AU1940900A - Functionalized heterocycles as chemokine receptor modulators - Google Patents

Functionalized heterocycles as chemokine receptor modulators Download PDF

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Publication number
AU1940900A
AU1940900A AU19409/00A AU1940900A AU1940900A AU 1940900 A AU1940900 A AU 1940900A AU 19409/00 A AU19409/00 A AU 19409/00A AU 1940900 A AU1940900 A AU 1940900A AU 1940900 A AU1940900 A AU 1940900A
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Prior art keywords
methyl
benzopyrano
quinolizine
decahydro
pyrrolo
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AU19409/00A
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Geraldine C. Harriman
Christine Nylund Kolz
Jay R Luly
Bruce David Roth
Yuntao Song
Bharat Kalidas Trivedi
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Millennium Pharmaceuticals Inc
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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)
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  • 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)
  • Molecular Biology (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

WO 00/42045 PCT/US99/30434 -1 FUNCTIONALIZED HETEROCYCLES AS CHEMOKINE RECEPTOR MODULATORS BACKGROUND OF THE INVENTION The present invention relates to functionalized heterocycles useful as 5 modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR1, CXCR2, CXCR-3, and/or 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. 10 Chemokines mediate a range of proinflammatory effects on leukocytes, such as chemotaxis, degranulation, and intigran activation (Baggiolini et al., ACv. Inmunol., 1994;55:97-179; Oppenheim et al., Annui. Rev. Immunol., 1991; 9:617-48; Miller et al., Grit. Rev. Innunol., 1992;12:17-46). These effects are mediated by binding to the seven-transmembrane-spanning G-protein coupled 15 receptors (Baggiolini et al., Adv. Immunol., 1994;55:97-179; Murphy, Annu. Rev. Immunol., 1994;12:593-633; Schall et al., Curr. Opin. hnniunol., 1994;6:865-73; Gerard et al., Curr. Opin. Immunol., 1994;6;140-5; Mackay, Curr. Bio., In press). Chemokine receptors also serve as coreceptors for HIV-l entry into cells. This came from observations that RANTES, MIP-la, and MIP-1 P suppressed infection 20 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-l strains (Feng et al., Science (Wash. DC), 1996;272:872-7). CCR-5, a RANTES, MIP-la, and MIP-1P receptor, was 25 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., Nature (Lond.) 1996;381:661-6; Dragic et al., Nature (Lond.), 1996;381:667-3). The importance of CCR-5 for HIV-1 transmission was underscored by the observation 30 that certain individuals who had been repeatedly exposed to HIV-1 but remained WO 00/42045 PCTIUS99/30434 -2 uninfected had a defect in CCR-5 expression (Liu et al., Cell, 1996; 86:367-77; Samson et al., Nature (Lond.), 1996;382:722-5; Dean et al., Science (Wash. DC), 1996;273:1856-62; Huang et al., Nature Med., 1996;2:1240-3). These noninfectable individuals were found to be homozygous for a defective CCR-5 5 allele that contains an internal 32-base pair deletion (CCR-5 A32). The truncated protein encoded by this gene is apparently not expressed at the cell surface. CCR-5 A32 homozygous individuals comprise -1% of the Caucasian population and heterozygous individuals comprise -20%. In studies of about 2700 HIV-1 infected individuals, no A32 homozygotes were found. Individuals who are 10 heterozygous for A32 CCR-5 allele have been shown to progress more slowly to AIDS than wild-type homozygous individuals (Samson et al., Nature (Lond.), 1996;382:722-5; Dean et al., Science (Wash. DC), 1996;273:1856-62; Huang et al., Nature Med., 1996;2:1240-3). Thus, the identity of CCR-5 as the principle coreceptor for primary HIV isolates provides an opportunity to 15 understand disease pathogenesis, and more importantly to identify a new avenue for the treatment of HIV-1 infection. The instant invention is a 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. 20 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 25 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, CXCRI, CXCR2, and/or CXCR-4. In particular, the compounds of the present invention are preferred as modulators of the chemokine receptor CCR-5.
WO 00/42045 PCT/US99/30434 -3 The compounds of the instant invention are those of Formula I which may exist in both closed and open form. R6 "R6
(CH
2 )n + (CH 2 )n
R
3 0 N R 3 0 y 5 4 O J R5 R O R 40 1 j ______ N0 X X Z- A A R2
R
2 z A ring close ring open or a pharmaceutically acceptable salt thereof wherein: 5 A is 0, S, and additionally A is NR 1 when X is C-R 9 ; X is N when A is NR 1 or X is C-R 9 wherein R 9 is halogen, hydrogen, alkyl, -CF 3 , CH 2 F, CHF 2 , -(CH2)m-ORl, aryl, arylalkyl, -(CH2)m-NR 7
R
8 , or C )r (CH2)q -r wherein m is an integer of from 0 to 2 and 10 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-NR 7
R
8 , -N(Rl)-(CH 2 )v
C(R
7
R
8 )-aryl, or OR 10 wherein R 10 is hydrogen, alkyl, cycloalkyl, cycloalkyl fused to an aryl ring, aryl, (CH 2 )saryl, 15
-CH
2
CF
3 , (CH2)tC(R7R 8
)-(CH
2 )uaryl, 0 R
(CH
2 NR 7
R
8 R CH2 OR 2(CH 2 )mC- O 7 Aryl Aryl 0 R
(CH
2 )m C-NR 7
R
8 Aryl WO 00/42045 PCTIUS99/30434 -4 O 2( m N 7
R
8 R (CH 2 )m C-OR 7 \ alkyl alkyl 0 R I
(CH
2 )m C-NR 7R 8 \ alkyl 0 R1 (CH 2 ) NR 7
R
8 R1 (CH 2 C- R 7 cycloalkyl cycloalkyl 0 R R (CH 2m -NR 7
R
8 cycloalkyl CCl3 CH 3 5 C=N , \ C=CH, ,or 5N 2 CH wherein s is an integer of from 1 to 3, t is an integer of from 0 to 3, u is an integer of from 0 to 3, v is an integer of from I to 3, and w is an integer of from 0 to 2; Z is CR or N; 10 R 1 is hydrogen or alkyl and each occurrence of RI is independently hydrogen or alkyl; R and R 2 are each independently selected from: hydrogen, alkyl, 15 halogen, -CN,
-NO
2 , -(CH2)m-NR 7
R
8
,
WO 00/42045 PCT/US99/30434 -5 -(CH2)m-COOR 7 ,
-(CH
2 )m-CONR 7
R
8 , 0
(CH
2 )m N R7 ' 0 5 || -(CH2)mN-S-R 7 , II 0 -(CH2)m-OR7, 10 -(CH 2 )m-SO 2
NR
7 R8, and -(CH2)m-S(O)pR7 wherein each occurrence of R 7 and R 8 are each independently hydrogen, alkyl, aryl, arylalkyl, -CF 3 , or R 7 and R 8 may be taken together to form a cyclic ring of from 3 to 7 atoms which ring may have 0, S, or NR 1 and p is an 15 integer of from 0 to 2;
R
3 is hydrogen or alkyl;
R
4 is hydrogen, alkyl, aryl, or aralkyl;
R
5 is alkyl, aryl, arylalkyl, acyl; or
R
4 and R 5 are taken together with the atoms to which they are attached to 20 form a cyclic ring of from 5 to 7 atoms;
R
6 is hydrogen or alkyl;
R
5 when not taken together with R 4 can be taken together with R 6 with the atoms to which they are attached to form a ring of from 5 to 7 atoms; 25 N-R 5 is also the corresponding N-oxide; RI I 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; WO 00/42045 PCTIUS99/30434 -6 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, 1 5-decahydro-2-methyl-, ethyl ester is not included. Preferred compounds are those of Formula 1 above wherein 5 R 1 is hydrogen. Other preferred compounds are those of Formula 1 above wherein
R
1 is hydrogen and X is C-R 9 . Still other preferred compounds are those wherein 10 R 1 is hydrogen and X is C-R 9 , wherein R 9 is alkyl. Still other preferred compounds are those wherein
R
1 is hydrogen, X is C-R 9 , wherein R 9 is alkyl; 15
R
4 and R 5 are taken together with the atoms to which they are attached to form a ring of from 5-7 atoms; and Y is OR 10 . Still other preferred compounds are those wherein
R
1 is hydrogen, 20 X is C-R 9 , wherein R 9 is alkyl;
R
4 and R 5 are taken together to form a 6-membered ring; and Y is OR 1 0 wherein R 10 is alkyl, aryl or -(CH 2 )saryl, -(CH2)t-C(R 7
R
8
)-(CH
2 )u-aryl. Still other preferred compounds are those wherein 25 RI is hydrogen, X is C-R 9 , wherein R 9 is Me;
R
4 and R 5 are taken together to form a 6-membered ring;
R
6 is hydrogen; n is 2; and WO 00/42045 PCT/US99/30434 -7 Y is OR 10 wherein R 10 is alkyl, aryl or R 10 is -(CH 2 )t-C(R 7
R
8
)
(CH2)u-aryl wherein t is 0, R 7 and R 8 can each independently be H, 5 alkyl,
-(CH
2 )vOH or (CH2)UCOOR 7 , and -(CH2)vNRIR 2 where u and v are as defined above. More preferred compounds are those of Formula 1 and selected from: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, methyl ester; Pyrrolo[3',2':5,6][I]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; Pyrrolo[3',2':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; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 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][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 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; 25 Pyrrolo[3',2':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 30 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; WO 00/42045 PCTIUS99/30434 -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-propyl-, 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-(2-methylpropyl)-, ethyl ester; 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1-dimethylethyl ester; 2,6a,7-Trimethyl-7,8,9,10,1 Ga, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza cyclopenta[a]anthracene-1-carboxylic acid ethyl ester; 7-Ethyl-2,6a-dimethyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa 10 3,7-diaza-cyclopenta[a]anthracene-1 -carboxylic acid ethyl ester; 6a-Ethyl-2,7-dimethyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa 3,7-diaza-cyclopenta[a]anthracene- 1 -carboxylic acid ethyl ester; 6a,7-Diethyl-2-methyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa 3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester; 15 7-Benzyl-2,6a-dimethyl-7,8,9,10,1 Ga, 11 -hexahydro-3H,6aH-6-oxa 3,7-diaza-cyclopenta[a]anthracene-1 -carboxylic acid ethyl ester; 2,7-Dimethyl-6a-phenyl-7,8,9,10,1 Ga, 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-e]indole-1-carboxylic acid, 20 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-, ethyl ester; 3H,7H-Pyrrolizino[1',8':5,6]pyrano[3,2-e]indole-1 -acetic acid, 8,9,11,12,12a, 13-hexahydro-2-methyl-, ethyl ester; 2-Methyl-8,9,1 0,1 Ga, 11,12,12a, 1 3-octahydro-3H,6aH,7H-6-oxa-3,6b diaza-benzo[a]cyclopenta[h]anthracene-1-carboxylic acid ethyl ester; 25 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-e]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, 30 8,9,11,12,13,13a,14,1 4 a-octahydro-2-methyl-N-(phenylmethyl)-; Pyrrolo[3',2':5,6][1 ]bcnzopyrano[3,2-i]quinolizine-I -carboxamide, N ethyl-8,9,1 1,1 2 ,1 3 ,13a,14,14a-octahydro-2-methyl-; WO 00/42045 PCT/US99/30434 -9 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, 14,1 4 a-octahydro-N,2-dimethyl-; 5 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, 10 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; 15 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, 20 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, 25 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, 30 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, phenylmethyl ester; WO 00/42045 PCT/US99/30434 -10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, 1-(4-fluorophenyl)ethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 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; I -Propanaminium, N,N,N-trimethyl-, salt with 1-(3-carboxyphenyl)ethyl 10 3
,
7
,
8
,
9 ,10,1 2 ,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, 1 5-decahydro-2-methyl-, (3-nitrophenyl)methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 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, 3,7,8,9,10,1 2 ,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, 20 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-phenylethy ester; Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 25 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, I 5-decahydro-2,-methyl-, (4-carboxyphenyl)methyl ester; 1-[ 3
-(
4 -Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-1 H-indol 30 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; WO 00/42045 PCT/US99/30434 -11 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,15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl] 5 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; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-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- I -carboxylate (1:1); Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 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; 20 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-(4-morpholinyl)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-[1,1 '-biphenyl]-4-ylethyl ester; 25 Pyrrolo[3',2':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, 3,7,8,9,10,12,13,14,1 4a, 15-decahydro-2-methyl-, (1-phenyl-2,2,2-trifluoro)ethyl 30 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; WO 00/42045 PCT/US99/30434 -12 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-(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; 5 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 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-, I-phenylcyclobutyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcylopropyl 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-, 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; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-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, 1 5-decahydro-2-methyl-, phenylmethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 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-iH-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, 25 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 30 3-[(phenylmethoxy)carbonyl]-1 H-indol-4-yl]methyfl-, 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; WO 00/42045 PCT/US99/30434 -13 Pyrrolo[3',2':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)- 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; 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15 -decahydro-2-methyl-, 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- I -phenyl I -(trifluoromethyl)ethyl ester; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 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; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-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, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(hydroxynethyl)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-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1 S)- 1 -(4-pyridinyl)ethyl ester; 25 Pyrrolo[3',2':5,6][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; 30 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-,
(
6 -carboxy-2-pyridinyl)methyl ester; WO 00/42045 PCT/US99/30434 -14 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (6-carboxy 2-pyridinyl)methyl 3,7,8,9,10,12,13,14,14a, 1 5-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, 5 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; 10 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- I -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] 15 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, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1 S,2R)-2-(dimethylamino) I -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 R,2S)-2-(dimethylamino) 1 -phenylpropyl ester; 25 Pyrrolo[3',2':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, 30 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2,3-dihydro-1H-inden-1-yl ester; WO 00/42045 PCT/US99/30434 -15 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,2-dihydro-1-acenaphthylenyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 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 10 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,1 5-decahydro-2-methyl-, [(2R,3R) 3-phenyloxiranyl]methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 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, 1 5-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, 20 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, (2-methylphenyl)phenylnethyl 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)methy ester; 25 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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, 1 5-decahydro-2-methyl-, (1 S)-1 -(2-bromophenyl)ethyl 30 ester; 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-, 2,2,2-trifluoroethyl ester; WO 00/42045 PCTIUS99/30434 -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-methyl-, [(2S,3S) 3-phenyloxiranyl]methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 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; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-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 15 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-i -phenyl-2-propynyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1 -diphenylethyl ester; Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl-1,2-diphenylethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 25 3,7,8,9,10,12,13,14,14a, I 5-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, 30 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, I-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; WO 00/42045 PCT/US99/30434 -17 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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 5 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, 10 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; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)-2,3-dihydro-1H-inden-l-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 S,2S)-2-(dimethylamino) 20 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, 25 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, 1 5-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; 30 Pyrrolo[3',2':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; WO 00/42045 PCTIUS99/30434 -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 S)- 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; 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carbothioic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[4-(trifluoromethyl)phenyl] ethyl ester; Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(pentafluorophenyl)ethyl ester; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2,6-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; 20 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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; 25 Pyrrolo[3',2':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; 30 Pyrrolo[3',2':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; WO 00/42045 PCT/US99/30434 -19 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, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1 R)-2-methoxy-2-oxo I -phenylethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, (R)-carboxy(phenyl)methyl ester; 10 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (R) carboxy(phenyl)methyl, 3,7,8,9,10,12,13,14,14a, 1 5-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; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-pyridinyl)ethyl ester; 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-pyridinyl)ethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,1 4a, 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, 1 5-decahydro-2-methyl-, (1 S)- 1 -(4-fluorophenyl)ethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 25 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, (1 R)- 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, 30 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; WO 00/42045 PCT/US99/30434 -20 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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; 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(2-chlorophenyl)ethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,1 4a, 15-decahydro-2-methyl-, carboxymethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 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, 1 5-decahydro-2-methyl-, 1-(2-methoxyphenyl)ethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 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; 20 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 I -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 25 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, 30 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, 1 5-decahydro-2-methyl-.alpha.