CA2372197A1 - Functionalized heterocycles as chemokine receptor modulators - Google Patents

Functionalized heterocycles as chemokine receptor modulators Download PDF

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CA2372197A1
CA2372197A1 CA002372197A CA2372197A CA2372197A1 CA 2372197 A1 CA2372197 A1 CA 2372197A1 CA 002372197 A CA002372197 A CA 002372197A CA 2372197 A CA2372197 A CA 2372197A CA 2372197 A1 CA2372197 A1 CA 2372197A1
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methyl
carboxylic acid
benzopyrano
quinolizine
decahydro
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French (fr)
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Christine Nylund Kolz
Yuntao Song
Jay R. Luly
Bruce David Roth
Bharat Kalidas Trivedi
Geraldine C. Harriman
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Millennium Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

The present invention is a novel series of functionalized heterocycles as chemokine receptor modulators of Formula (I) useful as modulators of chemoki ne 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.</ SDOAB>

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE I)E CETTE DEMANDE OU CE BREVETS
COMPRI~:ND PLUS D'UN TOME.
CECI EST ~.E TOME 1 DE 2 NOTE: Pour les tomes additionels, veillez contacter 1e Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional vohxmes please contact the Canadian Patent Oi~ice.

FUNCTIONALIZED HETEROCYCLES AS CHEMOKINE
RECEPTOR MODULATORS
BACKGROUND OF THE INVENTION
The present invention relates to functionalized heterocycles useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCRI, CXCR2, CXCR-3, and/or CXCR4 and to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier. More particularly, the present invention is directed to methods for inhibiting HIV infectivity.
Chemokines mediate a range of proinflammatory effects on leukocytes, such as chemotaxis, degranulation, and intigran activation (Baggiolini et al., Aclv.
Inzzzzunol., 1994;55:97-179; Oppenheim et al., Annu. Rev. Inzmunol., 1991;
9:617-48; Miller et al., Crit. Rev. Inzmunol., 1992;12:17-46). These effects are mediated by binding to the seven-transmembrane-spanning G-protein coupled I S receptors (Baggiolini et al., Adv. Immzznol., 1994;55:97-179; Murphy, Annu. Rev.
Izrtmzznol., 1994;12:593-633; Schall et al., Cttrr. OPin. I7711n1(I101., 1994;6:865-73;
Gerard et al., Curr. Opizt. Immunol., 1994;6;140-5; Mackay, Czzrr. Bio., In press).
Chemokine receptors also serve as coreceptors for HIV-1 entry into cells. This came from observations that RANTES, MIP-la, and MIP-1(3 suppressed infection of susceptible cells in vitro by macrophage-tropic primary HIV-1 isolates (Cocchi et al., Science (Wash. DC), 1995;270:1811-5). The chemokine receptor CXCR-4 was found to support infection and cell fusion of CD4+ cells by laboratory-adapted, T-tropic HIV-1 strains (Feng et al., Science (Wash. DC), 1996;272:872-7). CCR-5, a RANTES, MIP-la, and MIP-1(3 receptor, was subsequently identified as the principle coreceptor for primary macrophage-tropic strains (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., Nattn-e (Load.) 1996;381:661-6; Dragic et al., Natzzre (Loud.), 1996;381:667-3). The importance of CCR-5 for HIV-l transmission was underscored by the observation that certain individuals who had been repeatedly exposed to HIV-I but remained WO 00/42045 PCT/US99t30434 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). These noninfectable individuals were found to be homozygous for a defective CCR-5 allele that contains an internal 32-base pair deletion (CCR-5 X32). The truncated protein encoded by this gene is apparently not expressed at the cell surface.
CCR-5 X32 homozygous individuals comprise ~1% ofthe Caucasian population and heterozygous individuals comprise ---20%. In studies of about 2700 HIV-1 infected individuals, no X32 homozygotes were found. Individuals who are heterozygous for X32 CCR-5 allele have been shown to progress more slowly to AIDS than wild-type homozygous individuals (Samson et al., Nature (Loud.), 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 the principle coreceptor for primary HIV isolates provides an opportunity to 1 S understand disease pathogenesis, and more importantly to identify a new avenue for the treatment of HIV-1 infection.
The instant invention is a series of functionalized heterocycles that block the CD-4/GP-120 interaction with CCR-5 receptor, and thus can be useful in the treatment of HIV infection manifested in AIDS.
SUMMARY OF THE INVENTION
The compounds of the invention are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound.
The present invention is directed to the use of the foregoing substituted heterocycles as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, including CCR-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 present invention are preferred as modulators of the chemokine receptor CCR-5.
The compounds of the instant invention are those of Formula I which may exist in both closed and open form.
R6 R6\
~(Cl~)n ~(CH2)n RS 40 Rl\ J RSR40 ~R11 \ \
~X ~ ~ ~X
R Z A R Z~A

ring close I ring open or a pharmaceutically acceptable salt thereof wherein:
A is O, S, and additionally A is NR1 when X is C-R~;
X is N when A is NRl or X is C-R9 wherein R~ is halogen, hydrogen, alkyl, -CF3, CH2F, CHF2, -(CH2)m-OR1, aryl, arylalkyl, -(CH~)m-NR~Rg, or CH2) r (CH2)q wherein m is an integer of from 0 to 2 and each occurrence of m is independently an integer of from 0 to 2, q is an integer of from 0 to l, and r is an integer of from 0 to 3;
Y is hydrogen, alkyl, arylalkyl, aryl, (CH2)n~-NR~Rg, -N(Rl)-(CH2)v-C(R~Rg)-aryl, or ORlO wherein Rl0 is hydrogen, alkyl, cycloalkyl, cycloalkyl fused to an aryl ring, aryl, (CH2)saryl, -CH2CF3, (CH2)tC(R7R8)-(Cl-I2)uarYl~
O
R (CH2)m NR~R8 R (CH2)mC- ORS
~'I ~, Aryl O
R
~~(CH2)m C-NR~Rg ~z, Aryl WO 00/42045 PCTlUS99/30434 I I
R (CH2)m NR~RB R O
l~~(CH2)m C-ORS
~'z, alkyl ~ ~/'alkyl O
R I I
1~~(CH2)m C-NR~RB
~z, alkyl O
RI (CH2)m NR~RB RM (CH2)m C-ORS
'~cycloalkyl ~'~cycloalkyl O
R I I
(CH2)m C-NR~RB
' ~~~CCI
cycloalkyl 3 ~z,~C=N ~ ~~~C---CH , , or ~N~
S
R2 ~ ~ (CH2)w wherein s is an integer of from 1 to 3, t is an integer of from 0 to 3, a is an integer of from 0 to 3, v is an integer of from 1 to 3, and w is an integer of from 0 to 2;
ZisCRorN;
RI is hydrogen or alkyl and each occurrence of RI is independently hydrogen or alkyl;
R and R2 are each independently selected from:
hydrogen, alkyl, halogen, -CN, -(CH2)m-~7R8>
-(CH2)m-COORS, -(CH2)m-CONR~Rg, O
(CH2)m N~R7 ' O
-(CH2)mN-S-R7 O
-(CH2)m-OR~, -(CH2)m-S02NR~Rg, and -(CH2)m-S(O)pR~ wherein each occurrence of R~ and Rg are each independently hydrogen, alkyl, aryl, arylalkyl, -CF3, or R~
and Rg may be taken together to form a cyclic ring of from 3 to 7 atoms which ring may have O, S, or NR1 and p is an 1 S integer of from 0 to 2;
R3 is hydrogen or alkyl;
R4 is hydrogen, alkyl, aryl, or aralkyl;
RS is alkyl, aryl, arylalkyl, acyl; or R4 and RS are taken together with the atoms to which they are attached to form a cyclic ring of from 5 to 7 atoms;
Rg is hydrogen or alkyl;
RS when not taken together with R4 can be taken together with R6 with the atoms to which they are attached to form a ring of from 5 to 7 atoms;
N-RS is also the corresponding N-oxide;
R11 is hydrogen or alkyl;
n is an integer of from 1 to 3;
j is an integer of from I to 2, and j is the integer 0 when Y is hydrogen, alkyl, arylalkyl, or aryl;
with the proviso that 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-, ethyl ester is not included.
Preferred compounds are those of Formula 1 above wherein R1 is hydrogen.
Other preferred compounds are those of Formula 1 above wherein R1 is hydrogen and X is C-R9.
Still other preferred compounds are those wherein R1 is hydrogen and X is C-R9, wherein R9 is alkyl.
Still other preferred compounds are those wherein Rl is hydrogen, X is C-R~, wherein R9 is alkyl;
R4 and R5 are taken together with the atoms to which they are attached to form a ring of from 5-7 atoms; and Y is ORlO.
Still other preferred compounds are those wherein R1 is hydrogen, X is C-Rc~, wherein R~ is alkyl;
R4 and R5 are taken together to form a 6-membered ring; and Y is OR10 wherein R10 is alkyl, aryl or -(CH2)saryl, -(CH2)t-C(R7R8)-(CH2)u-aryl.
Still other preferred compounds are those wherein R1 is hydrogen, X is C-R9, wherein R9 is Me;
R4 and R5 are taken together to form a 6-membered ring;
R6 is hydrogen;
n is 2; and _7_ Y is OR10 wherein R10 is alkyl, aryl or Rlp 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)vNRlR2 where a and v are as defined above.
More preferred compounds are those of Formula I and selected from:
Pyrrolo[3',2':S,G][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrxno[3,2-i]quinolizine-1-carboxylic acid, 5-bromo-3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-; ethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13, I 4,14x,15-decahydro-2-methyl-, propyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-methylpropyl ester;
Pyrrolo[3',2':S,G][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I 5-decahydro-2-methyl-, 2,2-dimethylpropyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, l 5-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-methylcthyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9, I 0,12,13,14,14x,15-decahydro-2-methyl-, cyclopropylmethyl ester;
Pyrrolo[3',2':S,G][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-(1-piperidinyl)ethyl ester;
Pyrrolo[3',2':S,G][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I 5-decahydro-2-(phenylmethyl)-, ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 2-ethyl-3,7,8,9,10,12,13,14,14x,15-decahydro-, ethyl ester;
Pyrrolo[3',2':S,G][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14x,15-decahydro-, ethyl ester;

_g_ Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 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-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-(2-methylpropyl)-, ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x, l 5-decahydro-2-methyl-, I, I -dimethylethyl ester;
2,6x,7-Trimethyl-7,8,9,10,1 Oa, I 1-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester;
7-Ethyl-2,6x-dimethyl-7,8,9,10,1 Oa, l l -hexahydro-3H,GaH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester;
6a-Ethyl-2,7-dimethyl-7,8,9,10,1 Oa, l l-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyelopenta[a]anthracene-1-carboxylic acid ethyl ester;
6x,7-Diethyl-2-methyl-7, 8,9,10,1 Oa, l l -hexahydro-3H,GaH-6-oxa-3,7-diaza-cyclopenta[a]antbracene-1-carboxylic acid ethyl ester;
7-Benzyl-2,6x-dimethyl-7,8,9,10,1 Oa, l l -hexahydro-3H,6aH-6-oxa 3,7-diaza-cyclopenta[a]anthraccne-I-carboxylic acid ethyl ester;
2,7-Dimethyl-Ga-phenyl-7,8,9,10,1 Oa, l l-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-I-carboxylic acid ethyl ester;
Pyrrolo[3',2':S,G][1]benzopyrano[3,2-a]indole-I-carboxylic acid, 8,9,1 I , I 2, I 3,13a,14,14a-octahydro-2-methyl-, ethyl ester;
3H,7H-Pyrrolizino[1',8':S,G]pyrano[3,2-a]indole-I-acetic acid, 8,9,11,12,12x,13-hexahydro-2-methyl-, ethyl ester;
2-Methyl-8,9,10,1 Oa,11,12,12x,13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopcnta[h]anthracene-1-carboxylic acid ethyl ester;
3H-Pyrido[1",2":1'2']azepino[3'2':5,6]pyrano[3,2-a]indole-1-acetic acid, 7,8,9,10,12,13,14,15,15x,16-decahydro-2-methyl-, ethyl ester or 7H-Azepino[1",2":1'2']pyrido[3',2':5,6]pyrano[3,2-a]indole-1-acetic acid, 3,8,9,10,11,13,14,15,15x,16-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':S,G] [ 1 ]benzopyrano[3,2-i]quinolizine-1-carboxamide, 8,9,11,12,13,13x,14,14x-octahydro-2-methyl-N-(phenylmethyl)-;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxamide, N-ethyl-8,9,11,12,13,13 a,14,14a-octahydro-2-methyl-;
Pyrrolo[3',2': S, 6][ 1 ]benzopyrano[3,2-i]quinolizine-1-carboxaldehyde, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-;
Pyrrolo[3',2' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1-carboxamide,8,9,1 l,12,13,13a,14,14a-octahydro-N,2-dimethyl-;
Pyrrolo[3',2':5,6][lJbenzopyrano[3,2-i]quinolizine-1-carboxylic acid, 8,9, I 1,12,13,13a, l4, l4a-octahydro-2-methyl-, (4-fluorophenyl)-methyl ester;
Indazolo[4',S':5,6]pyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I S-decahydro-2-methyl-, 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-2,12,12-trimethyl-, 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-2,10, I 0-trimethyl-, phenyl methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-3,7, 8, 9,10,12, I 3,14,14a,15-decahydro-2-methyl-, phenylmethyl ester;
12H-Furo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester;
Pyrrolo(3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-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][1]benzopyrano[3,2-i]quinolizine-1-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, 3,7,8,9,10,12,13,14,14a,15-decahydro-4,5-dimethoxy-2-methyl-, 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-2,5-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;
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-, I-(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(3-carboxyphenyl)ethyl ester;
1-Propanaminium, N,N,N-trimethyl-, salt with 1-(3-carboxyphenyl)ethyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-pyrrolo[3',2':5,6] [ I ]-benzopyrano[3,2-i]quinolizine-1-carboxylate (I:1);
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-nitrophenyl)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-, 1-(3-cyanophenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14, I 4a,15-decahydro-2-methyl-, 1-[3-[(dimethylamino)carbonyl]phenyl]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-[3-[(dimethylamino)methyl)-phenyl]ethyl ester;
Pyrrolo[3',2':5,6][I]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][I]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][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,-methyl-, (4-carboxyphenyl)methyl ester;
I -[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-1 H-indol-4-ylmethyl]-1,2,3,4,6,7,8,9-octahydro-quinolizinylium; chloride;
Pyn-olo[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-(hydroxymethyl)phenyl]-methyl ester;

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1S-decahydro-2-methyl-, [3-(methoxycarbonyl)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,IS-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]-methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-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-, salt with (3-carboxypheny)-methyl 3,7,8,9,10, I 2,13,14,14a, I S-decahydro-2-methylpyrrolo[3',2':5,6][ I
]-benzopyrano[3,2-i]quinolizine-I-carboxylate (1:1);
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9, I 0,12,13,14,14a,15-decahydro-2-methyl-, [3-[(dimethylamino)methyl]-phenyl]methyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-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][1]benzopyrano[3,2-i]quinolizine-I-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][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-[1,1'-biphenylJ-4-ylethyl 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-, (2,6-difluorophenyl)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-, (1-phenyl-2,2,2-trifluoro)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-[3-(trifluoromethyl)phenyl]-ethyl ester;

Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-(1-pyrrolidinyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(1-naphthalenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-phenylcyclobutyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-phenylcylopropyl ester;
Pyn-olo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-pyrazinylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(4-quinolinyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2-pyrimidinyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl, 1-(4-fluorophenyl)ethyl ester;
Quinolizinium, 1-[[(4-fluorophenyl)methoxy]carbonyl]-5-hydroxy-2-methyl-1H-indol-4-yl]methyl]-1,2,3,4,6,7,8,9-octahydro-, chloride;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-1,2-dimethyl-, (4-fluorophenyl)methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-phenylpropyl ester;
Quinolizinium, 1,2,3,4,6,7,8,9-octahydro-1-[[5-hydroxy-2-methyl-3-[(phenylmethoxy)carbonyl]-1H-indol-4-yl]methyl]-, chloride;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I 5-decahydro-2-methyl-, (4-nitrophenyl)methyl ester;

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, l 5-decahydro-2-methyl-, ( 1 R)- I -phenyl ethyl ester;
Pyrrolo(3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, I-(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13, I 4,14x,15-decahydro-2-methyl-, phenyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2,2,2-trifluoro-I-phenyl-I-(trifluoromethyl)ethyl ester;
Pyrrolo[3',2':5,6][lJbenzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, bicyclo[2.2.1]hept-2-yl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9, I 0,12,13,14,14x,15-decahydro-2-methyl-, 1-(4-fluorophenyl)-1-methylethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-phenylcyclopentyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, I-phenylcyclohexyl ester;
Pyrrolo[3',2':5,6][lJbenzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9, I 0,12,13,14,14x,15-dccahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decalaydro-2-methyl-, (3-hydroxyphenyl)methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (IS)-I-(4-pyridinyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridinyl]methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (6-carboxy-2-pyridinyl)methyl ester;

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (6-carboxy-2-pyridinyl)methyl 3,7, 8,9,10, I 2,13,14,14x,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, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, [5-(methoxycxrbonyl)-3-pyridinyl]methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (5-carboxy-3-pyridinyl)methyl ester;
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (5-carboxy-3-pyridinyl)methyl 3,7,8,9,10,12,13,14,14x, I 5-decahydro-2-methylpyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylate (I:1);
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(4'-methyl[ I ,1'-biphenyl]-3-yl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2,6-dimethylphenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1S,2R)-2-(dimethylamino)-1-phenylpropyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (IR,2S)-2-(dimethylamino)-1-phenylpropyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-naphthalenyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I 5-decahydro-2-methyl-, diphenylmethyl ester;
Pyn-olo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1R)-2,3-dihydro-1H-inden-1-yl ester;

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,2-dihydro-1-acenaphthylenyl 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-, cyclohexyl(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-, 9H-fluoren-9-yl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,2,3,4-tetrahydro-1-naphthalenyl 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-, [(2R,3R)-3-phenyloxiranyl]methyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-oxo-1,2-diphenylethyl 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-, 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl 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-methylphenyl)phcnylmethyl ester;
Pymolo[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-m ethyl-, cyclopropyl(4-fluorophenyl)methyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)-1-(2-bromophenyl)ethyl ester;
Pyrrolo[3',2':5,6][lJbenzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2,2,2-trifluoroethyl ester;

Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, [(2S,3S)-3-phenyloxiranyl]methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, S 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethyl ester;
Pyrrolo[3°,2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2,2,2-trifluoro-1-(4-fluorophenyl)-1-(trifluoromethyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-cyclopentyl-1-phenylcthyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-[1,1'-biphenyl]-4-yl-1-methylethyl ester;
Pyn-olo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-methyl-1-phenyl-2-propynyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I 5-decahydro-2-methyl-, 1,1-diphenylethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-methyl-1,2-diphenylethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(4-fluorophenyl)cyclohexyl ester;
Pyn-olo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1,2-diphenylethyl ester;
Pyn-olo[3',2':5,6][1)benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I 5-decahydro-2-methyl-, 1-phenyl-2-propynyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, [1,1'-biphenyl]-4-ylmethyl ester;

WO 00/42045 PCTlUS99/30434 _17_ Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 4-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1,2,3,4-tetrahydro-7,8-dimethoxy-2-methyl-4-isoquinolinyl ester;
Pyrrolo[3',2':5,6)[1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-[3-(dimethylamino)phenyl]-ethyl ester;
Pyrrolo[3',2':5,6)[1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1,1-dimethyl-2-pyrazinylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 4-(dipropylamino)-1,1-dimethyl-2-butynyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (IS)-2,3-dihydro-1H-inden-1-yl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1S,2S)-2-(dimethylamino)-I-phenylpropyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]-methyl ester;
Pyn-olo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (4-chlorophenyl)methyl ester;
Pyrrolo[3',2':5,6)[1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-, phenylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-, ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-hydroxyethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i)qninolizine-1-carboxylic acid, 3,7,8,9, I 0,12, I 3,14,14x,15-decahydro-2-methyl-, (3-methylphenyl)methyl ester;

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, ( I S)-1-phenylethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, I-phenylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carbothioic acid, 3,7,8.,9,10,12,13,14,14x,15-decahydro-2-methyl-, S-(phenylmethyl) ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 3-pyridinylmethyl ester;
Pyrrolo[3',2':5,6](1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-[4-(trifluoromethyl)phenyl]-ethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, I-(pentafluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2,6-difluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1S)-I-(2-furanyl)cthyl ester Pyrrolo[3',2':5,6][1]benzopvrano[3,2-i]quinolizine-1-carboxylic acid, 3, 7,8,9,10,12,13,14, I 4x,15-decahydro-2-methyl-, 2-(4-morpholinyl)-1-phenylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1R)-I-(2-furanyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-methoxy-2-oxo-I-phenylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(3-pyridinyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester;

WO 00!42045 PCT/US99130434 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (S)-carboxy(phenyl)methyl, 3,7,8,9,10,12,13,14,14x,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, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1R)-2-methoxy-2-oxo-1-phenylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (R)-carboxy(phenyl)methyl ester;
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (R)-carboxy(phenyl)methyl, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methylpyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxyl ate (I:I);
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 4-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, I-(4-pyridinyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2-pyridinyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 3-thienylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1S)-1-(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1R)-1-(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 3-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 3-furanylmethyl ester;

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (2-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I S-decahydro-2-methyl-, 2-furanylmethyl ester;
S Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, I-(2-chlorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I 5-decahydro-2-methyl-, carboxymethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2,6-dichlorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2-methoxyphenyl)ethyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, I-(5-carboxy-3-pyridinyl)ethyl ester;
1,3-Benzenedicarboxylic acid, 5-[([(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][ 1 ]benzopyrano(3,2-i]quinolizin-1-yl)carbonyl]oxy]methyl]-, diethyl ester;
1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6] [ 1 ]benzopyrano[3,2-i]quinolizin-1-yl)carbonyl]oxy]methyl]-;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (5-xmino-2-chlorophenyl)methyl ester;
Pyrrolo(3',2':5,6)[1]benzopyrano[3,2-i]quinolizine-I-acetic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-.alpha.-oxo-, 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-2,4,5-trimethyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2,2,2-trichloro-1,1-dimethylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, tricyclo[3.3.1.137]dec-1-yl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-methyl-1-phenylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-methylcyclohexyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1,1,2-trimethylpropyl ester;
Pyrrolo[3',2':5,6][1]bcnzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-methylcyclopentyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-cyclohexyl-1-methylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidinyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 4-fluorophenyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-dccahydro-2-methyl-, 3-methylphenyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, phenyl ester;
Pyn-olo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 3-(methoxycarbonyl)phenyl 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-pyridinyl ester;
Pyrrolo(3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12, I 3,14,14a,15-decahydro-2-(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-, [5-[(dimethylamino)methyl]-2-furanyl]methyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-carboxy-2-methylpropyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(dimethylamino)-2,2-dimethylpropyl ester;
Propanedioic acid, monoanhydridc with 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6] [ 1 ]-benzopyrano[3,2-i)quinolizine-1-carboxylic acid, I,1-dimethylethyl 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-(dimethylamino)-2-methylpropyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(1H-imidazol-1-yl)ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-benzofuranylmcthyl 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-, (IR,2S)-2-(dimethylamino)-I-phenylpropyl ester;
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S,2R)-2-(dimethylamino)-1-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-, 1-(4-fluorophenyl)cyclopropyl ester;

WO 00142045 PCT/tJS99/30434 Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6] [ 1 ]benzopyrano [3,2-i]quinolizin-1-yl)carbonyl]oxy]methyl]-1-methyl-, methanesulfonate;
Pyrrolo[3',2':5,6] [ 1 ]benzopyrano[3,2-i]quinol izinium, 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)-1-phenylethyl ester, 11-oxide.
The instant invention includes pharmaceutical compositions of compounds of Formula 1 and methods of using the compounds for modulating chemokine receptor activity, for preventing or treating infection by HIV, delaying the onset of AIDS, treating AIDS, and treating inflammatory disease.
DETAILED DESCRIPTION OF THE INVENTION
In this present invention, compounds of Formula I can exist in two forms (close and open form) at the bicyclic aminal moiety. The equilibrium between these two forms is pH dependent. At a neutral or basic pH (pH ?7.0), these compounds predominantly exist in the closed form. However, at an acidic pH
range (pH <7.0), these molecules may exist as a mixture of both close and open form. The ratio of closed and open form may depend on pH and solvent, as well as the nature of substituents R, R2-R6, and n.
In the compounds of Formula I, the term alkyl means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, ti-heptyl, n-octyl, and the like. The alkyl can be substituted with fluorine, for example, additionally the alkyls can be substituted with from 1 to 3 substituents selected from alkoxy, carboxy, hydroxy, nitro, halogen, amino, and substituted amino to provide other active compounds. Alkyl includes cycloalkyl of from 3 to 7 carbons which can be substituted with, for example, I to 3 substituents selected from alkyl, alkoxy, carboxy, hydroxy, nitro, halogen, and amino and substituted amino. Cycloalkyl can be fused to an aryl ring such as phenyl, pyridyl, and the like.
Alkoxy is O-alkyl of from 1 to 6 carbon atoms as defined above for alkyl.
O
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 def ned above for alkyl, dialkylamino as defined for alkyl, nitro, cyano, carboxy, O O O
S03H, CHO, -C-alkyl as defined above for alkyl, -C-NH2, -C-NH-alkyl as O
defined above for alkyl, -C-N(alkyl)2 as deCned above for alkyl, -(CH2)112-NH2 wherein n2 is an integer of 1 to 5, -(CH2)1~2-NH-alkyl as defined above for alkyl and n2, -(CH2)112-N(alkyl)2 as defined above for alkyl and n2. The terns further includes heteroaryl which is a mono or bicyclic heteroaromatic radical having 5 to 10 atoms which may contain one or more of heteroatom such as N, O, S, including, for example, 2- or 3-thienyl, 2- or 3-furanyl, 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 above for aryl.
fhe term aralkyl or arylalkyl means an aryl radical attached to an alkyl radical 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 further forming N-oxides and N-quaternary alkyl salts with the ring nitrogen atom at N-11. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in R10. These structural forms are within the scope of the present invention.
Some of the compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, 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 as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M.
et al., "Pharmaceutical Salts,"J. ofPhczrj~ta. Sci., 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as canons are sodium, potassium, magnesium, calcium, and the like.
Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge supra., 1977}.
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or WO 00/42045 PCTlUS99130434 liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the earner is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyleellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing 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, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceridcs or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
Such liquid forms include solutions, suspensions, and emulsions. These preparations 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 preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 10U mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as agents for the treatment of HIV infection, the compounds utilized in the pharmaceutical method of this invention can be administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily. A daily dose range of about 25 mg to about 75 mg per kilogram is preferred.
The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached.
For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The compounds of Formula I are valuable antagonists of the CCR-5 chemokine receptor. Compounds which are antagonists of the CCR-5 chemokine receptor are expected to have efficacy in inhibiting HIV infection and are thus useful in the treatment of AIDS. The compounds of the present invention were evaluated in a CCR-5 receptor binding assay.
CCR-5 Receptor Binding Assay The 1251-gp 120/sCD4/CCR-5 binding assay was carried out similarly as described in Wu et al., Nature, 1996;384:179-183. Briefly, the envelope gp120 protein derived from HIV-1 JR-FL (Trkola et al., Nature, 1996;384:184-186), a M-tropic strain, was iodinated using solid phase lactoperoxidase to a specific activity of 20 pCi/pg. For each binding reaction (in a final volume of 100 p.L
binding buffer [50 mM HEPES, pH 7.5, 1 mM CaCl2, 5 mM MgCl2, and 0.5%
BSA]), 25 pL (2.5 pg) of membranes prepared from CCR-5/L 1.2 cells were mixed with 25 pL (3 nM) sCD4, followed by 25 ~tL (0.1 nM) radio-labeled gp120 in the presence or absence of 25 pL compound dissolved in DMSO (final concentration of DMSO 0.5%). The reactions were incubated at room temperature for 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 NaCI.
The plates were dried and MicroScint scintillation fluid was added before , counting.
The compounds of present invention, represented by Formula I, block the sCD-4/GP-120 binding to CCR-5 receptor with affinity less than or equal to 200 ~M.
Synthesis of CCR-5 Analogs Synthesis of the final target compounds is shown in Scheme 1.
Compound II in a protic solvent, preferably ethanol, was treated with aqueous forn~aldehyde and dimethylamine at temperatures which ranged from 0-90°C, preferably at 25-60°C, to give the Mannich base III. Condensation of III with a enamine at temperatures which ranged from 50-110°C, preferably at 80-100°C, under nitrogen atmosphere in an aprotic solvent, preferably dioxane, gives compound IV. Alkylation of IV with NaH and alkylhalides in an aprotic solvent, preferably DMF, under nitrogen atmosphere at temperatures which ranged from -10 to 25°C, preferably at 0-25°C, provides compound I (where R1 ~ H).
The preparation of indole intermediates is shown in Scheme II. Reaction of bromoacetate with nitriles in an aprotic solvent, preferably THF, in the presence of activated Zn at reflux under nitrogen atmosphere gives amino crotonates V.
Alternatively, amino crotonates V can be obtained by reacting the corresponding (3-ketoester with ammonia in EtOH. The (3-ketoestcrs can be derived from 2,2,6-trimethyl-4H-1,3-dioxin-4-one and the con-esponding alcohols. Condensation of amino crotonates V with substituted benzoquinone in a solvent, preferably acetic acid, ethanol, or nitromethane at temperatures which ranged from 25°C
to reflux affords substituted 5-hydroxyindoles VI. The indole ester VI is hydrolyzed to the corresponding acid VII using aqueous NaOH at temperatures which ranged from 50-100°C, preferably at reflux, under nitrogen. To suppress the decarboxylation reaction, it is important that after the reaction is done the reaction mixture was cooled to 0°C in an ice-water bath and acidified with a concentrated acid, preferably HCI, at 0°C to generate the acid. Esters or amides IX can be made from acid VIII following several standard esterification procedures or a standard procedure for amide synthesis using HBTU as the coupling reagent. For the ester synthesis, Mitsunobu procedure is preferred where appropriate alcohols, DEAD, and Ph3P are used, and the reaction is carried out at ambient temperature.
Another preferred procedure to make esters is treating the acid with a base, preferably DBU, and alkylhalides or arylalkylhalides in a polar solvent, preferably DMF
or acetonitrile at ambient temperature.
The following schemes are illustrative of the procedures useful in the preparation of final compounds. Variations known to skilled chemists are considered part of the invention.

WO 00/42045 PCT/~JS99/30434 Scheme 1 Preparation of Final Target Compounds -(CH2 )n HO / I ~ R11CH0 Y R4 X HO
N
R2 R H Me2NH ~ I N X dioxane R
II III
c6 R6~
~(CH2 )n ~(CH2 )n N R ~O
/ 3 NaH /N R3 O ~, R5 4 O / 1 \ Y ----~ RS 4 O / R11 X R1X I \X
N ~ ' N

IV I

Scheme 2 Preparation of Substituted Indole Derivatives O
O xylenes O O
+ R'OH ~ ~
O 150°C / v \0R' EtOH
O O
C02R' O activated Zn 1. Br~ + R~-CN ~ R2 R
OR' THF, reflux H N R

V
O OR~ O OH
HO / HO
N~R,/ Nap \ I N~R

VI VII
O O
OH y 2. R'0 R'O
\X ester or amide ~ ~ \X
R2 \ N formation R2 R H R H
R' = H or CI-I3C0 VIII IX

Scheme 3 O R3 O 02R~2 R %'~ , HO

\ I O>-- R3 O R3=Me, Ph R2 C
A
C(O)XR'2 ~N C(O)XR'2 HO / HO
/
\ ~R3 ~ \ ~ ~ R3 D E
X=O,N
~/ Z, N
~2 G
Substituted S-hydroxybenzofurans (C).
S 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 by recrystallization or flash chromatography on silica gel.
Mannich Bases (E).
The S-hydroxybenzofuran (C, D) was treated with aqueous dimethylamine and aqueous formaldehyde in ethanol at 50°C or, alternatively, with N,N,N',N'-tetramethyldiaminomethane in refluxing dioxane until the reaction was complete.

The solution was concentrated under reduced pressure, and the product was purified by recrystallization.
Benzofurans (G).
The mannich base (E) was added to a dioxane solution of enamine (F), which was freshly prepared by treating its perchlorate salt with aqueous sodium hydroxide, extracting the enamine into ether, drying and concentrating the extracts in vacuo. The resulting solution was heated between 80-100°C until the reaction was complete. The mixture was concentrated in vacuo and the product purified by recrystallization or flash chromatography on silica gel.

Scheme 4 Synthesis of 7-Azaindoles Analogs OH H ~ 'pH 1 OH H3C
II \J~' 1Z I ~ OH
P~N=N N pd/C, AcOH HZN N AcOH, rt HZN N Pd(dppf)C12 LiCI, NaZC03 DMF, 100°C
Pd(dppf)C12 3 LiCI, NaZC03 O
DMF, 100°C H3C-OH
O O
HO \ I I OH IC MnOq HO \ I I O R---~ O \ I I
_ OR
N H KZ O N~ HBTU N
H H

N~
O N
N O
CHZO HO ~ I I O O ~ OR
w~ ~ w HN(CH ) N N

Procedures:
Starting with commercially available 3-hydroxy-2-phenylazopyridine (1) the corresponding aminopyridine is synthesized by reducing 1 in the presence of H2 (57 bar) and Pd/C in acetic acid at 65°C (Synthesis, 1990: 681) to afford amine 2. Amine 2 is then transformed into 2-amino-5-hydroxy-3-iodopyridine through reaction with iodine and acetic acid (Synthesis, 1990:681) at room temperature. The iodopyridine 3 is then converted to the azaindole 4 via palladium catalyzed cyclization with the appropriately substituted alkyne (Tetrahedron Lett., 1998;39:5355; Tetrahedron Lett., 1993;34:2823). Conversion of 3 to 4 is followed by oxidation of the hydroxymethylene to the corresponding acid 5 using KMn04 in the presence of K2C03 (Gazz. Chim. Itnl., 1932;62:844) Alternatively, direct conversion of 3 to 5 is accomplished by using the carboxy substituted alkyne. Esterification of 5 to the desired ester is effected using diimide coupling reagents and the desired alcohol (J. Of g. CJrem., 1995;60:5214).
Substitution of the pyridine ring using formaldehyde and dimethyl amine (Tetrahedron Lett., 1966:4459) afforded 7. Intermediate 7 is then converted to the final azaindole analog 8 by reacting 7 and the quinolizidine imine shown in refluxing ethanol (J. Net. Chenz., 1970;7:131).

Scheme 5 Preparation of Final Target Compounds From Novel Intermediate 1. oxalyl chloride Rg 2. NHR~R8 Kl ~ RI
I II

---(CH2 ) n 1. oxalyl chloride /N R3 O O-R~
RS
2. HORS

R1 IV Rl I O III
~ 'O~
Cl~ R
'0I
O \
Halogen base --(CH2)n R,N R3 CORD
\X
N

Compound I in an aprotic solvent, preferably Et20, CH2C12, or THF, was treated with a solution of oxalyl chloride in the same aprotic solvent at temperatures ranged from -10°C to 30°C, preferably at 0°C to 25°C, followed by treatment of an amine of choice in an aprotic solvent to give the desired product II. The desired product III can be obtained by reacting compound I with oxalyl chloride in an aprotic solvent, preferably Et20, CH2Cl2, or THF, at temperatures ranged from -10°C to 30°C, preferably at 0°C to 25°C, followed by treatment of an alcohol of choice in an aprotic solvent. Alternatively, the desired product III can be made by reacting compound I with compound IV in an aprotic solvent such as Et20, CH2Cl2, or THF.

WO 00!42045 PCT/US99/30434 Scheme 6 Preparation of the Mixed Anhydride R6 R6.
CH2)n ~ ~ ~ CH2)n N R O
RS 3 O Pd/C (20%) R/N R3 O
R4 O -~' S R4 %X THF, Hz O / ~ X
N
R2 ' N

I RI
I II

O ~-- CH2)n O

Cl R4 O /
\\X
Et3N, THF i ".

Rl III
General Description 5 The benzylester I is subjected to hydrogenolysis reaction conditions in aprotic polar solvents, preferably THF, at ambient temperature to give acid II. The acid II is treated subsequently with benzoyl chloride in presence of an organic base, such as Et3N, to afford the mixed anhydride III.

Scheme 7 Synthesis of Esters From the Mixed Anhydride % 10 RS O
RS R4 O\ ~ ~O + RIO -OH 100-180°C

1Z1 ~ R1 I II
General Description The mixed anhydride I is mixed with the desired alcohol, the resultant reaction mixture was heated to 100°C to 180°C until the mixed anhydride is consumed affording the corresponding ester.

The present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the anti-HIV compounds, immunomodulators, anti-infectives, or prophactic or therapeutic vaccines known to those of ordinary skill in the art.

ANTIVIRALS
Drug Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor) GW141 W94/ Glaxo Wellcome HIV infection, AIDS, ARC

VX478 (protease inhibitor) Amprenavir GW 1592U89 Glaxo Wellcome HIV infection, AIDS, ARC

Abacavir (RT inhibitor) Acemannan Carrington LabsARC

(Irving, TX) Acyclovir Burroughs WellcomeHIV infection, AIDS, ARC, in Combination with AZT

AD-439 Tanox BiosystemsHIV infection, AIDS, ARC

AD-519 Tanox BiosystemsHIV infection, AIDS, ARC

Adefovir dipivoxilGilead SciencesHIV infection AL-721 Ethigen ARC, PGL HIV positive, AIDS

(Los Angeles, CA) Alpha InterferonGlaxo Wellcome Kaposi's sarcoma, HIV
in combination Alferon InterferonInterferon SciencesKaposi's sarcoma, HIV
in combination Ansamycin Adria LaboratoriesARC

LM 427 (Dublin,'OH) Erbamont (Stamford, CT) Antibody whichAdvanced BiotherapyAIDS, ARC

neutralizes Concepts pH

labile alpha (Rockville, MD) aberrant Interferon AR177 Aronex Pharm HIV infections, AIDS, ARC

beta-Iluoro-ddA Nat'I Cancer Institute AIDS-associated diseases WO 00!42045 PCT/US99/30434 ANTIVIRALS (cont'd) Dnig Name Manufacturer Indication BMS-232623 Bristol-Myers HIV infection, AIDS, ARC

(CGP-73547) SquibblNovartis(protease inhibitor) BMS-234475 Bristol-Myers HIV infection, AIDS, ARC

(CGP-61755) Squibb/Novartis(protease inhibitor) (-)6-Chloro-4(S)-Merck HIV infection, AIDS, ARC

cyclopropylethynyl- (non-nucleoside reverse 4(S)-trifluoro- transcriptase inhibitor) methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one CI-1012 Warner-Lambent HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Combivir AZT+3TCGlaxo Wellcome HIV infection, AIDS, ARC

Curdlan sulfateAJI Phanna USA HIV infection CytomegalovirusMedImmune CMV retinitis immune globin Cytovene GanciclovirSyntex/Roche Sight threatening CMV, peripheral CMV, retinitis Delaviridine Pharmacia-UpjohnHIV infection, AIDS, ARC

(RT inhibitor) Dextran SulfateUeno Fine Chem.AIDS, ARC, HIV positive Ind.

Ltd. (Osaka, asymptomatic Japan) HIVID (ddc) Hoffman-La RocheHIV infection, AIDS, ARC

Dideoxycytidine ddI DideoxyinosineBristol-Myers HIV infection, AIDS, Squibb ARC;

combination with AZT/d4T

DMP-450 Triangle HIV infection, AIDS, ARC

Pharmaceutical (protease inhibitor) Efavirenz (DMPDuPont Merck HIV infection, AIDS, 266) ARC

(non-nucleoside RT
inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline Herpes zoster, herpes simplex Foscavir/FoscarnetAstra CMV, HSV 1-2 ANTIVIRALS (cont'd) Drug Name Manufacturer Indication FTC Triangle HIV infection, AIDS, ARC

Pharmaceutical (reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC

(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection, AIDS, ARC

Roussel (non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC

Recombinant Triton BiosciencesAIDS, Kaposi's sarcoma, Human ARC

Interferon (Almeda, CA) Beta Interferon Interferon SciencesARC, AIDS
alpha-n3 Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV
positive, also in combination with AZT/ddI/ddC

ISIS 2922 ISIS PharmaceuticalsCMV retinitis JE 2147 (KNI-764)Japan Energy/ HIV infection, AIDS, ARC

Protease inhibitorAgouron PI (reverse transcriptase inhibitor);

also with AZT

KNI-272 Nat'1 Cancer HIV-associated diseases Institute Lamivudine, Glaxo Wellcome HIV infection, AIDS, (reverse transcriptase inhibitor);

also with AZT

Lobucavir Bristol-Myers CMV infection - HBV
Squibb infection Nelfinavir Agouron HIV infection, AIDS, ARC

Pharmaceuticals (protease inhibitor) Nevirapine Boeheringer HIV infection, AIDS, ARC

Ingleheim (RT inhibitor) Novapren Novaferon Labs, HIV inhibitor Inc.

(Akron, OH) Peptide T Peninsula Labs AIDS

Octapeptide (Belmont, CA) Sequence ANTIVIRALS (cont'd) Drug Name Manufacturer Indication PNU-140690 Pharmacia UpjohnHIV infection, AIDS, ARC

(protease inhibitor) Probucol Vyrex HIV infection, AIDS

RBD-CD4 Sheffield Med. HIV infection, AIDS, Tech ARC

(Houston, TX) Ritonavir Abbott HIV infection, AIDS, ARC

(protease inhibitor) S-1153 Agouron/ShionogiNnRTI

Saquinavir Hoffmann-La RocheHIV infection, AIDS, ARC

(protease inhibitor) Stavudine; Bristol-Myers HIV infection, AIDS, d4T Squibb ARC

Didehydrodeoxy-thymidine Valaciclovir Glaxo Wellcome Genital HSV & CMV infections Virazole RibavirinViratek/ICN Asymptomatic HN positive, (Costa Mesa, LAS, ARC
CA) Zidovudine; Glaxo Wellcome HIV infection, AIDS, AZT ARC, Kaposi's sarcoma, in combination with other therapies IMMUNO-MODULATORS
Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS

Bropirimine Pharmacia UpjohnAdvanced AIDS

Acemannan Carrington Labs,AIDS, ARC
Inc.

