopropanol H0

Following the procedure reported by Kulinkovich, O.G.; Sviridov, S.V.;Vasilevskii, D.A.; Savchenko, A.I.; and Pritytskaya, T.S. in J. Org. Chem. USSR(Engl) 1991;27(2):250 for the préparation of 1-phenylcyclopropanol,

4-fluorobenzoîc acid ethyî ester (65.72 mmol, 11.05 g) was converted to l-(4-fluorophenyl)cyclopropanol (5.34 g, 53%) as a yellow liquid; NMR 118 2 0 -268- (400 MHz, CDCI3) δ 0.99-1.02 (m, 2H, cyclopropyl CH2), 1.23-1.26 (m, 2H,cyclopropyl CH2), 2.22 (bs, 1H, OH), 6.98-7.05 (m, 2H, Artf), 7.26-7.32 (m, 2H,AtH)·, 19F NMR (CDCI3) δ -117.09 (d, 7=15.43 Hz); MS (APCI+) m/z 152.9(MH+).

Step B: Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclopropyl ester

Following the procedure from Example 47, Step B, l-(4-fluorophenyl)-cyclopropanol (35.1 mmol, 5.34 g) andpyrrolo[3',2':5,6][l]benzopyrano[3,2-ijquinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-,anhydride with benzoic acid (Example 86), (8.77 mmol, 3.90 g) were converted topyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclopropylester. The product was purified by silica gel flash column chromatography(25-50% ethyl acetate/hexanes, then 30-50% ether/hexanes) and recrystallizedfrom 2,2,4-trimethylpentane to afford a light yellow solid (0.364 g, 9%): mp 130-135°C; IR (KBr) 3302, 29.31,2857, 1689, 1515, 1429, 1221, 1194, 1147, 1068cm-1; ÎHNMR (400 MHz, DMSO-d6) δ 1.13-1.60 (m, 13H, aliphatic CH), 1.71-1.74 (m, 1H, aliphatic CH), 1.88 (d,7=13.18 Hz, 1H, aliphatic CH), 2.36 (d,7=10.74 Hz, 1H, aliphatic CH), 2.43-2.49 (m, 1H, aliphatic CH), 2.53 (s, 3H,AtCH3), 2.66-2.71 (m, 2H, aliphatic CH), 2.87-2.90 (m, 1H, aliphatic CH), 3.22(dd, 7=18.31, 6.84 Hz, 1H, aliphatic CH), 6.61 (d, 7=8.79 Hz, 1H, AtH), 7.04 (d,7=8.55 Hz, 1H, AtH), 7.11-7.15 (m, 2H, AtH), 7.28-7.32 (m, 2H, ΑτΗ), 11.57 (s,IH, Ntf); 19F NMR (DMSO-d6) δ -117.03; MS (APCI+) m/z 475.2 (MH+). Anal.Calcd for 029^^^()3: C, 73.40; H, 6.58; F, 4.00; N, 5.90. Found: C, 73.58;H, 6.79; F, 3.93; N, 5.52.

Claims (17)

11820 -269- CLAIMS

2. A compound according to Claim 1 wherein Rj is hydrogen.

3. A compound according to Claim 1 wherein: Rl is hydrogen and X is C-Rç.

4. A compound according to Claim 1 wherein: Rl is hydrogen and X is C-Rç, wherein R9 is alkyl.

5. A compound according to Claim 1 wherein: Rl is hydrogen, X is C-R9, wherein R9 is alkyl; R4 and R5 are taken together with the atoms to which they are attached toform a ring of from 5 to 7 atoms; and Y is OR10·

6. A compound according to Claim 1 wherein: Rl is hydrogen, X is C-R9, wherein R9 is alkyl; R4 and R5 are taken together to form a 6-membered ring; and Y is OR10 wherein Rio is alkyl, aryl or -(CH2)saryî, -(CH2)t-C(R7R8XCH2)u-aryl.

7. A compound according to Claim 1 wherein: Rl is hydrogen, 118 2 0 -273- X is C-R9, wherein R9 is Me; R4 and R5 are taken together to form a 6-membered ring; Rg is hydrogen;n is 2; and Y is OR 10 wherein Rjq is alkyl, aryl or R^q is -(CH2)t*C(R7Rg)-(CH2)u-aryl wherein t is 0, R7 and Rg can each independently be H,alkyl, -(CH2)vOH or (CH2)uCOOR7, and -(CH2)vNRlR2where u and v are as defined above.

8. A compound according to'Claim 1 and selected from: Pyrrolo[3 ’ ,2 ’ :5,6][1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, methyl ester; Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-bromo-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethylester; Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylicacid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, propyl ester; Pyrrolo[3 ’,2 ’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylicacid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methylpropylester; Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylicacid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2-dimethylpropylester; Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylicacid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester; Pyrrolo[3’,2 ’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1-carboxylicacid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -methylethylester; Pyrrolo[3 ’,2 ’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylicacid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclopropylmethylester; 11820 -274- Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylicacid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(l-piperidinyl)ethyl ester; Pyrrolo[3 ’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylicacid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-(phenylmethyl)-, ethyl ester; PyrTolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinoîizine-î-carboxylicacid, 2-ethyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester; Pyrrolo[3 ’ ,2 ’ : 5,6] [ 1 ]benzopyrano[3,2-i]quino lizine-1 -carboxylicacid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester; PynOlo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylicacid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-propyl-, ethyl ester; Pyrrolo[3 ’,2’ :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylicacid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(2-methyIpropyl)-, ethylester; Pyrrolo[3 ’ ,2 ’ :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylicacid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -dimethylethylester; 2,6a,7-Trimethyl-7,8,9,10,10a, 11 -hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester;

9. A compound named Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine,3,7,8,9,l0,12,13,14,14a,15-decahydro-, or Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-.

10. A pharmaceutical composition comprising a compound according toClaim 1 or Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethylester in admixture with a pharmaceutically acceptable excipient, diluent, orcarrier.

11. A method for modulation of a chemokine receptor activity in a mammalcomprising administering an effective amount of a compound according toClaim 1 or Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyI-, ethylester or a pharmaceutically acceptable sait thereof.

12. A method for modulation of the CCR-5 chemokine receptor activity in amammal comprising administering an effect amount of a compoundaccording to Claiml or Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]-quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or a pharmaceutically acceptable sait thereof.

13. A method for preventing infection by HIV, treating infection by HIV,delaying the onset of AEDS, or treating AIDS comprising administering toa mammal in need of said treatment a therapeutically effective amount of acompound according to Claim 1 orPyrrolo[3’,2’:5,6][l]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or a pharmaceutically acceptable sait thereof. 118 2 0 -293-

14. A method of treating inflammatory disease comprising administering to amammal in need of said treatment a therapeutically effective amount of acompound according to Claim 1 or Pyrrolo[3’,2’:5,6][l]benzopyrano[3,2-ijquinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2- 5 methyl-, ethyl ester or a pharmaceutically acceptable sait thereof.

15. A combination of a compound of Formula I with one or more agentsuseful in the prévention and/or treatment of AIDS.

16. A compound selected from: Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-10 2-methyIpyrrolo[3’,2':5,6][l]benzopyrano[3,2-i]quinolizin- 1 -yl)carbonyl]oxy]methyl]-l-methyl-, methanesulfonate; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizinium, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,11 -dimethyl-1 -£(S)-( 1 -phenylethoxy)carbonyl]-, methanesulfonate; and 15 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ( 1 S)-1 -phenylethylester, 11-oxide.

17. A compound named Pyrrolo[3',2':5,6J[l]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 20 anhydride with benzoic acid.