-oxo-, ethyl ester; WO 00/42045 PCT/US99/30434 -21 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-2,4,5-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; 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2,2,2-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[3.3.1.13, 7 ]dec-1-yl 10 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-i -phenylethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methylcyclohexyl ester; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1,2-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, 20 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -cyclohexyl- I -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, 25 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, 1 5-decahydro-2-methyl-, phenyl ester; 30 Pyrrolo[3',2':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; WO 00/42045 PCT/US99/30434 -22 Pyrrolo[3',2':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; 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [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; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(dimethylamino) 2,2-dimethylpropyl ester; Propanedioic acid, monoanhydride with 3,7,8,9,10,12,13,14,14a,15 decahydro-2-methylpyrrolo[3',2':5,6][l]-benzopyrano[3, 2 -i]quinolizine 15 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,1 5-decahydro-2-methyl-, 2-(dimethylamino) 2-methylpropyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-nethyl-, 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-, (1 R,2S)-2-(dimethylamino)- 1 25 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 S,2R)-2-(dimethylamino)- 1 phenylpropyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 30 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(4-fluorophenyl)cyclopropyl ester; WO 00/42045 PCT/US99/30434 -23 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, 5 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2,1 1-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, 1 5-decahydro-2-methyl-, (1 S)- I -phenylethyl ester, 11-oxide. 10 The instant invention includes pharmaceutical compositions of compounds of Formula I 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 15 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 20 form. The ratio of closed and open form may depend on pH and solvent, as well as the nature of substituents R, R 2
-R
6 , 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, 25 tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The alkyl can be substituted with fluorine, for example, additionally the alkyls can be substituted with from I 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 WO 00/42045 PCT/US99/30434 -24 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. 5 0 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, 10 alkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined for alkyl, nitro, cyano, carboxy, 0 0 0
SO
3 H, CHO, -C-alkyl as defined above for alkyl, -C-NH 2 , -C-NH-alkyl as 15 0 defined above for alkyl, -C-N(alkyl) 2 as defined above for alkyl, -(CH2)n2-NH2 wherein n 2 is an integer of 1 to 5, -(CH 2
)
1 2-NH-alkyl as defined above for alkyl and n 2 , -(CH 2 )n2-N(alkyl) 2 as defined above for alkyl and n 2 . The term further 20 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, 0, 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 25 for aryl. The 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. 30 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 WO 00/42045 PCT/US99/30434 -25 optionally present in R 10 . 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 5 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 10 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, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, 15 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 20 arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. of Pharma. 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 25 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 30 amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, WO 00/42045 PCTIUS99/30434 -26 choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge supra., 1977). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to 5 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 10 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. 15 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, 20 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, 25 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 30 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 PCTIUS99/30434 -27 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, 5 or an encapsulating material. In powders, the carrier 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 10 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 carboxymethylcellulose, a low melting wax, 15 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 20 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 glycerides 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 25 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. 30 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.
WO 00/42045 PCTIUS99/30434 -28 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. 5 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, 10 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 15 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 I mg to 1000 mg, preferably 10 mg to 100 mg according to the 20 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 25 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 30 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.
WO 00/42045 PCT/US99/30434 -29 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 5 evaluated in a CCR-5 receptor binding assay. CCR-5 Receptor Binding Assay The 12
.
5 1-gp120/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 10 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 pL binding buffer [50 mM HEPES, pH 7.5, 1 mM CaCl 2 , 5 mM MgCI 2 , and 0.5% BSA]), 25 pL (2.5 tg) of membranes prepared from CCR-5/L 1.2 cells were mixed with 25 PL (3 nM) sCD4, followed by 25 pL (0.1 nM) radio-labeled gp120 15 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 NaCl. The plates were dried and MicroScint scintillation fluid was added before 20 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 tM. Synthesis of CCR-5 Analogs 25 Synthesis of the final target compounds is shown in Scheme 1. Compound II in a protic solvent, preferably ethanol, was treated with aqueous formaldehyde 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 50-1 10 C, preferably at 80-100 C, 30 under nitrogen atmosphere in an aprotic solvent, preferably dioxane, gives WO 00/42045 PCT/US99/30434 -30 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 R 1 # H). The preparation of indole intermediates is shown in Scheme II. Reaction of 5 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 p-ketoester with ammonia in EtOH. The p-ketoesters can be derived from 2,2,6 trimethyl-4H-1,3-dioxin-4-one and the corresponding alcohols. Condensation of 10 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 15 reaction, it is important that after the reaction is done the reaction mixture was cooled to 0 0 C in an ice-water bath and acidified with a concentrated acid, preferably HCl, at 0 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 20 synthesis, Mitsunobu procedure is preferred where appropriate alcohols, DEAD, and Ph 3 P 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. 25 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/US99/30434 -31 Scheme 1 Preparation of Final Target Compounds R6
(CH
2 )n O- y |R1 R5-N/ R3 NO 0 HO
R
11 CHO N R4 X N HO _]0. 2 R H Me2NH N dioxane R \ 2 R H if III
(CH
2 )n
(CH
2 )n R 0 y NaH R3 5 0 5 40 R1 I X Rix I /1x X2 RR2\ R N R H R R IV
I
WO 00/42045 PCT/US99/30434 -32 Scheme 2 Preparation of Substituted Indole Derivatives 0 xylenes 0 0 O + R'OH 150 0 C OR'
NH
3 EtOH 0 0 0 activated Zn CO 2 R' 1.Br +R7-CN R 2 R OR' THF, reflux H 2 N R 7 V O OR' O OH HO HO NaOH R N N R2 H
R
2 H R R VI VII O 0 OH Y 2. R'O R'O 2\ X ester or amide \X N N RN formation R R H R H R'= H or CH 3 CO VIII Ix WO 00/42045 PCT/US99/30434 -33 Scheme 3 R 0
R
2
H
2 N
OR'
2 HO , II RR BO 0
R
3 =Me, Ph 2 A
C(O)XR'
2 C(O)XR' 2 HO~ HO RO R 03 30 R2 0 R3 2 D E X=O,N NN MN F N0 C(O)XR'2 R3 R2 G Substituted 5-hydroxybenzofurans (C). 5 The substituted 5-hydroxybenzofurans (C) were prepared by condensing the appropriate 1,4-benzoquinone (A) with the appropriate 3-aminocrotonate (B) in acetic acid. The solvent was removed in vacuo, and the product was purified by recrystallization or flash chromatography on silica gel. Mannich Bases (E). 10 The 5-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.