(Irving, TX) CL246,738 American CyanamidAIDS, Kaposi's sarcoma Lederle Labs EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharmBlocks HIV fusion with CD4+ cells Gamma InterferonGenentech ARC, in combination w/TNF

(tumor necrosis factor) IMMUNO-MODULATORS (cont'd) Drug Name Manufacturer Indication Granulocyte Genetics InstituteAIDS

Macrophage 5andoz Colony Stimulating Factor Granulocyte Hoeschst-RousselAIDS

Macrophage Immunex Colony Stimulating Factor Granulocyte Schering-PloughAIDS, combination w/AZT

Macrophage Colony Stimulating Factor HIV core ParticleRorer Seropositive HIV

Immunostimulant IL-2 Interleukin-2Cetus AIDS, in combination wIAZT

IL-2 Interleukin-2Hoffman-La AIDS, ARC, HIV, in roche Immunex combination w/AZT

IL-2 Interleukin-2Chiron AIDS, increase in CD4 cell (aldeslukin) counts Immune GlobulinCutter BiologicalPediatric AIDS, in combination Intravenous (Berkeley, w/AZT
CA) (human) IMREG-1 Imreg AIDS, Kaposi's sarcoma, ARC, (New Orleans, PGL
LA) IMREG-2 Imreg AIDS, Kaposi's sarcoma, ARC, (New Orleans, PGL
LA) Imuthiol DiethylMerieux InstituteAIDS, ARC

Dithio Carbamate Alpha-2 InterferonSchcring PloughKaposi's sarcoma w/AZT, AIDS

Methionine- TNI PharmaceuticalAIDS, ARC

Enkephalin (Chicago, IL) MTP-PE Muramyl-Ciba-Geigy Kaposi's sarcoma Corp.

Tripeptide Granulocyte Amgen AIDS, in combination Colony wIAZT

Stimulating Factor _47_ IMMLJNO-MODULATORS (cont'd) Drug Name Manufacturer Indication Remune Immune ResponseImmunotherapeutic Corp.

rCD4 RecombinantGenentech AIDS, ARC

Soluble Human rCD4-IgG hybrids AIDS, ARC

Recombinant Biogen AIDS, ARC
Soluble Human CD4 Interferon AlfaI-Ioffman-La Kaposi's sarcoma AIDS, 2a Roche ARC, in combination w/AZT

SK&FI06528 Smith Kline HIV infection Soluble T4 Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination w/gamma Factor; TNF Interferon ANTI-INFECTIVES
Drug Name Manufacturer Indication Clindamycen Pharmacia UpjohnPCP
with Primaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille NystatinSquibb Corp. Prevention of oral candidiasis Pastille Ornidyl EflornithineMerrell Dow PCP

Pentamidine LyphoMed PCP treatment Isethionate (Rosemont, IL) (IM &

IV) Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial Piritrexim Burroughs WellcomePCP treatment Pentamidine Fisons CorporationPCP prophylaxis isethionate for inhalation -4g ANTI-INFECTIVES (cont'd) Drug Name Manufacturer Indication Spiramycin Rhone-Poulenc Cryptosporidial diarrhea Intraconazole- 7anssen Pharm. Histoplasmosis; cryptococcal RS 1211 meningitis Trimetrexate Warner-Lambert PCP
OTHER
Drug Name Manufacturer Indication Daunorubicin NeXstar, SequusKarposi's sarcoma Recombinant Ortho Pharm. Severe anemia associated Human Corp. with Erythropoietin AZT therapy Recombinant Serono AIDS-related wasting, Human cachexia Growth Hormone Megestrol AcetateBristol-Myers Treatment of anorexia Squibb associated w/AIDS

Testosterone Alza, Smith AIDS-related wasting Kline Total Enteral Norwich Eaton Diarrhea and malabsorption Nutrition Pharmaceuticalsrelated to AIDS

It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
The following examples are illustrative of the intermediate and final compounds and methods for their preparation. They are not intended to limit the scope of the invention.

EXPERIMENTALS
Synthesis of Intermediate Indole derivatives 5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid (A) 5-Hydroxy-2-methyl-1-H-indole-carboxylic acid (8.54 g, 44.7 mmol) was dissolved in aqueous sodium hydroxide (2N, 45 mL). 1-acetyl-1H-2,3-triazolo(4,5-b-)-pyridine (7.24 g, 44.7 mmol) was dissolved in THF (30 mL), and the solution was added to the solution of 5-hydroxy-2-methyl-1-H-indole-carboxylic acid. The mixture was stirred until little or no starting material remained, ~30 minutes; a white precipitate formed. The mixture was cooled to 0°C and concentrated HCl was added dropwise until the pH was ~1. The resulting white solid was filtered, washed with water (2 x 50 mL), recrystallized from ethanol, and dried under vacuum, yield 6.95 g (67%); mp 233-235°C
(dec); IR:
3331, 1740, 1642, 1234, 1207 cm-l. 1H NMR (DMSO-d6) 8: 2.21 (s, 3H
CH3C02), 2.59 (s, 1H, ArCH3), 6.79 (d, J= 6.84 Hz, 1H, ArH), 7.27 (d, J= 8.55 Hz, 1H, ArH), 7.53 (s, 1H, ArH), 11.77 (s, 1H, NH) 11.93 (s, lI-I, COOH). MS(APCI+): m/z 234.1 (MH+). Analysis calculated for C12H11N104~
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 preparation of esters 5-Hydroxy-2-methyl-1-H-indole-carboxylic acid or 5-acetoxy-2-methyl-1H-indole-3-carboxylic acid (4-28 g) was combined with enough THF to effect dissolution. 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 overnight at ambient temperature. The solution was concentrated in vacuo to give an oily mixture; a solution of 1:1 hexanelcthyl acetate was used to redissolve the oil. The desired product was purified by flash chromatography. Residual diethylhydrazinedicarboxylate remaining in the product was removed by trituration with hot water; the resulting solid was dried under vacuum at 40°C. For compounds made with 5-acetoxy-2-methyl-1H-indole-3-carboxylic acid, the 5-acetyl group was removed in the following manner: the protected 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 S aqueous HCI, and a copious white precipitate occurred. The solid was filtered, washed with water (2 x 20 mL), and dried under vacuum at 40°C.
Alternatively, the pH of the solution was adjusted to 1 with the addition of aqueous HCI, and the solution was extracted with ethyl acetate (2 x 25 mL). The organic layer was dried over Na2S04 and evaporated to give a solid. The solid may be further purified by 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; 1H NMR
(DMSO-d6) 8 2.21 (s, 3H, CH3C02), 2.60 (s, 3H, ArCH3), 5.28 (s, 2H, CH2Ph), 6.82 (dd, J= 8.55, 2.44 Hz, IH, ArH), 7.26-7.41 (m, 6H, ArH), 7.53 (d, J= 2.44 Hz, 1H, ArH), 11.9 (s, 1H, NH). MS(APCI+): 324.1 (MH+). Analysis calculated for CI~H17N104: 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 (76%); mp 191-193°C; IR: 3227, 1654, 1472, 1429, 1094 cm-I. IH NMR
(DMSO-d6) 8 2.54 (s, 3H, alkyl CH3 ), 5.26 (s, 2H, PhCH2), 6.55 (d, J= 6.10 Hz, 1 H, ArH), 7.08 (d, J= 8.8 Hz, 1 H, ArH), 7.24-7.42 (m, 6H, ArH), 8.82 (s, 1 H, aromatic OH), 11.55 (s, 1H, NH). MS(APCI+): ntlz 282.0 (MI-I+). Analysis calculated for C17H15N103: C, 71.71; H, 5.44; N, 4.92. Found: C, 71.72; H, 5.49; N, 4.85.
Alternatively, Intermediate C can be synthesized from Intermediate B according to the procedure described in Example 9, Step A.

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. 1H
NMR
(DMSO-d6) 8 0.99 (t, J= 7.51 Hz, 3H, CH2CH2CH3), 1.71 (sextet, J= 7.33 Hz, 3H, CH2CH2CH3), 2.26 (s, 3H, CH3C0), 2.63 (s, 3H, ArCH3), 4.17 (t, S J= 6.41 Hz, 2H, CII2CH2CH3), 6.86 (dd, J= 8.61, 2.20 Hz, 1H, ArH), 7.34 (d, J= 8.61 Hz, IH, ArH), 7.55 (d, J= 2.20 Hz, 1H, ArH), I 1.9 (s, 1H, NH).
MS(APCI+): m/z 276.0 (MH+). Analysis calculated for CISH17N104: C, 65.44;
H, 6.22; N, 5.09. Found: C, 65.13; H, 6.28; N, 5.10.
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-isopropyl ester (E) Yield:
0.720 g (12%); mp 188-189°C; IR: 3409, 3391, 1663, 1467, 1181, 1095 (cm-1).
1H NMR (DMSO-d6) 8 1.27 (d, J= 6.35 Hz, 6H, CH(CH3)2) , 2.52 (s, 3H, CH3), 5.04 (septet, J= 6.35 Hz, 1H, CH(CH3)2), 6.53 (dd, J= 8.55, 2.44 Hz, 1H, ArH), 7.06 (d, J= 8.55 Hz, 1H, ArH), 7.25 (d, J= 2.44 Hz, 1H, ArH), 8.77 (s, 1H, OH) I 1.4 (s, 1H, NH). MS(APCI+): m/z 234.1 (MH+). Analysis calculated for C 13H 15N103 ~ C~ 66.94; H, 6.48; N, 6.00. Found: C, 66.79; H, 6.53; N, 5.88.
5-Hydroxy-2-methyl-1H-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-l. 1H NMR (DMSO-d6) 8 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, J= 7.32 Hz, 2H, CH2CH), 6.27 (dd, J= 8.55, 2.44 Hz, 1H, ArH), 6.79 (d, J---- 8.55, 1H, ArH), 6.99 (d, J= 2.20, IH, ArH), 8.51 (s, 1H, OH), 11.2 (s, 1H, NH). MS(APCI+): rnlz 246.1 (MH+). Analysis calculated for C14H15N103~ C~ 68.56; H, 6.16; N, 5.71. Found: C, 68.50; H, 6.19; N, 5.67.
S-Acetoxy-2-methylindole-3-carboxylic acid I-phenyl-propyl ester (G) Yield:
1.36 g (23%); mp 144-145.5°C; IR: 3289, 1755, 1661, 1459, 1216, 1204, 1089 cm-1. 1H NMR (DMSO-d6) 8 0.863 (t, J= 7.32 Hz, 3H, CH2CH3), 1.82-1.98 (m, 2H, CHCH2CH3), 2.22 (s, 3H, CH3C0), 2.63 (s, 3H, ArCH3), 5.80 (t, J= 6.84 Hz, 1H, benzylic CH), 6.83 (dd, J= 8.79, 2.20 Hz, 1H, ArH), 7.21-7.3G (m, 6H, ArH), 7.60 (d, J= 2.20 Hz, 1H, ArH), 11.9 (s, 1H, NH).
MS(APCI-): m/z 350.1 (M-1). Analysis calculated for C21H21N104~ C> 71.78;
H, G.02; N, 3.99. Found: C, 71.53; H, 6.02; N, 3.81.
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid isobutyl ester (H) 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid isobutyl ester was synthesized according to the general procedure A and was recrystallized from hexanelCH2Cl2 to give 1.39 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-d6) 8 0.95 (d, J= G.84 Hz, 6H, CH(CH3)2), 1.94 (n, J= 6.84 Hz, 1H, CH(CH3)2), 2.54 (s, 3H, CCH3), 3.95 (d, J= 1.95 Hz, 2H, OCH2), 6.54 (dd, J= 8.55, 2.44 Hz, 1H, ArH), 7.07 (d, J = 8, 1 H, ArH), 7.25 (s, 1 H, ArH), 8.81 (s, 1 H, OH), 11.49 (s, 1 H, NH);
MS(APCI+): m/z 248.1 (MH+). Analysis calculated for C 14H 17N03: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.92; H, 6.87; N, 5.54.
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl-propyl ester (I) 5-I-Iydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl-propyl ester was synthesized according to the general procedure A and was recrystallized from CH2CI2 to give 2.31 g (33.8%) of white solid: mp 195-196°C; IR
(KBr) 3262, 2960, 1652, 1464, 1170, 1094 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 0.97 (s, 9H, C(CH3)3), 2.55 (s, 3H, ArCH3), 3.87 (s, 2H, OCH2), 6.55 (dd, J= 8.55, 2.44 Hz, 1H, ArCH), 7.07 (d, J= 8.55 Hz, 1H, ArCH), 7.29 (s, 1H, ArH), 8.82 (s, 1H, OH), 11.50 (s, 1H, NH); MS(APCI+); m/z 2G2.1(MH+). Analysis calculated for C15H19N03~ 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 Preparation of Esters A solution of 5-acetoxy-2-methyl-1H-indole-3-carboxylic acid (Aldrich, 5.00 g, 21.4 mmol) and diethyl azodicarboxylate (Aldrich, 3.73 g, 21.4 mmol) in 7 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 32 mL of THF over an hour. After stirring at room temperature for 24 hours, the mixture was concentrated. The product was purified by flash column chromatography on silica gel (10% MeOH,CHCl3) to give the corresponding ester.
S 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperdin-1-yl-ethyl ester (J) 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperdin-lyl-ethyl ester was synthesized according to the procedure B and was recrystallized from hexane/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; 1H NMR (400 MHz, DMSO-d6) 8 1.31 (m, 2H, NCH2CH2CH2), 1.42 (m, 4H, NCH2CH2), 2,38 (m, 4H, NCH2CH2CH2), 2.53 (s, 3H, ArCH3), 2.59 (t, J= 6.10 Hz, 2H, OCH2CH2), 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 C17H22N203: 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 temperature for 15 minutes. The HCl solution was decanted, and this was repeated two times. The activated Zn was washed with distilled H20 (2x, 100 mL), ethanol (2x, 50 mL), and ether (2x, 50 mL). The activated Zn was then placed under reduced pressure for 12 hours at 40°C. To a stirred solution of dry THF (30 mL) and activated Zn (3.27 g, 50 mmol) in a flame dried 100 mL round bottom flask under an inert atmosphere was added 0.2 mL of ethylbromoacetate (1) at room temperature. The reaction was then heated to reflux. After the solution turned green (15-30 min), the alkyl cyanide (10 mmol) was added at once, and ethylbromoacetate (4.44 mL, 40 mmol) was added dropwise over 30 minutes and refluxed for an additional 30 minutes and then allowed to cool to room temperature. To the stirred solution was added THF

(30 mL) and K2C03 (13 mL, 50% w/w) and stirred vigorously for 30 minutes.
The solution was then placed in a centrifuge tube and centrifuged. The supernatant was decanted, and the pellet was resuspended in THF (30 mL), shaken vigorously and centrifuged (procedure repeated twice). The combined supernatant were dried over MgS04, filtered, and concentrated under reduced pressure to yield of ethyl 3-alkyl-3-aminocrotonate as a crude product which was used directly in the next step.
Ethyl 3-amino-3-benzylcrotonate (K) 1H NMR (250 MHz, CDC13) b 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, 5H).
Ethyl 3-amino-3-ethylcrotonatc (L) 1H NMR (250 MHz, CDC13) 8 1.47 (t, J=
7.5 Hz, 3H), 1.26 (t, J= 7.1 Hz, 3H), 2.16 (q, 5.7 Hz, 2H), 4.11 (q, J= 5.4 Hz, 2H), 4.55 (s, 1H). 13C NMR (62.5 MHz, CDCI3) c5 12.0, 14.5, 29.3, 30.3, 58.5, 82.6, 164.9, 170.5.
Ethyl 3-amino-3-cyclopropylcrotonate (M) IH NMR (250 MHz, CDCI3) 8 0.74 (m, 2H), 0.86 (m, 2H), 1.25 (t, J= 7 Hz, 3H), 2.27 (s, 1H), 4.10 (q, J= 7 Hz, 2H), 4.45 (s, 1H). 13C NMR (62.5 MHz, CDC13) 8 7.1, 14.6, 15.8, 58.5, 80.7, 165.1, 170.4. LC/MS (150 mm x 4.6 mm, C-18, S micron, 10 mM NH40Ac/
CH3CN, APCI+) t = 7.24 min, mlz = 156 (M+1).
Ethyl 3-amino-3-propylcrotonate (N) 1H NMR (250 MHz, CDCl3) 8 0.95 (t, J= 7.3 Hz, 3H), 1.26 (t, J= 7.1 Hz, 3H), 1.56 (s, J= 7.3 Hz, 2H), 2.10 (d, J= 7.3 Hz, 2H), 4.1 (q, J= 7.2 Hz, 2H), 4.53 (s, 1H). 13C NMR (62.5 MHz, CDC13) 6 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 NH40Ac/CH3CN, APCI+) t = 8.02 min, rnlz = 158.4 (M+1).

Ethyl 3-amino-3-isobutylcrotonate (O) 1H NMR (250 MHz, CDC13) 8 0.95 (d, J= 6.4 Hz, 6H), 1.26 (t, J= 7.1 Hz, 3H), 1.9 (m, IH), 1.96 (d, J= 7.0 Hz, 2H), 4.1 I (q, J= 7.1 Hz, 2H), 4.51 (s, 1H). LC/MS (150 mm x 4.6 mm, C-18, micron, 10 mM NH40Ac/CH3CN, APCI+) t = 8.69 min, m/z = 172.4 (M+1 ).
5 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) in acetic acid (50 mL) was added 1,4-benzoquinone (3.3 g, 30.5 mmol). The solution was stirred overnight at room temperature and then filtered through a frit.
The solid was washed with cold distilled water and dried in an Abderhalden over P205 to afford the ethyl 2-alkyl-5-hydroxy-3-indolecarboxylate.
Ethyl 2-benzyl-5-hydroxy-3-indolecarboxylate (P) 70% yield (from starting nitrile) of a white powder. 1 H NMR (250 MHz, DMSO) ~ 1.32 (t, J= 7.08 Hz, 3H), 4.26 (q, J= 7.05 Hz, 2H), 4.41 (s, 2H), 6.63 (dd, J= 8.5, 2.2 Hz, 1H), 7.25 (m, 7H), 8.88 (s, 1H), 11.64 (s, 1H). 13C NMR (62.5 MHz, DMSO) 8 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 mM
NH40AclCH3CN, APCI+) t = 7.83, ntlz = 296.3 (M+1 ).
Ethyl 2-ethyl-5-hydroxy-3-indolecarboxylate (Q) 54% yield (from starting nitrile) as a white powder. 1H NMR (250 MHz, DMSO) b 1.23 (t, J= 7.6 Hz, 3H), 1.33 (t, J= 7.1 Hz, 3H), 3.04 (q, J= 7.5 Hz, 2H), 4.24 (q, J= 7.1 Hz, 2H), 6.5 (dd, J= 8.7, 2.4 Hz, 1H), 7.14 (d, J= 8.5 Hz, 1H), 7.33 (d, .7= 2.4 Hz, 1H), 8.82, (s, IH), 11.48 (s, IH). 13C NMR (62.5 MHz, DMSO) 8 13.6, 14.4, 20.7, 58.4, 105.3, 111.3, I I 1.6, 127.9, 128.9, 150.0, 152.2, 165Ø LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH40Ac/CH3CN, APCI+) t = 7.60 min, m/z = 234.3 (M+1 ).
Ethyl 2-cyclopropyl-5-hydroxy-3-indolecarboxylate (R) 83% yield (from staring nitrile) as a white powder. 1H NMR (250 MHz, DMSO) 8 0.97 (m, 2H), 1.10 (m, 2H), 1.35 (t, .I= 7.1 Hz, 3H), 3.00 (m 1H), 4.26 (q, J= 7.0 Hz, 2H), 6.59 (dd, 8.7, 2.4 Hz, 1H), 7.8 (d, J= 8.7 Hz, 1H), 7.30 (d, J= 2.4 Hz, IH), 8.81 (s, 1H), 10.93 (s, 1H). 13C NMR (62.5 MHz, DMSO) 8 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 NH40Ac/CH3CN, APCI+) t = 7.03 min, m/z = 246.3 (M+1).
Ethyl 5-hydroxy-2-propyl-3-indolecarboxylate (S) 62% yield (from starting nitrile) as a white powder. /H NMR (250 MHz, DMSO) 8 0.93 (t, J= 7.3 Hz, 3H), 1.35 (t, J= 7.1 Hz, 3H), 1.67 (m, 2H) 3.01 (t, J= 9.0 Hz, 2H), 4.26 (q, J= 7.1 Hz, 2H), 6.77 (dd, J= 8.7, 2.2 Hz, 1H), 7.16 (d, J= 8.6 Hz, 1H), 7.35 (d, J= 2.2 Hz, 1H), 8.86 (s, 1H), I 1.51 (s, 1H). 13C NMR (62.5 MHz, DMSO) 8 13.7, 14.4, 17.2, 22.3, 29.2, 58.4, 105.2, I I I .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 NH40Ac/CH3CN, APCI+) t = 7.21 min, mlz = 248.4 (M+1 ).
Ethyl 2-isobutyl-5-hydroxy-3-indolecarboxylate (T) 68% yield (from starting nitrile) the as a white powder. 1H NMR (250 MHz, DMSO) 8 0.91 (d, J= 6.6 Hz, 6H), 1.35 (t, J= 7.1 Hz, 3H), 2.06 (m, 1H), 2.91 (d, J= 7.2 Hz, 2I I), 4.25 (q, J= 7.1 Hz, 2H), 6.62 (dd, J= 8.6, 2.4 Hz, 1H), 7.16 (d, J= 8.5 Hz, 1H), 7.35 (d, J= 2.4 Hz, 1H), 8.85 (s, 1H), 11.5 (s, 1H). 13C NMR (62.5 MHz, DMSO) a 14.4, 17.2, 22.3, 28.6, 36.2, 58.4, 102.0, 105.2, I 11.2, I 11.4, 127.9, 128.8, 147.6, 152.1, 165Ø LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH40Ac/CH3CN, APCI+) t = 7.69 min, »i/z = 262.4 (M+1 ).
Procedure E: General procedure for the preparation of indolc amides 5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid (I.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 stirred until the starting material was consumed, ~1 hour water was added. The pH of the resulting mixture was adjusted to 5 with HCl (1N), and extracted with ethyl acetate. The organic layer was dried and evaporated to give the crude product which can be further purified by flash chromatography or recrystallization.
Intermediates U-V were synthesized according to Procedure E. Acetic acid 2-methyl-3-methylcarbamoyl-1H-indol-5-yl ester (U) Yield: 0.093 g (18%);
mp 201-203°C; IR: 3402, 1748, 1609, 1218, 1170 cm-1. 1H NMR (DMSO-d6) 8 2.21 (s, 3H, CH3C0), 2.45 (s, 3H, ArCH3), 2.72 (d, J= 4.39 Hz, 3H, NHCH3), 6.76 (dd, J = 8.79, 1.46 Hz, 1 H, ArH), 7.24 (d, J = 8.79 Hz, 1 H, ArH), 7.25 (bs, 1 H, CONHCH3), 7.41 (s, 1 H, ArH), 11.5 (s, 1 H, indole NH). MS(APCI+); m/z 247.1 (MH+); Analysis calculated for C13H14N203'0.9 H20; C, 59.49; H, 6.07;
N, 10.67. Found: C, 59.51; H, 6.12; N, 10.55.
Acetic acid 3-benzylcarbamoyl-2-methyl-1H-indol-S-yl ester (V) Yield: 0.454 g (33%); mp 182-184°C; IR: 3413, 3319, 3222, 3191, 1750, 1609, 1228, 1216, 1170 cm-1. 1H NMR (DMSO-d6) c5 2.20 (s, 3H, CH3C0), 2.54 (s, 3H, ArCH3), 4.42 (d, J= 6.1 Hz, 2H, NHCH2Ph), 6.77 (dd, J= 8.55, 1.95 Hz, 1H, ArH), 7.1 S-7.19 (m, 1 H, ArH), 7.25-7.34 (m, SH, ArH), 7.45 (d, J= 1.71 Hz, 1 H, ArH), 7.89 (t, J= 6.10 Hz, 1H, CONIICH2Ph), 11.5 (s, 1H, indole NH). MS(APCI+):
m/z 323.2 (MH+); Analysis calculated for C 19H 1 gN203: C, 70.79, H, 5.63, N, 8.69. Found: C, 70.62, H, 5.78, N, 8.60.
Procedure F: General procedure for deacylation 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 material remained, ~45 minutes. The pH of the solution was adjusted to 1 with the addition of aqueous HCI, and the solution extracted with 2 x 25 mL of ethyl acetate.
The organic layer was dried and evaporated to give a solid. Recrystallization from ethyl acetate yields a white solid.
Intermediates W-X were synthesized according to Procedure F.
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl amide (W) Yield:
0.201 g (70%); mp 226-227°C;1R: 3366, 1602, 1558, 1552, 1215, 1198 cm-l. 1H

NMR (DMSO-d6) 8 2.45 (s, 3H, ArCH3~ obscured by DMSO peak), 2.70 (d, J= 4.40 Hz, 3H, CONHCH3), 6.51 (d, J= 8.55 Hz, I H, ArH), 7.02 (d, J= 8.55 Hz, 1H, ArH), 7.07 (s, 1H, ArH), 7.13-7.14 (m, 1H, CONHCH3), 8.65 (s, 1 H, OH), I 1.0 (s, I H, indole NH). MS(APCI+): m/z 205. I (MH+); Analysis S calculated for CI IH12N202~ C~ 64.69; H, 5.92; N, 13.72. Found: C, 64.53;
H, 5. 91; N, 13.44.
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl amide (X) Yield:
0.228 g (65.7%); mp: 194-196°C; IR: 3392, 3246, 1610, 1528, 1465, 1214, I 188 cm-1. 1H NMR (DMSO-d6) S: 2.48 (s, 3H, ArCH3), 4.41 (d, J= 5.86 Hz, 1U 2H, NHCH2Ph), 6.52 (d, J= 8.06, 1H, ArH), 7.04 (d, J= 8.55, 1H, ArH), 7.12 (s, 1H, ArH) 7.17-7.31 (m, SH, ArH), 7.71-7.78 (m, 1H, CONHCH2Ph), 8.68 (s, 1H, OH), 11.1 (s, 1H, indole NH). MS(APCI+): r~t/z 281.1 (MH+); Analysis calculated for C17H16N202: 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, ethyl ester H
_ y H3C \ ~ / ~ O
O, ~N
O
C

Synthesized according to procedures published in J. Het. Chem., 1970;7:131 I-1319.
20 Example 2 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 8,9, I 1,12,13, I 3a,14,14a-octahydro-2-methyl-, (4-fluorophenyl)methyl ester / -F
:,H3 Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-fluoro-benzyl ester To a solution of 5-hydroxy-2-methyl-1-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 at room temperature under nitrogen for 3 days and then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was separated, washed with water (2 x 100 mL) and then dried over Na2S04 and concentrated in vcacuo to give a white solid. Recrystallization from ethyl acetate gave 3.4 g (47%) of pure titled compound as a white solid: mp 209-210°C; IR 3412, 3377, 3305, 1667, 1512, 1466, 1221, 1176, 1094 cm-1; IH NMR (DMSO-d6) 8 2.53 (s, 3H, CH3), 5.23 (s, 2H, CH2), 6.55 (dd, J = 8.79, 2.20 Hz, 1 H, ArH), 7.08 (d, J= 8.79 Hz, 1H, ArH), 7.14-7.17 (m, 2H, ArH), 7.19 (d, J= 2.20 Hz, l II, ArH), 7.44-7.48 (m, 2H, ArH), 8.81 (s, 1H, OH), I 1.55 (s, lI-I, NII); MS(APCI+): m/z 300.1 (MH+).
Analysis calculated for C17H14F N 03: 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-1H-indole-3-carboxylic acid 4-fluoro-benzyl ester 5-Hydroxy-2-methyl-IH-indole-3-carboxylic acid 4-fluoro-benzyl ester (2.90 g, 9.69 mmol) and aqueous Me2NH (40%, 2.67 mL, 21.3 mmol) were mixed with 22 mL of EtOH, aqueous HCHO (37%, 0.940 g, 11.6 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°C for 16 hours. The reaction mixture was allowed to stand at 4°C for 15 hours, white precipitate formed. Filtration and drying under vacuum gave 1.56 g (45%) of pure titled compound as a white solid: mp 131-133°C (dec.); IR 3376, 3214, 1693, 1686, 1513, 1424, 1259, 1227, 1085, 806 cm-1; IH NMR (DMSO-dG) 8 2.12 (s, 6H, N(CH3)2), 2.45 (s, 3H, ArCH3), 3.97 (s, 2H, ArCH2NMe2), 5.23 (s, 2H, C02CH2Ar), 6.56 (d, J= 8.G1 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, exchangeable S proton); MS(APCI+): m/z 357.2 (MH+). Analysis Calculated for C20H21N203F1 ~O.1H20: C, 67.06; H, 5.97; N, 7.82; F, 5.30; H20, 0.50. Found:
C, 66.90; H, 5.81; N, 7.53; F, 5.33; H20, 0.20.
Step C: Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-, (4-fluorophenyl)methyl ester To a mixture ofperchlorate salt (1.27 g, 5.36 mmol, Example 3, Step B) and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 50 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual 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 rcfluxed under nitrogen for 5.5 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a brown solid. Recrystallization from CH3CN
gave 1.G3 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; 1H NMR
(DMSO-d6) 8 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.G0-2.70 (m, 2H, aliphatic CH), 2.84-2.91 (m, 1H, aliphatic CH), 3.17 (dd, J= 18.3, G.78 Hz, 1H, aliphatic CH), 5.21 (ABq, Jab = 11.9 Hz, vab = 19.0 Hz, 2H, C02CH2Ar), 6.59 (d, J-- 8.61 Hz, 1H, ArH), 7.03 (d, .I= 8.G1 Hz, IH, ArH), 7.17-7.25 (m, 2H, ArH), 7.48-7.52 (m, 2H, ArH), 11.5 (bs, 1H, NH); MS(APCI+): mlz 449.3 (MH+). Analysis calculated for C27H29N203F1~0.08CH3CN: 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-decahydro-Step A: 4-Dimethylaminomethyl-IH-indol-5-0l 5-Hydroxyindole (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 added followed by aqueous HCHO (37%, 3.65 g, 45.9 mmol). The resulting reaction mixture was stirred at ambient temperature for 1.5 hours during which time a precipitate formed. Filtration and drying under vacuum gave 4.13 g (57%) ofpure titled compound as a beige solid: mp 137-139°C; IR 3316, 1625, 1592, 1523, 1450, 1239, l 198, 724 cm-l; 1H NMR (DMSO-d6) 8 2.25 (s, 6H, CH2N(CH3)2, 3.76 (s, 2H, CH2N(CH3)2), 6.29-6.30 (m, 1H, ArH), 6.54 (d, J= 8.61 Hz, 1 H, ArH), 7.10 (d, J = 8.60 Hz, 1 H, ArH), 7.18-7.20 (m, 1 H, ArH), 10.8 (bs, 1H, exchangeable proton); MS(APCI+): m/z 191.1 (MH+). Analysis calculated for C 11 H 14N20- C, 69.45; H, 7.42; N, 14.72. Found: C, 69.36; H, 7.38; N, 14.71.
Step B: 1,2,3,4,6,7,8,9-Octahydro-quinolizinylium perchlorate N
C104 ~

The synthesis is found in David A. Evans, A new endocyclic enamine synthesis. JAC,S, 1970;92:7593-7595 and Leonard N.J., Hay A.S., Fulmer R.W., Gash V.W., Unsaturated amines. III. Introduction of a,(3-unsaturation by means of mercuric acetate: X1(10)-dehydroquinolizidine, J. Am. Che»t. Suc., 1955;77:439-444.
Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10, I 2,13,14,14x,15-decahydro-To a mixture of perchlorate salt (406 mg, 1.71 mmol, Example 3, Step B) and 20 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL).
The combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in 5 mL ofdioxane, then 4-dimethylaminomethyl-1H-indol-S-of (250 mg, 1.31 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature and a precipitate formed. Filtration and recrystallization from EtOAc gave 0.17 g (46%) of pure titled compound as a beige solid: mp >250°C;
IR 3414, 3148, 1454, 1242, 1148, 888 cm-1; 1H NMR (DMSO-d6) S 1.13-1.65 (m, 9H, aliphatic CH2 and CH), 1.76-1.91 (m, 2H, aliphatic CH), 2.36-2.52 (m, obscured by 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, lI-I, 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 CI gH22N20~0.1Ii20: C, 76.08; H, 7.87; N, 9.86; H20, 0.63. Found: C, 76.09; H, 7.81; N, 9.83; H20, 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-Step A: 2-Methyl-1H-indol-5-0l 5-Hydroxy-2-methyl-1H-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 70°C, the reaction solution was treated with concentrated aqueous HCl until pH = 1. The resulting dark brown solution was extracted with ether (3 x 300 mL). Combined ether solution was dried over Na2S04 and concentrated iu vucuo affording a brown solid. Recrystallization from EtOAc/CH2C12 gave 11.7 g (87%) ofpure titled compound as a light brown solid: mp 129-130°C; IR
3387, 3333, 1588, 1453, 1368, 1173, 783 cm-1; 1 H NMR (DMSO-d6) 8 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, J = 2.38 Hz, 1 H, ArH), 7.00 (d, J= 8.42 Hz, 1 H, ArH), 8.44 (s, 1 H, NH), 10.5 (bs, 1H, OH); MS(APCI+): mlz 148.1 (MH+). Analysis calculated for C9H9N0: 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-1H-indol-5-0l 2-Methyl-1H-indol-5-0l (5.00 g, 34.0 mmol) was dissolved in 20 mL of EtOH, 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 was stirred at ambient temperature for 2 hours, then mixed with 50 mL of water, precipitate formed. Filtration and recrystallization from ethanol (<SO°C) gave 3.0 g (43%) ofpure titled compound as a white solid: mp 133-135°C; IR
3404, 3385, 1598, 1515, 1428, 1271, 1204, 798, 778 cm-1; 1H NMR (DMSO-d6) 8 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, J= 8.79 Hz, IH, ArH), 10.6 (bs, IH, exchangeable proton); MS(APCI+): f~zlz 205.2 (MH+). Analysis calculated for C12H16N20- C, 70.56; H, 7.90; N, 13.71. Found: C, 70.39; H, 7.87; N, 13.75.
Step C: Pyrrolo[3',2':5,6][1]bcnzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12, I 3,14,14a,15-decahydro-2-methyl-To a mixture ofperchlorate salt (973 mg, 4.10 mmol, Example 3, Step B) and 30 mL of ether was added 40 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 40 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in 7 mL of dioxane, then 4-dimethylaminomethyl-2-methyl-1H-indol-5-0l (697 mg, 3.41 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vaca~o affording a brown solid.
Trituration with EtOAc gave 1.01 g (59%) of pure titled compound as a beige solid: mp 267-270°C (dec.); IR 3407, 3189, 2926, 1435, 1212, 1197, 774 cm-1;
1H NMR (DMSO-d6) 8 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, IH, aliphatic CH), 2.87-3.31 (m, 2H, aliphatic CH), 5.92 (m, 1 H, ArH), 6.45 (d, J = 8.61 I Iz, 1 H, ArH), 6.94 (d, J = 8.79 Hz, 1 H, ArH), 10.6 (bs, 1H, exchangeable proton); MS(APCI+): ntlz 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.

Example 5 Pyrrolo[3',2':5,6)[1)benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-bromo-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester O
O~CH3 Br N CHa H
Step A: 6-Bromo-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester 6-Bromo-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester, prepared according to the literature procedure [Bell M.R.; Oesterlin R.;
Beyler A.L.; Handing H.R.; Potts G.O., J. Merl. Chent., 1967;10:264-266], (3.01 g, 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 was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.982 g, 12.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 48 hours during which time white precipitate formed.
Filtration and drying under vacuum Gave 1.91 g (53%) of pure titled compound as a white solid: mp 179-180°C (dec.); IR 3339, 1700, 1688, 1426, 1092, 833 cm-1;

NMR (DMSO-d6) 8 1.30 (t, J= 7.14 Hz, 3H, CH2CH3), 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, CH2CH3), 7.38 (s, 1H, ArH), 11.6 (bs, 1H, exchangeable proton); MS(APCI+): rnlz 355.0 (MH+). Analysis calculated for C15H19N203Br: 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.
Step B:
To a mixture ofperchlorate salt (1.40 g, 5.90 mmol, Example 3, Step B) and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resulting N
O ~
mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x SO mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in 20 mL of dioxane, then bromoindole mannich base (1.61 g, 4.54 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to give a white foam, trituration with EtOAc/hexanes gave 1.42 g (54%) of pure titled compound as a white solid: mp 184-185°C; IR 3295, 2930, 1662, 1426, 1185, I I 10, 1081, 869 cm-1; 1H
NMR
(CDCl3) 8 1.15-2.08 (m, 11H, aliphatic CH2 and CH), 1.39 (t, J= 7.14 Hz, 3H, CH2CH3), 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, J= 18.0, 6.96 Hz, 1H, aliphatic CH), 4.34 (q, J= 7.14 Hz, CH2CH3), 7.35 (s, 1H, ArH), 8.10 (bs, IH, NH); MS(APCI+): nTlz 447.1 (MH+). Analysis calculated for C22H27N303Br: 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][1)benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12, I 3,14,14a, I S-decahydro-2-methyl-, propyl ester N O
I~l'O~CH3 N CHs H
Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid propyl ester 5-Acetoxy-2-methyl-IH-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 was stirred at ambient temperature for 1.5 hour. The reaction mixture was then mixed with 20 mL of water, the resulting reaction mixture was treated with 5% HCl until pH = 1 affording a white precipitate. The solid was isolated by filtration and recrystallized from EtOAc/hexanes to give 1.39 g (80%) pure titled compound as a beige solid, mp 188-189°C (dec.); IR 3381, 3297, 1661, 1457, 1178, 1090, 794, 783 cm-1; 1H NMR (DMSO-d6) 8 0.989 (t, J= 7.51 Hz, 3H, CH2CH2CH3), 1.72 (sextet, J= 7.14 Hz, 2H, CH2CH2CH3), 2.57 (s, 3H, ArCH3), 4.14 (t, J= 6.41 Hz, 2H, CH2CH2CH3), 6.58 (dd, J= 8.42, 2.20 Hz, 1H, ArH), 7.11 (d, J = 8.61 Hz, 1 H, ArH), 7.29 (d, J = 2.20 Hz, 1 H, ArH), 8.83 (s, 1 H, OH), 1 I .5 (bs, 1 H, NH); MS(APCI+): rnlz 234.1 (MH+). Analysis calculated for C13HISN03~0.06H20: C, 66.63; H, 6.50; N, 5.98. Found: C, 66.27; H, 6.38; N, 5.84.
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid propyl ester 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid propyl ester (1.27 g, 5.43 mmol) and aqueous Me2NH (40%, 1.50 mL, 12.0 mmol) were mixed with 10 mL of EtOH, the mixture was heated with a heat gun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.528 g, 6.52 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was then concentrated in vaccro to reduce the volume by half. Precipitate formed. Filtration and drying under vacuum gave 0.86 g (54%) of pure titled compound as a white solid: mp 135-137°C (dec.);
IR 3217, 2969, 1684, 1420, 1141, 1075 cm-1; IH NMR (DMSO-d6) 8 0.953 (t, J= 7.32 Hz, 3H, CH2CH2CH3), 1.70 (sextet, J= 7.33 Hz, 2H, CH2CH2CH3), 2.19 (s, 6H, N(CH3)2), 2.49 (s, 3H, obscured by DMSO peak, ArCI-I3), 4.06 (s, 2H, ArCH2NMe2), 4.13 (t, J= 6.78 Hz, 2H, CH2CH2CH3), 6.56 (d, J= 8.61 Hz, 1H, ArH), 7.07 (d, J= 8.42 Hz, 1H, ArH), 1 I.5 (bs, 1H, exchangeable proton);
MS(APCI+): ntlz 291.1 (MH+). Analysis calculated for C16H22N203~ C~ 66.19;
H, 7.64; N, 9.65. Found: C, 65.94; H, 7.67; N, 9.31.

Step C:
To a mixture of perchlorate salt (0.763 g, 3.21 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in S.0 mL of dioxane, then indole Mannich base (0.717 g, 2.47 mmol) was added; the resulting reaction mixture was refluxed under nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (50% EtOAc in hcxanes) to give a white solid. Recrystallization from CH3CN gave 0.67 g (70%) of pure titled compound as a white solid: mp 162-164°C; IR 3329, 2931, 1702, 1665, 1434, 1235, 1200, 1149, 1079, 948, 781 cm-1; 1H NMR (CDC13) d 0.992 (t, J= 7.32 Hz, 3H, CH2CH2CH3), 1.76 (sextet, J= 7.08 Hz, 2H, CH2CH2CH3), 1.29-1.86 (m, l OH, aliphatic CH2 and CH), 2.11 (d, J-- 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, J= 18.1, 6.84 Hz, 1H, aliphatic CH), 4.21 (t, J= 6.84 Hz, CH2CH2CH3), 6.73 (d, J- 8.79 Hz, 1H, ArFI), 7.01 (d, J= 8.79 Hz, lI-I, ArH), 8.06 (bs, 1H, NH); MS(APCI+): mlz 383.1 (MH+) Analysis calculated for C23H30N203~ 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-methylpropyl ester N O
v O CHa O
\~CHa N
H
Step A:
S-Hydroxy-2-methyl-1H-indole-3-carboxylic 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 resulting reaction mixture was heated with a heat gun until a clear solution was obtained. The reaction mixture was stirred at 50°C
for 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%) ofpure titled compound as a white solid: mp 122-124°C (dec.); IR
3229, 2957, 1686, 1424, 1242, 1085, 1000 cm-l; IH NMR (DMSO-d6) b 0.951 (d, J= 6.59 Hz, 6H, CH2CH(CH3)2), 1.98 (m, J= 6.59 Hz, 1H, CH2CH(CH3)2), 2.18 (s, 6H, N(CH3)2), 2.50 (s, 3H, obscured by DMSO peak, ArCH3), 3.97 (d, J= 6.59 Hz, 2H, CH2CH(CH3)2), 4.07 (s, 2H, ArCH2NMe2), 6.56 (d, J= 8.61 Hz, 1H, ArH), 7.06 (d, J= 8.42 Hz, 1H, ArH), 11.5 (bs, 1H, exchangeable proton); MS(APCI+): m/z 305.2 (MH+). Analysis calculated for C17H24N203M.03H20: 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 salt (0.458 g, I .93 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL).
Combined ether layer was dried over Na2S04 and concentrated irr vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole mannich base (0.451 g, 1.48 mmol) was added, the resulting reaction mixture was refluxcd under nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated in vaczso affording a thick oil. The crude product was 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 cm-l; 1H NMR (CDC13) 8 0.984 (d, J= 6.84 Hz, 6H, CH2CH(CH3)2), 1.32-1.90 (m, l OH, aliphatic CH2 and CH), 2.04 (m, J= 6.59 Hz, 1H, CH2CH(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, aliphatic CH), 2.97-3.10 (m, 1H, aliphatic CH), 3.46 (dd, J= 18.1, 6.84 Hz, 1H, aliphatic CH), 4.00-4.09 (m, 2H, CH2CH(CH3)2), 6.73 (d, J= 8.79 Hz, 1H, ArH), 7.02 (d, J= 8.79 Hz, IH, ArH), 8.05 (bs, 1H, NH); MS(APCI+): mlz 397.2 (MH+) Analysis calculated for C24H32N203 ~ 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][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 Ov ~ ~CH3 v O CHa ~/ ~~CH3 ~ ~N
H
Step A:
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl propyl ester (intern~ediate 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 heat gun until a clear solution was obtained. The reaction mixture was stirred at 50°C
for 4.5 hours. The reaction mixture was mixed with 50 mL of EtOAc, the mixture was washed with water (2 x 50 mL), the organic phase was dried over Na2S04 and concentrated in vacato affording a thick oil. The cnide product was further purified by flash chromatography (10%-20% methanol in CHC13 to give 0.90 g (48%) of pure titled compound as a white solid: mp I 50-151 °C
(dec.); IR
3251, 2953, 1690, 1424, 1238, 1081, 801 cm-1; 1H NMR (DMSO-d6) 8 0.970 (s, 9H, CH2C(CH3)3), 2.18 (s, 6H, N(CH3)2), 2.52 (s, 3H, ArCH3), 3.91 (s, 2H, CH2C(CH3)3), 4.08 (s, 2H, ArCH2NMe2), 6.57 (d, J= 8.42 Hz, IH, ArH), 7.07 (d, J= 8.61 Hz, 1H, ArH), 11.5 (bs, 1H, exchangeable proton); MS(APCI+):
m/z 319.2 (MH+). Analysis calculated for CI8H26N203: 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 salt (0.710 g, 2.23 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL).
Combined ether layer was dried over Na2S04 and concentrated in v~icuo. The residual 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 refluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature and concentrated iy7 vacuo affording a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to afford a white solid. Recrystallization from CH3CN gave 0.92 g (44%) ofpure titled compound as a white solid: mp 240-243°C; IR 3187, 2934, 1700, 1433, 1235, 1077, 883, 780 cm-1; 1H NMR (DMSO-d6) 8 0.96 (d, 9H, CH2C(CH3)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, ZH, obscured by DMSO peak aliphatic 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 peak aliphatic CH), 3.94 (ABq, Jab = 10.62 Hz, vab = 24.1 Hz, 2H, CH2C(CH3)3), 6.61 (d, J= 8.42 Hz, 1H, ArH), 7.04 (d, J= 8.61 Hz, 1H, ArH), 11.51 (bs, 1H, NH); MS(APCI+): nilz 411.3 (MH+). Analysis calculated for C24H32N203v 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 in EtOH by stirnng while warming the solution; the solution was cooled.
Aqueous HCHO (37%, 1.2 eq) and Me2NH (40%, 2.2 eq) were added, and the reaction was stirred at 50°C until the ratio of starting material to product was constant. The ethanol was removed in vacuo, the brown oil was purified by flash chromatography (using MeOH/CHC13 as the eluent) to afford the desired product.
Example 9 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,?,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester N O
~~ O
O~.
~ CHs ;y N
H
Step A:
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester was synthesized from intermediate C according to Procedure G
Yield: 3.36 g (55%); 1H NMR (DMSO-d6) 8 2.10 (s, 6H, CH2N(CH3)2), 2.45 (s, 3H, ArCH3), 3.97 (s, 2H, CH2NMe2), 5.21 (s, 2H, C02CH2Ph), 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), 11.5 (s, 1 H, NH). MS(APCI+): m/z 339.1 (MH+) Step B:
By a procedure similar to that described in Example 7, Step C
Yield: 3.30 g (77%); mp 162-164°C; IR: 2930, 2855, 1700, 1432, 1077 cm-1.
1H NMR (DMSO-d6) 8 1.11-1.67 (m, 10H, aliphatic CH2 and CH), 1.82-1.86 (m, IH, aliphatic CH), 2.30-2.48 (m, 2H, obscured by DMSO peak, aliphatic CH), 2.48 (s, 3H, ArCH3), 2.62-2.70 (m, 2H, aliphatic CH), 2.86-2.92 (m, IH, aliphatic CH), 3.19 (dd, J= 18.3, 6.78 Hz, IH, aliphatic CH), 5.23 (ABq, Jab = 12.1 Hz, vab = 16.4 Hz, 2H, C02CH2Ph), 6.59 (d, J= 8.61 Hz, 1H, ArH), 7.03 (d, J= 8.61 Hz, 1H, ArH), 7.30-7.46 (m, 5H, ArH), 11.5 (bs, 1H, NH); MS(APCI+):
431.2 (MH+). Analysis calculated for C27H3pN203: C, 75.35; H, 7.02; N, 6.51.
Found: C, 75.16; H, 6.97; N, 6.47.
Example 10 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methylethyl ester HsC CHa O
v O
O
~~--CHs ~~ N
H
Step A:
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid isopropyl ester was synthesized from intermediate E according to Procedure G.
Yield: 0.490 g (61 %); I H NMR 8 1.26 (d, J= 6.35 Hz, 6> I, CH(CH3)2), 2.17 (s, 6H, CH2N(CH3)2), 2.45 (s, 31-i, ArCH3), 4.03 (s, 2H, CH2NMe2), 5.04 (sextet, J= 6.35, 1H, C02CH(CH3)2), 6.52 (d, J= 8.55 Hz. 1FI, ArH), 7.02 (d, J= 8.55 Hz, 1H, ArH), 11.4 (s, 1H, NH). MS(APCI+): m/z 291.1 (MH+) Step B:
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-I. 1H NMR (DMSO-d6) 8 1.10-1.57 (m, 9H, aliphatic CH2 and CH), 1.23 (d, J= 5.62 Hz, 3H, CH3), 1.25 (d, J= 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 _74_ DMSO peak, aliphatic CH), 2.44 (s, 3H, ArCH3), 2.63-2.74 (m, 2H, aliphatic CH), 2.83-2.89 (m, 1H, aliphatic CH), 3.21-3.28 (m, 1H, aliphatic CH, obscured by water peak), 5.01 (septet, 1H, C02CH(CH3)2), 6.56 (d, J= 8.79 Hz, 1 H, ArH), 6.99 (d, J= 8.80 Hz, 1H, ArH), 11.4 (bs, 1H, NH); MS(APCI+): 383.1 (MH+).
Analysis calculated for C23H30N2~3~ C~ 72.22; H, 7.91; N, 7.32. Found:
C, 71.98; H, 7.85; N, 7.29.
Example 11 Pymolo[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-, cyclopropylmethyl ester N O
v-O
O

N
H
Step A:
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid cyclopropyl methyl ester was synthesized from intermediate F according to Procedure G. Yield: 0.406 g (62.1%); 1H NMR (DMSO-d6) ~ 0.309-0.346 (m, 2H, cyclopropyl CI-I2CH2), 0.538-0.584 (m, 2H, cyclopropyl CH2CH2), 1.16-1.24 (m, 1H, cyclopropyl CH), 2.23 (s, 6H, CH2N(CH3)2), 2.52 (s, 3H, ArCH3), 4.02 (d, J= 7.32, 2H, C02CH2CH), 4.10 (s, 2H, CH2NMe2), 6.58 (d, J= 8.55 Hz, 1H, ArH), 7.09 (d, J= 8.55 Hz, 1H, ArH), 11.5 (s, 1H, NH).
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-1. lII NMR (CDC13) 8 0.337-0.373 (m, 2H, cyclopropyl CH2CH2), 0.596-0.641 (m, 2H, cyclopropyl CH2CH2), 1.21-1.89 (m, 10H, aliphatic CI-I2 and CH), 2.15-2.18 (m, 1H, aliphatic CH), 2.48-2.64 (m, 2H, obscured by ArCH3 peak, aliphatic CH), 2.64 (s, 3H, ArCH3), 2.86-2.96 (m, 2H, aliphatic CH), 3.00-3.10 (m, 1H, aliphatic CH), 3.52 (dd, J= 18.1, 6.84 Hz, 1H, aliphatic CH), 4.07-4.17 (m, 1H, C02CH2), 6.77 (d, J= 8.55 Hz, 1H, ArH), 7.06 (d, J= 8.79 Hz, IH, ArH), 8.10 (bs, 1H, NH); MS(APCI+): 395.1 (MH+). Analysis calculated for C24H30N203 ~ 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][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(1-piperidinyl)ethyl ester Ov O
i ~ CH3 H
Step A:
5-Hydroxy-2-methyl-IH-indolc-3-carboxylic acid 2-piperdin-I-yl-ethyl ester (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 HCIIO (37%, 0.248 g, 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 at 50°C for 2 days. The reaction mixture was then diluted with EtOAc, then washed with water and dried over Na2S04. The solution was concentrated in vacuo affording an oil. The crude product was further purified by flash chromatography (10%-20% MeOH in CHCl3) to give an oil (402 mg, 44% crude yield) which was the desired product with minor impurities: IH NMR (DMSO-d6) 8 1.31-1.33 (m, 2H, piperidine CH2), 1.40-1.45 (m, 4H, 2 x piperidine CH2), 2.16 (s, 6H, CH2N(CH2N(CH3)2), 2.30-2.40 (m, 4H, 2 x piperidine CH2), 2.47 (s, 3H, ArCH3), 2.52-2.55 (m, 2H, OCH2CH2N), 4.01 (s, 2H, CH2N(CH3)2), 4.22 (t, .7=

5.86 Hz, 2H, OCH2CH2N), 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. 1H
NMR
(DMSO-d6) b 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 by DMSO peak, aliphatic CH), 2.47 (s, 3H, ArCH3), 2.52 (t, J= 5.62 Hz, 2H, OCII2Cf12N), 2.62-2.71 (m, 2H, aliphatic CH), 2.84-2.89 (m, 1H, aliphatic CH), 3.24-3.33 (m, IH, aliphatic CH, obscured by waterpcak), 4.14-4.26 (m, 2H, OCH2CH2N), 6.56 (d, J= 8.79 I-Iz, 1H, ArH), 7.00 (d, J= 8.55 Hz, 1H, ArH), 11.5 (bs, 1H, NH); MS(APCI+): m/z 452.3 (MH+). Analysis calculated for C27H37N303~0.15H20: C, 71.38; H, 8.28; N, 9.25; H20, 0.59. Found: C, 71.08;
H, 8.25; N, 9.02; H20, 0.21.
Procedure H: General Procedure for the Synthesis of Ethyl 2-alkyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylate. To a stirred solution of ethyl 2-alkyl-5-hydroxy-3-indolecarboxylate (2.63 mmol) in ethanol (8 mL) was added formaldehyde (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 concentrated under reduced pressure. The residue was subjected to flash column chromatography (Si02, 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-a]]indole-3-carboxylate. To a stin-ed solution of NaOH (50% w/w, 100 mL) and ether (20 mL) was added iminium perchlorate salt (0.42 g, 1.78 mmol, Example 3, Step B). The solution was extracted with ether ( 10 x 100 mL), dried over MgS04 and concentrated under reduced pressure to afford the enamine as a white solid. To a stirred solution of dioxane _77_ (2.5 mL/mmol) was added the enamine (0.197 g, 1.43 mmol) and indole (1.43 mmol). The solution was refluxed overnight, cooled to room temperature, concentrated under reduced pressure and subjected to flash column chromatography (Si02, 99:1 dichloromethane/methanol) to afford the desired product.
Example 13 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I S-decahydro-2-(phenylmethyl)-, ethyl ester ~~CH3 Step A:
Ethyl 2-benzyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylate 84% yield as a white solid was synthesized from intermediate P according to Procedure H. 1H NMR (250 MHz, CD30D) cS 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, 1H), 7.17 (m, SH) 7.47 (d, J =2.25 Hz, 1H). LC/MS (150 mm x 4.6 mm, C-18, S micron, 10 mM NH40Ac/CH3CN, APCI+) t = 7.86 min, mlz = 353.2 (M+1 ).
Step B:
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-(phenylmethyl)-, ethyl ester was synthesized according to Procedure I. 68% yield as a white solid. IH NMR
(250 MHz, CDCl3) b 1.36 (t, J= 7.2 Hz, 3H), 1.42 (m, 3H), 1.68 (m, SH), 1.92 (m, 2H), 2.15 (d,J= 13.3 Hz, 1H), 2.53 (m, 2H), 2.85 (m, 2H), 3.09 (m, IH), 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, SH), 7.90 (s, 1H). 13C NMR

_78_ (62.5 MHz, CDCl3) S 14.5, 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 NH40Ac/CH3CN, APCI+) t = 10.73, mlz = 445.6 (M+1 ) 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][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 2-ethyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester ,N
' o O
I ~~ O~CH3 i N y.~CHa H
Step A:
Ethyl 4-(dimethylamino)methylene-2-ethyl-5-hydroxy-3-indolecarboxylate was synthesized from intermediate Q according to Procedure H 55% yield as a white solid. I H NMR (250 MHz, DMSO) 8 I .23 (t, J= 7.4 Hz, 3H), 1.32 (t, J= 7.0 Hz, 3H), 2.46 (s, 6H), 2.91 (q, J= 7.6 Hz, 2H), 1 S 4.30 (q, J= 7.1 Hz, 2H), 4.44 (s, 2H), 6.61 (d, J= 8.6 Hz, 1 H), 7.11 (d, J
= 8.4 Hz, 1H), 9.70 (bs, 1H). 13C NMR (62.5 MHz, DMSO) d 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 NH40Ac/CH3CN, APCI+) t = 6.25 min, rnlz = 291.3 (M+1 ).
Step B:
Pyrrolo[3',2':5,6J[1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 2-ethyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester was synthesized according to Procedure I 43% yield as a white solid. 1H NMR (250 MHz, CDC13) ~ 1.34 (t, J= 7.6 Hz, 3H), 1.36 (t, J= 7.2 Hz, 3H), 1.63 (m, 5H), 1.88 (m, 3H), 2.15 (d, J= 13.3 Hz, 1H), 2.47 (m, 2I-I), 2.82 (m, 2H), 3.02 (q, J= 7.5 Hz, 2H), _79-3.48 (dd, J= 17.9, 6.8 Hz, 1H), 4.35 (q, J= 7.2 Hz, 2H), 6.77 (d, J= 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, CDC13) 8 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 NH40Ac/CH3CN, APCI+) t = 10.75, mlz = 383.5 (M+1 ) 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester >~CH3 Step A:
Ethyl 2-cyclopropyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylate was synthesized from intermediate R according to Procedure H. 64% yield as a white solid. 1H NMR (250 MHz, DMSO) ~ 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).

NMR (62.5 MHz, DMSO) 8 8.4, 8.9, 14.3, 1703, 43.9, 58.3, 59.2, 110.6, 111.3, 112.0, 129. l , 147.3, 152.8, 165.9.
Step B:
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester was synthesized according to Procedure I. 60% yield as a white solid. 1H NMR (250 MHz, CDC13) 8 0.79 (m, 2H), 1.07 (d, J= 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, J---- 15.0 Hz, 2H), 2.60 (m, 3H), 2.83 (m, 2H), 3.48 (dd, J= 17.9, 6.8 Hz, 1H), 4.37 (q, J= 7.1 Hz, 2H), 6.75 (d, J= 8.6 Hz, 1H), 7.03 (d, J= 8.7 Hz, 1H), 7.84 (s, 1H). 13C NMR (62.5 MHz, CDC13) 8 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, C-18, 5 micron, 10 mM NH40Ac/CH3CN, APCI+) t = 10.70 min, m/z = 395.5 (M+1). 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 ~~CH3 H CHs Step A:
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 was synthesized from intermediate S according to Procedure H. 24% yield as a white solid. LC/MS
(150 mm x 4.6mm, C-18, 5 micron, 10 mM NH40Ac/CI-I3CN, APCl+) t = 7.45 min, mlz = 305.3 (M+1).
Step B:
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-propyl-, ethyl ester was synthesized according to Procedure I. 28% yield as a white solid. 1H NMR (250 MHz, CDC13) 8 0.99 (t, J= 7.3 Hz, 3I-I), 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, J= 16.7, 6.6 Hz, 1H), 4.35 (q, J= 7.1 Hz, 2H), 6.77 (d, J= 8.7 I-Iz, 1H), 7.05 (d, J= 8.7 Hz, 1H), 8.12 (s, 1H). 13C NMR (62.5 MHz, CDC13) 8 13.9, 14.4, 19.8, 23.0, 25, 26, 27.0, 30.1, 30.5, 36.7, 49.6, 59.7, 87.1, I 10, 111, 113.8, 127, 129, 146, 149, 167. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM
NH40Ac/CH3CN, APCI+) t = 11.56 min, mlz = 397.5 (M+1 ). Elemental Analysis: 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14, I 4a, I S-decahydro-2-(2-methylpropyl)-, ethyl ester ~N O
O
W ~ wO~CHs N
H
H3C ~ CH3 Step A:
Ethyl 2-isobutyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylate was synthesized from intermediate T according to Procedure H. 39% yield as a white solid. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH40Ac/CH3CN, APCI+) t -- 7.86 min, mlz = 3 I 9.3 (M+1 ).
Step B:
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-(2-methylpropyl)-, ethyl ester was synthesized according to Procedure I. 27% yield as a white solid. l H NMR
(250 MHz, CDCl3) cS 0.95 (d, J= 4.3 Hz, 3H), 0.98 (d, J= 4.3 Hz, 3H) 1.23 (m, IH), 1.39 (t, J= 7.1 Hz, 3H), 1.42 (m, 6H), 1.63 (m, 6H), 1.88 (m, 1H), 2.00 (m, 1H), 2.16 (d, J= 13.3 Hz, 1H), 2.53 (m, 2H), 2.86 (m, 4H), 3.01 (m, 1H), 3.47 (dd, J= 17.4, 7.2 Hz, 1H), 4.34 (q, J= 7.1, 2H), 6.77 (d, J= 8.6 Hz, 1H), 7.06 (d, J= 8.7 Hz, IH), 8.04 (s, 1H). 13C NMR (62.5 MHz, CDC13) 8 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, 1 I 1.4, 113.8, 166.1. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM

NH40Ac/CH3CN, APCI+) t = 6.43 min, mlz = 411.4 (M+1 ). 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1-dimethylethyl ester H
Step A:
tent-Butyl 3-amino-3-methylcrotonate Activation of Zn: To a stirred 3N
HCI solution (50 mL) was added Zn (20 g) and stirred at room temperature for 15 minutes. The HCl solution was decanted, and this was repeated two times.
The activated Zn was washed with distilled H20 (2x, 100 mL), ethanol (2x, 50 mL), and ether (2x, 50 mL). The activated Zn was then placed under reduced pressure for 12 hours at room temperature. To a stirred suspension of anhydrous THF
(10 mL) and activated Zn (0.83 g, 13 mmol) in a flame dried 100 mL round bottom flask was added 5 drops of tert-butyl bromoacetate at room temperature.
1'he 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 turned to green when about 2/3 of tert-butyl bromoacetate was added. The mixture was refluxed for an additional 30 minutes and then allowed to cool to room temperature. To the stirred solution was added THF (30 mL) and K2C03 (2 g dissolved in 3 mL water) and stirred vigorously for 30 minutes. The solution was then placed in a centrifuge tube and centrifuged. The supernatant was decanted and the pellet was resuspended in THF (30 mL), shaken vigorously and centrifuged (2x). The combined supernatant was dried over MgS04, filtered, and concentrated under reduced pressure to yield 0.78 g (83%) of tert-butyl 3-amino-3-methylcrotonate as light yellow liquid which solidifies at 0°C to a light yellow solid. 1H
NMR

(250 MHz, CDC13) 8 1.45 (s, 9H), 1.84 (s, 3H), 4.43 (s, 2H). 13C NMR
(62.5 MHz, CDCI3) b 22.3, 28.6, 78.1, 86.0, 158.9, 171.1.
Step B:
tent-Butyl 5-hydroxy-2-methyl-3-indolecarboxylate. 1,4-Benzoquinone S (3.30 g, 30 mmol) in ethanol (15 mL) was heated up until all solid was dissolved.
tent-Butyl 3-amino-3-methylcrotonate (5.50 g, 35 mmol) in ethanol (15 mL) was added to the hot solution, and the reaction mixture was refluxed for 6 hours, cooled, and concentrated under reduced pressure. The residue was subjected to flash column chromatography (A1203, ethyl acetate) to afford 3.57 g of title compound (14.4 mmol, 48%) as a brown crystal. mp 114.0-116.0°C. 1H NMR
(250 MHz, DMSO) ~ 1.57 (s, 9H ), 2.55 (s, 3H), 6.57 (dd, J= 8.6, 2.3 Hz, 1H), 7.09 (d, .I= 8.6 Hz, 1H,), 7.28 (d, J= 2.3 Hz, 1H), 8.78 (s, 1H), I 1.41 (s, 1H). 13C
NMR (62.5 MHz, d6-MeOH) 8 14.4, 29.1, 80.6, 105.3, 106.8, 112.2, 129.9, 131.1, 145.9, 153.1, 161.7, 167.9.
Step C:
tert-Butyl 4-(dimethylamino)methylene-5-hydroxy-2-methyl-3-indolecarboxylate. To a stirred solution of tent-butyl 5-hydroxy-2-methyl-3-indolecarboxylate (1.48 g, 6.0 mmol) in ethanol (4.5 mL) was added formaldehyde (0.55 mL, 7.2 mmol) and dimethylamine (1.66 mL, 13.2 mmol).
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, evaporated solvent under reduced pressure again to afford 1.54 g of title compound (5.05 mmol, 84%) as a brown crystal. mp 151.0°C (decompose). 1H NMR
(250 MHz, d6-MeOH) c5 1.63 (s, 9H), 1.88 (s, 3H), 2.61 (s, 3H), 2.90 (s, 6H), 4.76 (s, 2H), 6.81 (d, J= 8.7 FIz, 1H), 7.27 (d, J= 8.6 Hz, 1H). 13C NMR
(62.5 MHz, d6-MeOH) 8 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 mM
NH40Ac/CH3CN, APCI+) t = 7.75 min, mlz = 305.4 (M+1 ).

Step D:
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1-dimethylethyl ester To a stirred solution of NaOH (50% w/w, 100 mL) and ether (20 mL) was added 0.082 g (0.20 mmol) of iminium salt (Example 3, Step B). The solution was extracted with ether (3 x 30 mL), dried over MgS04 and concentrated under reduced pressure to afford the enamine as a white solid. 1.0 mL dioxane was added to the enamine and then tort-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 overnight, cooled to room temperature, concentrated under reduced pressure and subjected to flash column chromatography (Si02, 1:1 hexane/ethyl acetate) to afford 0.031 g desired product (0.08 mmol, 40%) as a white solid; mp 214.0°C (decompose). /H NMR (250 MHz, CDC13) b 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, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 7.01 (d, J = 8.6 Hz, 1 H), 8.07 (s, 1 H). 13 C NMR
(62.5 MHz, CDCl3) b 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 NH40Ac/CH3CN, APCI+) t =7.98 min, rnlz = 397.4 (M+1 ). 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, I Oa, l l -hexahydro-3 H,6aH-6-oxa-3,7-diaza-cyclopenta[aJanthracene-1-carboxylic acid ethyl ester HaCH C~' O~~p'CH
3 O.
~~ CH3 N
H