WO 00/42045 PCT/US99/30434 -34 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), 5 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.
WO 00/42045 PCTIUS99/30434 -35 Scheme 4 Synthesis of 7-Azaindoles Analogs OH OH I OH H 3 C - 5
H
2 12 OH PhNN N Pd/C, AcOH H 2 N N AcOH, rt H 2 N' N Pd(dppf)C1 2 2 3 LiCI, Na 2
CO
3 Pd(dppoCl 2 DMF, 100*C LiCI, Na 2
CO
3 0 DMF, 100*C
H
3 C OH 0 0 HO OH KMnO 4 HO HOO -~ OH ROH - ~ OR N N HBT N, y 1 H K2CO3 HBTU 4 5 6
CH
2 0 HO OR N O OR
HN(CH
3
)
2 H N H 7 8 WO 00/42045 PCTIUS99/30434 -36 Procedures: Starting with commercially available 3 -hydroxy-2-phenylazopyridine (1) the corresponding aminopyridine is synthesized by reducing 1 in the presence of
H
2 (57 bar) and Pd/C in acetic acid at 65'C (Synthesis, 1990: 681) to afford 5 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 10 by oxidation of the hydroxymethylene to the corresponding acid 5 using KMnO4 in the presence of K 2
CO
3 (Gazz. Chim. Ital., 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. Org. Chemn., 1995;60:5214). 15 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. Het. Chem., 1970;7:131).
WO 00/42045 PCT/US99/30434 -37 Scheme 5 Preparation of Final Target Compounds From Novel Intermediate R6 (CH 2 )n R6 (CH 2 )n N R3 1. oxalyl chloride 0R3 N-R 8 R5 H ,_R5 40 \x 2.NHR 7
R
8 4 0 X X N N R2 R2 Ri R I II R6 (CH 2 )n R6
(CH
2 )n N R3 1. oxalyl chloride N 0 -R 7 R5 H R5 40 \ 2. HOR 7 40 0 /X / N N R2 R2 R IV R 1 0 Cl O R7 0 0 R7Halogen base R6
(CH
2 )n N R3 R5 3
COR
7 40 N R2
RI
WO 00/42045 PCT/US99/30434 -38 Compound I in an aprotic solvent, preferably Et 2 0, CH 2 Cl 2 , 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 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 5 product III can be obtained by reacting compound I with oxalyl chloride in an aprotic solvent, preferably Et 2 0, CH 2 Cl 2 , 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 Et 2 0, 10 CH 2 Cl 2 , or THF.
WO 00/42045 PCTIUS99/30434 -39 Scheme 6 Preparation of the Mixed Anhydride R 6 R 6 CH 2)n
CH
2 )n N R3 O
RR
3 0 Pd/C (20%) 3 OH \X THF, H 2 O N N R2 R R 1 2 R 111 I II RR6 O CH2)nO Et 3 N, THFX N R2 R 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 Et 3 N, to afford the mixed anhydride III.
WO 00/42045 PCTIUS99/30434 -40 Scheme 7 Synthesis of Esters From the Mixed Anhydride R6 R6 CH2)n 0 CH2)n
R
10
R
3 0
R
3 0 R4 0 + R 10 OH 100-180 0 C 05 R O \X \X N N R2 R2 RI RI General Description 5 The mixed anhydride I is mixed with the desired alcohol, the resultant reaction mixture was heated to 100 0 C to 180'C until the mixed anhydride is consumed affording the corresponding ester.
WO 00/42045 PCT/US99/30434 -41 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 5 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.
WO 00/42045 PCTIUS99/30434 -42 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 GW1592U89 Glaxo Wellcome HIV infection, AIDS, ARC Abacavir (RT inhibitor) Acemannan Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in Combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC, PGL HIV positive, AIDS (Los Angeles, CA) Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination Alferon Interferon Interferon Sciences Kaposi's sarcoma, HIV in combination Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha (Rockville, MD) aberrant Interferon AR177 Aronex Pharm HIV infections, AIDS, ARC beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases WO 00/42045 PCT/US99/30434 -43 ANTIVIRALS (cont'd) Drug Name Manufacturer Indication BMS-232623 Bristol-Myers HIV infection, AIDS, ARC (CGP-73547) Squibb/Novartis (protease inhibitor) BMS-234475 Bristol-Myers HIV infection, AIDS, ARC (CGP-61755) Squibb/Novartis (protease inhibitor) (-)6-Chloro-4(S)- 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-Lambert HIV1 infection Cidofovir Gilead Science CMV retinitis, herpes, papi Ilomavirus Combivir AZT+3TC Glaxo Wellcome HIV infection, AIDS, ARC Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis immune globin Cytovene Ganciclovir Syntex/Roche Sight threatening CMV, peripheral CMV, retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem. Ind. AIDS, ARC, HIV positive Ltd. (Osaka, Japan) asymptomatic HIVID (ddc) Hoffman-La Roche HIV infection, AIDS, ARC Dideoxycytidine ddl Dideoxyinosine Bristol-Myers Squibb HIV infection, AIDS, ARC; combination with AZ-T/d4T DMP-450 Triangle HIV infection, AIDS, ARC Pharmaceutical (protease inhibitor) Efavirenz (DMP 266) DuPont Merck HIV infection, AIDS, ARC (non-nucleoside RT inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline Herpes zoster, herpes simplex Foscavir/Foscamet Astra CMV, HSV 1-2 WO 00/42045 PCTIUS99/30434 -44 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 Human Triton Biosciences AIDS, Kaposi's sarcoma, ARC Interferon Beta (Almeda, CA) Interferon alpha-n3 Interferon Sciences ARC, ADS Indinavir Merck HIV infection, AIDS, ARC, asymnptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis JE 2147 (KNI-764) Japan Energy/ HIV infection, AIDS, ARC Protease inhibitor Agouron PI (reverse transcriptase inhibitor); also with AZT KNI-272 Nat'l Cancer Institute HIV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers Squibb CMV infection - HBV infection Nelfinavir Agouron HIV infection, AIDS, ARC Pharmaceuticals (protease inhibitor) Nevirapine Boeheringer HIV infection, AIDS, ARC Ingleheim (RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence WO 00/42045 PCTIUS99/30434 -45 ANTIVIRALS (cont'd) Drug Name Manufacturer Indication PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBD-CD4 Sheffield Med. Tech HIV infection, AIDS, ARC (Houston, TX) Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) S-1153 Agouron/Shionogi NnRTI Saquinavir Hoffmann-La Roche HIV infection, AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, ARC