_85_ Step A: 1,6-Dimethyl-1,2,3,4-tetrahydro-pyridine 1,6-Dimethyl-1,2,3,4-tetrahydro-pyridine was synthesized according to the procedure published in Lipp A., Liebigs AnrT. Chem., 1898;289:216.
Step B: 2,6a,7-Trimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-G-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester A solution of 1,6-dimethyl-1,2,3,4-tetrahydropyridine (0.100 g, 0.899 mmol, Example 19, Step A) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.200 g, 0.724 mmol) in dioxane (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. The solution was cooled to room temperature, concentrated, and the residue was purified by flash column chromatography on silica gel using 50%-75% ethyl acetate:hexane and recrystallized with ethyl acetate to give 12 mg (4.8%) of 2,6a,7-trimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[aJanthracene-1-carboxylic acid ethyl ester as a white powder: mp 169-173°C; 1H NMR (400 MHz, CDC13) 8 1.34 (m, 2H), 1.36 (t, J= 7.08 Hz, 3H, CH2CH3), 1.45 (s, 3H, CH3C(O)N), 1.56 (m, 2H), 1.66 (m, 1 H), I .93 (m, 1H), 2.56 (s, 3H, CH3), 2.58 (s, 3H, CH3), 2.87 (bd, J= 17.58 Hz, 2H), 3.50 (dd, J= 18.19, 6.72 Hz, 1H,), 4.31 (q, J= 7.08 Hz, 2H, CH2CH3), 6.68 (d, J= 8.79 Hz, 1H, ArH), 7.01 (d, J= 8.30 Hz, 1 H, ArH), 8.03 (bs, 1H, NFL; MS
(APCI+) m/z 343.2 (MH+). Analysis calculated for C2pH26N203'0.17 H20:
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-7,8,9,10,1 Oa, l l -hexahydro-3H,6aH-6-oxa-3, 7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester HsCuN~~. O ~-CHs HsC DLO
O~~
~~~ ~ ~CH3 N
H

Step A: I-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate I-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.
S Step B: 7-Ethyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a)anthracene-1-carboxylic acid ethyl ester 1-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 water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 10 mL of Et20, and the combined extracts were washed with 1 x 10 mL of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated into the reaction flask to give 90 mg (0.724 mmol) of I-ethyl-6-methyl-1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (0.750 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-IH-indole-3-carboxylic acid ethyl ester (0.200 g, 0.724 mmol) was added. The resulting solution was heated at reflux under N2 for 4 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 100% ethyl acetate and recrystallized with ethyl acetate to give 98 mg (38%) of 7-ethyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a)anthracene-1-carboxylic acid ethyl ester as a white powder: mp 173-174°C; IR (KBr) 3298, 2930, 2856, 1669, 1433, 1238, 1094 cm-l; 1H NMR (300 MHz, CDC13) 8 1.16 (m, 3H, CH3CH2N), 1.37 (m, IH), 1.40 (m, 1H), 1.48 (s, 2H), 1.56 (s, 2H), 1.64 (m, 2H), 1.97 (m, 1H), 2.61 (s, 3H, CH3), 2.72 (m, 1H), 2.84 (m, IH), 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, .I= 7.14, 1.65 Hz, 2H, OCH2CH3), 6.70 (d, J= 8.61 Hz, 1H, ArH), 7.03 (d, J= 8.61 Hz, ArH), 8.06 (bs, 1H, NI~; MS (APCI+) nrlz 357.1 (MH+). Analysis calculated for C21H28N2p3:
C, 70.76; H, 7.92; N, 7.86. Found: C, 70.49; H, 7.80; N, 7.66.

_87_ Example 21 I CHa H3C. N
t CH3 I ~ CH
t 3 N
H
Isomer A:
6a-Ethyl-2,7-dimethyl-7,8,9,10,1 Oa, I l -hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester Step A: 6-Ethyl-I-methyl-2,3,4,5-tetrahydropyridinium perchlorate 6-Ethyl-I-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Leonard N.J.; Hauck, Jr., F.P., J. Ana. Cheat. Soc., 1957;79:5279.
Step B: 6a-Ethyl-2,7-dimethyl-7,8,9,10,IOa,ll-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyelopenta[a]anthracene-I-carboxylic acid ethyl ester 6-Ethyl-1-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 water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et2O, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated into the reaction flask to 6-ethyl-1-methyl-1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (2.1 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.581 g, 2.10 mmol) was added. The resulting solution was monitored by tlc and MS as it was stirred at room temperature 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 temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 20-60% ethyl acctate:hexanes to give 56 mg (7.5 %) of a single isomer A of 6a-ethyl-2,7-dimethyl-7,8,9,10, I Oa, l l-hexahydro-3H,6aH-6-oxa-_88_ 3,7-diaza-cyclopenta[a]anthracene-I-carboxylic acid ethyl ester with a larger Rf value as a white powder: mp 144-147°C; IR (KBr) 3375, 2975, 2937, 2858, 1671, 1470, 1432, 1245, 1202 cm-I; IH NMR (400 MHz, CDCl3) b 0.91 (m, 3H, CH3CH2C(O)N), 1.34 (m, 2H), 1.36 (m, 3H, OCH2CH3), 1.54 (bs, 1H), 1.63 (m, S 1 H), 1.76 (m, 1 H), 1.84 (m, 1 H), 2.06 (m, I H), 2.46 (s, 3H, CH3), 2.52 (m, 1 H), 2.57 (2, 3H, CH3), 2.79 (d, J= 18.07 Hz, 1H), 2.88 (m, IH), 3.37 (dd, J=
18.07, 6.59 Hz, 1H), 4.31 (m, 2H, OCH2CH3), 6.67 (d, J= 8.79 Hz, 1H, ArH), 6.99 (d, J= 8.55 Hz, 1H, ArH), 8.03 (bs, 1H, NH); MS (APCI+) mlz 357.2 (MH+).
Analysis calculated for C21H2gN203~0.04 H20: C, 70.61; H, 7.92; N, 7.84;
water, 0.22. Found: C, 70.27; H, 7.92; I~T, 7.58; water, 0.22.
Example 22 H3C.N ~y_p C H3 \
N
H
Isomer B:
6a-Ethyl-2,7-dimethyl-7,8,9, 10,10a, I 1-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester 6-Ethyl-1-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 water and treated with SO% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 1 S mL of Et20, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated into the reaction flask to give 6-ethyl-1-methyl-1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (2.1 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.581 g, 2.10 mmol) was added. The resulting solution was monitored by tlc and MS as it was stirred at room temperature 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 temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 20-60% ethyl acetate:hexanes to give 37 mg (4.9 %) of a single isomerB of6a-ethyl-2,7-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester with a smaller Rf value 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) 8 1:08 (m, 3H, CH3CH2C(O)N), 1.20 (m, 1H), 1.37 (m, 3H, OCH2CH3), 1.41 (m, 1H), 1.52 (s, 3H, CH3), 1.59 (m, 2H), 1.85 (bd, J-- 13.18 Hz, 1H), 2.30 (m, 1H), 2.35 (m, 2H), 2.58 (s, 3H, CH3), 2.91 (m, 1H), 3.11 (m, 2H), 4.32 (m, 2H, OCH2CH3), 6.72 (d, J= 8.55 Hz, 1H, ArH), 7.00 (d, J= 8.79 Hz, IH, ArH), 8.03 (bs, 1H, NH); MS
(APCI+) ntlz 357.2 (MH+). Analysis calculated for C21H28N203: C, 70.76; H, 7.92; N, 7.86. Found: C, 71.45; H, 8.44; N, 6.65. HPLC (ALLTECH/ALLTIMA
C-18 I :I H20/CH3CN + 0.05% TFA): retention time = 4.940 min, 99.40% purity.
1 S Example 23 6a, 7-Diethyl-2-methyl-7,8,9,10,1 Oa, l l -hexahydro-3H,6aH-6-oxa-3, 7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester I
N\ O /~-CH3 O
CH O
3CH~ ~ ~ \ CHa N
H
Step A: 1,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate 1,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Leonard N.J., Hauck, Jr., F.P., J.
Arn.
Cheat. Soc., 1957;79:5279.
Step B: 6a,7-Diethyl-2-methyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester 1,6-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 and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et20, and the combined extracts were washed with 1 x I S mL of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated into the reaction flask to give 207 mg (1.49 mmol) of 1,6-diethyl-1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (1.3 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.373 g, 1.35 mmol) was added. The resulting solution was heated at 100°C
under N2 for 7 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 20-100%
ethyl acetate:hexanes and recrystallized with ethyl acetate to give 123 mg (25%) of 6a,7-diethyl-2-methyl-7,8,9, I 0,1 Oa,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopcnta[a]anthracene-1-carboxylic acid ethyl ester as a white crystalline solid:
mp 162-163°C; IR (KBr) 3390, 2972, 2929, 2859, 1654, 1432, 1201, 1097 cm-/;
1H NMR (400 MHz, CDC13) cS 0.900 (m, 2H, CH3CH2C(O)N), 1.11 (m, 2H, CH3CH2N), 1.34 (m, 2H), 1.36 (m, 3H, CH3CH20), 1.57 (m, 2H), 1.85 (m, 2H), 2.06 (m, 1H), 2.57 (s, 3H, CH3), 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, CH3CH20), 6.64 (d, J= 8.55 Hz, 1H, ArH), 6.98 (d, J---- 8.55 Hz, 1 H, Ar~~, 8.00 (bs, 1 H, NH);
MS
(APCI+) m/z 371.1 (MH+). Analysis calculated for C22H30N203v C> 71.32;
H, 8.16; N, 7.56. Found: C, 71.28; H, 7.77; N, 7.32.
Example 24 7-Benzyl-2,6a-dimethyl-7,8,9,10,1 Oa,11-hexahydro-3H,6aI-I-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester /I \
,f Ha( 7 Step A: 1-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate 1-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Mohrle H.; Dwuletzki H.Z., Nc~tatrforsch., B: Anorg. Chem., Org. Chenz, 1986;41b:1323.
Step B: 7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-I-carboxylic acid ethyl ester An excess of 1-benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 24, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et20, and the combined extracts were washed with 1 x 20 mL
of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated to give the enamine. 1-Benzyl-2-methyl-1,2,3,4-tetrahydro-pyridine (0.447 g, 2.39 mmol) was dissolved in dioxane (2.4 mL) and 4-dimcthylaminomethyl-5-hydroxy-2-methyl-1H-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 temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10-20% ethyl acetate:hexanes and recrystallized with ethyl acetate to give 208 mg (42%) of 7-benzyl-2,6a-dimethyl-7,8,9,10,1 Oa,11-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; IK
(KBr) 3397, 2983, 2923, 2897, 2854, 1668, 1432, 1200, 1097 cm-l; 1H NMR
(400 MHz, CDC13) ~ 1.36 (m, 1H), 1.37 (m, 3H, OCH2CH3), 1.50 (s, 3H, CH3C(O)N), 1.53 (m, 3H), 2.03 (m, 1H), 2.56 (m, 1H), 2.58 (s, 3H, CH3), 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, NCH(H)Ph), 4.32 (m, 2H, OCH2CH3), 4.47 (d, J= 14.89 I-Iz, 1H, NCH(H)Ph), 6.71 (d, J= 8.55 Hz, 1H, ArH), 7.01 (d, J= 8.55 Hz, 1H, ArH), 7.18 (t, J= 7.08 Hz, IH, PhH), 7.28 (m, 2H, PhI~, 7.35 (d, J= 7.33 Hz, 2I-I, PhH), 8.06 (bs, 1H, NH); MS (APCI+) m/z 419.2 (MH+). Analysis calculated for C26H3pN203~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.

WO 00/42045 PCT/US99l30434 Example 25 H3C-N O\

Isomer A:
2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aI-I-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester Step A: 1-Methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate A procedure for the synthesis of 1-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate is published in Leonard N..T.; Hauck Jr. F.P., J. Am.
Chern.
Soc., 1957;79:5279.
Step B: 2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester An excess of 1-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 25, Step A) u-as dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et20, and the combined extracts were washed with 1 x 20 mL
of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated to give the enamine. 1-Methyl-6-phenyl-1,2,3,4,-tetrahydro-pyridine(0.428 g, 2.47 mmol) was dissolved in dioxane (1.8 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol) was added. The reaction mixture was heated at 75-80°C under N2 for 16 hours, 1.0 mL
of dioxane was added and heating was continued at 90°C for 5 hours.
Dried toluene (1.0 mL) was added to the mixture and it was heated at 100°C
for 26 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10-50% ethyl acetate:hexanes to give a single isomer A with a smaller R f value, which was recrystallized with cther:hexanes to give 73 mg (15%) of 2,7-dimethyl-6a-phenyl-7, 8,9,10,1 Oa, I 1-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopcnta[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-l; 1H NMR
(400 MHz, CDCI3) 8 1.20 (m, 3H, OCH2CH3), 1.48 (m, 2H), 1.67 (d, J= 13.18 Hz, 1H), 1.84 (m, 1H), 2.13 (s, 3H, CH3), 2.35 (m, 1H), 2.52 (s, 3H, CH3), 2.58 (m, IH), 2.68 (m, 1H), 2.81 (d, J= 17.33 Hz, 1H), 2.90 (m, 1H), 4.17 (q, J= 7.08 Hz, 2H, OCH2CH3), 6.89 (d, J= 8.79 Hz, 1H, ArH), 7.06 (d, J= 8.79 Hz, 1H, ArH), 7.15 (m, 3H, PhH), 7.35 (m, 2H, Pl>H), 8.07 (bs, lI-I, NH);
MS (APCI+) ntlz 405.2 (MH+). Analysis calculated for C25H28N203: C, 74.23;
H, 6.98; N, 6.93. Found: C, 73.93; H, 7.11; N, 6.66.
Example 26 H3C-N O , O
O

N
H
Isomer B:
2,7-Dimethyl-6a-phenyl-7,8,9,10, I Oa, l I -hcxahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-I-carboxylic acid ethyl ester An excess of 1-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 25, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et20, and the combined extracts were washed with I x 20 mL
of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated to give the enamine. I-Methyl-6-phenyl-1,2,3,4,-tetrahydro-pyridine(0.428 g, 2.47 mmol) was dissolved in dioxane (1.8 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol) was added. The reaction mixture was heated at 75-80°C under N2 for 16 hours, 1.0 mL
of dioxane was added and heating was continued at 90°C for 5 hours.
Dried toluene (1.0 mL) was added to the mixture and it was heated at 100°C
for 26 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10-50% ethyl acetate:hexanes, recrystallized with ether:hexanes and the filtrate further purified by silica gel chromatography using 1-10% ethyl acetate:hexanes to give 70 mg (14%) of a single isomer B oft,7-dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a)anthracene-1-carboxylic acid ethyl ester with a larger Rfvalue as a course peach powder: mp 184-186°C; IR (KBr) 3380, 2926, 1698, 1684, 1436, 1073 cm-1; 1H NMR (400 MHz, CDCl3) 8 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, CH3), 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, OCH2CH3), 4.89 (bs, 1H), 6.74 (d, J= 8.55 Hz, 1H, ArH), 7.02 (d, J= 8.55 Hz, 1H, ArH), 7.33 (m, SII, PhH), 8.06 (bs, 1H, NH);
MS (APCI+) m/z 405.2 (MH+). Analysis calculated for C25H28N203: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.18; H, 6.90; N, 6.72 Example 27 1H,7H-Indolizino[8',8a':5,6]pyrano[3,2-a]indole-1-carboxylic acid, 8,9,11,12,13,13 a,14,14a-octahydro-2-methyl-, ethyl ester N o rC"3 N
H
Step A: 2,3,5,6,7,8-Hexahydro-1H-indolizinylium perchlorate 2,3,5,6,7,8-Hexahydro-1H-indolizinylium perchlorate was synthesized according to the procedure published in Reinecke M.G.; Kray L.R., J. Org.
Chem., 1964;29:1736.
Step B: 1H,7H-Indolizino[8',8a':5,6]pyrano[3,2-a]indole-1-carboxylic acid, 8,9,11,12,13,13 a, l 4,14a-octahydro-2-methyl-, ethyl ester 2,3,5,6,7,8-Hexahydro-1 H-indolizinylium perchlorate (0.330 g, 1.48 mmol, Example 27, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x I S mL of Et20, and the combined extracts were washed with I x 15 mL of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated into the reaction flask to give 143 mg (1.16 mmol) of enamine.
S 1,2,3,5,6,7-Hexahydro-indolizine was dissolved in dioxane (1.5 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.321 g, 1.16 mmol) was added. The resulting solution was heated at reflux under N2 for S hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 100%
acetone and recrystallized with ethyl acetate to give 129 mg (31%) of 1H,7H-Indolizino[8',8a':5,6]pyrano[3,2-a]indole-I-carboxylic acid, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-, ethyl ester as an off white powder:
mp 170-172°C; IR (KBr) 3396, 3353, 2929, 2853, 1668, 1434, 1156, 1096, 1075 cm-1; IH NMR (300 MHz, CDC13) c~ 1.38 (m, 2H), 1.40 (t, J= 7.14 Hz, 3H, OCH2CH3), 1.68 (m, 3H), 1.90 (m, 3H), 2.05 (m, IH), 2.61 (s, 3H, CH3), 2.74 (m, 1H), 2.84 (m, IH), 2.97 (d, J= 17.40 Hz, 1H), 3.09 (m, 2H), 3.47 (dd, J= 17.76, 6.78 Hz, IH), 4.36 (m, 2H, OCH2CH3), 6.67 (d, J= 8.61 Hz, 1H, ArH), 7.03 (d, J= 8.61 Hz, 1 H, Atl~, 8.06 (bs, 1 H, NH); MS (APCI+) m/z 355.2 (MH+). Analysis calculated for C21H26N203'0.23H20: C, 70.34; H, 7.44;
N, 7.81. Found: C, 70.35; H, 7.48; N, 7.61.

Example 28 3H,7H-Pyrrolizino[1',8':5,6]pyrano[3,2-a]indole-1-acetic acid, 8,9,11,12,12a,13-hexahydro-2-methyl-, ethyl ester N O ~CH3 O
O
\~ CHa N
H
S Step A: 1,2,3,5,6,7-Hexahydro-pyrrolizinylium perchlorate 1,2,3,5,6,7-Hexahydro-pyrrolizinylium perchlorate was synthesized according to the procedure published in Miyano S. et al., Syjithesis, 1978;9:701.
Step B: 3H,7H-Pyrrolizino[I',8':5,6]pyrano[3,2-a]indole-1-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 of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et20, and the combined extracts were washed with 1 x 15 mL
of saturated aqueous NaCl, dried with MgS04, filtered, and concentrated into the reaction flask to give 325 mg (2.98 mmol) of enamine, 2,3,5,6-tetrahydro-1H-pyrrolizine. The residue was dissolved in dioxane (2.8 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lI-I-indole-3-carboxylic acid ethyl ester (0.794 g, 2.88 mmol) was added. The resulting solution was heated at 80°C
under N2 for 17 hours, cooled to room temperature, and concentrated. The cmde residue was purified by flash column chromatography on silica gel using I S%
MeOH:CH2C12 and recrystallized with ether to give 105 mg (11%) of 3H,7H-pyrrolizino[1',8':5,6]pyrano[3,2-a]indole-I-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-I v IH NMR (400 MHz, CDCl3) S 1.37 (t, J= 7.08 Hz, 3H, OCH2CH3), 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, _97_ OCH2CH3), 6.76 (d, J= 8.55 Hz, 1H, ArH), 7.00 (d, J= 8.55 Hz, 1H, ArH), 8.26 (m, 1H, NH); MS (APCI+) m/z 341.1 (MH+). Analysis calculated for C20H24N203~ C~ 70.57; H, 7.1 l; 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-I-carboxylic acid ethyl ester ~ CH3 Step A: 1,3,4,8,9,9a-Hexahydro-2H-quinolizine 1,3,4,8,9,9a-Hexahydro-2H-quinolizine was synthesized according to the procedure published in Bohlmann F. et al., Cheat. Ber., 1973;106:3026.
Step B: 2-Methyl-8,9,10,10a,11,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopenta[h]anthracene-1-carboxylic acid ethyl ester 1,3,4,8,9,9a-Hexahydro-2H-quinolizine (0.372 g, 2.71 mmol, Example 29, Step A) was dissolved in dioxane (2.7 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-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 temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10-20%
ethyl acetate:CH2Cl2 and recrystallized with cyclohexane to give 71 mg (l4%) of 2-methyl-8,9,10,IOa,11,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopenta[h]anthracene-1-carboxylic acid ethyl ester as an off white powder: mp 178-180°C; IR (KBr) 3372, 2929, 2859, 1669, 1654, 1435, 1198, 1095, 1079 cm-1; 1H NMR (400 MHz, CDCl3) 8 1.15 (m, 1H), 1.35 (t, J= 7.08 Hz, 3H, OCH2CH3), 1.36 (m, 4H), 1.49 (m, 2H), 1.65 (m, 3H), 2.20 (m, 1H), 2.58 (s, 3H, CH3), 2.68 (m, IH), 2.82 (m, 1H), 2.89 (d, J= 17.58 Hz, 1H), 3.05 (m, 1H), 3.45 (m, 1H), 4.31 (m, 2H, OCH2CH3), 4.68 (s, 1H, CH(O)N), 6.68 (d, J= 8.79 Hz, 1H, ArH), 6.99 (d, J= 8.55 Hz, 1H, ArH), 8.03 (bs, I H, NH); minor diastereomer diagnostic peaks I H NMR (400 MHz, CDCl3) 8 6.75 (d, J= 8.55 Hz, 1H, ArH); MS (APCI+) nilz 369.1 (MH+). Analysis calculated for C22H28N203: C, 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 H20/CH3CN + 0.5% TFA): retention time = 3.526 min (11.26%), 3.882 min (85.82 %) (diastereomers), 97.08 % purity. HPLC (Alltima Silica 5 micron, 150 mm x 4.5 mm column, 95:5 hexane + 0.05 % Et2NH,ethanol + 0.05%
Et2NH): retention 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-a]indole-1-acetic acid, 7,8,9,10,12,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester, or 7H-Azepino[I",2":1"2']pyrido[3',2':5,6]pyrano[3,2-eJindole-1-acetic acid, 3,8,9,10,11,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester O ~ CH: ~ CH3 i v/ O 7 O
\>_ _CH3 CH3 N
H H
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[1,2-a]azepine perchlorate is published in McIntosh J.M. et al., CafT. J Chent., 1983;61:2016.
Step B:
An excess oft,3,4,6,7,8,9,10-octahydro-pyrido[1,2-a]azepine perchlorate (Example 30, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et20, and the combined extracts were washed with 1 x 20 mL

of saturated aqueous NaCI, dried with MgS04, filtered, and concentrated to give 582 mg (3.85 mmol) of the crude enamine. The residue was dissolved in dioxane (3.8 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic 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 temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10% ethyl acetate:CH2Cl2-100% ethyl acetate and recrystallization with iso-octane to give 18 mg (2%) of a single compound, either 3H-pyrido[1",2":1'2']azepino[3'2':5,6]pyrano[3,2-a]indole-1-acetic acid, 7, 8,9,10,12,13,14,15, I 5a,1 C-decahydro-2-methyl-, ethyl ester or 7H-azepino[I",2":1'2']pyrido[3',2':5,6]pyrano[3,2-a]indole-I-acetic acid, 3,8,9,10, I 1,13,14, I 5,15a, l 6-decahydro-2-methyl-, ethyl ester as a fine white powder: mp 118-121°C; IR (KBr) 3379, 3306, 2926, 2853, 1671, 1435, 1151, 1094, 10?3 cm-I; IH NMR (400 MHz, CDC13) b 0.86 (m, 1H), 1.35 (m, 3H), 1.36 (m, 3H, OCH2CH3), 1.45 (m, 3H), 1.60 (m, 3H), 1.69 (dd, J= 14.65, 10.01 Hz, 1 H), 1.95 (m, 1 H), 2.19 (m, 1 H), 2.41 (m, 1 H), 2.54 (m, 1 H), 2.57 (s, 3H, CH3), 2.80 (d, J= 18.56 Hz, 1H), 3.11 (m, 1H), 3.34 (m, 1H), 3.48 (m, 1H), 4.31 (m, 2H, OCH2CH3), 6.70 (d, J-- 8.55 Hz, 1 H, ArH), 6.98 (d, J= 8.55 Hz, IH, Ar~l), 8.01 (bs, IH, NH); MS (APCI+) ntla 383.1 (MH+). Analysis calculated for C23H30N203v 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.I mmol), 1 eq) was dissolved in EtOH by stirring while warming the solution: the solution was cooled. Aqueous HCHO (37%, 1.32 mmol, 1.2 eq) and Me2NH (40%, 2.42 mmol, 2.2 cq) were added, and the reaction was allowed to stir. After several hours, a white precipitate begins to form in the solution; the reaction may be heated to 5°C to speed the reaction. Upon completion, there is little or no starting material present. Water was added to the solution, and the mixture was then cooled in an ice bath. The resulting white solid was collected by filtration and dried under vacuum.

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 the enamine in the following manner: the imine was dissolved in 1N NaOH (10 mL) and the solution extracted with 2 x 20 mL of diethyl ether. The extracts were combined dried, and evaporated under vacuum to yield a white solid. The solid was dissolved in dioxane (10 mL). A solution of the 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl or benzyl 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 white precipitate. The mixture was cooled in an ice bath, and the resulting solid was collected by filtration. The solid was washed sparingly with CH3CN and dried under vacuum at 50 degrees for 24 hours.
Example 31 8,9,11,12,13,13a, I 4, I 4a-Octahydro-N,2-dimethyl-pyrrolo[3',2' :5,6] [ 1 ]-benzopyrano[3,2-i]quinolizine-1-carboxamide H
O
~~-CH3 N
H
Step A:
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl amide was synthesized from Intermediate W according to Procedure J.
Yield: 0.186 g (63.2%); mp: decomposition at >210°C; IR: 3319, 1615, 1515, 1433, 1218, 801 cm-1. 1H NMR (DMSO-d6) 8: 2.14 (s, 6H, CH2N(CH3)2), 2.28 (s, 3H, ArCH3), 2.70 (d, J= 3.91 Hz, 3H, CONHCH3), 3.69 (s, 2H, CH2N(CH3)2), 6.48 (d, J= 8.55 Hz, 1H, ArH), 6.97 (d, J= 8.55 Hz, 1H, ArH), 8.06 (s, 1H, CONHCH3), 10.88 (s, 1H, indole NH). MS(APCI+): m/z 262.1 (MH+); Analysis calculated for C14H1c~N302: C, 64.35, H, 7.33, N, 16.08.
Found: C, 64.26, H, 7.44, N, 15.87.

Step B:
8,9,11,12,13,13a,14,14a-Octahydro-N,2-dimethyl-pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxamide was synthesized according to Procedure K. Yield: 0.057 g (9.8%); mp: decomposition at >210°C; IR: 3392, 3057, 2935, 2857, 1625, 1429, 1215 cm-1; 1H NMR
(DMSO-d6) 8 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, CONHCH3), 2.87-2.95 (m, 1H, aliphatic CH), 3.05 (dd, J= 18.3, 5.37 Hz, IH, aliphatic CH), 6.49 (d, J= 8.79 Hz, 1H, ArH), 6.94 (d, J= 8.79 Hz, 1 H, ArH), 7.70-7.75 (m, 1 H, CONHCI I3), 10.9 (s, 1 H, NH); MS(APCI+): m/z 354.2 (MH+); Analysis calculated for C21H27N302~O.SC4H802(CH3C02Et): C, 69.49, H, 7.86, N, 10.57. Found:
C, 69.64, H, 7.75, N, 10.54.
Example 32 8,9,11,12,13,13 a,14, I 4a-octahydro-2-methyl-N-(phenylmethyl)-pyrrolo[3',2':5,6][ I ]benzopyrano[3,2-i]quinolizine-I-carboxamide N O
v-N
O H
i ~ CH3 N
H
Step A:
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl 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). 1H NMR (DMSO-d6) 8: 2.05 (s, 6H, CH2N(CH3)2), 2.31 (s, 3H, ArCH3), 3.67 (s, 2H, CH2N(CH3)2), 4.40 (d, J= 5.86 Hz, 2H, CONHCH2), 6.46 (d, J= 8.55, IH, ArH), 6.98 (d, J= 8.55, 1H, ArH), 7.18-7.34 (m, 5H, ArH), 8.63 (t, J= 5.86, 1H, CONHCH2), 10.76 (s, 1H, aromatic OH), 10.91 (s, 1H, indole NH). MS(APCI+): m/z 338.2 (MH+); Analysis calculated for C20H23N302~ 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-/. 1H NMR
(DMSO-d6) 8 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, IH, aliphatic CH), 4.33-4.43 (m, 2H, CONHCH2Ph), 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, CONHCH2Ph), 10.9 (s, 1H, indole NH); MS(APCI+): m/z 430.2 (MH+); Analysis calculated for C27H31N302~O.1C4Hg02: 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][1]benzopyrano[3,2-i]quinolizine-1-carboxamide, N-ethyl-8,9,1 I ,12, I 3,13 a,14,14a-octahydro-2-methyl-_N~ O /-CHs H
O
~~CH3 N
H
Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid ethylamide 5-Hydroxy-2-methyl-1-H-indole carboxylic acid (3.28 g, 17.2 mmol) was dissolved in dry DMF (20 mL) under nitrogen atmosphere and cooled to 0°C in an ice-water bath. To this solution were added in succession triethylamine (2.39 mL, 17.2 mmol) and solid O-benzotriazol-I-yl-N,I~T,I~T',N'-tetramethyluronium hexafluorophosphate (6.51 g, 17.2 mmol). The resulting reaction mixture was stirred at that temperature for 15 minutes, gaseous ethylamine was bubbled in for minutes. After sequentially 15 minutes stirnng at 0°C and 15 minutes at ambient temperature, reaction mixture was mixed with 60 mL of EtOAc, the resulting mixture was successively washed with 1N HCl aqueous solution (2 x 60 mL), brine (2 x 60 mL), and was dried over Na2S04. The solution was 5 concentrated in vacuo affording a solid. The crude product was further purified by flash chromatography (100% EtOAc) followed by recrystallization from EtOAc to provide 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; 1H NMR (DMSO-d6) ~ 1.1 l (t, J= 7.14 Hz, 3I-I, CH2CH3), 2.48 (s, 3H, ArCH3), 3.25 (quintet, 10 J= 6.96 Hz, 2H, NHCH2CH3), 6.54 (dd, J= 8.61, 2.20 Hz, 1H, ArH), 7.06 (d, J= 8.42 Hz, 1H, ArH), 7.09 (d, J= 2.01 Hz, 1 H, ArH), 7.23 (t, J= 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 C12H14N202'0.13H20: 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-1H-indole-3-carboxylic acid ethylamide 5-Hydroxy-2-methyl-1H-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). A
clear reaction solution was obtained. The resulting reaction mixture was stirred at ambient temperature for 2 hours during which time precipitate formed.
Filtration and drying under vacuum gave 0.298 g (33%) of pure titled compound as a white solid: mp 198-200°C (dec.); IR 3346, 3189, 2986, 1615, 1436, 1215, 801 cm-1;
1H NMR (DMSO-d6) 8 1.11 (t, J= 7.14 Hz, 3I-I, CH2CH3), 2.18 (s, 6H, N(CH3)2), 2.32 (s, 3H, ArCH3), 3.24 (quintet, J= 6.78 Hz, 2H, CH2CH3), 3.78 (s, 2H, ArCH2NMe2), 6.50 (d, J= 8.42 Hz, 1H, ArH), 7.01 (d, J= 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 C15H21N302~ C~ 65.43;
H, 7.69; N, 15.26. Found: C, 65.24; H, 7.73; N, 14.92.

WO 00/42045 PCTliJS99/30434 Step C: Pyn-olo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxamide, N-ethyl-8,9,11,12,13,13a,14,14a-octahydro-2-methyl-To a mixture of perchlorate salt (263 mg, 1.11 mmol, Example 3, Step B) and 30 mL of ether was added 40 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 40 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in 20 mL of dioxane, then 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethylamide (234 mg, 0.851 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a brown solid. The crude product was recrystallized from CH3CN, and then further purified by chromatography (10%
MeOH in HCCl3) to give 0.070 g (17%) of pure titled compound as a yellow solid: mp 264-266°C (dec.); IR 3313, 2930, 1623, 1604, 1435, 1216, 872 cm-I;
1H NMR (DMSO-d6) 8 1.08 (t, J= 7.14 Hz, 3H, CH2CH3), 1.18-1.58 (m, 9H, aliphatic CH2 and CI-I), 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, IH, 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, NHCH2CH3), 6.53 (d, J= 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 C22H29N302~ 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][ I ]benzopyrano[3,2-i]quinolizine-1-carboxaldehyde, 8,9,11,12,13,13a,14, I 4a-octahydro-2-methyl-N
_O
O
\~ ~~--CH3 N
H
To a solution of DMF (642 pL, 8.29 mmol) in CH2C12 was added POC13 (736 pL, 7.89 mmol) dropwise under nitrogen atmosphere. After stirring at ambient temperature for 10 minutes, pyrrolo[3',2':5,6][1]bcnzopyrano[3,2-i]-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 reaction mixture was poured into 300 mL of saturated aqueous NaHC03 solution and stirred vigorously for 10 minutes. The resulting mixture was extracted with CHC13 (4 x 100 mL), the combined organic phase was washed with water (1 x 200 mL) and brine (1 x 200 mL), dried over Na2S04, and concentrated in vacuo affording a golden solid. The crude product was further purified by flash chromatography (25% acetone in EtOAc). Recrystallization from EtOH/Et20 gave 0.63 g (49%) of pure titled compound as a white solid: mp 262°C
(dce.); IR
3178, 2931, 1633, 1617, 1484, 1474, 1436, 1391, 1130, 1085, 868, 772 cm-1; 1H
NMR (DMSO-d6) 8 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, J= 8.55 Hz, 1H, ArH), 7.04 (d, J= 8.55 Hz, 1H, ArH), 10.0 (s, 1H, ArCHO), 11.9 (bs, 1H, exchangeable proton); MS(APCI+): m/z 325.2 (MH+). Analysis calculated for C20H24N202v C~ 74.05; H, 7.46; N, 8.63. Found: C, 73.97; II, 7.48; N, 8.58.

Example 35 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7, 8,9,10,12,13,14,14a,1 S-decahydro-2-methyl-, methyl ester O
O
~~-CHs N
H
Step A: 5-Hydroxy-2-methyl-1H-indolc-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-1 H-indole-3-carboxylic acid methyl ester 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl ester (10.0 g, 49.0 mmol) and aqueous Me2NH (40%, 12.0 mL, 107 mmol) were mixed with 32 mL of EtOH, aqueous HCHO (37%, 4.75 mL, 58 mmol) was then added. After stirring at ambient temperature for 16 hours, the reaction mixture was mixed with I 5 I 00 mL of water. The resulting mixture was extracted with EtOAc (3 x 100), the combined organic phase was washed with water (l x 100 mL) and brine (1 x 100 mL), dried over Na2S04 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 of white solid. The white solid was suspended in 150 mL
of EtOAc and mixed with 100 mL of 10% aqueous K2C03 solution, the mixture was stirred until a clear solution is obtained, two layers were separated, the aqueous layer was extracted with EtOAc (50 mL). The combined organic phase was over Na2S04 and concentrated ijz vacuo to give 3.22 g (25%) of light tan crystals.
Recrystallization of small portion of the crude product from acetone/water gave pure titled compound as white crystals: mp 145-146°C; IH NMR (CDC13) 8 2.33 (s, 6H, N(CH3)2), 2.55 (s, 3H, ArCH3), 3.84 (s, 3H, C02CH3), 4.19 (s, 2H, ArCH2NMe2), 6.72 (d, J= 8.55 Hz, 1H, ArH), 7.04 (d, J= 8.55 Hz, 1H, ArH);

MS(APCI+): nilz 263,1 (MH+). Analysis calculated for C14HI8N2O3: 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 salt (2.17 g, 9.10 mmol, Example 3, Step B) and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 50 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual 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 nitrogen for 2.5 hours followed by stirring at ambient temperature for 16 hours. The reaction mixture was concentrated in vacuo affording a thick oil.
Crystallization from CH3CN gave 1.75 g (63%) ofpurc titled compound as a white solid: mp 205-205.5°C; IR 3242, 2938, 1696, 1441, 1236, 1079, 884 cm-I~ 1H NMR
(CDC13) 8 1.21-1.80 (m, 9H, aliphatic CH2 and CH), 1.82-1.95 (m, 1H, aliphatic CH), 2.09-2.13 (m, 1H, aliphatic CH), 2.41-2.77 (m, 2H, obscured by ArCH3 peak, aliphatic CH), 2.77 (s, 3H, ArCH3), 2.82-2.86 (m, 2II, aliphatic CH), 3.00-3.07 (m, IH, aliphatic CH), 3.44 (dd, J= 18.1, 6.59 Hz, IH, aliphatic CH), 3.83 (s, 3H, C02CH3), 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 for C21H26N203v 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,12,12-trimethyl-, phenylmethyl ester and/or Pyrrolo(3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14, I 4a,15-decahydro-2,10,10-trimethyl-, phenylmethyl ester or I-I
Step A: 4,4-Dimethyl-1,2,3,4,6,7,8,9-octahydro-quinolizinylium perchlorate 'NJ

ClO4O
The synthesis of 4,4-dimethyl-1,2,3,4,6,7,8,9-octahydro-quinolizinylium perchlorate from 1-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 v1, p 819. 1H NMR (400 MHz, CDC13) 8 1.52 (s, 6H, C(CH3)2), 1.75-1.86 (m, 4H, aliphatic CII), 1.88-2.00 (m, 4H, aliphatic CH), 2.80-2.87 (m, 4H, aliphatic Cll), 2.65-2.75 (m, 2H, NCH2); MS
(APCI+) m/z 166.0 (parent MH+) Step B: 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-2,12,12-trimethyl-, phenylmethyl ester and/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 One equivalent of 4,4-dimethyl-1,2,3,4,6,7,8,9-octahydro-quinolizinylium perchlorate (1.45 mmol, 0.385 g) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et20 and the combined extracts were washed with 1 x 20 mL of saturated aqueous NaCl, dried with MgS04, filtered, and concentrated to give the enamine. The residue was dissolved in dioxane (14 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester (1.45 mmol, 0.490 g) was added. The reaction mixture was heated at 90°C under N2 for I 8 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 100% ethyl acetate and trituration with ether to give 90 mg (14%) of pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2,12,12-trimethyl-, phenylmethyl ester and/or pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2,10,10-trimethyl-, phenylmethyl ester as a yellow foam: IR (KBr) 3383, 2932, 2857, 1675, 1432, 1090, 1072 cm-1; 1H NMR
(400 MHz, DMSO-d6) 8 1.07 (s, 3H, CH3), 1.23 (s, 3II, CH3), 1.09-1.26 (m, SH, aliphatic CH), 1.42-1.61 (m, 6H, aliphatic CH), 1.90 (d, J--12.70 Hz, 1H, aliphatic CH), 2.58 (d, J--18.56 Hz, 1H, aliphatic CH), 2.64-2.75 (m, 3H, aliphatic CI~, 3.11-3.19 (m, 2H, aliphatic CH), 3.24-3.30 (m, IH, aliphatic CH), 5.15-5.25 (m, 2H, OCH2Ar), 6.52 (d, J--8.79 Hz, 1H, ArH), 6.99 (d, J--8.55 Hz, IH, ArH), 7.30-7.42 (m, SH, ArH), 11.50 (s, 1H, NH); MS (APCI+) ntlz 459.3 (MH+). Anal.
Calcd for C2c~H34N203~0.19 H20: C, 75.39; H, 7.50; N, 6.06; H20, 0.74. Found:
C, 75.00; H, 7.73; N, 5.79; H20, 0.36.
Example 37 Pyn-olo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, ethyl ester 1e Step A: 6-Fluoro-5-hydroxy-2-methyl-IH-indole-3-carboxylic acid ethyl ester O
O
HO
i Me F N
H
6-Fluoro-5-hydroxy-2-methyl-IH indole-3-carboxylic acid ethyl ester was synthesized according to the procedure published in Littell, R.; Allen, G.R., Jr.
J. Org. Chem. 1968;33:2064.
Step B: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester Me2N O
O
HO
i Me F ~ N
H
4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-IH indole-3-carboxylic acid ethyl ester was prepared according to Procedure G from 6-fluoro-S-hydroxy-2-methyl-1H indole-3-carboxylic acid ethyl ester (4.51 mmol, 1.07 g). The product precipitated out of the reaction solution upon reducing the volume 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, 1443, 1124, 1078 cm-1; 1H NMR (400 MHz, DMSO-d6) b 1.32 (t, J--7.08 Hz, 3H, OCH2CH3), 2.26 (s, 6H, N(CH3)2), 2.50 (s, 3H, ArCH3), 4.17 (s, 2H, NCH2Ar), 4.24 (q, J--7.08 Hz, 2H, OCH2CH3), 7.05 (d, J--10.50 Hz, 1H, ArH), 11.56 (bs, 1H, NH); 19F NMR (DMSO-d6) 8 -141.69 (d, J--10.68 Hz); MS
(APCI+) fnlz 295.1 (MH+). Anal. Calcd for C15H1yF1N203: C, 61.21; H, 6.51;
N, 9.52; F, 6.45. Found: C, 61.32; H, 6.55; N, 9.51; F, 6.61.

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester was synthesized according to Procedure I from 4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H 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 white solid (32%): mp 184-186°C; IR (KBr) 3367, 2932, 2858, 1670, 1456, 1437, 1135 cm-1; 1H NMR (400 MHz, CDC13) 8 1.37 (t, J--7.08 Hz, 3H, OCH2CH3), 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, J--13.43 Hz, 1H, aliphatic CH), 2.43-2.49 (m, 2H, aliphatic CH), 2.57 (s, 3H, ArCH3), 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, J--7.08 Hz, 2H, OCH2CH3), 6.86 (d, J--10.01 Hz, 1H, ArH), 8.09 (bs, 1H, NH);
19F NMR (CDCI3) 8 -140.62 (d, J--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 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester H

Step A: 6-Fluoro-5-hydroxy-2-methyl-IH indole-3-carboxylic acid O
OH
HO
i Me F \ H
6-Fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (Example 37, Step A, 9.02 mmol, 2.14g) was dissolved in 40 mL of 2N sodium hydroxide and heated at reflux for 1 hour. The solution was cooled to 0°C and carefully acidified to pH 9 with concentrated HCI. The solution was extracted with CH2CI2, the extracts were discarded and the aqueous layer was further acidified at 0°C to pII 4 with concentrated HCI. The precipitate was filtered off and dried in vacuo for 18 hours to afford a tannish pink solid (1.16 g, 62%):
mp L0 202-204°C (dec); IR (KBr) 3584, 3358, 1649, 1471, 1109 cm-l; 1H
NMR
(400 MHz, DMSO-d6) cS 2.53 (s, 3H, ArCH3), 7.04 (d, J--11.23 Hz, 1H, ArH), 7.46 (d, J--9.03 Hz, I H, ArH), 9.17 (s, 1 H, ArOH), 11.46 (s, 1 H, NH or COOK, 11.76(s, 1H, COOH or NH); 19F NMR (DMSO-d6) 8 -141.60 (t, J--10.68 Hz);
Ms (APCI-) ~~iZ 2os.o (M-1).
Step B: 6-Fluoro-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester To a suspension of 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (4.92 mmol, 1.03 g) in 10.0 mL of DMF at room temperature under N2 was added dropwise via syringe 1,8-diazabicyclo[5.4.0]undec-7-ene (4.92 mmol, 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, and recrystallized from chloroform to give a white, cottony solid (0.677 g, 46%):
mp 191-193°C; IR (KBr) 3384, 3254, 1662, 1475, 1327, 1129, 1098 cm-1; 1H
NMR

(400 MHz, DMSO-d6) 8 2.59 (s, 3H, ArCH3), 5.32 (s, 2H, OCH2C6H5), 7.12 (d, J--10.99 Hz, 1H, ArH), 7.31-7.49 (m, 6H, ArH), 9.29 (s, 1H, ArOH), 11.67 (s, 1H, NH); 19F NMR (DMSO-d6) b -140.96-141.01 (m); MS (APCI-) m/z 298.1 (M-1 ).
Anal. Calcd for C17H14F1N103'0.04 H20: C, 68.06; H, 4.73; N, 4.67; F, 6.33;
H20, 0.24. Found: C, 67.69; H, 4.63; N, 4.57; F, 6.61; H20, 0.10.
Step C: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester ~l MeZN O
O
HO
~>-Me F ~ N
H
A solution of 6-fluoro-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester (2.26 mmol, 0.677 g) and N,N,N',N'-tetramethyldiaminomethane (2.49 mmol, 0.34 mL) in 5 mL of dioxane under N2 was heated at reflux for 21 hours. An additional aliquot ofN,N,N',N'-tetramethyldiaminomethane (2.49 mmol, 0.34 mL) was added, and the reaction was continued at reflux for 24 hours, cooled to room temperature, and concentrated. The residue was recrystallized from ethyl acetate to afford a light yellow solid (0.260 g, 32%): mp 167-169°C; IR (KBr) 3280, 2951, 1692, 1443, 1123, 1081 cm-1; 1H NMR
(400 MHz, DMSO-d6) 8 2.12 (s, 6H, N(CH3)2), 2.44 (s, 3H, ArCH3), 4.04 (s, 2H, NCH2Ar), 5.23 (s, 2H, OCH2C6H5), 7.01 (d, J--10.50 Hz, 1H, ArH), 7.31-7.44 (m, 5I-I, ArH), 11.57 (s, 1H, NH); 1~F NMR (DMSO-d6) 8 -141.55 (d, J 10.68 Hz); MS (APCI+) m/z 357.1 (MH+). Anal. Calcd for C20H21F1N203-0.07 C4H802: 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.

Step D: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-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-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-fluoro-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester (0.601 mmol, 0.214 g), heating at 80°C for 40 hours. The product was purified by silica gel flash column chromatography (30-50% ethyl acetate/hexanes) and recrystallized from ether to give a white solid (0.169 g, 63%): mp 179-181 °C; IR (KBr) 2932, 2857, 1699, 1453, 1131, 1075 cm-1; 1H NMR (400 MHz, CDCl3) 8 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, J--12.94 Hz, 1H, aliphatic CH), 2.42-2.48 (m, 2H, aliphatic CH), 2.55 (s, 3H, ArCH3), 2.79 (d, J--17.58 Hz, 1H, aliphatic CH), 2.85-2.92 (m, 1H, aliphatic CH), 3.04-3.17 (m, 1H, aliphatic CH), 3.35 (dd, J--18.31, 6.51 Hz, 1H, aliphatic CH), 5.25-5.37 (m, 2H, OCH2C6H5), 6.86 (d, J--10.25 Hz, 1H, ArH), 7.28-7.38 (m, 3H, ArH), 7.40-7.44 (m,2H, ArH), 8.07 (bs, 1H, NH); 19F NMR
(CDCl3) 8 -142.0 (m); MS (APCI+) nTlz 449.1 (MH+). Anal. Calcd for C27H29F1N203: C, 72.30; H, 6.52; N, 6.25; F, 4.24. Found: C, 72.28; H, 6.45;
N, 6.09; F, 4.50.
Example 39 12H-Furo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester 1e Step A: 6-Fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester O
O
HO
i \ Me F ~ O
To a solution oft-fluoro-[1,4]benzoquinone (38.3 mmol, 4.82 g) in 300 mL of glacial acetic acid was added 3-amino-but-2-enoic acid ethyl ester (31.9 mmol, 4.12 g). The solution was heated at reflux for 1.5 hours, cooled to room temperature, and concentrated. The product was isolated by silica gel flash column 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, I 110 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 1.36 (t, J--7.08 Hz, 3H, OCH2CH3), 2.68 (s, 3H, ArCH3), 4.32 (q, J--7.08 Hz, 2H, OCH2CH3), 7.43 (d, J--8.79 Hz, 1 H, ArH), 7.55 (d, J--10.74 Hz, 1 H, ArH), 9.82 (s, 1 H, ArOH); I