Didehydrodeoxy thymidine Valaciclovir Glaxo Wellcome Genital HSV & CMV infections Virazole Ribavirin Viratek/ICN Asymptomatic HIV positive, (Costa Mesa, CA) LAS, ARC Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies IMMUNO-MODULATORS Drug Name Manufacturer Indication AS-H i t Wyeth-Ayerst AIDS Bropirimine Pharmnacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi's sarcoma Lederle Labs ELGO Elan Core, PLC HIV infection (Gainesville, GA) FP-21399 Fuki Immunoharm Blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) WO 00/42045 PCT/US99/30434 -46 IMMUNO-MODULATORS (cont'd) Drug Name Manufacturer Indication Granulocyte Genetics Institute AIDS Macrophage Sandoz Colony Stimulating Factor Granulocyte Hoeschst-Roussel AIDS Macrophage Immunex Colony Stimulating Factor Granulocyte Schering-Plough AIDS, combination w/AZT Macrophage Colony Stimulating Factor HIV core Particle Rorer Seropositive HIV Immunostimulant IL-2 Interleukin-2 Cetus AIDS, in combination w/AZT IL-2 Interleukin-2 Hoffman-La roche AIDS, ARC, HIV, in Immunex combination w/AZT IL-2 Interleukin-2 Chiron AIDS, increase in CD4 cell (aldeslukin) counts Immune Globulin Cutter Biological Pediatric AIDS, in combination Intravenous (Berkeley, CA) w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's sarcoma, ARC, (New Orleans, LA) PGL IMREG-2 Imreg AIDS, Kaposi's sarcoma, ARC, (New Orleans, LA) PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate Alpha-2 Interferon Schering Plough Kaposi's sarcoma w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PE Muramyl- Ciba-Geigy Corp. Kaposi's sarcoma Tripeptide Granulocyte Colony Amgen AIDS, in combination w/AZT Stimulating Factor WO 00/42045 PCTIUS99/30434 -47 IMMUNO-MODULATORS (cont'd) Drug Name Manufacturer Indication Remune Immune Response Immunotherapeutic Corp. rCD4 Recombinant Genentech AIDS, ARC Soluble Human CD4 rCD4-IgG hybrids AIDS, ARC Recombinant Soluble Biogen AIDS, ARC Human CD4 Interferon Alfa 2a Hoffman-La Roche Kaposi's sarcoma AIDS, ARC, in combination w/A-ZT SK&F106528 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-TNFECTIVES Drug Name Manufacturer Indication Clindamycen with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille Nystatin Squibb Corp. Prevention of oral candidiasis Pastille Omidyl Eflomnithine Merrell Dow PCP Pentamidine LyphoMed PCP treatment Isethionate (IM & (Rosemont, IL) IV) Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation WO 00/42045 PCT/US99/30434 -48 ANTI-INFECTIVES (cont'd) Drug Name Manufacturer Indication Spiramycin Rhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen Pharm. Histoplasmosis; cryptococcal R51211 meningitis Trimetrexate Warner-Lambert PCP OTHER Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemia associated with Erythropoietin AZT therapy Recombinant Human Serono AIDS-related wasting, cachexia Growth Hormone Megestrol Acetate Bristol-Myers Squibb Treatment of anorexia associated w/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton Diarrhea and malabsorption Nutrition Pharmaceuticals related 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 5 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.
WO 00/42045 PCT/US99/30434 -49 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 5 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 10 0 0 C and concentrated HCI 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- 1 . IH NMR (DMSO-d 6 ) 6: 2.21 (s, 3H
CH
3
CO
2 ), 2.59 (s, 1H, ArCH 3 ), 6.79 (d, J= 6.84 Hz, 1H, ArH), 7.27 (d, 15 J= 8.55 Hz, 1H, ArH), 7.53 (s, 1H, ArH), 11.77 (s, 1H, NH) 11.93 (s, 1H, COOH). MS(APCI+): m/z 234.1 (MH+). Analysis calculated for C 12 HI IN 1 0 4 : 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 20 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 25 concentrated in vacuo to give an oily mixture; a solution of 1:1 hexane/ethyl acetate was used to redissolve the oil. The desired product was purified by flash chromatography. Residual di ethylhydrazinedicarboxylate 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- WO 00/42045 PCT/US99/30434 -50 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 I with the addition of 5 aqueous HCl, and a copious white precipitate occurred. The solid was filtered, washed with water (2 x 20 mL), and dried under vacuum at 40'C. Alternatively, the pH of the solution was adjusted to 1 with the addition of aqueous HCl, and the solution was extracted with ethyl acetate (2 x 25 mL). The organic layer was dried over Na 2
SO
4 and evaporated to give a solid. The solid may be further purified by 10 recrystallization from appropriate solvents. According to the Procedure A, Intermediates B-G were synthesized. 5-Acetoxy-2-methylindole-3-carboxylic acid benzyl ester (B) Yield: 8.32 g (21.6%); mp 152-154*C; IR: 3310, 1752, 1662, 1226, 1094 cm- 1 ; IH NMR (DMSO-d 6 ) 8 2.21 (s, 3H, CH 3
CO
2 ), 2.60 (s, 3H, ArCH 3 ), 5.28 (s, 2H, CH 2 Ph), 15 6.82 (dd, J= 8.55, 2.44 Hz, 1H, ArH), 7.26-7.41 (in, 6H, ArH), 7.53 (d, J= 2.44 Hz, 1H, ArH), 11.9 (s, 1H, NH). MS(APCI+): 324.1 (MH+). Analysis calculated for C 19
H
1 7
N
1 0 4 : C, 70.58; H, 5.30; N, 4.33. Found: C, 70.47; H, 5.43; N, 4.24. 5-Hydroxy-2-methylindole-3-carboxylic acid benzyl ester (C) Yield: 5.03 g 20 (76%); mp 191-193*C; IR: 3227, 1654, 1472, 1429, 1094 cm- 1 . IH NMR (DMSO-d 6 ) 6 2.54 (s, 3H, alkyl CH 3 ), 5.26 (s, 2H, PhCH 2 ), 6.55 (d, J= 6.10 Hz, 1H, ArH), 7.08 (d, J= 8.8 Hz, 1H, ArH), 7.24-7.42 (in, 6H, ArH), 8.82 (s, 1H, aromatic OH), 11.55 (s, 1H, NH). MS(APCI+): m/z 282.0 (MH+). Analysis calculated for C 1 7
H
15
N
1 0 3 : C, 71.71; H, 5.44; N, 4.92. Found: C, 71.72; H, 25 5.49; N, 4.85. Alternatively, Intermediate C can be synthesized from Intermediate B according to the procedure described in Example 9, Step A.