~F
NMR (DMSO-d6) 8 -137.42 (t, J--9.16 Hz); MS (APCI-) tnlz 237.1 (M-1). Anal.
Calcd for C12H11F104~ C~ 60.50; H, 4.65; F, 7.98. Found: C, 60.50; H, 4.46; F, 8.20.
Step B: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester Me2N O
O
HO
Me p ~ O
A solution of 6-fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester (1.90 mmol, 0.452 g) and N,N,N;N'-tetramethyldiaminomethane (2.09 mmol, 0.285 mL) in 4 mL of dioxane under N2 was heated at reflux for 4.5 hours, cooled to room temperature, and concentrated. Water (10 mL) was added to the residue, and the resultant precipitate was filtered off, dried, and recrystallized from t-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;

NMR (400 MHz, DMSO-d6) 8 1.34 (t, J 7.08 Hz, 3H, OCH2CH3), 2.21 (s, 6H, N(CH3)2), 2.57 (s, 3H, ArCH3), 4.03 (s, 2H, NCH2Ar), 4.32 (q, J--7.08 Hz, 2H, OCH2CH3), 7.48 (d, J--10.25 Hz, 1H, Arl~; 19F NMR (DMSO-d6) 8 -137.69 (d, J--10.68 Hz); MS (APCI+) rnlz 296. I (MH+). Anal. Calcd for C 15H 18F I N I
04:
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)[1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 5-fluoro-7, 8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester 12H-Furo[3',2':5,6][IJbenzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester was synthesized according 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; IH NMR (400 MHz, CDC13) 8 1.25-1.37 (m, 2H, aliphatic CH), 1.38 (t, J--7.08 Hz, 3H, OCH2CH3), 1.40-I .52 (m, ZH, aliphatic CH), 1.57-1.80 (m, SH, aliphatic CH), 1.84-1.96 (m, 1H, aliphatic CH), 2.02 (d, J--13.43 Hz, IH, 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, J--17.82 Hz, IH, aliphatic CH), 3.06-3.16 (m, 1H, aliphatic CH); 3.34-3.40 (m, 1H, aliphatic CH), 4.34 (q, J--7.08 Hz, 2H, OCH2CH3), 7.03 (d, J--9.77 Hz, 1H, ArH); 19F NMR (CDC13) 8 -137.90 (d, J--9.16 Hz); MS (APCI+) rn/z 388.2 (MH+). Anal. Calcd for C22H26FIN104~ 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 4,5-difluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester O
O
O
~~Me F ~ N
H
F
Step A: 2,3-Difluoro-benzene-1,4-diol OH
F
F
OH
2,3-Difluorophenol (Aldrich, 183.2 mmol, 24.32 g) was oxidized using potassium persulfate nitrate following the procedure of Feiring, A.E.;
Sheppard, W.A. J. Org. Chem. 1975;40:2543. The crude material was purified by silica gel flash column chromatography (10% acetonitrile/chloroform) and recrystallized from chloroform to give a light yellow solid (7.32 g, 27%): mp 156-158°C; IR
(KBr) 3343 (br), 1514, 1505, 1259, 1199, 1041 cm-1; 1H NMR (400 MHz, DMSO-d6) ~ 6.52 (d, J--5.37 Hz, 2H, Arl~, 9.45 (s, 2H, ArOl~; 1 ~F NMR
(DMSO-d6) 8 -159.78 (d, J--4.58 Hz); MS (APCI-) m/z 145.0 (M-1). Anal. Calcd for C6H4F202: C, 49.33; H, 2.76; F, 26.01. Found: C, 49.09; H, 2.73; F, 26.37.
Step B: 2,3-Difluoro-[1,4)benzoquinone O
F
~F
O
2,3-Difluoro-benzene-1,4-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. Client. 1975;40:2543 to afford a bright yellow solid (6.63 g, 94%):
mp 97.0-98.5°C; IR (KBr) 3352, 1684, 1333 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 6.98 (s, 2H, ArI~; 1'~F NMR (DMSO-d6) 8 -144.85 (s); MS (APCI-) m/z 144.0 (M-). Anal. Calcd for C6H2F202: 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-111-indole-3-carboxylic acid benzyl ester O
O
HO
i ~>--Me F \ N
F H
To a solution of2,3-difluoro-[1,4]benzoquinone (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 to room temperature, and the precipitate was filtered off. The beige solid was washed with glacial acetic acid and dried in vaczco to give clean product. The filtrate was neutralized, water (20 mL) was added, and the solution was extracted with ethyl acetate (4 x 20 mL). The extracts were dried over MgS04, filtered, concentrated and the residue purified by silica gel flash column chromatography (20% ethyl acetate/hexancs). The pure portions were combined to give 0.174 mg (52%) of off white solid, which was recrystallized from acetonitrile: mp 215-217°C; IR
(KBr) 3457, 3243, 1658, 1480, 1338, 1150 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 2.58 (s, 3H, ArCH3), 5.31 (s, 2H, OCH2C6H5), 7.29-7.45 (m, 6H, ArH), 9.75 (s, 1H, ArOH), 12.13 (s, 1H, NH); MS (APCI+) m/z 318.0 (MH+). Anal.
Calcd for C17H13F2N103~0.04 C2H402: C, 64.17; H, 4.15; N, 4.38; F, 11.89.
Found: C, 63.80; H, 4.15; N, 4.05; F, 12.18.

Step D: 4-Dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester Me2N O
O
HO
>--Me F \ H
F
4-Dimcthylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-I H-indole-3-carboxylic acid benzyl ester was prepared according to Procedure G from 6,7-difluoro-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester (8.08 mmol, 2.56 g). The reaction was heated at 50°C for 21 hours, the precipitate was filtered off, washed with ethanol, 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; 1H NMR (400 MHz, DMSO-d6) 8 2.13 (s, 6H, N(CH3)2), 2.46 (s, 3H, ArCH3), 4.00 (s, 2H, ArCH2N), 5.24 (s, 2H, OCH2C6H5), 7.27-7.38 (m, 3H, ArH), 7.41-7.44 (m, 2H, ArH), 12.08 (s, IH, NH); 1~F NMR
(DMSO-d6) 8 -168.26 (d, J--21.4 Hz), -159.68 (d, J--21.4 Hz); MS (APCI+) m/z 375.0 (MH+). Anal. Calcd for C2pH2pF2N2O3: 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][1)benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4,5-difluoro-3,7,8,9, I 0,12, I 3,14,14a,15-decahydro-2-methyl-, phenylmethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 4,5-difluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester was synthesized according to Procedure I (90°C, 18 hours) from 4-dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (3.82 mmol, 1.43 g). The product was purified by silica gel flash column chromatography (5-10% ethyl acetate/dichloromethane) to give 1.37 g (77%) of cream colored solid. A portion was recrystallized from t-butyl methyl ether/hexanes to afford a white solid: mp 159-160°C; IR (KBr) 3297, 2933, 2857, 1704, 1455, 1141, 1124 cm-1; 1H NMR (400 MHz, CDCl3) ~ 1.17-1.36 (m, 3H, aliphatic CH), 1.43-1.49 (m, 1H, aliphatic CI~, 1.57-1.78 (m, 6H, aliphatic CH), 2.00 (d, J--13.7 Hz, 1H, aliphatic CH), 2.46 (d, J--9.77 Hz, 1H, aliphatic CH), 2.53-2.57 (m, IH, aliphatic CH), 2.57 (s, 3H, ArCH3), 2.71 (d, J--18.31 Hz, 1H, 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, OCH2C6H5), 7.32-7.38 (m, 3H, ArH), 7.42 (d, J--6.84 Hz, 2H, ArH), 8.21 (s, 1H, NH); 19F NMR (CDC13) ~
-166.80 (d, J--19.84 Hz), -162.52 (d, J--21.36 Hz); MS (APCI+) m/z 467.1 (MH+).
Anal. Calcd for C27H28F2N203: C, 69.51; H, 6.05; N, 6.00; F, 8.14. Found: C, 69.36; H, 5.99; N, 5.88; F, 8.37.
Example 41 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 4,5-dichloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester 1e Step A: 6,7-Dichloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester O
O
HO
~--Me Cl \ H
Cl 6,7-Dichloro-5-hydroxy-2-methyl-IH indole-3-carboxylic acid benzyl ester was prepared from 2,3-dichloro-[1,4]benzoquinone (16.8 mmol, 2.98 g) and 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, LA.; Shvedov, V.L; 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; IH
NMR
(400 MHz, DMSO-d6) 8 2.59 (s, 3H, ArCH3), 5.29 (s, 2H, OCH2C6H5), 7.30 (t, J--7.08 Hz, 1H, Arl~, 7.34-7.38 (m, 2H, ArH), 7.42 (d, J--7.32 Hz, 2FI, ArH), 7.51 (s, 1H, ArH); MS (APCI-) m/z 348.0 (M-1). HPLC (ALLTECH/ALLTIMA
C-18, 1:1-2:98 H20/CH3CN + 0.05% TFA): retention time=6.573 min, 98.41 purity.
Step B: 4-Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-IH indole-3-carboxylic acid ben~yl ester MezN O
O
HO
i ~~--Me CI ~ N
H

4-Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester was prepared according to Procedure G from 6,7-dichloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (3.06 mmol, I .07 g). The reaction was heated at 50°C for 22.5 hours, concentrated and 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, I 107 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 2.18 (s, 6H, N(CH3)2), 2.52 (s, 3H, ArCH3), 4.06 (s, 2H, ArCH2N), 5.27 (s, 2H, OCH2C6H5), 7.30-7.39 (m, 3H, ArH), 7.41-7.47 (m, 2H, ArH), 11.84 (s, 1H, NH); MS (APCI+) m/z 407.1 (M+). Anal. Calcd for C2pH2pC12N203: 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.

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 4,S-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, S 4,S-dichloro-3,7,8,9,10,12,13,14,14a,1S-decahydro-2-methyl-, phenylmethyl ester was synthesized according to Procedure I (80°C, 18 hours) from 4-dimethylaminomethyl-6,7-dichloro-S-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester (1.82 mmol, 0.742 g). The product was purified by silica gel flash column chromatography (10% acetone/hexanes) to give 0.684 g (7S%) peach colored foam: mp 100-lOS°C; IR (KBr) 3424, 2932, 2853, 1685, 1430, 1125, 1076 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 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, ArCH3), 2.63-2.69 (m, 2H, aliphatic CH), 2.95-2.99 (m, 1H, aliphatic CH), 3.17 (dd, J--18.31, 6.74 Hz, 1I-/, aliphatic 1S CH), 5.23 (dd, J--28.08, 12.21 Hz, 2H, OCH2C6HS), 7.31-7.39 (m, 3H, ArH), 7.42-7.44 (m, 2H, ArH), 11.85 (s, 1 H, NH); MS (APCI+) ntlz 499.1 (M/-/+).
Anal.
Calcd for C27H28C12N203~0.07 H20: C, 64.77; H, 5.66; N, S.S9; Cl, 14.16;
H20, 0.25. Found: C, 64.37; H, 5.64; N, S.S1; C1, 13.96; H20, 0.32.
Example 42 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1S-decahydro-4,S-dimethoxy-2-methyl-, phenylmethyl ester Step A: 6,7-Dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester O
O
HO
~>--Me Me0 ~ N
H
OMe 2,3-Dimethoxy-[1,4]benzoquinone (10.4 mmol, 1.74 g) was added to a solution of 3-amino-but-2-enoic acid benzyl ester (8.62 mmol, 1.65 g) in ethanol (25 mL) at 0°C. The reaction was warmed to room temperature and then heated at reflux for 18 hours. The solvent was removed and the product was purified by silica gel flash column chromatography (30-50% ethyl acetate/hexanes) and recrystallized from toluene to give a peach colored solid (0.621 g, 21%): mp 154-156°C; IR (KBr) 3336, 3267, 1660, 1468, 1327, 1146, 1081 cm-I; IH
NMR
(400 MHz, DMSO-d6) 8 2.56 (s, 3H, ArCH3), 3.73 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.29 (s, 2H, OCH2C6H5), 7.1 I (s, 1 H, ArH), 7.29-7.43 (m, 5H, ArH), 8.79 (s, 1H, ArOH), 11.59 (s, 1H, NH); MS (APCI-) m/z 340.0 (M-1). Anal. Calcd for C19H19N105: C, 66.85; H, 5.61; N, 4.10. Found: C, 66.69; H, 5.55; N, 3.79.
Step B: 4-Dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester MezN O
O
HO
t ~>--Me Me0 ~ N
H
OMe 4-Dimethylaminomethyl-6,7-methoxy-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester was prepared according to procedure G from 6,7-dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester ( 1.69 mmol, 0.577 g). The reaction was heated at 50°C for 18 hours, concentrated and purified by silica gel flash column chromatography (0-3%
triethylamine/ethyl 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, I 129 cm-1; 1H NMR (400 MHz, DMSO-d6) ~ 2.10 (s, 6H, N(CH3)2), 2.44 (s, 3H, ArCH3), 3.73 (s, 3H, ArOCH3), 3.86 (s, 3H, ArOCH3), 3.94 (s, 2H, ArCH2N), 5.21 (s, 2H, OCH2C6H5), 7.29-7.38 (m, 3H, ArH), 7.41-7.43 (m, 2H, ArH), 11.48 (s, 1H, NH); MS (APCI+) m/z 399.0 (MH+). Anal. Calcd for C22H26N205~ C~ 66.32; H, 6.58; N, 7.03. Found: C, 66.47; H, 6.58; N, 6.73.
Step C: Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-4, 5-dimethoxy-2-methyl-, phenylmethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10, I 2,13,14,14x,15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethyl ester was synthesized according to Procedure I (90°C, 21 hours) from 4-dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid bcnzyl ester (0.595 mmol, 0.237 g). The product was purified by silica gel flash column chromatography (50% ethyl acetate/hexanes) and recrystallized from 2,2,4-trimethylpentane to give 0.089 g (30%) white solid:
mp 130-136°C; IR (KBr) 3307, 2931, 2856, 1833, 1700, 1684, 1448, 1418, 1282, I 137, 1123 cm-I; IH NMR (400 MHz, CDCl3) 8 1.24-1.38 (m, 4H, aliphatic CH), 1.44-1.55 (m, IH, aliphatic CSI), 1.59-1.80 (m, 6H, aliphatic CH), 2.09 (d, J--13.98 Hz, IH, aliphatic CH), 2.51 (d, J--10.37 Hz, 1H, aliphatic CH), 2.58 (s, 3H, ArCH3), 2.78 (d, J--18.08 Hz, IH, aliphatic CH), 2.85-2.91 (m, IH, aliphatic CH), 3.08-3.14 (m, 1H, aliphatic CH), 3.29-3.36 (m, 1H, aliphatic CH), 3.96 (s, 3H, OCH3), 4.05 (s, 3H, OCH3), 5.26-5.37 (m, 2H, OCH2C6H5), 7.31-7.40 (m, 3H, ArH), 7.44 (d, J--6.99 Hz, 2H, ArH), 8.29 (s, 1H, NH); MS (APCI+) m/z 491.1 (MH+). HPLC (ALLTECH/ALLTIMA C-18, 1:1-2:98 H20/CH3CN +
0.05 % TFA): retention time=4.527 min, 100.00% purity.

Example 43 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, phenylmethyl ester O
O
O
t Me Me ~ N
H
Step A: 6-Methyl-5-hydroxy-2-methyl-IH indole-3-carboxylic acid benzyl ester o ~l HO
t ~ Me Me 6-Methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (2.42 g, 10%) was obtained from methyl-[1,4]benzoquinone (Aldrich, 81.9 mmol, 10.0 g) and 3-amino-but-2-enoic acid benzyl ester (79.5 mmol, 15.2 g) following 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 reaction product consisted of a mixture of the desired 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester and the regioisomer, 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester. The regioisomers were separated following the procedure for the corresponding ethyl esters reported by Poletto, 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 give X-ray quality crystals. Single crystal X-ray analysis indicated that the higher Rf isomer (silica gel, 50% ethyl acetatc/hexanes) was 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester: mp 196-197°C; 1R (KBr) 3399, 3314, 1655, 1469, 1438, 1086 cm-I; IH NMR (400 MHz, DMSO-d6) b 2.14 (s, 3H, ArCH3), 2.53 (s, 3H, ArCH3), 5.28 (s, 2H, OCH2C6H5), 6.99 (s, IH, ArH), 7.28-7.42 (m, 6H, ArH), 8.81 (s, 1 H, ArOH), 11.42 (s, 1 H, NII); MS (APCI+) ntlz 296.0 (MH+). Anal. Calcd for C18H17N103~0.25 H20: 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-S-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester MeZN O
O
HO
i ~ Me Me \ H
4-Dimethylaminomethyl-6-methyl-S-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester was prepared according to Procedure G from 6-methyl-5-hydroxy-2-methyl-1H-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 formaldehyde. 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 was recrystallized from ethyl acetate to give a light yellow solid: mp 162-164°C; IR
(KBr) 3313, I 688, 1432, 1227, 1119, 1075 cm l ; 1 H NMR (400 MHz, DMSO-d6) 8 2.13 (s, 9H, N(CH3)2 and ArCH3), 2.44 (s, 3H, ArCH3), 4.01 (s, 2H, ArCH2N), 5.22 (s, 2H, OCH2C6H5), 6.95 (s, 1H, Arll), 7.29-7.44 (m, 5H, ArH), 11.40 (s, 1H, NI~; MS (APCI+) m/z 353.1 (MH+). Anal. Calcd for C21H24N203: 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][1]benzopyrano[3,2-i)quinolizine-1-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-2,5-dimethyl-, phenylmethyl ester was synthesized according to Procedure I (90°C, 24 hours) from 4-dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-IH indole-3-carboxylic acid benzyl ester (4.45 mmol, 1.57 g). The product was purified by silica gel flash column chromatography (20-50% acetone/hexanes then 20-40% ethyl acetate/dichloromethane) 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-d6) 8 1.05-1.16 (m, 2H, aliphatic CH), 1.21-1.25 (m, 1H, aliphatic CH), 1.33-1.42 (m, 2H, aliphatic CH), 1.45-1.66 (m, 5H, aliphatic CH), 1.78 (d, J--13.67 Hz, 1H, aliphatic CH), 2.18 (s, 3H, ArCH3), 2.34 (d, J 9.28 Hz, 1H, aliphatic CH), 2.44 (s, 3H, ArCH3), 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, J--18.07, 6.59 Hz, 1H, aliphatic CI~, 5.19 (dd, J--25.15, 12.21 Hz, 2H, OCH2C6H5), 6.90 (s, 1H, ArH), 7.28-7.37 (m, 3H, ArH), 7.41 (d, J--6.84 Hz, 2H, ArH), 11.37 (s, 1H, NH); MS (APCI+) mlz 445.3 (MH+). Anal. Calcd for C28H32N203~0.16 H20: C, 75.16; H, 7.28; N, 6.26; H20, 0.64. Found: C, 74.76;
H, 7.35; N, 6.07; H20, 0.34.
Example 44 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 N O
O
O
i ~Me 'N
N
Me Step A: 7-Methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester O \
O
HO
---Me N
H
Me 7-Methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (2.04 g, 8.7% yield) was obtained as an off white powder from methyl-[1,4]benzoquinone (81.9 mmol, 10.0 g) and 3-amino-but-2-enoic acid benzyl ester (79.5 mmol, 15.2 g) as in Example 43, Step A. Single crystal X-ray analysis indicated that the lower R f isomer (silica gel, 50% ethyl acetate/hexanes) was 7-methyl-5-hydroxy-2-methyl-1H indole-3-carboxylic acid benzyl ester: mp 188-189°C; IR (KBr) 3430, 3286, 1641, 1446, 1294, 1153, 1098 cm-1; 1H
NMR
(400 MHz, DMSO-d6) b 2.32 (s, 3H, ArCH3), 2.58 (s, 3H, ArCH3), 5.27 (s, 2H, OCH2C6H5), 6.39 (d, J--1.22 Hz, 1H, ArH), 7.10 (d, J--1.71 Hz, I H, ArH), 7.26-7.31 (m, 1H, ArH), 7.34-7.38 (m, 2H, ArH), 7.42 (d, J--7.81 Hz, 1H, ArH), 8.71 (s, 1H, ArOH), 11.42 (s, 1H, NH); MS (APCI-~) rnlz 296.0 (MH+). Anal.
Calcd for C18H17N103: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.02; H, 5.70; N, 4.40.
Step B: 4-Dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester MezN O
O
HO
>--Me N
H
Me 4-Dimethylaminomethyl-7-methyl-S-hydroxy-2-methyl-1 H-indole-3-carboxylic acid benzyl ester was prepared according to procedure G from 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (6.62 mmol, 1.85 g), 41.3 mmol of dimethylamine, and 22.5 mmol of formaldehyde. The reaction was heated at SO°C for 46 hours, concentrated, purified by silica gel flash column chromatography (0-5% triethylamine/ethyl acetate) and recrystallized from ethyl acetate to give a light tan solid (0.900 g, 41%): mp 161-164°C; IR (KBr) 3307, 1684, 1292, 1220, 1070 cm-1; IH NMR
(400 MHz, DMSO-d6) 8 2.08 (s, 6H, N(CH3)2), 2.30 (s, 3H, ArCH3), 2.47 (s, 3H, ArCH3), 3.89 (s, 2H, ArCH2N), 5.22 (s, 2H, OCH2C6H5), 6.37 (s, 1H, ArH), 7.28-7.38 (m, 3H, ArH), 7.43 (d, J--7.08 Hz, 2H, ArH), 11.28 (s, 1H, NH); MS

(APCI+) m/z 353.2 (MH+). Anal. Calcd for C21H24N203~ 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][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 Pyrrolo[3',2':5,6](1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2,4-dimethyl-, phenylmethyl ester was synthesized according to Procedure I (80°C, 39 hours) from 4-dimethylaminomethyl-7-methyl-S-hydroxy-2-methyl-IH-indole-3-carboxylic acid benzyl ester (2.55 mmol, 0.900 g). The product was purified by silica gel flash column chromatography (30% ethyl acetatelhexanes then 20-50% ethyl acetate/dichloromcthane) to give 0.569 g (50%) off white solid: mp 183-187°C;
IR (KBr) 3325, 2929, 1664, 1431, 1279, 1221, I 107, 1075 cm-/; 1H NMR
(400 MHz, DMSO-d6) 8 1.06-1.15 (m, 2H, aliphatic CH), 1.19-1.22 (m, 1H, aliphatic CH), 1.31-1.62 (m, 8H, aliphatic CII), 1.81 (d, J--12.94 Hz, IH, aliphatic CH), 2.30 (s, 3H, ArCH3), 2.33-2.42 (m, 1H, aliphatic CH), 2.45 (s, 3H, ArCH3), 2.55 (d, J--17.82 Hz, 1H, aliphatic CH), 2.61-2.66 (m, 1H, aliphatic CH), 2.82-2.88 (m, 1H, aliphatic CII), 3.09-3.15 (m, 1H, aliphatic CII), 5.20 (dd, .l--24.90, 12.21 Hz, 2H, OCH2C6H5), 6.41 (s, IH, ArH), 7.28-7.43 (m, SH, ArH), 11.31 (s, 1 H, NH); MS (APCI+) na/z 445.3 (MH+). Anal. Calcd for C28H32N203: 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, 1-(4-fluorophenyl)ethyl ester Me N O \
O
O
i ~ Me Me \ N
H

Step A: 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-2,5-dimethyl-, anhydride with benzoic acid H
$ To a solution ofpyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-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)2lC (0.200 g, 24 wt%). The mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 20 minutes and filtered through celite, rinsing with tetrahydrofuran, to give the carboxylic acid: MS (APCI+) m/z 355.2 (MH+). To the filtrate under N2 at room temperature was added benzoyl chloride (1.88 mmol, 0.218 mL) dropwise. After 60 hours at room temperature, the precipitate was filtered off, the filtrate was concentrated, and the residue was triturated with ether to afford a light peach solid (0.517 g, 60%): IH NMR (400 MHz, DMSO-d6) selected diagnostic peaks 8 2.23 (s, 3H, ArCH3), 2.48 (s, 3H, ArCH3), 7.00 (s, 1H, ArH), 7.57 (t, J 7.81 Hz, 2H, ArH), 7.73 (t, J--7.57 Hz, 1H, ArH), 8.06 (d, J--7.32 Hz, 2I-I, ArH), 11.94 (s, 1H, NH); MS (APCI+) mlz 459.2 (MH+).
Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, 1-(4-fluorophenyl)ethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-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-methylbenzyl alcohol (3.38 mmol, 0.427 mL) and heated with stirnng at 150°C for 2 minutes. A homogeneous solution formed, was cooled to room temperature, dissolved with ethyl acetate (10 mL), and stirred with a saturated aqueous solution of NaHC03. The layers were separated, and the aqueous phase was extracted with 3 portions (10 mL) of ethyl acetate. The combined extracts were concentrated, and the product was purified by silica gel flash column chromatography (10-1S% acetone/hexanes) to S give a shiny beige powder (0.256 g, 48%): mp 124-128°C; IR (KBr) 3378, 2933, 1675, 1425, 1228, 1127, 1059 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 1.07-1.28 (m, 3H, aliphatic CH), 1.42-1.65 (m, 6H, aliphatic CH), 1.57 (d, J--6.75 Hz, 3H, OCH(CH3)Ar), 1.71-1.74 (m, 1H, aliphatic CH), 1.79-1.87 (m, 1H, aliphatic CH), 2.21 & 2.22 (s, 3H, ArCH3, diastereomers), 2.38 (d, J--11.09 Hz, 1H, aliphatic CH), 2.46-2.49 (m, 1H, aliphatic CH), 2.50 & 2.52 (s, 3H, ArCH3, 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, OCII(CH3)Ar), 6.92 & 6.93 (s, 1H, ArH, diastereomers), 7.16-7.22 (m, 2H, ArH), 7.45-7.51 (m, 2H, ArH), 11.40 (s, 1H, NH); 19F NMR (DMSO-d6) -115.13 & -114.94 (s, 1S diastereomers); MS (APCI+) nTlz 477.3 (MH+). Anal. Calcd for C2~H33F1N2O3:
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,1S-decahydro-2,4-dimethyl-, 1-(4-fluorophenyl)ethyl ester F
O
Me Me Step A: Pyrrolo[3',2':5,6][1]bcnzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, anhydride with benzoic acid 1e Following the procedure in Example 45, Step A, 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 (1.10 mmol, 0.491 g) was converted to the mixed anhydride intermediate (cream colored solid, 0.512 g, 100%): MS (APCI+) m/z 459.3 (MH+).
Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-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-carboxylic acid, 3,7,8,9, I 0,12,13, I 4,14a, I 5-decahydro-2,4-dimethyl-, 1-(4-fluorophenyl)ethyl ester was synthesized following the procedure in Example 45, Step B 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-2,4-dimethyl-, anhydride with benzoic acid (1.12 mmol, 0.512 g). The product was purified by silica gel flash column chromatography (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; IH NMR (400 MHz, DMSO-d6) b 1.12-1.26 (m, 3H, aliphatic CH), 1.39-1.72 (m, 7H, aliphatic CH), 1.57 (d, .l--6.51 Hz, 3H, OCH(CH3)Ar), 1.82-1.91 (m, IH, aliphatic CH), 2.31-2.36 (m, 1H, aliphatic CH), 2.33 & 2.34 (s, 3H, ArCH3, diastereomers), 2.43-2.47 (m, 1H, aliphatic CH), 2.54 & 2.56 (s, 3H, ArCH3, diastereomers), 2.58-2.70 (m, 2H, aliphatic CH), 2.86-2.91 (m, 1H, aliphatic CH), 3.06-3.25 (m, 1 H, aliphatic CH), 5.94-6.01 (m, 1 H, OCH(CH3)Ar), 6.43 & 6.45 (s, 1H, ArH, diastereomers), 7.16-7.22 (m, 2H, ArH), 7.45-7.51 (m, 2H, ArH), 11.31 & 11.32 (s, 1H, NH, diastereomers); 19F NMR (DMSO-d6) -(I 15.13-115.08) & -(114.92-I 14.91) (m, diastereomers); MS (APCI+) m/z 477.3 (MH+). Anal. Calcd for C29H33F1N203~0~12 H20: C, 72.75; H, 7.00; N, 5.85; F, 3.97; H20, 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][1]bcnzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-[3-(methoxycarbonyl)phenyl]ethyl ester )ZMe I-i Step A: 3-(1-Hydroxyethyl)benzoic acid methyl ester HO ~ C02Me A 500 mL stainless steel reactor was purged with N2 and charged successively with I-(3-bromophenyl)ethanol (0.126 mol, 25.4 g), DMSO
(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 1,3-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.
The reactor was re-pressurized to 724 psi with CO, rocked and heated to I
00°C for 70 hours. The reaction was cooled to room temperature, filtered through celite, concentrated, and partitioned between H20 and CH2C12. The aqueous phase was extracted with CH2C12 (3 x 100 mL), and the extracts were washed with water (3 x 100 mL), dried over MgS04, and concentrated to an oil. The product was purified by silica gel flash column chromatography (10-25% ethyl acetate/hexanes) to give 3-(1-hydroxyethyl)benzoic acid methyl ester (15.1 g, 66%): IH NMR (400 MHz, CDCl3) 8 1.50 (d, J--6.59 Hz, 3H, CH(CH3)OH), 1.86 (d, J--3.66 Hz, 1H, CH(CH3)OH), 3.90 (s, 3H, C02CH3), 4.92-4.97 (m, IH, CH(CH3)OH), 7.39-7.43 (m, IH, ArF~, 7.57 (d, J 7.57 Hz, 1H, ArH), 7.92 (d, J--7.57 Hz, 1 H, ArH), 8.02 (s, 1 H, ArH).
Step B: Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, 1-[3-(methoxycarbonyl)phenyl]ethyl ester A 100 mL flask was charged with 3-(I-hydroxyethyl)bcnzoic acid methyl ester (18.0 mmol, 3.24 g) followed by 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-, anhydride with benzoic acid (Example 86, 4.50 mmol, 2.00 g) and heated with stirring at 150°C until a homogeneous solution was obtained (4.5 min).
The solution was cooled to room temperature, dissolved in ethyl acetate and stirred with a saturated aqueous solution of NaHC03. A white solid precipitated out and was filtered away. The layers of the filtrate were separated, the aqueous phase was extracted with ethyl acetate (3 x 25 mL), and the combined extracts were dried and concentrated to give a thick oil. The product was purified by silica gel flash column 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 cm-1; 1H NMR (400 MHz, CDCI3) 8 1.20-1.29 (m, 1H, aliphatic CH), 1.32-1.34 (m, 2H, aliphatic CH), 1.38-1.47 (m, 1H, aliphatic CH), 1.53-1.58 (m, 2H, aliphatic CH), 1.62-1.82 (m, 4H, aliphatic CH), 1.68 (d, J--6.59 Hz, 3H, OCI-I(CH3)Ar), 2.01-2.12 (m, 1H, aliphatic CH), 2.41-2.45 (m, IH, aliphatic CH), 2.50-2.53 (m, 1H, aliphatic CH), 2.60 & 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, C02CH3), 6.09-6.17 (m, 1H, OCH(CH3)Ar), 6.73 & 6.74 (d, J--8.55 Hz, 1H, ArH, diastereomers), 7.01 &
7.02 (d, J--8.79 & 8.55 Hz, 1 H, ArH, diastereomers), 7.41 & 7.42 (t, J--7.81 &

7.57 Hz, 1H, ArH, diastereomers), 7.61 & 7.63 (d, J--7.57 Hz, 1H, ArH, diastereomers), 7.93-7.95 & 7.95-7.97 (m, IH, ArH, diastereomers), 8.06 (bs, IH, NH), 8.10 & 8.13 (s, 1H, ArH, diastereomers); MS (APCI+) nalz 503.1 (MH+).
Anal. Calcd for C3pH34N2O5: C, 71.69; H, 6.82; N, 5.57. Found: C, 71.58; H, 6.95; N, 5.42.
Example 48 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-(3-carboxyphenyl)ethyl ester zH
A solution ofpyrrolo[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-[3-(methoxycarbonyl)phenyl]ethyl ester (1.43 mmol, 0.717 g) in methanol (18 mL) and 1N NaOH (5.71 mmol, 5.71 mL) was heated at 55-60°C for 1 hour. The solution was cooled to room temperature, the methanol was removed by rotary evaporation, and the aqueous phase was neutralized with 1N HCI. A precipitate formed and was filtered off and purified by silica gel flash column chromatography (10-15% MeOH/CHC13) to afford a cream colored powder (0.522 g, 75%): mp 244-250°C (dce); IR (KBr) 3413-3229 (b), 2931, 1685, 1432, 1195, 1150, 1078, 1063 cm-1; lI-I NMR (400 MHz, DMSO-d6) ~ 1.03-1.22 (m, 3H, aliphatic CH), 1.38-1.72 (m, 7H, aliphatic CH), 1.57 (d, J--6.35 Hz, 3H, OCH(CH3)Ar), 1.78-1.88 (m, 1H, aliphatic CH), 2.28-2.38 (m, 1H, aliphatic CH), 2.40-2.47 (m, 1H, aliphatic CH), 2.51 & 2.55 (s, 3H, ArCH3, diastereomers), 2.56-2.69 (m, 2H, aliphatic CH), 2.81-2.92 (m, 1H, aliphatic CH), 3.06-3.23 (m, IH, aliphatic CH), 5.96-6.04 (m, 1H, OCH(CH3)Ar), 6.57 & 6.58 (d, J--8.55 &
8.30 Hz, 1H, ArH, diastereomers), 7.01 & 7.02 (d, J 8.30 Hz, 1H, ArH, diastereomers), 7.45-7.50 (m, IH, ArH, diastereomers), 7.64 & 7.67 (d, J--10.25 &
8.55 Hz, 1H, ArH, diastereomers), 7.83 & 7.85 (d, J--6.10 & 7.32 Hz, 1H, ArH, diastereomers), 7.96 & 7.98 (s, 1H, ArH, diastereomers), 11.54 (s, 1H, NH), 13.00 (s, 1H, C02H); MS (APCI+) rnlz 489.1 (MH+). Anal. Calcd for C29H32N205'0.50H20~0.20 Si02: C, 68.35; H, 6.53; N, 5.50; H20, 1.77. Found:
C, 67.96; H, 6.81; N, 5.22; H20, 1.81. HPLC (ALLTECH/ALLTIMA C-18, 60:40-20:80 H20/CH3CN + 0.05% TFA): retention time=4.843 & 4.970 min (diastereomers), 95.53% purity.
Example 49 I-Propanaminium, N,N,N-trimethyl-, salt with I-(3-carboxyphenyl)ethyl 3,7,8,9,10,12,13,14,14a, I S-decahydro-2-methylpyrrolo[3',2':5,6)[ 1 ]-benzopyrano[3,2-i]quinolizine-1-carboxylate (1:1) NMe3 Ol-1 H
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-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, I-(3-carboxyphenyl)ethyl ester (0.935 mmol, 0.457 g) in ethanol (23 mL), and the mixture was heated at 75-80°C for 30 minutes, cooled to room temperature, and filtered. The filtrate was concentrated. The residue was stirred vigorously with ether and filtered to give a light yellow solid. The solid was dissolved in hot CHC13, 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-/; IH NMR (400 MHz, DMSO-d6) 8 1.03-1.26 (m, 3H, aliphatic CH), 1.36-1.72 (m, 6H, aliphatic CH), I .55 (d, J--6.35 Hz, 3H, OCH(CH3)Ar), 1.80-1.88 (m, 1H, aliphatic CH), 2.30-2.42 (m, 2H, aliphatic CH), 2.51 & 2.52 (s, 3H, ArCH3, diastereomers), 2.61-2.70 (m, 2H, aliphatic CH), 2.81-2.92 (m, 1H, aliphatic CH), 3.07 (s, 9H, N(CH3)3), 3.11-3.23 (m, 1H, aliphatic CH), 3.26-3.35 (m, 2H, CH20H & aliphatic CH), 3.36 (t, J--4.88 Hz, 2H, OCH2CH2N(CH3)3), 3.77-3.83 (m, 2H, OCH2CH2N(CH3)3), 5.91-5.99 (m, 1H, OCH(CH3)Ar), 6.54-6.58 (m, 1H, ArH), 7.01-7.04 (m, IH, ArH), 7.21-7.28 (m, 1H, ArH), 7.32-7.38 (m, 1H, ArH), 7.71-7.79 (m, 1H, ArH), 7.91 & 7.93 (s, 1H, ArH, diastereomers), 11.70 (s, IH, NH); MS (APCI-) m/z 487.1 (parent M-I).
Anal. Calcd for C29H31N205'0~88 C5H14N0~0.50 H20~0.50 CHCI3: C, 62.84;
H, 6.97; N, 6.23; H20, 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-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-nitrophenyl)methyl ester NOZ
O
Me H
Following the procedure from Example 47, Step B, 3-nitrobenzyl alcohol (18.0 mmol, 2.81 g) and 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-, anhydride with benzoic acid (Example 86, 4.50 mmol, 2.00 g) were converted to pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-nitrophenyl)methyl ester.
The product was purified by silica gel flash column chromatography (25-50% ethyl acetate/hexanes) and recrystallized from ethyl acetate to afford a light yellow powder (1.10 g, 51%): mp 203-205°C; IR (KBr) 3383, 3181, 2929, 2855, 1709, 1532, 1430, 1351, 1236, 1075, 886 cm-I; 1H NMR (400 MHz, DMSO-d6) 8 1.02-1.16 (m, 2H, aliphatic CH), 1.19-1.24 (m, IH, aliphatic CH), 1.32-1.62 (m, 7H, aliphatic CH), 1.82 (d, .I 13.18 Hz, 1H, aliphatic CH), 2.33 (d, J--9.76 Hz, 1H, aliphatic CH), 2.41 (d, J--11.23 Hz, 1H, aliphatic CH), 2.48 (s, 3H, ArCH3), 2.60-2.67 (m, 2H, aliphatic CH), 2.84-2.89 (m, 1H, aliphatic CH), 3.15-3.21 (m, IH, aliphatic CH), 5.32-5.40 (m, 2H, OCH2Ar), 6.59 (d, J--8.79 Hz, 1H, ArH), 7.03 (d, J 8.55 Hz, 1H, ArH), 7.65-7.69 (m, 1H, ArH), 7.89 (d,.l--7.57 Hz, IH, ArH), 8.18 (d, J--8.06 Hz, 1H, ArH), 8.29 (s, 1H, ArH), 11.58 (s, 1H, NH); MS
(APCI+) m/z 476.1 (MH+). Anal. Calcd for C27H29N305: 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, l 5-decahydro-2-methyl-, 1-(3-cyanophcnyl)ethyl ester Step A: 3-(1-Hydroxyethyl)benzonitrile HO I ~ CN
To a solution of 3-acetylbenzonitrile (68.9 mmol, 10.0 g) in MeOH
(230 mL) at 0°C under N2 was added NaBH4 (68.9 mmol, 2.61 g) in portions.
After 2 hours of gradual warming to room temperature, 1 N HCI was added and the solvent removed under reduced pressure. Dichloromethane (50 mL) was added, the layers were separated, and the aqueous phase was extracted with 3 portions of CH2C12 (50 mL). The combined extracts were washed with NaHC03 (1 x 50 mL), saturated NaCl (1 x 50 mL), dried over MgS04, and concentrated under vacuum to give pure product as a yellow oil (10.0 g, 98%):
1H NMR (400 MHz, CDCl3) 8 1.47 (d, J--6.35 Hz, 3H, ArCH(CH3)OH), 1.99 (bs, 1H, OH), 4.92 (q, J--6.35 Hz, 1H, ArCH(CH3)OH), 7.43 (t, J 7.81 Hz, 1H, ArH), 7.53 (d, J--7.57 Hz, 1H, ArH), 7.59 (d, J--7.81 Hz, 1H, ArH), 7.66 (s, 1 H, ArI~.
Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(3-cyanophenyl)ethyl ester Following the procedure from Example 47, Step B, 3-(1-hydroxyethyl)-benzonitrile (13.5 mmol, 1.98 g) and pyrrolo[3',2':5,6][1]benzopyrano[3,2-i)-quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 3.37 mmol, 1.50 g) were converted pyrrolo[3',2':5,6][1]-benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,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%): mp 131-134 and 171-173°C (diastereomers); IR (KBr) 3377, 2931, 2856, 2230, 1702, 1432, 1148, 1077, 1066 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 1.02-1.25 (m, 3H, aliphatic CH), 1.31-1.72 (m, 7H, aliphatic CI~, 1.57 (d, J--6.35 Hz, 3H, OCH(CH3)Ar), 1.79-1.88 (m, 1H, aliphatic CH), 2.32-2.44 (m, 2H, aliphatic CI~, 2.46 (s, 3H, ArCH3), 2.56-2.69 (m, 2H, aliphatic CH), 2.80-2.91 (m, 1H, aliphatic CH), 3.02-3.28 (m, 1H, aliphatic CH), 5.93-6.01 (m, 1H, OCH(CH3)Ar), 6.56-6.60 (m, 1 H, ArH), 7.00-7.04 (m, 1 H, ArH), 7.51-7.59 (m, 1 H, ArH), 7.71-7.80 (m, 2H, ArH), 7.86 & 7.90 (s, 1H, ArH, diastereomers), 11.56 (s, 1H, NH); MS (APCI+) m/z 470.1 (MH+). Anal. Calcd for C2yH31N303~0.25 H2O:
C, 73.47; H, 6.70; N, 8.86; H20, 0.95. Found: C, 73.18; H, 6.73; N, 8.56, H20, 0.58.
Example 52 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-[3-[(dimethylamino)carbonyl]phenyl]ethyl ester O NMe2 O
Me Step A: 3-(1-Hydroxyethyl)benzoic acid OH O
~OH
A mixture of 3-(1-hydroxyethyl)benzonitrile (Example 51, Step A, 6.79 mmol, 1.00 g) in 10% aqueous NaOH (68 mL) was heated at reflux for 4.5 hours, cooled to room temperature, and extracted with ether (2 x 50 mL).
The extracts were discarded. The aqueous phase was acidified with concentrated HCI, extracted with ether (3 x 50 mL), and the combined extracts were washed with brine, dried over MgS04, and concentrated to give a white solid (0.98 g, 87%):
mp 107-110°C; 1H NMR (400 MHz, DMSO-d6) S 1.29 (d, J=6.35 Hz, 3H, ArCH(CH3)OH), 4.71-4.78 (m, 1H, ArCH(CH3)OH), 5.25 (d, J--4.40 Hz, 1H, OH), 7.39 (t, J=7.57 Hz, 1H, ArH), 7.53 (d, J=7.57 Hz, 1H, ArH), 7.76 (d, J 7.57 Hz, 1H, Arty, 7.91 (s, 1H, Arln, 12.87 (s, lII, COOH); MS (APCI-) mlz 165.1 (M-1 ).
Step B: 3-(1-Hydroxyethyl)-N,N dimethylbenzamide OH O
~NMe2 To a solution of 3-(1-hydroxyethyl)benzoic acid (54.8 mmol, 9.10 g), dimethylamine (54.8 mmol, 27.4 mL of 2.0 M THF solution), and iPr2NEt (109 mmol, 19.1 mL) in 55 mL of DMF at 0°C under N2 was added HBTU
(54.8 mmol, 20.8 g) in two portions. After 45 minutes, 1 N HC1 (50 mL) and ether (50 mL) were added, and the layers were separated. The aqueous phase was further acidified with 1N HCI and extracted with ether (4 x 50 mL). The extracts were combined and concentrated. The aqueous phase was concentrated also. The concentrates were combined, dissolved in CH2C12, washed with 10% HCl (1 x 20 mL), saturated NaHC03 (1 x 20 mL), brine (1 x 20 mL), dried over MgS04 and concentrated. The residue was purified by silica gel flash column chromatography (50-100% ethyl acetate/hexanes) to give a mixture of 3-(1-hydroxyethyl)-N,N dimethylbenzamide, iPr2NEt, and N,N,N',N'-tetramethylurea. The yield based on 1H NMR was 6.56 g (62%). A small portion was rechromatographed to give pure product as a clear, colorless oil: 1H NMR
(400 MHz, DMSO-d6) 8 1.28 (d, J--6.59 Hz, 3H, ArCH(CH3)OH), 2.8G (s, 3H, NCH3), 2.93 (s, 3H, NCH3), 4.67-4.73 (m, 1H, ArCH(CH3)OH), 5.20 (d, J--4.15 Hz, 1H, OH), 7.18-7.20 (m, 1H, ArH), 7.31-7.37 (m, 3H, Arl~; MS
(APCI+) m/z 194.0 (MH+).
Step C: 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-[3-[(dimethylamino)carbonyl]phenyl]ethyl ester Following the procedure from Example 47, Step B, 3-(1-hydroxyethyl)-N,N dimethylbenzamide (14.9 mmol, 2.88 g) and 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-, 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 to form 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-[3-[(dimethylamino)-carbonyl]phenyl]ethyl ester. The product was purified by silica gel flash column chromatography (0-5% Et3N/ethyl acetate), dissolved in ether/ethyl acetate and washed with water (15 x 20 mL) to remove unreacted 3-(1-hydroxyethyl)-N,N
dimethylbenzamide. The organic phase was concentrated and the residue was recrystallized from acetonitrile to give a white powder (1.65 g, 86%): mp 199-202°C; IR (KBr) 3416 (br), 3219 (br), 2930, 2855, 1684, 1622, 1432, 1188, 1146, 1091, 1062 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 1.02-1.28 (m, 3H, aliphatic CH), 1.32-1.70 (m, 7H, aliphatic CH), 1.57 (d, J--6.84 Hz, 3H, OCH(CH3)Ar), 1.76-1.88 (m, 1H, aliphatic CH), 2.32-2.43 (m, 2H, aliphatic CH), 2.50 & 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), 3.06-3.30 (m, 1H, aliphatic CH), 5.94-6.01 (m, 1H, OCH(CH3)Ar), 6.57 &
6.58 (d, J--8.55 Hz, 1H, ArH, diastereomers), 7.01 & 7.02 (d, J--8.55 Hz, IH, ArH, diastereomers), 7.29 (t, J--7.33 Hz, 1H, ArH), 7.37-7.50 (m, 3H, ArH), 11.53 (s, 1 H, NH); MS (APCI+) m/z S 16.3 (MH+). Anal. Calcd for C31H37N304: C, 72.21; H, 7.23; N, 8.15. Found: C, 71.96; H, 7.25; N, 8.22.
Example 53 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13, I 4,14a,15-decahydro-2-methyl-, I-[3-[(dimethylamino)methyl]phenyl]ethyl ester NMe2 O
Me H
Step A: 1-(3-Dimethylaminomethylphenyl)ethanol OH
~NMe2 i To a suspension of LiAlH4 (23.3 mmol, 0.931 g/95 %) in THF (40 mL) at 0°C under N2 was added a solution of 3-(I-hydroxyethyl)-N,N-dimethylbenzamide (Example 52, Step B, 15.5 mmol, 3.00 g) in 10 mL of THF.
After the evolution of H2 had ceased, the reaction was warmed to room temperature. After 4 hours at room temperature, the mixture was cooled to 0°C
and ethyl acetate (0.74 mL) and 10% aqueous NaOH were sequentially added.
The mixture was warmed to room temperature for 30 minutes, MgS04 and celite WO 00/42045 PCTlUS99/30434 were added with stirring, and the mixture was filtered through celite, washing with 20 mL of THF. The filtrate was concentrated to afford 2.73 g (99%) of pure 1-(3-dimethylaminomethylphenyl)ethanol: 1H NMR (400 MHz, DMSO-d6) 8 1.26 (d, J--6.59 Hz, 3H, ArCI-I(CII3)OH), 2.09 (s, 6H, N(CH3)2), 3.31 (s, 2H, ArCH2N), 4.64-4.67 (m, 1 H, ArCH(CH3)OH), 5.08 (d, J--4.1 S Hz, 1 H, OH), 7.07 (d, J--7.08 Hz, 1 H, ArH), 7.1 S-7.25 (m, 3H, ArH); MS (APCI+) m/z 180.0 (MH+) Step B: Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,1 S-decahydro-2-methyl-, 1-[3-[(dimcthylamino)methyl]phenyl)ethyl ester Following the procedure from Example 47, Step B 1-(3-dimethylaminomethylphenyl)ethanol (15.2 mmol, 2.73 g) and pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 3.81 mmol, 1.69 g) were combined with xylenes (10 mL) and heated at 150°C for 5 minutes to form pyrrolo(3',2':5,6)[1]benzopyrano[3,2-i)quinolizine-I -carboxylic acid, 3,7,8,9,10,12,13,14,14x,1 S-decahydro-2-methyl-, 1-[3-[(dimethylamino)methyl]phenyl)ethyl ester. The usual extractive work-up (ethyl acetate) was followed. The aqueous phase was diluted with 100 mL of acetone and the inorganic salts filtered off. The filtrate was concentrated.
The organic and aqueous residues were combined, mixed with 15 mL of CH2CI2 at room temperature under N2 and treated r~~ith pyridine (68.5 mmol, 5.54 mL) and acetic anhydride (34.3 mmol, 3.23 mL) sequentially. After 48 hours, the white precipitate was filtered off, and the filtrate was washed with water (3 x 20 mL).
2S The aqueous washes were concentrated and the product was purified by silica gel flash 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. 1H NMR (400 MHz, DMSO-d6) 8 1.09-1.27 (m, 3H, aliphatic CH), 1.32-1.68 (m, 7H, aliphatic CH), 1.54 (d, J--6.35 Hz, 3H, OCH(CH3)Ar), 1.79-1.84 (m, 1H, aliphatic CH), 2.07 & 2.08 (s, 6H, N(CH3)2, diastcreomers), 2.29-2.43 (m, 2H, aliphatic CH), 2.49 & 2.50 (s, 3H, ArCH3, 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 & 3.34 (s, 2H, ArCH2N, diastereomers), 5.90-5.98 (m, 1H, OCH(CH3)Ar), 6.56-6.59 (m, 1H, ArH), 7.00-7.03 (m, 1H, ArH), 7.12-7.21 (m, 1H, ArH), 7.26-7.33 (m, 3H, ArH), 11.50 & 11.51 (s, 1H, NH, diastcreomers); MS (APCI+) m/z 502.2 (MH+). Anal. Calcd for C31H39N303'0.27 C4H802: C, 73.33; H, 7.90; N, 8.00. Found: C, 72.94; H, 7.90; N, 8.10.
General Procedure J.
Diethyl azodicarboxylate (Aldrich, 1 eq.) was added dropwise to a mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (1 eq.), triphenylphosphine (1 eq.), and an alcohol of choice (1.5 eq.) in THF over an hour period. After stirring at room temperature for 24 hours, the mixture was concentrated. The product was purified by recrystallization or flash column chromatography on silica gel (45% ethyl acetate:hexanes) to give the corresponding ester.
General Procedure K.
Under a nitrogen atmosphere, DBU (Aldrich, 1 eq.) was added to a solution of 5-acetoxy-2-methyl-1H-indole-3-carboxylic acid (1 eq.) in DMF by the syringe technique. To this reaction mixture, a solution of an alkyl halide of choice (Aldrich, 1.1 eq.) in DMF was added. After stirring at room temperature for 24 hours, the reaction mixture was diluted with CH2CI2 which induced precipitation of the desired product. The solid product was filtered off and washed with H20.
General Procedure L.
Dimethylamine (2.2 eq.) and formaldehyde (1.2 eq.) were added to a solution of the ester of choice (1.0 eq.) in 10 mL of denatured ethanol. The mixture was stirred under a nitrogen atmosphere at reflux for 24 hours. After the reaction was complete according to MS and TLC, the mixture was concentrated. The product WO 00!42045 PCT/US99/30434 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 in 2N NaOH (excess). The solution was extracted with diethyl ether. The combined organic layers were concentrated to give a clear oil. This oil was dissolved in dioxane and added to a solution of the desired Mannich base (1 eq.) dioxane.
After heating at 1 lOoC for 24 hours, the reaction was cooled to room temperature and dioxane was removed to afford a brown oil. The product was purified by flash column 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.) was heated at 1 SO°C for 5 minutes or until the reaction was homogeneous.
After being cooled to room temperature, the oil was diluted with ethyl acetate and washed with saturated NaHC03. The organic layer was separated and concentrated to afford a brown oil. The product was purified by flash column chromatography on silica gel.
General Procedure O.
To a solution of a ester (1 eq.) in methanol was added 2N NaOH (4 eq.). After heating at 55°C for 1 hour, the reaction became clear. The reaction mixture was cooled to 0°C and neutralized with concentrated HCI. The product precipitated out of solution as a white solid and was filtered off. The mother liquor was extracted with 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 added slowly solid LiBH4 (5 eq.). MeOH (5 eq.) was immediately added dropwise via syringe. The resulting mixture was heated at reflux for 1 hour. After cooling to 0°C, 1N HCl was added to neutralize the reaction. The product precipitated out of solution as a white solid. The mother liquor was extracted with CH2C12. The combined organic layers were dried with MgS04, and solvent was removed to yield more product.
Example 54 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 N O
O
O
w I y--N
H
Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid phenylethyl ester O
O
HO
N
H
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid phenylethyl ester was 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 white powder: mp 186-188°C; IR (KBr) 3231, 2978, 1644, 1463, 1173, 1101 cm-1;
1H NMR (400 MHz, DMSO-d6) 8 2.49 (s, 3H, CCH3), 3.03 (t, J--6.99 Hz, 2H, OCH2CII2), 4.40 (t, J--6.75 Hz, 2H, OCH2CH2), 6.57 (dd, J--8.60, 2.29 Hz, 1H, ArH), 7.09 (d, J--8.68 Hz, 1H, ArH), 7.20 (d, J--6.99 Hz, 1H, ArH), 7.26-7.33 (m, 5H, ArH), 8.81 (s, IH, OH), 11.49 (s, 1H, NH); MS(APCI+): nalz 326.1 (MH+) Anal. Calcd for C18H17N103: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.23; H, 5.74; N, 4.67.
-14?-Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenylethyl ester l~
/N O
O
HO /
N
H
4-Dimethylaminomethyl-5-hydroxy-2-methyl-IH-indole-3-carboxylic acid phenethyl ester was synthesized according to Procedure L from 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenylethyl ester (2.89 g, 9.78 mmol) and recrystallized from ethyl acetate to give 0.250 g ( 15.0%) of a white solid:
mp 200-201°C; iR (KBr) 3138, 2971, 1673, 1585, 1437, 1279, 1099 cm 1; 1H
NMR
(400 MHz, DMSO-d6) 8 2.34 (s, 3H, CCI13) 2.68 (s, 6H, N(CH3)2), 3.00 (t, J--6.59 Hz, 2H, OCH2CH2), 4.43 (t, J--6.59 Hz, 2H, OCH2CH2), 4.67 (s, 2H, NCH2Ar), 6.81 (d, J 8.79 Hz, 1H, ArH), 7.17-7.20 (m, 1H, ArH), 7.23-7.28 (m, SH, ArH), 11.93 (s, 1H, NH); MS(APC1+): ntlz 353.2 (MH+). Anal. Calcd for C21H24N203~ 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][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, 3,7,8,9,10,1,13,14,14a,15-decahydro-2-methyl-,2-phenylethyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenethyl ester (0.250 g, 0.709 mmol) and recrystallized from ethyl acetatelhexanes 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-l;

NMR (400 MHz, CDC13) 8 1.20-1.81 (m, 10H, aliphatic CH), 2.07 (d, J--13.92 Hz, 1H, aliphatic CH), 2.41 (s, 3H, CCH3), 2.44-2.53 (m, 2H, aliphatic CH), 2.73-2.84 (m, 2H, aliphatic CH), 2.98-3.04 (m, 1H, aliphatic CH), 3.05-3.08 (m, 2H, OCH2CH2), 3.38 (dd, J--17.95, 6.71 Hz, 1H, aliphatic CH), 4.50-4.53 (m, 2H, OCH2CH2), 6.72 (d, J--8.79 Hz, 1 H, ArH), 6.99 (d, J--8.79 Hz, 1H, ArF~, 7.17-7.29 (m, 5H, ArH), 7.99 (s, IH, NH); MS(APCI+): m/z 445.3 (MH+). Anal. Calcd for C28H32N203: C, 75.56; H, 7.26; N, 6.30. Found:
C, 75.36; H, 7.28; N, 6.13.
Example 55 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, I 0,12,13,14,14a,15-decahydro-2-methyl-, [4-(methoxycarbonyl)phenyl]methyl ester O
Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-bcnzyl ester O
O \ ~ O
O
HO
N
H
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-1 S 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 diethyl ether to give 4.88 g (55.0%) of light lavender powder: mp 232-234°C; IR (KBr) 3322, 2950, 1696, 1654, 1465, 1288, 1093 em-1; 1H NMR (400 MHz, DMSO-d6) 8 2.57 (s, 3H, CCH3), 3.80 (s, 3I-I, OCH3), 5.34 (s, 2H, OCH2Ar), 6.55 (dd, J--8.67, 2.32 Hz, 1H, ArH), 7.09 (d, J--8.55 Hz, 1H, ArH), 7.24 (d, J--2.20 Hz, 1 H, ArH), 7.54 (d, J--8.06 Hz, 2H, ArH), 7.94 (d, J--8.30 Hz, 2H, ArH), 8.83 (s, 1 H, OH), 11.59 (s, IH, NH); MS(APCI+): m/z 340.1 (MH+). Anal. Calcd for C19H17N105: C, 67.25; H, 5.05; N, 4.13. Found: C, 66.88; H, 5.06; N, 4.05.
Step B: 4-Dimethylaminomcthyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester O
N O ~ I \O
O
HO
N
H
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester was synthesized according to Procedure L from 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (17.2 g, 50.7 mmol) and triturated with ethyl acetate to give 8.50 g (43.0%) of white solids: mp 125-126°C; IR (KBr) 3142, 2959, 1672, 1585, 1434, 1285, 1095 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 2.12 (s, 6H, N(CH3)2), 2.49 (s, 3H, CCH3), 3.84 (s, 3H, OCH3), 4.02 (s, 2H, NCH2Ar), 5.34 (s, 2H, OCH2Ar), 6.58 (d, J--8.44 Hz, 1H, ArH), 7.09 (d, J--8.44 Hz, 1H, ArH), 7.60 (d, J--8.20 Hz, 2H, ArH), 7.98 (d, J 8.20 Hz, 2H, ArH), 11.56 (s, 1H, NH); MS(APCI+): na/z 397.2 (MH+). Anal. Calcd for C22H24N205~ C> 66.41; H, 6.12; N, 7.04. Found:
C,66.41;H,6.OI;N,6.97.
Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-dccahydro-2-methyl-, [4-(methoxycarbonyl)phenyl]methyl ester Pyrrolo(3',2':5,6][I)benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I S-decahydro-2-methyl-,[4-(methoxycarbonyl) phenyl]methyl ester was synthesized according to Procedure M from 4-dimethylaminomcthyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (0.200 g, 0.505 mmol) and recrystallizcd from t-butyl methyl ether to give 0.090 g (23.0%) of granular off white solids: mp 179-180°C; IR (KBr) 3173, 2930, 2856, 1725, 1615, 1433, 1275, 1079 cm-1;
1 H NMR (400 MHz, CDCl3) 8 1.21-1.81 (m, 10H, aliphatic CH), 2.06 (d, J--8.79 Hz, 1H, aliphatic CH), 2.43 (d, J--12.70 Hz, IH, aliphatic CH), 2.50-2.53 (m, 1H, aliphatic CH), 2.55 (s, 3H, CCH3), 2.73-2.84 (m, 2H, aliphatic CH), 2.96-3.05 (m, 1H, aliphatic CH), 3.38 (dd, J--17.70, 7.20 Hz, 1H, aliphatic CH), 3.89 (s, 3H, OCH3), 5.34 (dd, J--16.36, 12.70 Hz, 2H, OCH2Ar), 6.73 (d, J 8.79 Hz, I H, ArH), 7.01 (d, J-- 8.79 Hz, 1 H, ArH), 7.47 (d, J--8.06 Hz, 2H, ArH), 8.01 (d, J--8.30 Hz, 2H, ArH), 8.06 (s, 1H, NH); MS(APCI+); rnlz 489.3 (MH+). Anal. Calcd for C2gH32N205: 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,-methyl-, (4-carboxyphenyl)methyl ester O
OH
N O
O
O
N
H
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-carboxyphenyl)methyl ester was synthesized according to Procedure O and triturated with methanol to give 0.030 g (11.0%) of fine off white powder : mp 243-244°C; IR (KBr) 2932, 2863, 1698, 1592, 1432, 1077 cm-1; IH NMR (400 MHz, DMSO-d6) 8 1.05-1.26 (m, 3H, aliphatic CH) 1.39-1.66 (m, 6H, aliphatic CH), 1.85 (d, J--13.67 Hz, 1H, aliphatic CH), 2.44 (d, J--11.23 Hz, 1H, aliphatic CH), 2.47-2.48 (m, lI-I, aliphatic CH), 2.48 (s, 3H, CCH3), 2.63-2.69 (m, 2H, aliphatic CH), 2.85-2.91 (m, 1H, aliphatic CH), 3.19 (dd, J--18.07, 6.84 Hz, 1H, aliphatic CH), 3.41-3.43 (m, 1H, aliphatic CH), 5.31 (dd, J--20.02, 12.94 Hz, 2H, OCH2Ar), 6.60 (d, .l--8.55 Hz, 1H, ArH), 7.04 (d, J--8.55 Hz, IH, ArH), 7.54 (d, J--8.30 Hz, 2H, ArH), 7.94 (d, J-- 8.30 Hz, 2H, ArH), 11.57 (s, 1H, NIA, 12.98 (s, 1H, C02H); MS(APCI+): mlz 475.3 (MH+). Anal. Calcd for C28H3pN205: C, 70.17; H, 6.42; N, 5.85. Found:
C, 69.78; H, 6.50; N, 5.62.
Example 57 1-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-l II-indol-4-ylmethyl]-1,2,3,4,6,7,8,9-octahydro-quinolizinylium; chloride O
OH
To a solution ofpyrrolo[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 (Example 56, Step C, 1.00 g, 2.05 mmol) 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 turned to a clear solution. The reaction mixture was cooled to 0°C and concentrated HCl was added slowly until pH 3. The aqueous layer Was extracted with ethyl acetate (5 x 50 mL), and the combined organic layers were dried with MgS04, and solvent was removed. The residue was triturated with dichloromethane to give 0.967 g (92.0%) of fine white powder: mp 230-231°C; IR (KBr) 3361, 2941, 2360, 1709, 1589, 1428, 1227, 1083 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 1.20-1.30 (m, lI-I, aliphatic CH) 1.43-1.51 (m, 4H, aliphatic CH), 1.69-2.30 (m, 5H, aliphatic CH), 2.48 & 2.49 (s, 3H, CCH3, opened and closed forms) , 2.48-2.55 (m, 2H, aliphatic CI-I), 2.85-3.30 (m, 2H, aliphatic CH), 3.40-3.80 (m, 3H, aliphatic CH), 5.33-5.36 (m, 2H, OCH2Ar), 6.79 & 6.82 (d, J--8.55 & 8.06 Hz, 1H, ArH, opened & closed forms), 7.11 & 7.20 (d, J--8.55 & 8.55 Hz, IH, ArH, opened & closed forms), 7.54-7.56 (m, 2H, ArH), 7.94-7.96 (m, 2H, ArH), 9.19 (s, 1H, OH, opened), 11.79 &
11.85 (s, 1H, NH, opened & closed forms), 13.00 (s, 1H, C02H); MS(APCI+):

m/z 475.3 (MH+). Anal. Calcd for C28H31N205C11: C, 65.35; H, 6.12; N, 5.44.
Found: C, 65.06; H, 6.17; N, 5.15.
Example 58 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl ester N O \ . ~ ~O H
O
O
N
H
Step A: 4-Dimcthylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-hydroxymethyl-bcnzyl ester I OH
/N O
O
HO /
.
N
H
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester was synthesized according to Procedure P from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (Example 56, Step B, 2.32 g, 5.84 mmol) and 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; IH NMR (400 MHz, DMSO-d6) 8 2.51 (s, 3H, CH3), 2.71 (s, 6H, N(CH3)2), 4.47 (d, J--5.13 Hz, 2H, ArCH20H), 4.73 (s, 2H, NCH2Ar), 5.18 (t, J 5.62 Hz, 1H, ArCH20H), 5.25 (s, 2H, OCH2Ar), 6.84 (d, J--8.55 Hz, 1 H, Arll), 7.28 (d, J--8.55 Hz, 1 H, ArH), 7.31 (d, J--7.81 Hz, 2H, ArH ), 7.40 (d, J--7.81 Hz, 2H, ArH), 8.60 (s, 1 H, OH), 11.97 (s, IH, NH); MS(APCI+): m/z 369.2 (MH+). HPLC (ALLTCH/ALLTIMA

C-18 1:1-2:98 H20/CH3CN + 0.05% TFA): rentention time=4.57 min, 95.23%
purity.
Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1 S-decahydro-2-methyl-, [4-(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-, [4-(hydroxymethyl)-phenyl]methyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester (0.969 g, 2.63 mmol) and triturated with acetone to give 0.890 g (49.0%) of a white solid: mp 198-200°C; IR (KBr) 3405, 3237, 2931, 1660, 1424, 1237, 1081 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 1.1 l-1.27 (m, 3H, aliphatic CH),1.39-1.70 (m, 7I-I, aliphatic CH), 1.85 (d, J--13.50 Hz, 1H, aliphatic CH), 2.36 (d, J--10.37 Hz, 1H, aliphatic CH), 2.41-2.43 (m, 1H, aliphatic CH), 2.47 (s, 3H, CCH3), 2.65-2.69 (m, 2H, aliphatic CH), 2.86-2.92 (m, 1H, aliphatic CH), 3.23 (dd, J--16.64, 9.64 Hz, 1H, aliphatic CH), 4.48 (d, J--5.78 Hz, 2H, ArCl120H), 5.17 (t, J--5.55 Hz, 1 H, ArCH20H), 5.21 (dd, J--22.42, 12.06, Hz, 2H, OCH2Ar), 6.59 (d, J 8.44 Hz, 1H, ArH), 7.03 (d, J--8.68 Hz, 1H, ArH), 7.31 (d, J-- 7.72 Hz, 2H, ArFl), 7.39 (d, J=7.96 Hz, 2H, ArH), 11.52 (s, 1 H, NFL;
MS(APCI+): mlz 461.2 (MH+). Anal. Calcd for C28H32N204: 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][1]bcnzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmcthyl ester Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl S ester was synthesized according to Procedure K from 2-bromomethyl-naphthalene (7.63 g, 34.5 mmol) and precipitated out of CH2C12 to give 5.01 g (48.1 %) of pale lavender powder: mp 243-245°C; IR (KBr) 3408, 3306, 3058, 1665, 1596, 1465, 1172, 1093 cm-/; IH NMR (400 MHz, DMSO-d6) 8 2.59 (s, 3H, CCH3), 5.46 (s, 2H, OCH2Ar), 6.59 (dd, J--8.44, 2.41 Hz, IH, ArH), 7.12 (d, J 8.44 Hz, 1H, ArH), 7.30 (d, J--2.41 Hz, IH, ArH), 7.51 (dd, J--6.03, 3.38 Hz, IH, ArH), 7.59 (d, J 1.69 Hz, IH, ArH), 7.61 (d, J--1.69 Hz, 1H, ArH), 7.90-7.96 (m, 4H, ArH), 8.83 (s, IH, OH), 11.58 (s, 1H, NH); MS(APCl+): rr~lz 332.2 (MH+). HPLC
(ALLTCH/ALLTIMA C-18 35:65-2:98 H20/CH3CN + 0.05% TFA): rentention time=3.70 min, 95.81 % purity.
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester /N O
O
HO
N
H
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester synthesized according to the Procedure L from 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester (Example 57, Step A, 3.38 g, 10.2 mmol) and recrystallized from CH2Cl2 to give 0.750 g (19.0%) of a white solid: mp 170-171°C; IR (KBr) 3120, 2964, 2853, 1675, 1592, 1431, 1257, 1088 cm-1; 1H NMR (400 MHz, DMSO-d6) S 2.11 (s, 6H, N(CH3)2), 2.49 (s, 3H, CCH3), 4.03 (s, 2H, NCH2Ar), 5.43 (s, 2H, OCH2Ar), 6.57 (d, J--8.68 Hz, 1H, ArH), 7.08 (d, J--8.44 Hz, 1H, ArH), 7.51-7:53 (m, 2H, ArH), 7.60 (d, J--8.44 Hz, 1H, ArH), 7.91-7.99 (m, 4H, ArH), I 1.55 (s, 1H, NH); MS(APCI+): m/z 389.2 (MH+). HPLC (ALLTCH/ALLTIMA
C-18 55:45-15:85 H20/CH3CN + 0.05% TFA): rentention time=4.80 min, 94.36% purity.
Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmethyl ester Pyrrolo[3',2':5,6][I]bcnzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmethyl ester was synthesized according to Procedure M from 4-dimcthylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic 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 MI-Iz, CDC13) 8 1.19-1.45 (m, 4H, aliphatic CH) 1.55-1.78 (m, 6H, aliphatic CH), 2.07 (d, J--13.99 Hz, IH, aliphatic CH), 2.43-2.46 (m, 1H, aliphatic CH), 2.52-2.55 (m, 1H, aliphatic CH), 2.58 (s, 3H, CCH3), 2.77-2.86 (m, 2H, aliphatic CH), 3.01-3.07 (m, 1H, aliphatic CH), 3.41 (dd, J--18.08, 6.75 Hz, IH, aliphatic CH), 5.48 (dd, J=19.53, 10.61 Hz, 2H, OCH2Ar), 6.75 (d, J--8.68 Hz, 1 H, ArH), 7.03 (d, J--8.68 Hz, 1 H, ArH), 7.48-7.50 (m, 2H, ArH), 7.55-7.57 (m, 1H, ArH), 7.82-7.86 (m, 3H, ArFl), 8.11 (s, 1 H, NH); MS(APCI+): m/z 481.3 (MH+). Anal. Calcd for C3 I H32N203 ~ C
77.47; H, 6.71; N, 5.83. Found: C, 77.13; H, 6.84; N, 5.51.

Example 60 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9, I 0,12, I 3,14,14a,15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester O
H
Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester O
O
O
O
HO
N
H
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-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 to give 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-d6) b 2.56 (s, 3H, CCH3), 3.81 (s, 3H, OCH3), 5.35 (s, 2H, OCH2Ar), 6.57 (dd, J--8.55, 2.20 Hz, IH, ArH), 7.10 (d, J--8.55 Hz, 1H, ArH), 7.25 (d, J 2.20 Hz, 1 H, ArH), 7.53 (t, J--7.81 Hz, 1 H, ArH), 7.70 (d, J--7.81 Hz , I H, ArH), 7.89 (d, J
7.5 7 Hz, 1H, ArH), 8.01 (s, 1H, ArH), 8.82 (s, 1H, OH), 11.58 (s, 1H, NH); MS(APCI+):
rnlz 340.1 (MH+). Anal. Calcd for C19H17N105: C, 67.25; H, 5.05; N, 4.13.
Found: C, 67.22; H, 4.75; N, 4.05.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester o /

HO /
N
H
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester was synthesized according to Procedure L from S-hydroxy-2-methyl-1H-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 fine white powder: mp 164-167°C; IR (KBr) 3031, 2951, 1725, 1683, 1432, 1285, 1077 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 2.10 (s, 6H, N(CH3)2), 2.49 (s, 3H, CCH3), 3.81 (s, 3H, OCH3), 3.96 (s, 2H, NCH2Ar), 5.31 (s, 2H, OCH2Ar), 6.55 (d, J--8.55 Hz, 1H, ArH ), 7.06 (d, J--8.55 Hz, 1H, ArH), 7.52 (t, J--7.81 Hz, 1H, ArH), 7.72 (d, J--7.57 Hz, 1H, ArH), 7.90 (d, J--7.81 Hz, 1H, Arf~, 8.03 (s, 1H, ArH), 11.54 (s, 1H, NH); MS(APCI+): ntlz 397.0 (MH+). HPLC
(ALLTCH/ALLTIMA C-18 65:3$-15:85 H20/CH3CN + 0.05% TFA): rentention time=4.91 min, 92.97% purity.
Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12, I 3,14,14a,15-decahydro-2-methyl-, [3-(methoxycarbonyl)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,1S-decahydro-2-methyl-, [3-(methoxycarbonyl)-phenyl]methyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-S-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (2.09 g, 5.27 mmol) and recrystallized from t-butyl methyl ether to give 1.21 g (47.1 %) of fine white powder: mp 169-170°C;
IR (ICBr) 3380, 2931, 2855, 1721, 1433, 1289, 1076 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 1.03-1.21 (m, 3H, aliphatic CH) 1.36-1.63 (m, 7H, aliphatic CH), 1.81 (d, J--13.43 Hz, 1H, aliphatic CH), 2.33 (d, J--10.50 Hz, 1H, aliphatic CH), 2.40-2.42 (m, 1H, aliphatic CH), 2.46 (s, 3H, CCH3), 2.56-2.67 (m, 2H, aliphatic CH), 2.82-2.88 (m, 1H, aliphatic CH), 3.14 (dd, J--18.07, 6.84 Hz, IH, aliphatic CH), 3.81 (s, 3H, OCH3), 5.29 (dd, J--25.15, 12.45 Hz, 2H, OCH2Ar), 6.57 (d, S J--8.79 Hz, 1 H, ArH), 7.02 (d, J-- 8.79 Hz, 1 H, ArH), 7.52 (t, J--7.57 Hz, 1 H, ArH), 7.71 (d, J--7.57 Hz, 1H, ArH), 7.90 (d, J--7.81 Hz, 1H, ArH), 8.02 (s, 1H, ArH), 11.55 (s, 1H, NH); MS(APCI+): m/z 489.2 (MH+). Anal. Calcd for C29H32N205~ C~ 71.29; H, 6.60; N, 5.73. Found: C, 71.22; H, 6.91; N, 5.43.
Example 61 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7, 8,9,10,12,13,14,14a,1 S-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]methyl ester OH
Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester OH
o ~I
O
HO
N
H
4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester was synthesized according to procedure P from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (Example 60, Step B, 2.21 g, 5.58 mmol) and triturated with CH2Cl2 to give 1.11 g (54.0%) of white powder: mp 199-201 °C;
IR (KBr) 3065, 2884, 1681, 1586, 1432, 1090 cm-1 ~ I H NMR (400 MHz, DMSO-d6) b 2.25 (s, 3H, CCH3) 2.72 (s, 6H, N(CH3)2), 4.48 (d, J 5.37 Hz, 2H, ArCH20H), 4.75 (s, 2H, NCH2Ar), 5.22 (t, J--5.62 Hz, IH, ArCH20H), 5.28 (s, 2H, OCH2Ar), 6.87 (d, J--8.55 Hz, 1H, ArH), 7.25-7.34 (m, 4H, ArH), 7.40 (s, 1H, ArH ), 8.59 (s, 1H, ArOH), 12.06 (s, 1H, NH); MS(APCI+): m/z 369.2 (MH+). HPLC (ALLTCH/ALLTIMA C-18 98:2-75:25 H20/CH3CN +
0.05% TFA): retention time=2.11 min, 98.74% purity.
Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10, I 2,13,14,14a,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-(hydroxymethyl)-phenyl]methyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-IH-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester (0.980 g, 2.66 mmol) and triturated with t-butyl I S methyl ether to give 0.420 g (44.2%) of a light yellow green crystal: mp 183-185°C; IR (KBr) 3381, 3197, 2931, 1682, 1430, 1249, 1076 cm-1; 1H
NMR
(400 MHz, DMSO-d6) 8 1.06-1.37 (m, 3H, aliphatic CH) 1.40-1.65 (m, 6H, aliphatic CH), 1.82 (d, J--13.43 Hz, 1H, aliphatic CH), 2.33 (d, J--10.01 Hz, 1H, aliphatic CH), 2.40-2.43 (m, 1H, aliphatic CH), 2.46 (s, 3H, CCI13), 2.61-2.68 (m, 2H, aliphatic CH), 2.83-2.89 (m, 1H, aliphatic CH), 3.12-3.16 (m, 1H, aliphatic CH), 3.18 (dd, J--18.31, 6.84 Hz, 1H, aliphatic CH), 4.46 (d, J--5.62 Hz, 2H, ArCH20H), 5.18 (t, J--6.10 Hz, 1H, ArCH20H), 5.21 (dd, J--20.27, 12.21 Hz, 2H, OCH2Ar), 6.58 (d, J--8.79 Hz, 1H, ArH), 7.01 (d, J--8.55 Hz, IH, ArH), 7.23-7.32 (m, 3H, ArH), 7.36 (s, 1H, ArH), 11.51 (s, 1H, NH); MS(APCI+): ntlz 461.1 (MH+). Anal. Calcd for C28H32N204: C, 73.02; H, 7.00; N, 6.08. Found:
C, 72.84; H, 7.07; N, 5.91.

Example 62 Pyrrolo[3',2':5,6][I]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) OH
N O
O
O /
H
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 was synthesized according to Procedure O from pyrrolo[3',2':5,6][I]-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 (Example 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; 1H NMR (400 MHz, DMSO-d6) ~ 1.08-1.36 (m, 3H, aliphatic CH) 1.39-1.63 (m, 7H, aliphatic CH), 1.81 (d, J--13.18 Hz, 1H, aliphatic CH), 2.33 (d, J--11.23 Hz, 1H, aliphatic CH), 2.40-2.43 (m, IH, aliphatic CH), 2.47 (s, IS 3H, CCH3), 2.56-2.67 (m, 2H, aliphatic CH), 2.84-2.88 (m, IH, aliphatic CH), 3.15 (dd, J=17.82, 6.35 Hz, 1 H, aliphatic CH), 5.28 (dd, J--24.17, 12.45 Hz, 2H, OCH2Ar), 6.57 (d, J--8.79 Hz, 1H, ArH), 7.02 (d, J 8.55 Hz, 1H, ArH), 7.48 (t, J--7.57 Hz, 1H, ArH), 7.65 (d, J 7.57 Hz, 1H, ArH), 7.87 (d, J--7.81 Hz, IH, Arl~, 8.00 (s, 1H, ArH), 11.55 (s, 1H, NH); MS(APCI+): m/z 475.1 (MH+). Anal.
Calcd for C28H3pN2O5: C, 69.18; H, 6.50; N, 5.75. Found: C, 68.83; H, 6.40; N, 5.63.
Example 63 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (3-carboxypheny)methyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2' :5,6] [ 1 ]-benzopyrano[3,2-i]quinolizine-I-carboxylate (1:1) ~+
o ~ ~~oH
N o o , N
H
To a suspension ofpyrrolo[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 (Example 62, 0.100 g, 0.211 mmol) in 5 mL of EtOH was added choline carbonate (0.037 mL, 0.211 mmol, 5.66 M). The reaction mixture was heated at reflux for 1 hour resulting in a clear solution. After cooling to room temperature, the mixture was concentrated to give a yellow oil.
Triturating this oil with diethyl ether yielded 0.097 g (88.0%) of beige solid: mp 165-170°C; IR (KBr) 2930, 2855, 1685, 1566, 1436, 1077 cm-1; 1H NMR
(400 MHz, DMSO-d6) c5 1.09-1.28 (m, 3H, aliphatic CH) 1.39-1.70 (m, 7H, aliphatic CH), 1.86 (d, J--13.50 Hz, IH, aliphatic CH), 2.35 (d, J--10.37 Hz, 1H, aliphatic CH), 2.42-2.45 (m, 1H, aliphatic CH), 2.47 (s, 3H, CCH3), 2.65-2.72 (m, 2H, aliphatic CH), 2.87-2.91 (m, IH, aliphatic CH), 3.09 (s, 9H, N(CH3)3), 3.23 (dd, J--15.19, 8.44 Hz, 1 H, aliphatic CH), 3.35-3.40 (m, 2H, NCH2CH20H), 3.81-3.85 (m, 2H, NCH2CH20H), 5.20 (dd, J--23.63, 12.30 Hz, 2H, OCHZAr), 6.55 (d, J--8.44 Hz, 1 H, ArH), 7.03 (d, J-- 8.44 Hz, 1 H, ArH), 7.22 (t, J--7.47 Hz, IH, ArH), 7.29 (d, J--7.23 Hz, 1H, ArH), 7.75 (d, J--7.48 Hz, 1H, ArH), 7.89 (s, 1H, ArH), 11.55 (s, 1H, NH); MS(APCI+): ntlz 475.1 (MH+). Anal. Calcd for C33H43N306~ C~ 65.23; H, 7.68; N, 6.92. Found: C, 64.95; H, 7.68; N, 6.92.
Example 64 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12, I 3,14, I 4a,15-decahydro-2-methyl-, [3-[(dimethylamino)methyl]phenyl]methyl ester N
N O
O
O
N
H
To a stirred solution of Ph3P (0.161 g, 0.616 mmol) and pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-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 anhydrous THF at -18°C was added dropwise a solution of N-bromosuccinimide (0.110 g, 0.616 mmol) in 2 mL of THF. After 10 minutes, the cold bath was removed, and dimethylamine was introduced in one portion. The reaction was heated at 80°C for 1 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) and recrystallized from CH2Cl2 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-/; IH NMR
(400 MHz, DMSO-d6) ~ 1.06-1.36 (m, 3H, aliphatic CH) 1.39-1.63 (m, 7H, aliphatic CH), 1.82 (d, J--13.18 Hz, IH, aliphatic CH), 2.11 (s, 6H, N(CH3)2) 2.34 (d, J 10.74 Hz, 1H, aliphatic CH), 2.40-2.46 (m, IH, aliphatic CH), 2.45 (s, 3H, CC113), 2.59-2.67 (m, 2H, aliphatic CH), 2.83-2.89 (rri, IH, aliphatic CH), 3.15 (dd, J--18.31, 6.84 Hz, IH, aliphatic CH), 3.37 (s, 2H, ArCH2N(CH3)2), 5.20 (dd, J 23.93, 12.21 Hz, 2H, OCH2Ar), 6.57 (d, J 8.79 Hz, 1H, ArH), 7.02 (d, J--8.79 Hz, 1H, ArH), 7.22-7.31 (m, 3H, ArH), 7.34 (s, 1H, ArH), 11.53 (s, IH, NH); MS(APCI+): m/z 488.1 (MH+). Anal. Calcd for C3pH37N303: 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, I 2, I 3,14,14a,15-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]phenyl]methyl ester N
Step A: 3-Hydroxymethyl-N,N-dimethyl-benzamide HO ~ ~ N~
To a mixture of 3-(hydroxymethyl)benzoic acid (9.87 g, 64.9 mmol), dimethylamine (2 M in THF, 32.4 mL, 64.9 mmol), N,N-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 turned orange. After stirring at 0°C for 1 hour, the reaction mixture was diluted with diethyl ether, washed with 10% HCI, saturated NaHC03, brine, dried with MgS04, and concentrated to give a brown oil. The product was purified by flash column chromatography on silica gel (3% MeOH:CH2C12) to afford 7.5 g (64.5%) of a yellow oil: 1H NMR (400 MHz, DMSO-d6) 8 2.88 (s, 3H, NCH3), 2.96 (s, 3H, NCH3), 4.51 (d, J--5.55 Hz, 2H, OCH2Ar), 5.25 (t, J 5.79 Hz, 1H, OH), 7.21-7.25 (m, 1H, ArH), 7.31-7.47 (m, 3H, ArH); MS(APCI+): m/z 180.1 (MH+).
Step B: 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][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]-phenyl]methyl ester was synthesized according to Procedure N from 3-hydroxymethyl-N,N-dimethyl-benzamide (1.04 g, 5.81 mmol) and triturated with acetone to give 0.250 g (25.7%) of fluffy white powder: mp 112-116°C; IR
(KBr) 2929, 2854, 1698, 1624, 1432, 1077 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 1.09-1.62 (m, 10H, aliphatic CH), 1.82 (d, J--14.16 Hz, IH, aliphatic CH), 2.33 (d, J--10.25 Hz,lH, aliphatic CH), 2.40-2.43 (m, 1H, aliphatic CH), 2.45 (s, 3H, CCH3), 2.46 (s, 6H, N(CH3)2), 2.59-2.67 (m, 2H, aliphatic CH), 2.86-2.93 (m, 1H, aliphatic CH), 3.16 (dd, J--18.80, 7.81 Hz, IH, aliphatic CH), 5.24 (dd, J 20.75, 12.45 Hz, 2H, OCH2Ar), 6.57 (d, J--8.55 Hz, 1H, ArH), 7.02 (d, J--8.55 Hz, 1H, ArH), 7.33 (d, J--7.57 Hz, 1H, ArH), 7.40-7.44 (m, 2H, Arl~, 7.49 (d, J--7.57 Hz, 1H, ArH), 11.54 (s, 1H, NH); MS(APCI+): m/z 502.2 (MH+). Anal. Calcd for C3pH35N3O4: C, 71:83; H, 7.03; N, 8.38. Found:
C, 71.44; H, 7.05; N, 8.21.
Example 66 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [2-(4-morpholinyl)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 a white solid: mp 188-190°C; IR (KBr) 2931, 2854, 1696, 1588, 1432, 1148 cm 1;
1H NMR (400 MHz, DMSO-d6) 8 1.14-1.75 (m, 10H, aliphatic CH), 1.90 (d, J--13.18 Hz, IH, aliphatic CH), 2.34-2.46 (m, 2H, aliphatic CH), 2.46 (s, 4H, N(CH2CH2)20), 2.49 (s, 3H, CCH3), 2.59 (t, J--5.62 Hz, 2H, C02CH2CH2), 2.64-2.73 (m, 2H, aliphatic CH), 2.86-2.91 (m, 1H, aliphatic CH), 3.29 (dd, J--19.29, 10.25 Hz, 1H, aliphatic CH), 3.52 (s, 4H, N(CH2CH2)20), 4.18-4.30 (m, 2H, C02CH2CI-I2), 6.58 (d, J-- 8.55 Hz, 1H, ArH), 7.02 (d, J 8.55 Hz, IH, ArH), 11.48 (s, 1H, NH); MS(APCI+): rnlz 454.1 (MH+). Anal. Calcd for C26H35N304~ 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-[1,1'-biphenyl]-4-ylethyl 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-[1,1'-biphenyl]-4-ylethyl ester was synthesized according to Procedure N from 1-biphenyl-4-yl-ethanol (2.68 g, 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; 1H
NMR
(400 MHz, DMSO-d6) 8 1.11-1.67 (m, 10H, aliphatic CH), 1.59 (d, J--6.59 Hz, 2H, OCHCH3), 1.79-1.89 (m, 2H, aliphatic CH), 2.33-2.47 (m, 1H, aliphatic CH), 2.53 & 2.54 (s, 3H, CCH3, diastereomers), 2.60-2.67 (m, 2I-I, aliphatic CH), 2.79-2.95 (m, 1H, aliphatic CH), 3.14 (dd, J--28.08, 10.12 I-Iz, 1H, aliphatic CH), 5.96-6.03 (m, 1H, OCHCH3), 6.55-6.59 (m, 1H, ArH), 7.00-7.03 (m, 1H, ArH), 7.31-7.34 (m, 1/-I, Arl~, 7.40-7.51 (m, 4H, ArH), 7.60-7.64 (m, 4H, ArH), 11.53 (s, 1H, NH); MS(APCI+): nZ/z 521.1 (MH+). Anal. Calcd for C34H36N203: C, 78.25; H, 7.36; N, 5.14. Found: C, 78.20; H, 7.76; N, 4.85.
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 H
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 was synthesized according to Procedure N from (2,6-difluoro-phenyl)-methanol (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-I; 1H NMR (400 MHz, DMSO-d6) 8 1.03-1.35 (m, 3H, aliphatic CH), 1.38-1.56 (m, 7H, cylic CH), 1.78 (d, J--13.18 Hz, 2H, aliphatic CH), 2.32-2.34 (m, 2H, aliphatic CH), 2.41 (s, 3H, CCH3), 2.55-2.66 (m, 2H, aliphatic CH), 2.83-2.88 (m, 1H, aliphatic CH), 3.08 (dd, J--18.31, 7.08 Hz, 1H, aliphatic CH), 5.20 (d, J 11.96 Hz, 1 H, OCHZAr), 6.57 (d, J--8.55 Hz, 1 H, ArH), 7.01 (d, J--8.55 Hz, 1H, ArH), 7.16 (t, J 7.81 Hz, 2H, ArH), 7.48-7.53 (m, 1H, ArH), 11.57 (s, 1H, NH); MS(APCI+): m/z 467.1 (MH+). Anal. Calcd for C27H28N203F2: C, 69.32; H, 6.19; N, 5.80. Found: C, 69.51; H, 6.05; N, 6.00.
Example 69 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12, I 3,14,14a,15-decahydro-2-methyl-, ( I -phenyl-2,2,2-tri fluoro)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-phenyl-2,2,2-trifluoro)ethyl ester was synthesized according to Procedure N from 2,2,2-trifluoro-1-phenyl-ethanol (1.58 g, 9.00 mmol) and triturated with t-butyl methyl ether to give 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) 8 1.07-1.68 (m, l OH, 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 & 2.62 (s, 3H, CCH3, diastereomers), 2.62-2.90 (m, 1H, aliphatic CH), 3.18 (dd, J--17.82, 6.84 Hz, 1H, aliphatic CH), 6.52-6.57 (m, 1H, OCHCF3), 6.61-6.63 (m, 1H, ArH), 7.05-7.07 (m, 1H, ArH), 7.43-7.44 (m, 3H, ArH), 7.55-7.57 (m, 2H, ArH), 11.83 (s, 1H, NH); MS(APCI+):
m/z 499.1 (MH+). Anal. Calcd for C28H29N203F3: C, 67.46; H, 5.86; N, 5.62.
Found: C, 67.40; H, 6.03; N, 5.44.
Example 70 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-[3-(trifluoromethyl)phenyl]ethyl ester F F
F
N O
O
O /
N
H
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-[3-(trifluoromethyl)phenyl]-ethyl ester was synthesized according to Procedure N from 1-(3-trifluoromethyl-phenyl)-ethanol (2.06 mL, 13.5 mmol) and triturated with diethyl ether to give 0.793 g (45.8%) ofwhite solid: mp 102-105°C; IR (KBr) 3380, 2931, 1680, 1432, 1075 cm-l; 1H NMR (400 MHz, DMSO-d6) d 1.05-1.59 (m, 10H, aliphatic CH) 1.59 (d, J--6.59 Hz, 3H, OCHCll3), 1.77-1.88 (m, 1H, aliphatic CH), 2.33 (d, J--9.03 Hz, 1H, aliphatic CH), 2.41 (d, J--8.55 Hz, 1H, aliphatic CH), 2.51 &
2.52 (s, 3H, CCH3, diastereomers), 2.51-2.67 (m, 2H, aliphatic CH), 2.83-2.86 (m, 1H, aliphatic CH), 3.06 (dd, J--18.07, 6.84 Hz, 1H, aliphatic CH), 6.01-6.05 (m, 1H, OCHCH3), 6.58-6.60 (m, 1H, ArH), 7.01-7.04 (m, 1H, ArH), 7.57-7.67 WO 00/42045 PCTlUS99130434 (m, 2H, ArH), 7.71-7.75 (m, 2H, ArH), 11.56 (s, 1H, NH); MS(APCI+): m/z 513.1 (MH+). Anal. Caled for C29H31N203F3: C, 67.69; H, 6.08; N, 5.44.
Found: C, 67.34; H, 6.35; N, 5.24.
Example 71 S Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-dccahydro-2-methyl-, 2-(dimethylamino)ethyl ester N
N O
O
O
N
H
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 was synthesized according to Procedure N from 2-dimethylamino-ethanol (1.36 mL, 13.5 mmol) and triturated with diethyl ether to give 0.489 g (34.9%) of granular off white solid: mp 190-191 °C; IR (KBr) 3274, 2950, 1653, 1518, 1248 cm-I; 1H NMR (400 MHz, DMSO-d6) c5 1.13-1.59 (m, 10H, aliphatic CH), 1.71-1.76 (m, 1H, aliphatic CH), 1.90 (d, J--13.43 Hz, IH, aliphatic CH), 2.05 (s, 6H, N(CH3)2), 2.35 (d, J--10.25 Hz, lI-I, aliphatic CH), 2.48 (s, 3H, CCH3), 2.52 (t, J--5.86 Hz, 2H, OCH2CH2), 2.64-2.74 (m, 2H, aliphatic CH), 2.85-2.89 (m, 1H, aliphatic CH), 3.31 (dd, J--18.56, 7.08 Hz, 1H, aliphatic CH), 4.14-4.27 (m, 2H, OCHZCH2), 6.58 (d, J--8.55 Hz, 1H, ArH), 7.02 (d, J--8.79 Hz, 1H, ArH), 11.56 (s, 1H, NH); MS(APCI+): m/z 412.2 (MH+). Anal. Calcd for C24H33N303~ 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][I]benzopyrano[3,2-i]quinolizine-I-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][IJbenzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(1-pyrrolidinyl)ethyl ester was synthesized according to Procedure N from 2-pyrrolidin-I-yl-ethanol (1.02 g, 8.85 mmol) and triturated with t-butyl methyl ether to give 0.253 g (26.0%) of white solid: mp 195-196°C; IR (KBr) 3377, 2930, 1700, 1432, 1081 cm-/;
IH NMR (400 MHz, DMSO-d6) 8 1.12-1.78 (m, 10H, aliphatic CH), 1.61-1.69 (m, 8H, cyclic CHZ), 1.92 (d, J--13.26 Hz, IH, aliphatic CH), 2.37 (d, J--10.61 Hz, 1H, aliphatic CH), 2.47-2.49 (m, 1H, aliphatic CH), 2.50 (s, 3H, CH3), 2.66-2.76 (m, 2H, aliphatic CH), 2.72 (t, J 6.51 Hz, 2H, OCH2CH2), 2.87-2.93 (m, 1H, aliphatic CH), 3.32 (dd, ,l--19.05, 13.02 Hz, 1H, aliphatic CH), 4.19-4.30 (m, 2H, OCH2CH2), 6.60 (d, J--8.68 Hz, 1 H, ArH), 7.04 (d, J--8.68 Hz, 1 H, ArH), 11.49 (s, 1H, NH); MS(APCI+): m/z 438.2 (MH+). Anal. Calcd for C26H35N303v 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-1-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][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, I-(1-naphthalenyl)ethyl ester was synthesized according to Procedure N from I-naphthalen-1-yl-ethanol (2.32 g, 13.5 mmol) and triturated with diethyl ether to give 0.707 g (40.9%) of fine white powder: mp 140-145°C; IR (KBr) 3387, 2929, 1682, 1432, 1078 cm-l;
1H NMR (400 MHz, DMSO-d6) 8 0.94-1.72 (m, 10H, aliphatic CH), 1.72 (d, J--2.69 Hz, 3H, OCHCH3), 1.83 (d, J--12.94 Hz, IH, aliphatic CH), 2.30-2.63 (m, 3H, aliphatic CH), 2.50 & 2.52 (s, 3H, CCH3, diastereomers), 2.83-2.88 (m, 2H, aliphatic CH), 3.21 (dd, J 32.72, 26.12 Hz, 1H, aliphatic CH), 6.52-6.58 (m, 1H, ArH), 6.74-6.75 (m, IH, OCHCH3), 6.98-7.03 (m, 1H, ArH), 7.46-7.65 (m, 4H, ArH), 7.84-7.89 (m, 1 H, ArH), 7.93-7.96 (m, 1 H, ArH), 8.12-8.14 (m, 1 H, ArH), 11.54 (s, 1H, NH); MS(APCI+): m/z 513.1 (MH+). Anal. Calcd for 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][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylcyclobutyl ester N O
O
O
N
H
Step A: I-Phenyl-cyclobutanol OOH
To a solution ofphenylmagnesium 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 bath for I hour. Saturated ammonium chloride was added and stirred for 10 minutes. The reaction mixture was washed with H20 (2 x 250 mL), dried with MgS04, and concentrated to give a yellow oil. The product was purified by flash column chromatography on silica gel (10% acetone:hexanes) to give 10.1 g (47.7%) of a yellow oil: IH NMR (400 MHz, CDCl3) 8 1.62-1.73 (m, 1H, CCH2CH2), 1.94-2.09 (m, 1H, CCH2CH2), 2.29-2.38 (m, 2H, CCH2), 2.50-2.57 (m, 2H, CCH2), 2.68 (s, 1H, OH), 7.21-7.29 (m, IH, ArH), 7.31-7.38 (m, 2H, ArH), 7.38-7.50 (m, 2H, ArH); MS(APCI+): m/z 171.5 (MH+).
Step B: Pyrrolo[3',2':5,6][I]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-i-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylcyclobutyl ester was synthesized according to Procedure N from i-phenyl-cyclobutanol (1.33 g, 9.00 mmol) and triturated with diethyl ether to give 0.201 g ( 19.0%) of white powder: mp 218-220°C; IR (KBr) 3328, 2930, 1674, 1434, 1080 cm-1; 1H
NMR
(400 MHz, DMSO-d6) 8 1.09-1.84 (m, 10H, aliphatic CH), 1.94-2.00 (m, 1H, aliphatic CH), 2.33 (d, J--9.03 Hz, 1H, aliphatic CH), 2.40-2.46 (m, IH, aliphatic CH), 2.46 (s, 3H, CCH3), 2.56 (s, 6H, cyclic C(CH2)3Ar), 2.52-2.64 (m, 2H, aliphatic CH), 2.83-2.88 (m, 1H, aliphatic CH), 3.15 (dd, J--18.80, 7.08 Hz, IH, aliphatic CH), 6.56 (d, J--8.55 Hz, 1 H, ArFl), 7.00 (d, .1--8.55 Hz, I H, ArH), 7.22 (t, J--7.08 Hz, 1H, ArH), 7.33 (t, J--7.57 Hz, 2H, ArF~, 7.47 (d, .I--7.32 Hz, 2H, ArH), 11.48 (s, 1H, NH); MS(APCI+): nrlz 671.1 (MH+). Anal. Calcd for C3pH35N2O3: 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 Step A: 1-Phenyl-cyclopropanol ~oH
i I-Phenyl-cyclopropanol was synthesized according to the procedure published in Kulinkovich, O.G.; Sviridov, S.V.; Vasilevskii, D.A.; Savchenko, A.L; Pritytskaya, T.S. J. Org. Chem. USSR (Engl.) 1991;27:250-253.
Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylcylopropyl 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-, I-phenylcylopropylesterwas synthesized according to Procedure N from 1-phenyl-cyclopropanol (1.22 g, 9.00 mmol) and triturated with diethyl ether to give 0.078 g (7.57%) of shiny yellow powder: mp 130-135°C; 1R (KBr) 3384, 2929, 1690, 1431, 1069 cm-l; 1H
NMR (400 MHz, DMSO-d6) 8 1.06-1.69 (m, I OH, aliphatic CH), 1.86 (d, .13.43 Hz, 1H, aliphatic CH), 2.34 (d, J--10.01 Hz, 1H, aliphatic CH), 2.41-2.44 (m, 1H, aliphatic CH), 2.46 (s, 3H, CCH3), 2.52 (s, 4H, cyclic C(CII2)2Ar), 2.63-2.70 (m, 2H, aliphatic CH), 2.81-2.89 (m, 1H, aliphatic CH), 3.20 (dd, J--18.56, 7.33 Hz, I H, aliphatic CH), 6.59 (d, J--8.55 Hz, 1 H, Arf~, 7.03 (d, J--8.55 Hz, 1H, ArH), 7.15-7.19 (m, 3H, Arl~, 7.26-7.30 (m, 2H, ArH), 11.57 (s, 1H, NH); MS(APCI+): mlz 457.1 (MH+). Anal. Calcd for C29H32N203v 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][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-pyrazinylethyl ester N
N O ~ /N
O
O

WO 00142045 PCTlUS99/30434 Step A: 1-Pyrazin-2-yl-ethanol OH
CN
i N
To a solution of I-pyrazin-2-yl-ethanone (5.00 g, 40.9 mmol) in 100 mL of MeOH at 0°C was added NaBH4 (0.774 g, 20.5 mmol) in portions. After stirnng at room temperature for 24 hours, the reaction mixture was quenched with 1 N
HCl and extracted with CH2C12 (3 x 100 mL). The organic layers were dried with Na2S04 and concentrated to give 2.60 g (51.2%) of a yellow oil: 1H NMR
(400 MHz, CDC13) 8 1.54 (d, J--6.59 Hz, 3H, CHCH3), 3.54 (s, l I-I, OH), 4.97 (q, J=6.59 Hz, I H, CH3CII), 8.49 (s, 2H, NCHCHN), 8.65 (s, 1 H, CCNN);
MS(APCI+): ~?z/z 125.1 (MH+) Step B: Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-pyrazinylethyl 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-, I-pyrazinylethyl ester was synthesized according to Procedure N from 1-pyrazin-2-yl-ethanol (1.12 g, 9.00 mmol) and triturated with cold acetone to give 0.303 g (30.3%) of coarse white powder: mp 224-225°C; IR (KBr) 3172, 2930, 1704, 1431, 1073 cm-1;

NMR (400 MHz, DMSO-d6) b 1.06-1.63 (m, l OH, aliphatic CH), 1.61 (d, J--3.17 Hz, 3H, OCHCH3), 1.77-1.98 (m, 1H, aliphatic CH), 2.34 (d, J--10.25 Hz, 1H, aliphatic CH), 2.40-2.43 (m, 1H, aliphatic CH), 2.52 & 2.53 (s, 3H, CCH3, diastereomers), 2.62-2.68 (m, III, aliphatic CH), 2.84-2.87 (m, 1H, aliphatic CH), 3.12 (dd, J--19.04, C.84 Hz, IH, aliphatic CI-I), 5.99 (q, J--7.08 Hz, 1H, OCHCH3), 6.56-6.60 (m, 1H, ArH), 7.01-7.04 (m, IH, ArH), 8.57 (s, 1H, ArH), 8.62 (s, 1 H, Arll), 8.71 & 8.73 (s, 1 H, ArH, diastereomers), I 1.56 (s, I H, NH);
MS(APCI+): n1/z 447.1 (MH+). Anal. Calcd for C26H30N403 ~ C~ 69.90; H, 6.79;
N, 12.50. Found: C, 69.51; H, 6.78; N, 12.35.

Example 77 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(4-quinolinyl)ethyl ester w N
N O \
O
O
N
H
Step A: 1-Quinolin-4-yl-ethanol W
~oH
N
To a solution of quinoline-4-carbaldehyde (5.00 g, 31.8 mmol) in 127 mL
of anhydrous THF at -40°C was added methylmagnesium bromide (13.8 mL, 41.4 mmol). After stirnng for 5 hours, the reaction mixture was quenched with saturated NH4C1 and extracted with ethyl acetate (5 x 100 mL). The organic layers were washed with brine, dried with Na2S04, and concentrated to give a purple solid. The solid was triturated with acetone to yield 4.52 g (82.2%) of light purple solid: 1H NMR (400 MHz, CDC13) 8 1.60 (d, J--6.35 Hz, 3H, CHCH3), 3.70 (s, 1H, OH), 5.62 (q, J=6.35 Hz, 1H, CHCH3), 7.50 (t, J--7.57 Hz, 1H, CCCHCH), 7.56 (d, J--4.40 Hz, 1H, NCHCH), 7.63 (t, J--7.32 Hz, 1H, NCCHCH), 7.97 (d, J--8.55 Hz, 1H, CCCHCH), 8.05 (d, J--8.30 Hz, 1H, NCCHCH), 8.73 (d, J--4.39 Hz, 1H, NCHCH), MS(APCI+): m/z 174.1 (MH+) Step B: Pyrrolo[3',2':5,6][1]bcnzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1~-decahydro-2-methyl-, 1-(4-quinolinyl)ethyl ester Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(4-quinolinyl)ethyl ester was synthesized according to Procedure N from 1-quinolin-4-yl-ethanol (1.56 g, 9.00 mmol) and triturated with acetone to give 0.192 g (17.1 %) of pale yellow powder: mp 165-168°C; IR (KBr) 2930, 2853, 1690, 1429, 1074 cm-/; 1H
NMR
(400 MHz, DMSO-d6) 8 1.00-1.46 (m, l OH, aliphatic CH), 1.70 (d, J--6.35 Hz, 3H, OCHCH3), 1.85 (d,J--13.18 Hz, IH, aliphatic CH), 2.32-2.63 (m, 3H, aliphatic CH), 2.57 & 2.58 (s, 3H, CCH3, diastercomers), 2.83-2.86 (m, 2H, aliphatic CH), 3.20 (dd, J--18.31, 6.84 Hz, 1 H, aliphatic CH), 6.55-6.58 (m, 1H, ArH), 6.65 (q, J--6.59 Hz, IH, OCHCH3), 7.01-7.05 (m, 1H, ArH), 7.50-7.54 (m, I H, ArH), 7.63-7.67 (m, .I H, ArH), 7.75-7.79 (m, I H, ArH), 8.04-8.06 (m, 1 H, ArH), 8.21=8.23 (m, 1 H, ArH), 8.84-8.88 (m, I H, ArH), 11.61 (s, I H, NH);
MS(APCI+): rnlz 496.2 (MH+). Anal. Calcd for C31H33N303v C> 74.12; II, 7.00;
N, 7.83. Found: C, 73.73; H, 7.09; N, 7.44.
Example 78 Pyrrolo[3',2':5,6][1 ]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(2-pyrimidinyl)ethyl ester N
N O
O N
O
N
H
IS Step A: 1-Pyrirnidin-2-yl-ethanone N
\ N
1-Pyrimidin-2-yl-ethanone was synthesized according to the procedure published in Naumenko, I. L; Mikhaleva, M. A.; Mamaev, V. P. Chem.
Het. Crnpcls. 1981;17:710-714.
Step B: I-Pyrimidin-2-yl-ethanol N\ ~
~OH
SIN

To a solution of 1-pyrimidin-2-yl-ethanone (2.34 g, 19.2 mmol) in 65 mL
of MeOH at 0°C was added NaBH4 (0.726 g, 19.2 minol) in portions. After stirring at room temperature for 4 hours, the reaction mixture was quenched with 1N HCI and extracted with CH2C12 (3 x 100 mL). The organic layers were dried with Na2S04 and concentrated to afford 0.984 g (41.3%) of a yellow oil: IH
NMR (400 MHz, DMSO-d6) 8 1.36 (d, J--6.59 Hz, 3H, CHCH3), 4.73 (q, J 6.59 Hz, 1H, CH3CH), 5.21 (s, 1H, OI~, 7.33-7.36 (m, 1H, NCHCH), 8.73-8.77 (m, 2H, NCHCH); MS(APCI+): m/z 125.1 (MH+) Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2-pyrimidinyl)ethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, l-(2-pyrimidinyl)ethyl ester was synthesized according to Procedure N from 1-pyrimidein-2-yl-ethanol (1.01 g, 8.10 mmol) and triturated with acetone to give 0.360 g (29.9%) of fine off white powder: mp 220-222°C; IR (KBr) 3176, 2932, 1686, 1426, 1078 cm-1; IH
NMR
(400 MHz, DMSO-d6) cS 1.06-1.54 (m, l OH, aliphatic CH), 1.59 (d, J--6.59 Hz, 3H, OCHCH3), 1.84 (d, J--13.92 Hz, IH, aliphatic CH), 2.34-2.55 (m, 2H, aliphatic CII), 2.58 (s, 3H, CCH3), 2.64-2.69 (m, 2H, aliphatic C.H), 2.81-2.86 (m, 1H, aliphatic CI I), 3.17 (dd, J--18.31, 6.59 Hz, 1H, aliphatic CH), 5.84 (q, J--6.84 Hz, 1H, OCHCH3), 6.57 (d, J--8.79 Hz, 1H, ArH), 7.02 (d, J=9.03 Hz, 1H, ArH), 7.37-7.38 (m, 1H, ArFl), 8.76-8.77 (m, 2H, ArH), 11.53 (s, 1H, NH);