WO 00/42045 PCTIUS99/30434 -51 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
.
1 H NMR (DMSO-d 6 ) 8 0.99 (t, J= 7.51 Hz, 3H, CH 2
CH
2
CH
3 ), 1.71 (sextet, J= 7.33 Hz, 3H, CH 2
CH
2
CH
3 ), 2.26 (s, 3H, CH 3 CO), 2.63 (s, 3H, ArCH 3 ), 4.17 (t, 5 J= 6.41 Hz, 2H, CH 2
CH
2
CH
3 ), 6.86 (dd, J= 8.61, 2.20 Hz, 1H, ArH), 7.34 (d, J= 8.61 Hz, 1H, ArH), 7.55 (d, J= 2.20 Hz, 1H, ArH), 11.9 (s, 1H, NH). MS(APCI+): m/z 276.0 (MH+). Analysis calculated for C 15
H
17
N
1 0 4 : 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: 10 0.720 g (12%); mp 188-189'C; IR: 3409, 3391, 1663, 1467, 1181, 1095 (cm-1). 1 H NMR (DMSO-d 6 ) 6 1.27 (d, J= 6.35 Hz, 6H, CH(CH 3
)
2 ), 2.52 (s, 3H, CH 3 ), 5.04 (septet, J= 6.35 Hz, 1H, CH(CH 3
)
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) 11.4 (s, 1H, NH). MS(APCI+): m/z 234.1 (MH+). Analysis calculated for 15 C 13
H
15
N
1 0 3 : C, 66.94; H, 6.48; N, 6.00. Found: C, 66.79; H, 6.53; N, 5.88. 5-Hydroxy-2-methyl- I H-indole-3-carboxylic acid cyclopropylmethyl ester (F) Yield: 0.532 g (8.3%); mp 187-188'C; IR: 3388, 3297, 1663, 1466, 1179, 1094 cm- 1
.
1 H NMR (DMSO-d 6 ) 8 0.00-0.04 (in, 2H, cyclopropyl CH 2
CH
2 ), 0.22-0.26 (in, 2H, cyclopropyl CH 2
CH
2 ), 0.86-0.93 (in, 1H, CH 2 CH), 2.27 (s, 20 3H, ArCH 3 ), 3.72 (d, J= 7.32 Hz, 2H, CH 2 CH), 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, 1H, ArH), 8.51 (s, 1H, OH), 11.2 (s, 1H, NH). MS(APCI+): m/z 246.1 (MH+). Analysis calculated for
C
14
H
15
N
1 0 3 : C, 68.56; H, 6.16; N, 5.71. Found: C, 68.50; H, 6.19; N, 5.67. 5-Acetoxy-2-methylindole-3-carboxylic acid 1 -phenyl-propyl ester (G) Yield: 25 1.36 g (23%); mp 144-145.5'C; IR: 3289, 1755, 1661, 1459, 1216, 1204, 1089 cm- 1 . 1H NMR (DMSO-d 6 ) 6 0.863 (t, J= 7.32 Hz, 3H, CH 2
CH
3 ), 1.82-1.98 (in, 2H, CHCH 2
CH
3 ), 2.22 (s, 3H, CH 3 CO), 2.63 (s, 3H, ArCH 3
),
WO 00/42045 PCT/US99/30434 -52 5.80 (t, J= 6.84 Hz, 1H, benzylic CH), 6.83 (dd, J= 8.79, 2.20 Hz, 1H, ArH), 7.21-7.36 (in, 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 C 2 1
H
2 1
N
1 0 4 : C, 71.78; H, 6.02; N, 3.99. Found: C, 71.53; H, 6.02; N, 3.81. 5 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 hexane/CH 2
C
2 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 0.95 (d, 10 J= 6.84 Hz, 6H, CH(CH 3
)
2 ), 1.94 (n, J= 6.84 Hz, 1H, CH(CH 3
)
2 ), 2.54 (s, 3H,
CCH
3 ), 3.95 (d, J= 1.95 Hz, 2H, OCH 2 ), 6.54 (dd, J= 8.55, 2.44 Hz, 1H, ArH), 7.07 (d, J= 8, 1 H, ArH), 7.25 (s, 1H, ArH), 8.81 (s, 1H, OH), 11.49 (s, 1H, NH); MS(APCI+): m/z 248.1(MH+). Analysis calculated for C 14
H
17
NO
3 : C, 68.00; H, 6.93; N, 5.66. Found: C, 67.92; H, 6.87; N, 5.54. 15 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl-propyl ester (I) 5-Hydroxy-2-methyl- 1 H-indole-3-carboxylic acid 2,2-dimethyl-propyl ester was synthesized according to the general procedure A and was recrystallized from
CH
2
CI
2 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-d 6 ) 6 0.97 (s, 20 9H, C(CH 3
)
3 ), 2.55 (s, 3H, ArCH 3 ), 3.87 (s, 2H, OCH 2 ), 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 262.1(MH+). Analysis calculated for C 15
H
19
NO
3 : 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 25 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 WO 00/42045 PCTIUS99/30434 -53 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,CHCl 3 ) to give the corresponding ester. 5 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperdin- 1 -yl-ethyl ester (J) 5-Hydroxy-2-methyl- 1 H-indole-3-carboxylic acid 2-piperdin- 1 yl-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 ; IH NMR (400 MHz, 10 DMSO-d 6 ) 5 1.31 (in, 2H, NCH 2
CH
2
CH
2 ), 1.42 (m, 4H, NCH 2
CH
2 ), 2.38 (m, 4H, NCH 2
CH
2
CH
2 ), 2.53 (s, 3H, ArCH 3 ), 2.59 (t, J= 6.10 Hz, 2H, OCH 2
CH
2 ), 4.22 (t, J= 6.10 Hz, 2H, OCH 2
CH
2 N), 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 C 1 7
H
2 2
N
2 0 3 : C, 15 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 HC solution (50 mL) was added Zn (20 g) and stirred at room temperature for 15 minutes. The HCI solution was 20 decanted, and this was repeated two times. The activated Zn was washed with distilled H 2 0 (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 25 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 WO 00/42045 PCTIUS99/30434 -54 (30 mL) and K 2
CO
3 (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 5 over MgSO 4 , filtered, and concentrated under reduced pressure to yield of ethyl 3-alkyl-3-aminocrotonate as a crude product which was used directly in the next step. Ethyl 3-amino-3-benzylcrotonate (K) 1 H NMR (250 MHz, CDCl 3 ) S 1.26 (t, J= 7.1 Hz, 3H), 3.46 (s, 2H), 4.12 (q, J= 7.15 Hz, 2H), 4.64 (s, 1H), 7.27 (m, 10 5H). Ethyl 3-amino-3-ethylcrotonate (L) 1 H NMR (250 MHz, CDCl 3 ) 6 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). 1 3 C NMR (62.5 MHz, CDCI 3 ) 6 12.0, 14.5, 29.3, 30.3, 58.5, 82.6, 164.9, 170.5. 15 Ethyl 3 -amino-3-cyclopropylcrotonate (M) 1 H NMR (250 MHz, CDCI 3 ) 6 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). 13 C NMR (62.5 MHz, CDCL 3 ) 6 7.1, 14.6, 15.8, 58.5, 80.7, 165.1, 170.4. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH 4 0Ac/
CH
3 CN, APCI+) t = 7.24 min, mn/z = 156 (M+1). 20 Ethyl 3 -amino-3-propylcrotonate (N) 1 H NMR (250 MHz, CDC1 3 ) 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,
CDCI
3 ) 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 NH 4 0Ac/CH 3 CN, APCI+) t = 8.02 min, m/z = 158.4 (M+1).
WO 00/42045 PCT/US99/30434 -55 Ethyl 3-amino-3-isobutylcrotonate (0) 1 H NMR (250 MHz, CDCI 3 ) 6 0.95 (d, J= 6.4 Hz, 6H), 1.26 (t, J= 7.1 Hz, 3H), 1.9 (m, 1H), 1.96 (d, J= 7.0 Hz, 2H), 4.11 (q, J= 7.1 Hz, 2H), 4.51 (s, 1H). LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH 4 0Ac/CH 3 CN, APCI+) t = 8.69 min, mn/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 10 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) 6 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), 15 7.25 (in, 7H), 8.88 (s, 1H), 11.64 (s, 1H). 13 C NMR (62.5 MHz, DMSO) 6 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
NH
4 0Ac/CH 3 CN, APCI+) t = 7.83, mn/z = 296.3 (M+1). Ethyl 2 -ethyl-5-hydroxy-3-indolecarboxylate (Q) 54% yield (from starting nitrile) 20 as a white powder. IH NMR (250 MHz, DMSO) 8 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, J= 2.4 Hz, IH), 8.82, (s, 1H), 11.48 (s, IH). 13 C NMR (62.5 MHz, DMSO) 5 13.6, 14.4, 20.7, 58.4, 105.3, 111.3, 111.6, 127.9, 128.9, 150.0, 152.2, 165.0. LC/MS (150 mm x 4.6 mm, C-18, 25 5 micron, 10 mM NH 4 0Ac/CH 3 CN, APCI+) t = 7.60 min, m/z = 234.3 (M+ 1). Ethyl 2 -cyclopropyl-5-hydroxy-3-indolecarboxylate (R) 83% yield (from starting nitrile) as a white powder. 1 H NMR (250 MHz, DMSO) 5 0.97 (m, 2H), 1.10 (m, 2H), 1.35 (t, J= 7.1 Hz, 3H), 3.00 (m 1H), 4.26 (q, J= 7.0 Hz, 2H), 6.59 (dd, 8.7, WO 00/42045 PCT/US99/30434 -56 2.4 Hz, 1H), 7.8 (d, J= 8.7 Hz, 1H), 7.30 (d, J= 2.4 Hz, 1H), 8.81 (s, 1H), 10.93 (s, 1H). 1 3 C NMR (62.5 MHz, DMSO) 6 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 NH 4 0Ac/CH 3 CN, APCI+) 5 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. I H NMR (250 MHz, DMSO) 6 0.93 (t, J= 7.3 Hz, 3H), 1.35 (t, J= 7.1 Hz, 3H), 1.67 (in, 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, 10 J= 2.2 Hz, 1H), 8.86 (s, 1H), 11.51 (s, lH). 13 C NMR (62.5 MHz, DMSO) 6 13.7, 14.4, 17.2, 22.3, 29.2, 58.4, 105.2, 111.3, 115.5, 127.9, 128.9, 148.4, 149.6, 152.1, LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH 4 0Ac/CH 3 CN, APCI+) t = 7.21 min, n/z = 248.4 (M+1). Ethyl 2-isobutyl-5-hydroxy-3-indolecarboxylate (T) 68% yield (from starting 15 nitrile) the as a white powder. 1 H NMR (250 MHz, DMSO) 6 0.91 (d, J= 6.6 Hz, 6H), 1.35 (t, J= 7.1 Hz, 3H), 2.06 (in, 1H), 2.91 (d, J= 7.2 Hz, 2H), 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, IH). 1 3 C NMR (62.5 MHz, DMSO) 6 14.4, 17.2,22.3,28.6,36.2, 58.4, 102.0, 105.2, 111.2, 111.4, 127.9, 128.8, 147.6, 152.1, 20 165.0. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH40Ac/CH 3 CN, APCI+) t = 7.69 min, ni/z = 262.4 (M+1). Procedure E: General procedure for the preparation of indole amides 5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid (1.0 g, 4.3 mmol) was dissolved in 10 mL of DMF, and Et 3 N (0.6 mL, 1 eq) was added. The solution 25 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 HCI (IN), and extracted with ethyl acetate. The organic layer was dried and WO 00/42045 PCT/US99/30434 -57 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-y ester (U) Yield: 0.093 g (18%); 5 mp 201-203*C; IR: 3402, 1748, 1609, 1218, 1170 cm- 1
.
1 H NMR (DMSO-d 6 ) 6 2.21 (s, 3H, CH 3 CO), 2.45 (s, 3H, ArCH 3 ), 2.72 (d, J= 4.39 Hz, 3H, NHCH 3 ), 6.76 (dd, J= 8.79, 1.46 Hz, 1H, ArH), 7.24 (d, J= 8.79 Hz, lH, ArH), 7.25 (bs, 1H, CONHCH 3 ), 7.41 (s, 1H, ArH), 11.5 (s, 1H, indole NH). MS(APCI+): m/z 247.1 (MH+); Analysis calculated for C 13
H
14
N
2
O
3 -0.9 H 2 0; C, 59.49; H, 6.07; 10 N, 10.67. Found: C, 59.51; H, 6.12; N, 10.55. Acetic acid 3-benzylcarbamoyl-2-methyl-1H-indol-5-yl ester (V) Yield: 0.454 g (33%); mp 182-184'C; IR: 3413, 3319, 3222, 3191, 1750, 1609, 1228, 1216, 1170 cm- 1 . IH NMR (DMSO-d 6 ) 6 2.20 (s, 3H, CH 3 CO), 2.54 (s, 3H, ArCH 3 ), 4.42 (d, J= 6.1 Hz, 2H, NHCH 2 Ph), 6.77 (dd, J= 8.55, 1.95 Hz, IH, ArH), 15 7.15-7.19 (in, 1H, ArH), 7.25-7.34 (in, 5H, ArH), 7.45 (d, J= 1.71 Hz, IH, ArH), 7.89 (t, J= 6.10 Hz, 1H, CONHCH 2 Ph), 11.5 (s, IH, indole NH). MS(APCI+): m/z 323.2 (MH+); Analysis calculated for C 1 9
H
1 8
N
2 0 3 : 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 20 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 I with the addition of aqueous HCl, 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 25 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; IR: 3366, 1602, 1558, 1552, 1215, 1198 cm-1. 1
H
WO 00/42045 PCTIUS99/30434 -58 NMR (DMSO-d 6 ) 5 2.45 (s, 3H, ArCH 3 , obscured by DMSO peak), 2.70 (d, J= 4.40 Hz, 3H, CONHCH 3 ), 6.51 (d, J= 8.55 Hz, 1H, ArH), 7.02 (d, J= 8.55 Hz, 1H, ArH), 7.07 (s, 1H, ArH), 7.13-7.14 (in, IH, CONHCH 3 ), 8.65 (s, 1H, OH), 11.0 (s, 1H, indole NH). MS(APCI+): m/z 205.1 (MH+); Analysis 5 calculated for C 1 1
H
12
N
2 0 2 : 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, 1188 cm- 1
.