MS(APCI+): m/z 447.1 (MH+}. Anal. Calcd for C26H30N403~ C~ 69.86; H, 7.04;
N, 12.07. Found: C, 69.50; H, 6.94; N, 1 I .71.
Example 79 Pyrrolo[3',2':5,6][1]bcnzopyrano[3,2-i]quinolizine-I-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, phenylmethyl ester N O
O
O
CI \ ~ N
H
Step A: 6-Chloro-5-hydroxy-2-methyl-lII-indole-3-carboxylic acid benzyl ester HO
CI \ ~ N
H
To a solution of 3-amino-but-2-enoic acid benzyl ester (10.1 g, 52.9 mmol) in 211 mL of EtOH was added 2-chloro-1,4-benzoquinone (9.04 g, 63.4 mmol).
After heating at 50°C for 24 hours, the mixture was cooled to room temperature and concentrated to afford a brown oil. The product was purified by flash column chromatography on silica gel (20% ethyl acetate:hexanes) and recrystallized from ethyl acetate to give 1.02 g (5.12%) of light yellow powder: nip 221-224°C; IR
(KBr) 3409, 3226, 1642, 1461, 1181 cm-1; 1H NMR (400 MHz, DMSO-d6) 8 2.55 (s, 3H, CCH3), 5.29 (s, 2H, OCH2Ar), 7.27 (s, 1H, ArH), 7.30 (d, J--6.84 Hz, 1H, ArH), 7.36 (t, J--8.30 I-Iz, 2H, ArH), 7.42 (d, J--7.57 Hz, 2H, ArH), 7.50 (s, 1H, ArH), 9.56 (s, 1H, OH), 11.67 (s, 1H, NH); MS(APCI+): m/~ 316.1 (MH+) HPLC (ALLTCH/ALLTIMA C-18 50:50-2:98 H20/CH3CN + 0.05% TFA):
rentention time=5.47 min, 95.86% purity.
Step B: 6-Chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester 6-Chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid benzyl ester was synthesized according to Procedure L from 6-chloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (7.77 g, 24.6 mmol) and triturated with cold EtOH to give 6.778 (73.8%) of a white solid:
mp 178-180°C; IR (KBr) 3298, 2951, 1687, 1425, 1437, 1264, 1078 cm-1;

NMR (400 MHz, DMSO-d6) 8 2.14 (s, 6H, N(CH3)2) 4.06 (s, 2H, NCH2Ar), 5.23 (s, 2H, OCH2Ar), 7.22 (s, 1H, ArH), 7.31-7.39 (m, 3H, ArH), 7.44 (d, J--6.84 Hz, 2H, ArH), 11.85 (s, 1 H, NH); MS(APCI+): mlz 373.1 (MH+). HPLC
(ALLTCH/ALLTIMA C-18 50:50-2:98 H20/CH3CN + 0.05% TFA): retention time=3.10 min, 99.09% purity.
Step C: 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-, phenylmethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 5-chloro-3,7,8,9,10,12,13, l 4,14a,15-decahydro-2methyl-, phenylmethyl ester was synthesized according to Procedure M from 6-chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (6.77 g, 18.2 mmol) and triturated with acetone to give 6.05 g (71.7%) of shiny white powder: mp 90-93°C; IR (KBr) 3291, 2933, 2858, 1673, 1427, 1076 cm-1; 1H NMR
(400 MHz, DMSO-d6) 8 1.01-1.71 (m, l OH, aliphatic CH), 1.75 (d, J--13.43 Hz, 1H, aliphatic CH), 2.37 (d,.1--10.50 Hz, 1H, aliphatic CH), 2.45-2.46 (m, 1H, aliphatic CH), 2.46 (s, 3H, CC~13), 2.64-2.74 (m, 2H, aliphatic CH), 2.94-2.99 (m, 1H, aliphatic CH), 3.38 (dd, J--18.56, 7.08 Hz, 1H, aliphatic CH), 5.21 (dd, J--26.12, 12.21 Hz, 2H, OCH2Ar), 7.18 (s, 1H, ArH), 7.29-7.43 (m, 5H, ArH), 11.62 (s, 1H, NH); MS(APCI+); m/z 465.2 (MH+). Anal. Calcd for C27H29N203C11: C, 69.74; H, 6.29; N, 6.02. Found: C, 69.45; H, 6.68; N, 5.82.
Example 80 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)ethyl ester F
N O
O
O
CI \ ~ N
H
Step A: Pyrrolo[3',2':5,6][M]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl, anhydride with benzoic acid S CI H

In a 250 mL, three-necked, round bottom flask was added 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-2methyl-, phenylmethyl ester (Example 79, Step C, 5.44 g, 11.7 mmol), THF (58.6 mL, 0.2 M), Et3N (1.63 mL, 11.7 mmol), and 10% Pd(OH)2/C (1.26 g) sequentially. The mixture was stirred under a H2 atmosphere (balloon) for 1 hour. The reaction mixture was filtered through a pad of celite, and the yellow filtrate was carried on the next step. To this yellow filtrate was added benzoyl chloride in a dropwise fashion (1.36 mL, 11.7 mmol).
The mixture was stirred at room temperature for 48 hours and the solvent removed to give a brown oil. Trituration with acetone afforded 3.50 g (62.4%) of yellow powder: mp 160-165°C; 1H NMR (400 MHz, DMSO-d6) ~ 1.10-1.58 (m, 10H, aliphatic CH), 1.83 (d, J--12.94 Hz, 1H, aliphatic CH), 2.41-2.46 (m, 2H, aliphatic CH), 2.51 (s, 3H, CCH3), 2.66-2.71 (m, 1H, aliphatic CH), 2.98-3.01 (m, 2H, aliphatic CH), 3.38 (dd, J--17.82, 6.59 Hz, 1H, aliphatic CH), 7.29 (s, IH, Ark, 7.58 (t, J--7.57 Hz, 2H, Arl~, 7.74 (t, J--7.57 Hz, 1H, ArI~, 8.07 (d, J--7.08 Hz, 2H, Arl~, 12.14 (s, 1H, NI~; MS(APCI+): na/z 479.1 (MH+).
Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, N O
O
O
N
5-chloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl, 1-(4-fluorophenyl)ethyl ester Pyrrolo[3',2':5,6][lJbenzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2methyl-, 1-(4-fluorophenyl)ethyl ester was synthesized according to Procedure N from 1-(4-fluoro-phenyl)-ethanol (0.900 g, 7.16 mmol) and pyrrolo[3',2':5,6][I]-benzopyrano[3,2-i]quinolizine-1-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 recrystallized from t-butyl methyl ether to give 0.210 g (23.6%) of white powder: mp 102-107°C; IR (KBr) 2934, 2859, 1674, 1428, 1055 cm-I; 1H NMR (400 MHz, DMSO-d6) S 1.06-1.81 (m, 11H, aliphatic CH), 1.55 (d, J--6.59 Hz, 3H, OCHCH3), 2.37 (d, J--10.25 Hz, IH, aliphatic CH), 2.44-2.46 (m, 1H, aliphatic CH), 2.46 (s, 3H, CCH3), 2.63-2.75 (m, 2H, aliphatic CH), 2.97-3.14 (m, IH, aliphatic CH), 3.20 (dd, J--13.18, 6.59 Hz, 1H, aliphatic CH), 5.95 (q, J--6.59 Hz, 1H, OCHCH3), 7.15-7.19 (m, 3H, ArH), 7.43-7.49 (m, 2H, ArH), 11.62 (s, IH, NH); MS(APCI+): ratlz 497.2 (MH+). Anal. Calcd for C28H3pN203FIC11: C, 66.82; H, 6.15; N, 5.57. Found: C, 66.96; H, 6.39; N, 5.46.
Example 81 Quinolizinium, I-[[(4-fluorophenyl)methoxy]carbonyl]-5-hydroxy-2-methyl-1H-indol-4-yl]mcthylJ-1,2,3,4,6,7,8,9-octahydro-, chloride ct~
~F
I-I
To a solution ofpyrrolo[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-fluorophenyl)methyl ester (0.500 g, 1.11 mmol) in 125 mL of CH2C12 was added ethereal HCl in portions until the solution turned cloudy. After the solvent was removed, the yellow residue was triturated with acetone to give 0.307 g (61.0%) ofwhite powder: mp 179-185°C; IR (KBr) 3408, 3193, 2934, 1697, 1431, 1152 cm-1; 1H NMR (400 MHz, CDC13) ~ 1.37-1.52 (m, IH, aliphatic CH), 1.52-I.77 (m, 8H, aliphatic CH), 2.07-2.15 (m, IH, aliphatic CH), 2.26 (d, J 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, J--14.65, 12.45 Hz, 2H, OCHZAr), 6.78 (d, J--14.65 Hz, 1H, ArH), 7.05 (t, J--8.55 Hz, 1H, ArH), 7.14 (d, J--8.79 Hz, IH, ArH), 7.41 (t, J--5.37 Hz, 1H, ArH), 8.58 (s, IH, OH), 12.52 (s, 1H, NH); MS(APCI+): m/z 449.3 (MH+).
Anal. Calcd for C27H3pN203F1C11: C, 66.87; H, 6.23; N, 5.78; Cl, 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-1,2-dimethyl-, (4-fluorophenyl)methyl ester ~F
N O
O
O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinoli?ine-1-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 in mineral oil, 0.049 g, 1.23 mmol, washed with hexanes) and was stirred at room temperature for I hOlll'. Methyl iodide (0.076 mL, 1.23 mol) was added to the reaction mixture. The reaction was stirred for 2 hours, quenched with 15 mL of H20 and extracted with diethyl ether (5 x50 mL). The organic layers were concentrated to afford a yellow solid which was triturated with acetone to give 0.274 g (52.7%) of white solid: mp 179-180°C; IR (KBr) 3466, 2932, 2854, 1673, 1482, 1155 cm-1; 1 H NMR (400 MHz, CDCl3) S 1.06-1.21 (m, 3H, aliphatic CH), 1.36-1.58 (m, 7H, aliphatic CH), 1.79 (d, J--14.20 Hz, IH, aliphatic CH), 2.34 (d, J--10.74 Hz, 1H, aliphatic CH), 2.42-2.49 (m, 2H, aliphatic CH), 2.49 (s, 3H, CCH3), 2.64 (t, J--10.74 Hz, IH, aliphatic CH), 2.86 (t, J--11.48 Hz, 1H, aliphatic CH), 3.10 (dd, .l--18.31, 6.84 Hz, 1H, aliphatic CH), 3.59 (s, 3H, NCH3), 5.21 (dd, J--29.05, 11.96 Hz, 2H, OCH2Ar), 6.64 (d, J 8.79 Hz, 1H, ArH), 7.16-7.22 (m, 3H, Arl~, 7.48 (t, J--7.81 Hz, 1H, Arl~; MS(APCI+): mlz 463.1 (MH+). Anal. Calcd for C28H31N203F1: 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylpropyl ester N O
O
O
N
H
Step A: 5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid 1-phenyl-propyl ester W
O O
O
O
N
H
This compound was made according to Procedure A. White solid, mp 144-145.5°C; MS(APCI-): mlz 350.1 (M-H).
Step B: S-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 1-phenyl-propyl ester O
O
O
N
5-Acetoxy-2-methyl-1H-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, 15.4 mmol) was then added. The resulting reaction mixture was stirred at reflux for 1 minute, then allowed to cool to ambient temperature. The reaction mixture was then mixed with 10 mL of water, the resulting reaction mixture was treated with 5% HCl until pH = 1 affording a white precipitate. The mixture was 6 extracted with EtOAc (2 x 60 mL). The combined organic mixture was dried over Na2S04 and concentrated in vacuo to give a black thick oil which was further purified by chromatography using 10% MeOH in HCCl3 as the eluant to give 1.13 g (98%) of the desired product as a brown solid:..l H NMR (DMSO-d6) ~
0.917 (t, J= 7.33 Hz, 3H, CHCH2CH3), 1.84-2.03 (m, 2H, CHCH2CH3), 2.59 (s, 3H, ArCH3), 5.84 (t, J= 5.68 Hz, 2H, CHCH2CH3), 6.59 (dd, J= 8.61, 2.38 Hz, 1 H, ArH), 7.12 (d, J= 8.61 Hz, 1 H, ArH), 7.23-7.41 (m, 6H, ArH), 8.87 (s, 1 H, exchangeable proton), 11.6 (bs, 1H, exchangeable proton).
Step C: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester O O
HO
N
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester (1.07 g, 3.60 mmol) and aqueous Me2NII (40%, 0.99 mL, 7.92 mmol) were mixed with 2.4 mL of EtOH, the mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO
(37%, 0.35 g, 4.3 mmol) was added. The resulting reaction mixture was stirred at 50°C for 4 hours, then at ambient teperature for 12 hours. The racoon mixture was diluted with EtOAc (30 mL), washed with water (2 x 30 mL), and dried over Na2S04. Concentration in vacuo followed by chromatography using 100%
EtOAc, then 10% MeOH in HCC13 as the eluants gave 0.50 g (38%) ofpure titled compound as a yellow foam: mp 50-62°C (dec.); MS(APCI+): ntlz 367.2 (MI-I+).

Step D: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1 S-decahydro-2-methyl-, 1-phenylpropyl ester H
To a mixture of perchlorate salt (0.38 g, 1.6 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory fimnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. 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 for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to 0.40 g (71 %) of titled compound as a white foam: mp 90-115°C; MS(APCI+): m/z 459.3 (MH+).
Example 84 Quinolizinium, 1,2,3,4,6,7,8,9-octahydro-1-[[5-hydroxy-2-methyl-3-[(phenylmethoxy)carbonyl]-1H-indol-4-yl]methyl]-, chloride CI
O
~--O
HO~
To a solution ofpyrrolo[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-, phenylmethyl ester (0.209 g, 0.485 mmol) in CH2Cl2 was added etheral HC1. After stirring at ambient temperature 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 C27H3pN203M.0 HC1~0.3H20: C, 68.65; H, 6.74; N, 5.93; Cl, 7.50; H20, 1.14. Found: C, 68.62; H, 6.80; N, 6.00; Cl, 7.54;
H20, 0.93.
Example 85 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10, I 2,13,14,14x,15-decahydro-2-methyl-, (4-nitrophenyl)methyl ester N
O O

N O
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,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/C (20%, 0.125 g). The resulting reaction solution was stirred at ambient temperature under hydrogen atmosphere until the benzyl ester was completely consumed. The catalyst was removed by filtration, and the filtrate was concentrated in vc~cuo at ambient temperature and used in the next step without further purification.
To a solution of crude product of debenzylation reaction in DMF were added para-nitrobenzylbromide and DBU. The resulting reaction solution was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with 50 mL of EtOAc and washed successively with saturated aqueous NaHC03 (3 x 50 mL) and water (3 x 50 mL). After drying over Na2S04, the solution was concentrated in vacuo and purified by chromatography twice using 10% MeOH in HCCL3 and 50% EtOAc in hexanes to give 28 mg (17%) of desired product as a yellow solid: mp 240-242°C; MS(APCI+): m/z 476.3 (MH+).
Example 86 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-, anhydride with benzoic acid O
N O
O
O
N
H
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-, phenylmethyl ester (10.15 g, 23.58 mmol) was dissolved in 110 mL of THF, and the solution was transferred to a round bottom flask equipped with a stir bar and a three-way stopcock connected to 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 with hydrogen gas several times. The resulting reaction solution was stirred at ambient temperature under hydrogen atmosphere until the benzyl ester was completely 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 resulting reaction solution was stirred at ambient temperature for 16 hours under nitrogen.
White precipitate formed was removed by filtration. The filtrate was concentrated in vacuo affording thick oil; trituration with Et20 gave 9.188 (88% over two steps) the desired product as a white solid: mp 159-160°C; MS(APCI+):
ntlz 443.3 (MH+).

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 was obtained. After cooling down to ambient temperature, the solution was diluted with EtOAC, then mixed with aqueous NaHC03 (saturated). The mixture was for 5 minutes. Two layers were separated, and the organic layer was washed with brine and water, then dried over MgS04. Purification with flash chromatography or recrystallization gave the desired product.
Example 87 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)-l -phenylethyl ester N O
~-O
O
~N
H
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-, (1R)-1-phenylethyl ester was synthesized according to procedure Q from (R)-(+)-1-phenylethanol. The crude product was chromatographed on a preparative silica gel plate using 100%
acetonitrile as eluant to give 25 mg of the desired product as a white solid:
mp 100-112°C; MS(APCI+): nr/z 445.3 (MH+).
Example 88 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(4-fluarophenyl)ethyl ester F
N O
O
O
N
H
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(4-fluorophenyl)ethyl ester was synthesized according to procedure Q from I-(para-fluorophenyl)ethanol.
The crude product was chromatographed first on a silica gel column (30% of EtOAc in hexanes as eluant) then on a preparative silica gel plate (100% acetonitrile as eluant) to give 54.5 mg (37%) of the desired product as a yellow foam: mp 98-110°C; MS(APCI+): 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.) were mixed in a VWR 60826-202 tube. The tube was loosely capped and submerged in oil-bath at 120°C for 7 minutes. After cooling to ambient temperature, 10 mL of ether and 10 mL of saturated aqueous Na2S04 were added to the tube. The mixture was stirred for 1 minute, then the ether layer was transferred into a new tube with MgS04. After 10 minutes, the MgSO4 was removed by filtration. The filtrate was blown down with a nitrogen stream and the residue was re-dissolved in 0.2 mL of ether and transferred onto a SPE cartridge containing 1 g of silica gel. The short column was eluded with 20 mL of a 10% of EtOAc in hexanes solution. The fractions collected contained mainly the corresponding alcohol and were dicarded. The column was then eluded with 5 mL of a 10% of EtOAc in hexanes solution. The fraction collected was concentrated down (blown down with a nitrogen stream) to give the crude product.
Example 89 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,I3,14,14a,15-decahydro-2-methyl-, phenyl ester i N O
O
O
N
H
Pyrrolo[3',2':5,6J[I]benzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, phenyl ester was synthesized according to procedure R from phenol. The crude product was not further purified: white solid; MS(APCI+): m/z 417.1 (MH+).
Example 90 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,IS-decahydro-2-methyl-, 2,2,2-trifluoro-1-phenyl-I-(trifluoromethyl)ethyl ester F FF F
F
F
N O
O
~N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-deeahydro-2-methyl-, 2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl ester was synthesized according to procedure R from 1,1,1,3,3,3-hexfluoro-2-phenyl-2-propanol. The crude product was not further purified: white solid; MS(APCI-): m/z 565.1 (M-H).
Example 91 Pyrrolo[3',2':5,6][lJbenzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x, I S-decahydro-2-methyl-, bicyelo[2.2.1 ]kept-2-yl ester -190=
O
O
O
N
H
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-, bicyclo[2.2.1 )hept-2-yl ester was synthesized according to procedure R from exo-norborneol. The crude product was not further purified: white solid; MS(APCI-): ntlz 433.2 (M-H).
Example 92 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(4-fluorophenyl)-1-methylethyl ester N
O
O ~ O ~ / F
~l N
H
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-(4-fluorophenyl)-I-methylethyl ester was synthesized according to procedure Q from 2-(4-fluoropbenyl)-2-propanol. The crude product was chromatographed on a silica gel column (SO-70% of ether in hexanes as eluant) to give 0.15 g (9%) of the desired product as a white solid mp 110-112°C; MS(APCI+): m/z 477.1 (MH+).
Example 93 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1 S-decahydro-2-methyl-, 1-phenylcyclopentyl ester N
O
O O
N
H
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-phenylcyclopentyl ester was synthesized according to procedure Q from 1-phenyl-1-cyclopentanol. The crude S product was chromatographed on a silica gel column (8O% of ether in hexanes as cluant) to give 0.15 g (6%) of the desired product as a white solid: mp 20~-206°C;
MS(APCI+): m/z 483.1 (MH+) Example 94 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-phenylcyclohexyl ester N
O
O
O
N
H
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylcyclohexyl ester was synthesized according to procedure Q from I-phenylcyclohexanol. The cmde product was chromatographed on a silica gel column (50-70% of ether in hexanes as eluant) to give 0.13 g (5%) of the desired product as a yellow solid: mp 217-219°C; MS(APCI-): m/z 497 (M-H).
Example 95 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-(hydroxymethyl)phenyl ester W
N O
O OH
O /
N
H
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester was synthesized according to procedure Q from 3-hydroxybenzyl alcohol. The crude product was chromatographed on a silica gel column (50-100% of EtOAc 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-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester OH
N O
O
O
N~-H
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester was synthesized according to procedure Q from 3-hydroxybenzyl alcohol. The crude product was chromatographed on a silica gel column (50-100% of EtOAc in hexanes as eluant) to give 0.4818 g (39%) of the desired product as a white solid:
mp 231-233°C; MS(APCI+): nilz 447.1 (MH+).
Example 97 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1S)-1-(4-pyridinyl)ethyl ester N O
I

N
H
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-, (1S)-1-(4-pyridinyl)ethyl ester was synthesized according to procedure Q from (S)-(-)-1-(4-pyridyl)ethanol.
The crude product was chromatographed on a silica gel column (100% EtOAc as eluant) to give 0.09 g of the desired product as a yellow foam: mp 105-1 I
5°C;
MS(APCI+): ~at/z 447.2 (MH+).
Example 98 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-, [6-(methoxycarbonyl)-2-pyridinyl]methyl ester O
N O N~ O

O O /
N
H
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-, [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 the crude product was mixed with 40 mL of 0.5 N HCI solution in a reparative funnel and shaken well, then the aqueous phase was basified with 2N NaOH solution to pH = 1, shaken well. The two layers were then separated. The organic layer was dried over Na2S04. 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+): ntlz 490.1 (MH+).

Example 99 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-pyridinylmethyl ester N O ~ l O N
O
N
H
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-pyridinylmethyl ester was synthesized according to procedure Q from 2-pyridylmethanol. The EtOAc solution (40 mL) of the enzde product was mixed with 40 mL of 0.5N HCl solution in a reparative funnel and shaken well, then the aqueous phase was basified with 2N NaOH solution to pH = 1, shaken well. The two layers were then separated. After this process was repeated for three times, the organic layer was separated and dried over Na2S04. Chromatography on a silica gel column (60-100% of EtOAc in hexanes as eluant) to give 1.39 g (72%) of the desired product as a white foam: mp 85-95°C; MS(APCI+): m/z 432.2 (MH+) Example 100 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-, (6-carboxy-2-pyridinyl)methyl ester O
N O N OH
I
O ~ ~ ~ O
~N~
H
To a solution ofpyrrolo[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-, [6-(methoxycarbonyl)-2-pyridinyl]methyl ester (797.4 mg, 1.629 mmol) in MeOH

(20 mL) was added 1N NaOH (6.5 mL, 6.5 mmol). The resulting reaction mixture was refluxed for 15 minutes, then concentrated in vacato. The residue was purified by chromatography (10-30% MeOH in HCCI3 as eluant) to give 0.62 g of a mixture of free acid and the sodium salt. 0.5 g of the mixture was dissolved in MeOH/HCCl3, then mixed with 0.64 mL of 1N HCI. The mixture was concentrated iiz vacuo, the residue was purified by chromatography (10-30%
MeOH in HCC13 as eluant) followed by recrystallization from MeOH to give 0.25 g of the desired product as a white solid: MS(APCI-): m/z 474.1 (M-H).
Example 101 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (6-carboxy-2 pyridinyl)methyl 3,7,8,9, I 0,12,13,14,14a,1 S-decahydro-2 methylpyn-olo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylate (1:1) o N
O N O_ O ~ ~ O
N
H
~~+
N
OOH
To a suspension ofPyrrolo[3',2':5,6](1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (6-carboxy-2-pyridinyl)mcthyl ester (167.5 mg, 0.3522 mmol) in ethanol was added aqueous choline bicarbonate (5.66 M, 0.056 mL, 0.32 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated ijz vacaro, and the residue was dissolved in 2 mL of ethanol and then diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was collected by filtration to give 0.15 g (74%) of the desired product as a yellow solid: mp 120-130°C; MS(APCI-): m/z 474.1 (M-H). Anal. Calcd for C27H28N305'1.OCSH14N101~0.2CSH15N102M.8H20: C, 62.38; H, 7.71; N, 9.26. Found: C, 62.40; H, 7.58; N, 9.03.

Example 102 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridinyl]methyl ester O
N O O
I
O / ~ ~ O
N~
H
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 was synthesized according to procedure Q from 5-hydroxymethyl-nicotinic acid methyl ester. The EtOAc solution (40 mL) of the crude product was mixed with 40 mL of 0.5 N HCl solution in a reparative funnel and shaken well, then the aqueous phase was basified with 2N NaOH solution to pH = 1, shaken well. The two layers were then separated. After this process was repeated twice, the organic layer was separated and dried over MgS04.
Chromatography on a silica gel column (50-100% of EtOAc in hexanes as eluant) followed by crystallization from ether gave 0.4254 g (25%) of the desired product as a yellow solid: mp 195-197°C; MS(APCI+): nz/z 490.1 (MH+).
Example 103 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-carboxy-3-pyridinyl)methyl ester O
N O OH
I
O / O
N II N
~H
To a solution ofPyrrolo[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-, WO 00/42045 PCTlUS99/30434 [5-(methoxycarbonyl)-3-pyridinyl]methyl ester (391.6 mg, 0.7999 mmol) in MeOH (30 mL) was added IN NaOH (3.2 mL, 3.2 mmol). The resulting reaction mixture was stirred at 50°C for 60 minutes. After cooling down to ambient temperature, 3.2 mL of IN aqueous HCl was added, then concentrated iji vacuo.
The residue was purified by chromatography (10-30% MeOH in HCCl3 as eluant) followed by trituration with ether to give 0.25 g (67%) of the desired product as a white solid: mp 224-227°C; MS(APCI-): rnlz 474.1 (M-H).
Example 104 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (5-carboxy-3-pyridinyl)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:l) N O O
I
O / O ~ i N
N
H
~ ~.
,N
~ OH
To a suspension ofPyr-rolo[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-carboxy-3-pyridinyl)methyl ester (170.3 mg, 0.3580 mmol) in ethanol was added aqueous choline bicarbonate (5.66 M, O.OS69 mL, 0.322 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and then diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was collected by filtration to give 0.163 g (79%) of the desired product as a beige solid: mp 147-152°C; MS(APCI-): m/z 474 (M-H). Anal. Calcd for C27H28N305'1.OCSH14N101-0.28C4H100~1.2Si102M.4H20: C, 57.09; H, 6.89; N, 8.04. Found: C, 57.09; H, 6.70; N, 7.77.

Example 105 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-(4'-methyl[1,1'-biphenyl]-3-yl)ethyl ester H
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-(4'-methyl[I,l'-biphenyl]-3-yl)ethyl ester was synthesized according to procedure Q from I-(4'-methyl-biphenyl-3-yl)-ethanol. The crude product was chromatographed on a silica gel 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][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(2,6-dimethylphenyl)ethyl ester N o \

N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i)quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(2,6-dimethylphenyl)ethyI
ester was synthesized according to procedure Q from 1-(2,6-dimethyl-phenyl)-ethanol. The crude product was chromatographed on a silica gel column (30-50%

of EtOAc in hexanes as eluant) to give 1.02 g of the desired product which was impure as a yellow foam: mp 100-105°C; MS(APCI+): rnlz 473.3 (MH+).
Procedure S: procedure for the array synthesis:
The mixed anhydride (1 eq.) and the corresponding alcohol (2-4 eq.) were mixed in a VWR 60826-202 tube. The tube was loosely capped and submerged in oil-bath at 120°C until a clear solution was obtained (generally 5-7 minutes). After cooling to ambient temperature, 6 mL of EtOAc and 5 mL of saturated aqueous Na2S04 were added to the tube. The mixture was shaken and stin-ed for 1 minute, then the organic layer was pipeted out and filtered through a pack of MgS04 (packed in a syringe filter) followed by washing with 1 mL of EtOAc. The filtrate was collected in a 2-dram vial and sample was blown dry with a stream of nitrogen. The residue was chromatagraphed on a silica gel column using ISCO
system to give the desired product.
The Example 107 through Example 142 were made following Procedure S
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-, (1S,2R)-2-(dimethylamino)-1-phenylpropyl ester \N' N O
O
O
N
H
MS(APCI+): rn/z 502 (MH+) Example 108 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-, (1R,2S)-2-(dimethylamino)-1-phenylpropyl ester i N
O~--O
i w /~
MS(APCI+): m/z 502 (MH+) Example 109 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-naphthalcnyl ester i i N O
O
O
N
H
Ms(APCr+): nz/z 467 (MH+) Example 110 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-, diphenylmethyl ester N
O
O
O
N
H
MS(APCI+): ntlz 507 (MH+).
Example 111 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-, (1R)-2,3-dihydro-1H-inden-1-yl ester w N O
O
O
N
H
MS(APCI+): ntlz 457 (MH+) Example 112 Pyrrolo[3',2':5,6][1]bcnzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,2-dihydro-1-acenaphthylenyl ester N O
O
O
N
H
MS(APCI+): m/z 493 (MH+).
Example 113 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-, cyclohexyl(phenyl)methyl ester N
O
O
O
\
N
H
MS(APCI+): m/z 513 (MH+).
Example 114 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-, 9H-fluoren-9-yl ester N O
O
O
N
H
MS(APCI+): nz/z 505 (MH+) Example 11 S
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-, 1,2,3,4-tetrahydro-1-naphthalenyl ester MS(APCI+): rnlz 471 (MH+) Example 116 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-, [(2R,3R)-3-phenyloxiranyl]methyl ester /O1 _ N O ~,~~~n O
O
N
H
MS(APCI+): m/z 473 (MH+).
Example 117 Pyrrolo[3',2':5,6)(1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-oxo-1,2-diphenylethyl ester MS(APCI+): rrtlz 535 (MH+) Example 118 Pyn-olo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 10,11-dihydro-SII-dibenzo[a,d]cyclohepten-5-yl ester O
O
O
N
H
MS(APCI+): ntlz 533 (MH+) Example 119 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (2-methylphenyl)phenylmcthyl ester N O i O
O
N
H
MS(APCI+): rralz 521 (MH+) Example 120 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14, I 4a,15-decahydro-2-methyl-, cyclopropyl(4-fluorophenyl)mcthyl ester N
O
O
O
/~
H
MS(APCI+): m/z 489 (MH+).
Example 121 Pyrrolo[3',2':S,6J[1]benzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, l 5-decahydro-2-methyl-, 3,4-dihydro-2H-1-benzothiopyran-4-yl ester i S
N
O~-O
O

MS(APCI+): m/z 489 (MH+).
Example 122 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-, (1S)-1-(2-bromophenyl)ethyl ester Br N
O
O
O
N
H
MS(APCI+): n~/z 524 (MH+) Example 123 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-trifluoroethyl ester F
~F
N ' IO
O F
O
N
H
MS(APCI+): nalz 423 (MH+).
Example 124 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-, [(2S,3S)-3-phenyloxiranyl]methyl ester O
i"", O
N
H
MS(APCI+): m/z 475 (MH+) Example 125 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethyl ester F
F FF
N O ~F
O F
O
N
H
Ms(aPCI+): ~~Z/~ sos (MH+).
Example 126 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2,2,2-trifluoro-I-(4-fluorophenyl)-1-(trifluoromethyl)ethyl ester F

F

F F

F F
w 0, F

MS(APCI+): m/z 585 (MH+).
Example 127 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-cyclopentyl-1-phenylethyl ester L /
N
H
MS(APCI+): m/z 513 (MH+).
Example 128 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-[1,1'-biphenyl]-4-yl-1-methylethyl ester WO 00/42045 PCT/US99l30434 N O ~ / /
O '--i O
N
H
MS(APCI+): mlz 535 (MH+).
Example 129 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methyl-1-phenyl-2-propynyl ester ..
/
N O
O
O
N
H
MS(APCI+): m/z 469 (MH+) Example 130 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-, 1,1-diphenylethyl ester N O
O
O
N
H
MS(APCI+): m/z 521 (MH+).

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-methyl-, 1-methyl-1,2-diphcnylethyl ester w N O
O
O
N
H
MS(APCI+): m/z 535 (MH+) Example 132 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-(4-fluorophenyl)cyclohexyl ester N O I \
O
O / F
I
N
H
MS(APCI+): nilz 517 (MH+).
Example 133 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-diphenylethyl ester N O
O
O ~
N
I-I
MS(APCI+): »i/z 521 (MH+) Example 134 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenyl-2-propynyl ester N O
O
O
N
H
MS(APCI+): m/z 455 (MH+).
Example 135 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-, [1,1'-biphenyl]-4-ylmethyl ester N O
O
O
N
H
MS(APCI+): nalz 507 (MH+).

WO 00/42045 PCTlUS99130434 Example 136 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-pyridinyhnethyl ester y N
N O
O
O
N
H
MS(APCI+): nt/z 432 (MH+).
Example 137 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-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 H
MS(APCI+): ~aT/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-, 1-[3-(dimethylamino)phenyl]ethyl ester H
MS(APCI+): m/z 488 (MH+).
Example 139 Pywolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1,1-dimethyl-2-pyrazinylethyl ester MS(APCI+): m/z 475 (MH+).
Example 140 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,1 S-decahydro-2-methyl-, 4-(dipropylamino)-1,1-dimethyl-2-butynyl ester N
~N

WO 00!42045 PCT/US99/30434 N O --O N
O
/ N
H
MS(APCI+): m/z 520 (MH+) Example 141 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decabydro-2-methyl-, (1S)-2,3-dihydro-IH-inden-I-yl ester N O
O
O
N
H
MS(APCI+): m/z 457 (MH+) Example 142 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-, (1S,2S)-2-(dimethylamino)-I-phenylpropyl ester \N' N O
O
O
/~T~~
MS(APCI+): m/z 502 (MH+) Example 143 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1 S-decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]methyl ester N O
O
O /
N
Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-trifluoromethylbenzyl ester O
O
HO
N
To a mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (4.S g, 23.54 mmol) and 1,8-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 temperature for 2 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2S04 and concentrated i~z vaci.~o to give a residue, which was recrystallized from ethyl acetate to give 4.26 g (S2%) of the desired product as a white solid: mp 224-225°C; MS(APCI+): m/z 350.1 (MII+); Anal. Calcd for C18H14F3N103: C, 61.89; H, 4.04; N, 4.01. Found: C, 61.87; H, 4.00; N, 3.98.
Step B: 4-Dimethylaminomethyl-S-hydroxy-2-methyl-I H-indole-3-carboxylic acid 4-trifluoro-methylbenzyl ester O
/N O
O
N
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-trifluoromethylbenzyl ester (3.0 g, 8.59 mmol) and aqueous dimethylamine (40%, 2.37 mL, 18.9 mmol) were mixed with 6.7 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.83 g, 10.31 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated irt vacavo to half volume to give a solid, which was filtered. The solid was washed with ethanol-water and dried ift vacuo to give 1.8 g (52%) of pure titled compound as an off white foam: MS(APCI+): m/z 407.2 (MH+) Step C: Pyrrolo[3',2':5,6][lJbenzopyrano[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 1 S To a mixture of perchlorate salt (1.37 g, 5.75 mmol, Example 3, step B) and 100 mL of ether was added 150 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 50 mL). Combined ether layer was dried over Na2S04 and concentrated in vacuo.
The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (1.8 g, 4.42 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (10%-30% ethyl acetate in hexanes) to give 1.21 g (SS%) of titled compound as a white foam: mp 97-99°C; MS(APCI+): m/z 499.2 (MH+);
Anal. Calcd for C28H29F3N203: 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':5,6)[1)benzopyrano[3,2-i)quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (4-chlorophenyl)methyl ester \ CI
N O
O
O
N
Step A: S-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-chlorobenzyl ester Ci HO
N
To a mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (5.0 g, 26.15 mmol) and 1,8-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). The mixture was stirred at room temperature for 2 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2S04 and concentrated in vacuo to give a residue, which was recrystallized from ethyl acetate to give 5.0 g (61 %) of the desired product as an off white solid: mp 236-237°C; MS(APCI-): m/z 314.1 (M-H).

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-chlorobenzyl ester CI
O
/N O
HO
N
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-chlorobenzyl ester (4.0 g, 12.7 mmol) and aqueous dimethylamine (40%, 3.5 mL, 27.8 mmol) were mixed with 10.4 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO
(37%, 1.24 g, 15.2 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vact~o to give a residue, which was chromatographed using 100% ethyl acetate as eluant to give 2.3 g (49%) of pure titled compound as an off white foam: MS(APCI+): m/z 373.2 (MH+).
Step C: Pyn-olo[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-chlorophenyl)methyl ester Cl N O
O
O
N
To a mixture of perchlorate salt (1.9 g, 8.02 mmol, Example 3, Step B) and 150 mL of ether was added 200 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 100 mL).
Combined ether layer was dried over Na2S04 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 temperature and concentrated 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 titled compound as a white solid: mp 220-221 °C; MS(APCI+): m/z 465.3 (MH+).
Example 145 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-, phenylmethyl ester N O ~J
O
O
N
Step A: 5-Hydroxy-1H-indole-3-carboxylic acid benzyl ester O a O
HO
N
To a mixture of 5-hydroxy-1H-indole-3-carboxylic acid (4.5 g, 25.4 mmol) and 1,8-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 room temperature for 2 days and then partitioned between ethyl acetate and water.
The organic phase was washed with water and brine, dried over Na2S04 and concentrated in vacuo to give a residue, which was recrystallized from ethyl 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).

Step B: 4-Dimethylaminomethyl-5-hydroxy-1 H-indole-3-carboxylic acid benzyl ester O
/N O
HO
y N
5-Hydroxy-1H-indole-3-carboxylic acid benzyl ester (2.3 g, 8.6 mmol) and aqueous dimethylaminc (40%, 2.37 mL, 18.9 mmol) were mixed with 6.67 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.84 g, 10.32 mmol) was added. The resulting reaction mixture was stirred at 50°C
overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using 50%-100% ethyl acetate in hexanes as eluant to 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)[1)benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9, I 0,12,13,14,14a,15-decahydro-, phenylmethyl ester -To a mixture of pcrchlorate salt (1.91 g, 8.02 mmol, Example 3, Step B) and 150 mL of ether was added 200 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 100 mL). Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannich base (2.0 g, 6.17 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give a thick oil, which was 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, I 3,14,14a,15-decahydro-, ethyl ester Step A: 5-Hydroxy-IH-indole-3-carboxylic acid ethyl ester O
O
HO
N
To a mixture of 5-hydroxy-1 H-indole-3-carboxylic acid (4.5 g, 25.4 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.87 g, 25.4 mmol) in DMF (50 mL) was added iodoethane (4.36 g, 27.94 mmol). The mixture was stirred at room temperature overnight and then partitioned between ethyl acetate and water.
The organic phase was washed with water and brine, dried over Na2S04 and concentrated in vacuo to give a residue, which was recrystallized from ethyl acetate-hexanes to give 2.2 g (42%) of the desired product as a light brown solid:
MS(APCI+): m/z 206.2 (MH+).
Step B: 4-Dimethylaminomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester O
/N O
HO
N
5-Hydroxy-1H-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 ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.99 g, 12.28 mmol) was added. The resulting reaction mixture was stirred at 50°C
overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using SO%-100% ethyl acetate in hexanes as eluant to give 2.1 g (78%) of pure titled compound as a gum: MS(APCI+): zn/z 263.1 (MH+) Step C: 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 N O
O
N
To a mixture of perchlorate salt (2.36 g, 9.9 mmol, Example 3, Step B) and 1 SO mL of ether was added 250 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 100 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole marmich base (2.0 g, 7.6 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours.
The reaction mixture was cooled to ambient temperature and concentrated in vczcuo to give a thick 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 Pyrrolo[3',2':5,6J[1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-hydroxyethyl ester OH
Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid hydroxyethyl ester OH
HO
To a mixture of 5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid (5.0 g, 26.15 mmol) and 1,8-diazabicyclo[5.4.0]undee-7-ene (3.91 g, 26.15 mmol) in DMF (100 mL) was added 2-bromoethanol (3.6 g, 28.77 mmol). The mixture was stirred at room temperature for 7 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2S04 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-1H-indole-3-carboxylic acid hydroxyethyl ester OH
O
/N O
HO
N
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid hydroxyethyl ester (2.3 g, 9.8 mmol) and aqueous dimethylamine (40%, 2.7 mL, 21.5 mmol) were mixed with 7.4 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO
(37%, 0.95 g, 11.7 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using 100% ethyl acetate followed by 20% methanol in methylene chloride as eluant to give 2.0 g (70%) of pure titled compound as a gum: MS(APCI+): ntlz 293.2 (MH+).
Step C: 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-hydroxyethyl ester OH
O
O
O
N
To a mixture of perchlorate salt (2.1 g, 8.9 mmol, Example 3, step B) and 150 mL of ether was added 250 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 100 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 6.84 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours.
The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give a residue as thick oil, which was recrystallized from acetonitrile to 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][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 N O
O
O
N
Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methylbenzyl ester O
O
HO
N
To a mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (4.0 g, 20.92 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.18 g, 20.92 mmol) in DMF (100 mL) was added a-bromo-m-xylene (4.28 g, 23.1 mmol). The mixture was stirred at room temperature for 7 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2S04 and concentrated in vacuo to give a residue, which was chromatographed using 20%-50% ethyl acetate in hexane as eluant to give 3.0 g (48%) of the desired product as a tan solid: mp 165-167°C; MS(APCI+): m/z 296.2 (MH+).
Step B: 4-Dimethylaminomethyl-S-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methylbenzyl ester O
/N o HO
N
S-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methylbenzyl ester (2.7 g, 9.14 mmol) and aqueous dimethylamine (40%, 2.52 mL, 20.1 mmol) were mixed with 7.4 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO
(37%, 0.89 g, 10.97 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using 50%-100% ethyl acetate in hexanes as eluant to give 2.0 g (62%) of pure titled compound as a gum: MS(APCI+): m/z 353.3 (MH+).
Step C: 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-mcthylphenyl)methyl ester N O
O
O
N
To a mixture of perchlorate salt (1.75 g, 7.38 mmol, Example 3, step B) and 100 mL of ether was added 150 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 50 mL).
Combined ether layer was dried over Na2S04 and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 5.67 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature 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 titled compound as a white solid: mp 80-82°C; MS(APCI+): m/z 445.4 (MH+).
Example 149 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (IS)-1-phenylethyl ester N O
O
O
N
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (IS)-1-phenylethyl ester was synthesized according to procedure Q from (S)-(-)-1-phenylethanol. The crude product was chromatographed using 30% ethyl acetate in hexanes as eluant to give 75 mg of the desired product as a white solid: mp 98-100°C;
MS(APCI+):
mlz 445.2 (MH+).
Example 150 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylethyl ester N O
O
O
N

WO 00/42045 PCT/tJS99/30434 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, I-phenylethyl ester was synthesized according to procedure Q froml-phenylethanol. The crude product was chromatographed using 40% ether in hexanes followed by 50% ethyl acetate 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][1]benzopyrano[3,2-i]quinolizine-I-carbothioic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, S-(phenylmethyl) ester -Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carbothioic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, S-(phenylmethyl) ester was synthesized according to procedure Q from benzyl mercaptan. The crude product was chromatographed using 50% ether in hexanes as eluant to give 150 mg of the desired product as a white solid: MS(APCI+): m/z 447.1 (MH+) Example 152 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester N O ~ N
O
O
N

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1 S-decahydro-2-methyl-, 3-pyridinylmethyl ester was synthesized according to procedure Q from 3-pyridylcarbinol. The crude product was 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 a white solid: MS(APCI-): m/z 430.1 (M-H).
Example 153 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7, 8,9,10,12,13, I 4,14a,15-decahydro-2-methyl-, 1-[4-(trifluoromethyl)phenyl]ethyl ester ''. CFs N O
O
O
N
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-[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 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13, I 4,14a,15-decahydro-2-methyl-, 1-(pentafluorophenyl)ethyl ester F
F
F
N O
~F
O
N
Pyrrolo[3',2'a,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1 s-decahydro-2-methyl-, 1-(pentafluorophenyl)ethyl ester was synthesized according to procedure Q from pentafluoro-a-methylbenzyl alcohol. The crude product was chromatographed using 40% ether in hexanes as eluant to give 160 mg of the desired product as a white solid: mp 93-9s°C;
Ms(APCI+): ~n/Z s3s.1 (MH+) Example 1s5 Pyrrolo[3',2'a,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1s-decahydro-2-methyl-, 1-(2,6-difluorophcnyl)ethyl ester F
N O
O F/
O
N
Pyrrolo[3',2'a,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1s-decahydro-2-methyl-, 1-(2,6-difluorophcnyl)ethyl ester was synthesized according to procedure Q from 2,6-difluoro-a-methylbenzyl alcohol. The crude product was chromatographed using 40% ether in hcxanes as eluant to give 180 mg of the desired product as a white solid: mp 8s-87°C;
MS(APCI+): m/z 481.1 (MH+) Example 156 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, ( 1 S)-1-(2-furanyl)ethyl ester O
~N O~O
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ( 1 S)-1-(2-furanyl)ethyl ester was synthesized according to procedure Q from S(-)-1-(2-furyl)ethanol. The crude product was chromatographed using 40%-60% ether in hexanes as cluant to give 300 mg of the desired product as a white solid: mp 84-86°C; MS(APCI+):
m/z 435.1 (MH+) Example 157 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-(4-morpholinyl)-1-phenylethyl ester O
N
~O
~ ~N
Pyrrolo[3',2':5,6][lJbcnzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(4-morpholinyl)-1-phenylethyl ester was synthesized according to procedure Q from a-phenyl-WO 00!42045 PCT/US99/30434 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 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-, (1R)-1-(2-furanyl)ethyl ester O
~N \\,O
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-, (1R)-1-(2-furanyl)ethyl ester was synthesized according to procedure Q from R(+)-1-(2-furyl)ethanol. The cnide product was chromatographed using 40%-60% ether in hexanes as eluant to give 300 mg of the desired product as a white solid: mp 79-81 °C;
MS(APCI+):
ntlz 435.1 (MH+).
Example 159 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-1-phenylethyl ester O' O
N~ ~ O
O / \
i N

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-1-phenylethyl ester was synthesized according to procedure Q from (S)-(+)-methyl mandelate.
The crude product was chromatographed using 40%-60% ether in hexanes as 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 Pyn-olo[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-(3-pyridinyl)ethyl ester p ~N
\\r O
O
N
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-(3-pyridinyl)ethyl ester was synthesized according to procedure Q from 1-(3-pyridyl)ethanol. The crude product was chromatographcd using 50% ether in hexanes followed by 10%
methanol in methylene chloride as eluant to give 300 mg of the desired product as a white solid: mp 78-80°C; MS(APCl+): fnlz 446.2 (MH+).
Example 161 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester OH
O
N O
O
O
N
To a solution ofpyrrolo[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-1-phenylethyl ester (650 mg, 1.33 mmol) in methanol (60 mL) was added S 1N NaOH solution (5.32 mL, 5.32 mmol). The resulting reaction mixture was stirred at 50°C for 1 hour, then concentrated iu vaczro. The residue was purified by chromatography (10-30% methanol in chloroform as eluant) to give 0.58 g of a mixture of free acid and the sodium salt. All of the mixture (0.58g) was dissolved in methanol-chloroform, then mixed with 0.53 mL of 1N HCI. The mixture was concentrated in vacuo, the residue was purified by chromatography (10-30%
methanol in chloroform as eluant) followed by recrystallization from methanol to give 0.35 g of the desired product as a white solid: mp 250-251 °C;
MS(APCI-):
nZ/z 473.1 (M-H), Anal. Calcd for C2gH3pN205~0.36H20: C, 69.91; H, 6.44; N, 5.82. Found: C, 69.96; H, 6.33; N, 5.59.
Example 162 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (S)-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) O
O-:
N O
\\r O
p / H3C\N Ha H3C~ ~OH
N

To a suspension of pyrrolo[3',2':5,6] [ 1 ]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester (181 mg, 0.38 mmol) in ethanol (5 mL) was added aqueous choline bicarbonate (5.66 M, 0.06 mL, 0.34 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and then diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was collected by filtration to give 0.17 g (77%) of the desired product as an off white solid: mp 223-225°C; MS(APCI+): m/z 475.2 (MH+). Anal. Calcd for C2gH29N205~C5H14NOM.2H20: 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1R)-2-methoxy-2-oxo-1-phenylethyl ester O' O
N O
O
O /
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1R)-2-methoxy-2-oxo-1-phenylethyl ester was synthesized according to procedure Q from (R)-(-)-methyl mandelate. The cnide product was chromatographed using 40%-60% ether in hexanes as eluant to give 750 mg of the desired product as a white solid: mp 106-108°C; MS(APCI+): m/z 489.2 (MH+).

Example 164 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-, (R)-carboxy(phenyl)methyl ester OH
O
N O
\\~ O
N
To a solution of 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-, (1R)-2-methoxy-2-oxo-1-phenylethyl ester (670 mg, 1.37 mmol) in methanol (60 mL) was added 1N NaOH (5.5 mL, 5.5 mmol). The resulting reaction mixture was stirred at 50°C for 1 hour and 1N 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 from methanol to give 0.35 g of the desired product as a white solid: mp 248-250°C;
MS(APCI-): n~lz 473.1 (M-H).
Example 165 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (R)-carboxy(phenyl)methyl, 3, 7,8,9,10,12,13,14,14x,15-decahydro-2-methylpyn-olo[3',2':5,6][1]benzopyrano[3,2-i)quinolizine-1-carboxylate (l:1) O
O-O
\\-O
O
~OH
N

To a suspension ofpyrrolo[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-, (R)-carboxy(phenyl)methyl ester (210 mg, 0.44 mmol) in ethanol (5 mL) was added aqueous choline bicarbonate (5.66 M, 0.07 mL, 0.40 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and then diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was collected by filtration to give 0.2 g (78%) of the desired product as an off white solid: mp 215-217°C; MS(APCI+): m/z 475.2 (MH+). Anal. Calcd for C28H2c~N205~C5H14N0~1.8H20: C, 64.96; H, 7.7.70; N, 6.89. Found: C, 65.04;
H, 7.59; N, 6.55.
Example 166 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-pyridinylmethyl ester w /N
N O
O
O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 4-pyridinylmethyl ester was synthesized according to procedure Q from 4-pyridylcarbinol. The crude product was chromatographed using 50% ethyl acetate in hexanes followed by 100% ethyl acetate as eluant to give 260 mg of the desired product as a white solid: mp 199-201 °C; MS(APCI+): m/z 432.5 (MH+).
Example 167 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-(4-pyridinyl)ethyl ester w /N
N O
O
O
N
Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(4-pyridinyl)ethyl ester was synthesized according to procedure Q from 1-(4-pyridyl)ethanol. The crude product was chromatographed using 50% ethyl acetate in hexanes followed by 100% ethyl acetate as eluant to give 210 mg of the desired product as a white solid: mp 219-221 °C; MS(APCI+): m/z 446.2 (MH+).
Example 168 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, I -(2-pyridinyl)ethyl ester N O N
O
O /
N
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 was synthesized according to procedure Q from I-(2-pyridyl)ethanol. The crude 1 S product was chromatographed using 50%-75% ethyl acetate in hexanes as eluant to give 200 mg of the desired product as a white solid: mp 87-89°C;
MS(APCI+):
ntlz 446.2 (MH+).

Example 169 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 3-thienylmethyl ester N O
O
O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 3-thienylmethyl ester was synthesized according to procedure Q from 3-thiophenemethanol. The crude product was chromatographed using 50% ether in hexanes as eluant to give 330 mg of the desired product as a white solid: mp 115-116°C;
MS(APCI+): m/z 437.5 (MH+).
Example 170 Pyrrolo[3',2':5,6][lJbenzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (IS)-I-(4-fluorophenyl)ethyl ester F
N \~ O
O
I
~N
Pyrrolo[3',2':5,6][1]benzopyrxno[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1S)-1-(4-fluorophenyl)ethyl ester was synthesized according to procedure Q from S(-)-1-(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-I 10°C; MS(APCI+): ntlz 463.3 (MH+) Example 171 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i)quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R)-1-(4-fluorophenyl)ethyl ester ' F
,.
-O
~/ ~ N
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-, (IR)-1-(4-fluorophenyl)ethyl ester was synthesized according to procedure Q from R(+)-1-(4-florophcnyl)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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester N O ~N
O
O
~I
'N
Pyrrolo[3',2':5,6)[I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester was synthesized according to procedure Q from 3-pyridylcarbinol. The crude product was chromatographed (1:1 hexane/EtOAc) to give 1.43g (49.4%) of desired product as a solid: mp 73-80°C; MS(APCI +): m/z 432.6 (MH+) 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 N
O
O ~ O~O~
O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester was synthesized according to procedure Q from ethyl glycolate. The crude product was chromatographed (I :1 hexane/EtOAc) to give 0.52878 (36.8%) of desired product as 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, I 5-decahydro-2-methylpywolo[3',2':5,6] [ 1 ]benzopyrano[3,2-i]quinolizin-1-yl)carbonyl]oxy]methyl]-1-methyl-, methanesulfonate N O ~ N~
O
O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13, I 4,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester ( 1 eq) and methyl methanesulfonate (4 eq) was mixed together in 1,2 dichloroethane and refluxed at 88°C for 30 minutes. After cooling down to ambient temperature the precipitate was isolated by suction filtration and washed with ether to give 86m8 (41.2%) of pure desired product as crystals: mp 228-232°C; MS(APCI +):
m/z 446.2 (M+).

Some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with the ring nitrogen atom at N-I 1. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in R10. These structural forms are within the scope of the present invention.
Example 175 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizinium, 3,7,8,9,10,12,13,14,14a,15-dccahydro-2,I 1-dimethyl-1-[(S)-(1-phenylethoxy)carbonyl]-, methanesulfonate ~N + O
O
O
N
Pyrrolo[3',2':S,G][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)-1-phenylethyl ester (0.6 g, 1.349 mmol) and methyl methanesulfonate (1.089 g, 10.7964 mmol) were mixed together in 1,2 dichlorocthane (8m1) and refluxed at 88°C for 18 hours.
The IS reaction mixture was concentrated I71 VC1C110. The crude product was chromatographed (2:10 MeOH/CH2C12) to give 0.41 g (G 1.5%) of desired product as 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 forming N-oxides and N-quaternary alkyl salts with the ring nitrogen atom at N-1 I . Further, some of the compounds of ring close Fornmla I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in RI O. These structural forms are within the scope of the present invention.

Example 176 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-furanylmethyl ester N o ~ °

N
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-furanylmethyl ester was synthesized according to procedure Q from furan-3-yl-methanol. The crude product was chromatographed (I:1 hexane/EtOAc) to give 0.40 g (42.4%) of desired product as a solid: mp 174-177°C; MS(APCI +): m/z 421.4 (MH+).
Example 177 Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (2-nitrophenyl)methyl ester O
I+
O /N
i N O
O
O
~I
'N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, (2-nitrophenyl)methyl ester was synthesized according to procedure Q from 2-nitrobenzylalcohol. The crude product was chromatographed (1:1 hexane/EtOAc) to give 0.39 g (35.9%) of desired product: mp 200-203°C; MS(APCl +): m/z 476.5 (MH+) Example 178 Pyrrolo(3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,1 S-decahydro-2-methyl-, 2-furanylmethyl ester N O O
O
O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 2-furanylmethyl ester was synthesized according to procedure Q from furan-2-yl-methanol. The crude product was chromatographed (I :1 hexane/EtOAc) to give 0.24 g (24.8%) of desired product as a solid: mp 65-77°C; MS(APCI +): m/z 421.4 (MH+).
Example 179 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2-chlorophenyl)ethyl ester CI
N O
O
O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1S-decahydro-2-methyl-, 1-(2-chlorophenyl)ethyl ester was synthesized according to procedure Q from 1-(2-chlorophenyl) ethanol. The crude product was chromatographed (1:1 hexane/cthcr) to give 80 mg (S.0%) of desired product as a solid: mp 95-105°C; MS(APCI +): m/z 479.2 (MH+) Example 180 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-, carboxymethyl ester O
N O / -O
/ 1 ~O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinc-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester (0.47 g, 0.96 mmol) was mixed with 1N NaOH (5.73 mmol, 5.73 mL) in MeOH
and kept it in a oil bath at 50°C for 3 hours. Then the reaction mixture was cooled to ambient temperature followed by addition of 1N HC1 to neutralize. The reaction mixture was concentrated in vacuo, and the erode product was chromatographed (initially 1:1 hexane/ether, then 10% MeOH in CHCl3) to give 0.3748 of cmde solid. The crude solid was redissolved in CHCl3 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 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)ethyl ester CI
N o o CI
N
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)ethyl ester was synthesized according to procedure Q from 1-(2,2-dichloro phenyl) ethanol. The crude product was chromatographed ( 1:1 hexane/ether) to give 93 mg (5.30%) of desired product as a solid: mp 130-135°C; MS(APCI +):
m/z 513.1 (M+) Example 182 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-I-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2-methoxyphenyl)ethyl ester O
N O
O
O
N
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 1-(2-methoxyphenyl)ethyl ester was synthesized according to procedure Q from 1-(2-methoxyphenyl) ethanol.
The crude product was chromatographed (1:1 hexane/ether) to give 0.90 g (42%) of desired product as a solid; mp I 15-125°C; MS(APCI +): m/~ 475.2 (MH+).
Example 183 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1S)-1-phenylethyl ester, 11-oxide o~N+ o o Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, (1S)-1-phcnylethyl ester (0.3 g) was mixed with 50% H202 in MeOH and the mixture was stirred at room temperature for 3 hours. Then excess H2O2 was destroyed using Pd/C. The reaction solution was filtered and concentrated in vacuo. The crude product was chromatographed (10% MeOH in CH2CI2) to give 52 mg (48.2%) ofpure desired 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-quaternary alkyl salts with the ring nitrogen atom at N-11. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in R10. These structural forms are within the scope of the presentinvention.
Example 184 Pyrrolo[3',2':5,6J[lJbenzopyrano[3,2-iJquinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(5-carboxy-3-pyridinyl)ethyl ester O
O
N p ~ N
O
O
N
Step A: 1-(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 H2S04 and the mixture was refluxed for 24 hours.
The reaction solution was then neutralized with solid NaHC03 and extracted with 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+).

Step B: 1-(5-Bromo-pyridin-3-yl)-ethanol Compound 1-(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 added slowly. The reaction was monitored by TLC. When the starting material was completely consumed mixture was neutralized by NaHC03 solution and extracted with ether to give the crude product. Crude product was mixed with 1:1 hexane/
ethyl acetate and filtered. The filtrate was concentrated to give the pure desired product. MS(APCI +): m/z 203 (MH+).
Step C: 5-(1-Hydroxy-ethyl)-nicotinic acid methyl ester 1-(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) were mixed together and the reaction mixture was stirred at 100-110°C for 18 hours.
End of the reaction mixture was filtered to remove the solids and the filtrate was concentrated under vacuum. The residue was triturated with EtOAc and filtered, the filtrate and the solid were collected. The solid was dissolved in NaI-IC03 and extracted with EtOAc. The extracts and the filtrate were combined together and dried over Na2S04. Concentration in vacuo gave the crude product which was chromatographed with 1:1 hexane/EtOAc to give 3.32 g (61.8%) of the pure desired product: MS(APCI+): m/z 182 (MH+).
Step D: 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-[5-(methoxycarbonyl)-3-pyridinyl]ethyl ester O
O
N O ~ N
O
O
N

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPRI~:ND PLUS D'UN TOME.
CECI EST L,E TOME 1 DE 2 NOTE: Pour les tomes additionels, veillez contacter 1e Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional valumes please contact the Canadian Patent Office.

Claims (17)

-269-
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof wherein:
A is O, S, and additionally A is NR1 when X is C-R9;
X is N when A is NR1 or X is C-R9 wherein R9 is halogen, hydrogen, alkyl, -CF3, CH2F, CHF2, -(CH2)m-OR1, aryl, arylalkyl, -(CH2)m-NR7R8, or , wherein m is an integer of from 0 to 2 and 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, (CH2)m-NR7R8, -N(R1)-(CH2)v-C(R7R8)-aryl, or OR10 wherein R10 is hydrogen, alkyl, cycloalkyl, cycloalkyl fused to an aryl ring, aryl, (CH2)s aryl, -CH2CF3, (CH2)t C(R7R8)-(CH2)u aryl, wherein s is an integer of from 1 to 3, t is an integer of from 0 to 3, a is an integer of from 0 to 3, v is an integer of from 1 to 3, and w is an integer of from 0 to 2;
Z is CR or N;
R1 is hydrogen or alkyl and each occurrence of R1 is independently hydrogen or alkyl;
R and R2 are each independently selected from:
hydrogen, alkyl, halogen, -CN, -NO2, -(CH2)m-NR7R8, -(CH2)m-COOR7, -(CH2)m-CONR7R8, -(CH2)m-OR7, -(CH2)m-SO2NR7R8, and -(CH2)m-S(O)p R7 wherein each occurrence of R7 and R8 are each independently hydrogen, alkyl, aryl, arylalkyl, -CF3, or R7 and R8 may be taken together to form a cyclic ring of from 3 to 7 atoms which ring may have O, S, or NR1 and p is an integer 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 to form a cyclic ring of from 5 to 7 atoms;
R6 is hydrogen or alkyl;
R5 when not taken together with R4 can be taken together with R6 with the atoms to which they are attached to form a ring of from 5 to 7 atoms;
N-R5 is also the corresponding N-oxide;
R11 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;

with the proviso that 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-, ethyl ester is not included.
2. A compound according to Claim 1 wherein R1 is hydrogen.
3. A compound according to Claim 1 wherein:
R1 is hydrogen and X is C-R9.
4. A compound according to Claim 1 wherein:
R1 is hydrogen and X is C-R9, wherein R9 is alkyl.
5. A compound according to Claim 1 wherein:
R1 is hydrogen, X is C-R9, wherein R9 is alkyl;
R4 and R5 are taken together with the atoms to which they are attached to form a ring of from 5 to 7 atoms; and Y is OR10.
6. A compound according to Claim 1 wherein:
R1 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 R10 is alkyl, aryl or -(CH2)s aryl, -(CH2)t-C(R7R8)-(CH2)u-aryl.
7. A compound according to Claim 1 wherein:
R1 is hydrogen, X is C-R9, wherein R9 is Me;
R4 and R5 are taken together to form a 6-membered ring;
R6 is hydrogen;
n is 2; and Y is OR10 wherein R10 is alkyl, aryl or R10 is -(CH2)t-C(R7R8)-(CH2)u-aryl wherein t is 0, R7 and R8 can each independently be H, alkyl, -(CH2)v OH or (CH2)u COOR7, and(CH2)v NR1R2 where a 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][1 ]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-bromo-3,7,8,9,10,12,13,14,14x,15-decahydro-2-methyl-, 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-, propyl 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-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][1]benzopyrano[3,2-i]quinolizine-1-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]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methylethyl 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-, cyclopropylmethyl 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-(1-piperidinyl)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-(phenylmethyl)-, ethyl ester;
Pyrrolo[3',2' :5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 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]quinolizine-1-carboxylic acid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, 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-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;
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-, 1,1-dimethylethyl ester;
2,6a,7-Trimethyl-7,8,9,10,10a, 11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester;
7-Ethyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester;
6a-Ethyl-2,7-dimethyl-7, 8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester;
6a,7-Diethyl-2-methyl-7, 8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester;
7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a)anthracene-1-carboxylic acid ethyl ester;
2,7-Dimethyl-6a-phenyl-7;8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-a]indole-1-carboxylic acid, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-, ethyl ester;

3H,7H-Pyrrolizino[1',8':5,6]pyrano[3,2-a]indole-1-acetic acid, 8,9,11,12,12a,13-hexahydro-2-methyl-, ethyl ester;
2-Methyl-8,9,10,10a,11,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopenta[h]anthracene-1-carboxylic acid ethyl ester;
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 or 7H-Azepino[1",2":1'2']pyrido[3',2':5,6]pyrano[3,2-a]indole-1-acetic acid, 3,8,9,10,11,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxamide, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-N-(phenylmethyl)-;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxamide, N-ethyl-8,9,11,12,13,13a,14,14a-octahydro-2-methyl-;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxaldehyde, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxamide,8,9,11,12,13,13a,14,14a-octahydro-N,2-dimethyl-;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-,(4-fluorophenyl)-methyl ester;
Indazolo[4',5':5,6]pyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 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-2,12,12-trimethyl-, 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-2,10,10-trimethyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester;

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-3,7,8,9,10;12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester;
12H-Furo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-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][1]benzopyrano[3,2-i]quinolizine-1-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, 3,7,8,9,10,12,13,14,14a,15-decahydro-4,5-dimethoxy-2-methyl-, 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-2,5-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;
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)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-[3-(methoxycarbonyl)phenyl]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-(3-carboxyphenyl)ethyl ester;
1-Propanaminium, N,N,N-trimethyl-, salt with 1-(3-carboxyphenyl)ethyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-pyrrolo[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-, (3-nitrophenyl)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-, 1-(3-cyanophenyl)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-[3-[(dimethylamino)carbonyl]phenyl)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-[3-[(dimethylamino)methyl]phenyl]ethyl 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,-methyl-, [4-carboxyphenyl)methyl ester;
1-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-1H-indol-4-ylmethyl]-1,2,3,4,6,7,8,9-octahydro-quinolizinylium; chloride;
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-(hydroxymethyl)phenyl]methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmethyl 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-(methoxycarbonyl)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-(hydroxyrnethyl)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-, salt with (3-carboxypheny)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-, [3-[(dimethylamino)methyl]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-[(dimethylamino)carbonyl]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-, [2-(4-morpholinyl)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-[1,1'-biphenyl]-4-ylethyl 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-, (2,6-difluorophenyl)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-,(1-phenyl-2,2,2-trifluoro)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-[3-(trifluoromethyl)phenyl]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-(dimethylamino)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-(1-pyrrolidinyl)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-(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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-pyrazinylethyl 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-(4-quinolinyl)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-pyrimidinyl)ethyl 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-, 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)ethyl ester;
Quinolizinium, 1-[[(4-fluorophenyl)methoxy]carbonyl]-5-hydroxy-2-methyl-1H-indol-4-yl]methyl]-1,2,3,4,6,7,8,9-octahydro-, chloride;

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-1,2-dimethyl-, (4-fluorophenyl)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-, 1-phenylpropyl ester;
Quinolizinium, 1,2,3,4,6,7,8,9-octahydro-1-[[5-hydroxy-2-methyl-3-[(phenylmethoxy)carbonyl)-1H-indol-4-yl]methyl]-, chloride;
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-nitrophenyl)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-,(1R)-1-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-, 1-(4-fluorophenyl)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-, phenyl 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-phenyl-1-(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-, bicyclo[2.2.1]hept-2-yl 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-(4-fluorophenyl)-1-methylethyl 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-phenylcyclopentyl 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-phenylcyclohexyl 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-(hydroxymethyl)phenyl 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-hydroxyphenyl)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-, (1S)-1-(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-, [6-(methoxycarbonyl)-2-pyridinyl]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-, 2-pyridinylmethyl 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-, (6-carboxy-2-pyridinyl)methyl ester;
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (6-carboxy-2-pyridinyl)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][1]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 ester;
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (5-carboxy-3-pyridinyl)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-, 1-(4'-methyl[1,1'-biphenyl]-3-yl)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-(2,6-dimethylphenyl)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-, (1S,2R)-2-(dimethylamino)-1-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-,(1R,2S)-2-(dimethylamino)-1-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-, 1-naphthalenyl 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-, diphenylmethyl 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-,(1R)-2,3-dihydro-1H-inden-1-yl 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-dihydro-1-acenaphthylenyl 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-, cyclohexyl(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-, 9H-fluoren-9-yl 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-, 1,2,3,4-tetrahydro-1-naphthalenyl 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-, [(2R,3R)-3-phenyloxiranyl]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-, 2-oxo-1,2-diphenylethyl 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-, 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl 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-methylphenyl)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-methyl-, cyclopropyl(4-fluorophenyl)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-, 3,4-dihydro-2H-1-benzothiopyran-4-yl 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-,(1S)-1-(2-bromophenyl)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-trifluoroethyl 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-, [(2S,3S)-3-phenyloxiranyl]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-, 2,2,2-trifluoro-1-methyl-1-(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)-1-(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-, 1-cyclopentyl-1-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-, 1-[1,1'-biphenyl]-4-yl-1-methylethyl 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-methyl-1-phenyl-2-propynyl 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-, 1,1-diphenylethyl 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-methyl-1,2-diphenylethyl 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-(4-fluorophenyl)cyclohexyl 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-diphenylethyl 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-phenyl-2-propynyl 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-, [1,1'-biphenyl]-4-ylmethyl 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-pyridinylmethyl 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-, 1,2,3,4-tetrahydro-7,8-dimethoxy-2-methyl-4-isoquinolinyl 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-[3-(dimethylamino)phenyl]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-, 1,1-dimethyl-2-pyrazinylethyl 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-(dipropylamino)-1,1-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-,(1S)-2,3-dihydro-1H-inden-1-yl 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-, (1S,2S)-2-(dimethylamino)-1-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-methyl-, (4-chlorophenyl)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-, 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-, 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-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;
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-, (1S)-1-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-, 1-phenylethyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carbothioic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, S-(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-methyl-, 3-pyridinylmethyl 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-[4-(trifluoromethyl)phenyl]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-(pentafluorophenyl)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-(2,6-difluorophenyl)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-,(1S)-1-(2-furanyl)ethyl este;
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-(4-morpholinyl)-1-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-,(1R)-1-(2-furanyl)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-methoxy-2-oxo-1-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-, 1-(3-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-,(S)-carboxy(phenyl)methyl ester;
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (S)-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);
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-, (1R)-2-methoxy-2-oxo-1-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-,(R)-carboxy(phenyl)methyl ester;
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt 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);
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-pyridinylmethyl 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-(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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-thienylmethyl 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-,(1S)-1-(4-fluorophenyl)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-,(1R)-1-(4-fluorophenyl)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-, 3-pyridinylmethyl 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-ethoxy-2-oxoethyl 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-furanylmethyl 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-nitrophenyl)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-, 2-furanylmethyl 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-chlorophenyl)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-, carboxymethyl 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-(2,6-dichlorophenyl)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-methoxyphenyl)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-(5-carboxy-3-pyridinyl)ethyl ester;
1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizin-1-yl)carbonyl]oxy]methyl]-, diethyl ester;
1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizin-1-yl)carbonyl]oxy]methyl]-;
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-chloro-5-nitrophenyl)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-, (2-chloro-5-nitrophenyl)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-, (5-amino-2-chlorophenyl)methyl ester;
Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-acetic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-.alpha.-oxo-, 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-2,4,5-trimethyl-, 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-methyl-, 1,1-dimethyl-2-propynyl 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-trichloro-1,1-dimethylethyl 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-, tricyclo[3.3.1.1 3,7]dec-1-yl 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-methyl-1-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-, 1-methylcyclohexyl 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-, 1,1,2-trimethylpropyl 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-methylcyclopentyl 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-cyclohexyl-1-methylethyl 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-, 1,4-dimethyl-4-piperidinyl 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-fluorophenyl 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 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-, phenyl 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-(methoxycarbonyl)phenyl 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-pyridinyl 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-(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-, [5-[(dimethylamino)methyl]-2-furanyl)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-,2-carboxy-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-, 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][1]-benzopyrano[3,2-i)quinolizine-1-carboxylic acid, 1,1-dimethylethyl 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-(dimethylamino)-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-(1H-imidazol-1-yl)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-benzofuranylmethyl 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-, (1R,2S)-2-(dimethylamino)-1-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-, (1S,2R)-2-(dimethylamino)-1-phenylpropyl ester; and 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-(4-fluorophenyl)cyclopropyl ester.
9. A compound named Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a,15-decahydro-, 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-methyl-.
10. A pharmaceutical composition comprising a compound according to Claim 1 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-methyl-, ethyl ester in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.
11. A method for modulation of a chemokine receptor activity in a mammal comprising administering an effective amount of a compound according to Claim 1 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-methyl-, ethyl ester or a pharmaceutically acceptable salt thereof.
12. A method for modulation of the CCR-5 chemokine receptor activity in a mammal comprising administering an effect amount of a compound according to Claim1 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-methyl-, ethyl ester or a pharmaceutically acceptable salt thereof.
13. A method for preventing infection by HIV, treating infection by HIV, delaying the onset of AIDS, or treating AIDS comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to Claim 1 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-methyl-, ethyl ester or a pharmaceutically acceptable salt thereof.
14. A method of treating inflammatory disease comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to Claim 1 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-methyl-, ethyl ester or a pharmaceutically acceptable salt thereof.
15. A combination of a compound of Formula I with one or more agents useful in the prevention and/or treatment of AIDS.
16. A compound selected from:
Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizin-1-yl)carbonyl]oxy)methyl]-1-methyl-, methanesulfonate;
Pyrrolo[3',2':5,6][1]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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)-1-phenylethyl ester, 11-oxide.
17. A compound named 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-, anhydride with benzoic acid.
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