1 H NMR (DMSO-d 6 ) S: 2.48 (s, 3H, ArCH 3 ), 4.41 (d, J= 5.86 Hz, 10 2H, NHCH 2 Ph), 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 (in, 5H, ArH), 7.71-7.78 (in, 1H, CONHCH 2 Ph), 8.68 (s, 1H, OH), 11.1 (s, 1H, indole NH). MS(APCI+): m/z 281.1 (MH+); Analysis calculated for C 1 7
H
16
N
2 0 2 : 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, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, ethyl ester H N H3C Ose N CH3 Synthesized according to procedures published in J Het. Chemn., 1970;7:1311-1319. 20 Example 2 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 WO 00/42045 PCTIUS99/30434 -59 N 0 F 00
CH
3 N H 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 5 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 Na 2
SO
4 and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate gave 3.4 g (47%) of pure 10 titled compound as a white solid: mp 209-210'C; IR 3412, 3377, 3305, 1667, 1512, 1466, 1221, 1176, 1094 cm- 1 ; 1 H NMR (DMSO-d 6 ) 6 2.53 (s, 3H, CH 3 ), 5.23 (s, 2H, CH 2 ), 6.55 (dd, J = 8.79, 2.20 Hz, 1H, ArH), 7.08 (d, J= 8.79 Hz, IH, ArH), 7.14-7.17 (in, 2H, ArH), 7.19 (d, J= 2.20 Hz, I H, ArH), 7.44-7.48 (in, 2H, ArH), 8.81 (s, 1H, OH), 11.55 (s, 1H, NH); MS(APCI+): n/z 300.1 (MH+). 15 Analysis calculated for C 17
H
1 4 F 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-1H-indole-3-carboxylic acid 4-fluoro-benzyl ester 20 (2.90 g, 9.69 mmol) and aqueous Me 2 NH (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 25 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, WO 00/42045 PCTIUS99/30434 -60 1513, 1424, 1259, 1227, 1085, 806 cm- 1 ; 1 H NMR (DMSO-d 6 ) 5 2.12 (s, 6H,
N(CH
3
)
2 ), 2.45 (s, 3H, ArCH 3 ), 3.97 (s, 2H, ArCH 2 NMe 2 ), 5.23 (s, 2H,
CO
2
CH
2 Ar), 6.56 (d, J= 8.61 Hz, 1H, ArH), 7.06 (d, J= 8.61 Hz, 1H, ArH), 7.18-7.24 (m, 2H, ArH), 7.49-7.54 (in, 2H, ArH), 11.5 (bs, 1H, exchangeable 5 proton); MS(APCI+): m/z 357.2 (MH+). Analysis Calculated for
C
2 0
H
2 1
N
2
O
3 Fj-0.1H 2 0: C, 67.06; H, 5.97; N, 7.82; F, 5.30; H 2 0, 0.50. Found: C, 66.90; H, 5.81; N, 7.53; F, 5.33; H 2 0, 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 10 ester To a mixture of perchlorate 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). 15 Combined ether layer was dried over Na 2
SO
4 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 refluxed under nitrogen for 5.5 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a brown solid. Recrystallization from CH 3 CN 20 gave 1.63 g (88%) of pure titled compound as a brown solid: mp 209-214'C (decomposed); IR 2934, 1704, 1152, 1431, 1235, 1148, 1078, 827 cm- 1 ; IH NMR (DMSO-d 6 ) 8 1.06-1.67 (m, 1OH, aliphatic CH 2 and CH), 1.81-1.86 (m, 1H, aliphatic CH), 2.30-2.46 (in, 2H, obscured by DMSO peak, aliphatic CH), 2.46 (s, 3H, ArCH 3 ), 2.60-2.70 (in, 2H, aliphatic CH), 2.84-2.91 (in, 1H, aliphatic CH), 25 3.17 (dd, J= 18.3, 6.78 Hz, lH, aliphatic CH), 5.21 (ABq, Jab = 11.9 Hz, Pab = 19.0 Hz, 2H, CO 2
CH
2 Ar), 6.59 (d, J= 8.61 Hz, 1H, ArH), 7.03 (d, J= 8.61 Hz, 1H, ArH), 7.17-7.25 (in, 2H, ArH), 7.48-7.52 (m, 2H, ArH), 11.5 (bs, 1H, NH); MS(APCI+): m/z 449.3 (MH+). Analysis calculated for WO 00/42045 PCTIUS99/30434 -61
C
2 7
H
2 9
N
2
O
3 F-0.O8CH 3 CN: C, 72.20; H, 6.52; N, 6.45; F, 4.20. Found: C, 71.88; H, 6.35; N, 6.42; F, 4.15. Example 3 (Intermediate) Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine, 3 ,7,8,9,10,12,13,14,14a,15 5 decahydro N N H Step A: 4-Dimethylaminomethyl-1H-indol-5-ol 5-Hydroxyindole (Aldrich, Milwaukee, WI, 5.09 g, 38.2 mmol) was dissolved in 25 mL of EtOH, aqueous Me 2 NH (40%, 5.28 mL, 42.1 mmol) was 10 added followed by aqueous HCHO (37%, 3.65 g, 45.9 mmol). The resulting reaction mixture was stirred at ambient temperature for 1.5 hours during which time a precipitate formed. Filtration and drying under vacuum gave 4.13 g (57%) of pure titled compound as a beige solid: mp 137-139'C; IR 3316, 1625, 1592, 1523, 1450, 1239, 1198, 724 cm- 1 ; 1 H NMR (DMSO-d 6 ) 6 2.25 (s, 6H, 15 CH 2
N(CH
3
)
2 , 3.76 (s, 2H, CH 2
N(CH
3
)
2 ), 6.29-6.30 (m, 1H, ArH), 6.54 (d, J= 8.61 Hz, 1H, ArH), 7.10 (d, J= 8.60 Hz, 1H, ArH), 7.18-7.20 (m, 1H, ArH), 10.8 (bs, 1H, exchangeable proton); MS(APCI+): m/z 191.1 (MH+). Analysis calculated for C 1 1
H
14
N
2 0: C, 69.45; H, 7.42; N, 14.72. Found: C, 69.36; H, 7.38; N, 14.71. 20 Step B: 1,2,3,4,6,7,8,9-Octahydro-quinolizinylium perchlorate C1O4 WO 00/42045 PCT/US99/30434 -62 The synthesis is found in David A. Evans, A new endocyclic enamine synthesis. JA CS, 1970;92:7593-7595 and Leonard N.J., Hay A.S., Fulmer R.W., Gash V.W., Unsaturated amines. III. Introduction of c,p-unsaturation by means of mercuric acetate: A 1 0 )-dehydroquinolizidine, J Am. Chem. Suc., 1955;77:439 5 444. Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine, 3
,
7
,
8
,
9 ,10,1 2 ,13,14,14a,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 10 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 Na 2
SO
4 and concentrated in vacuo. The residual oil was dissolved in 5 mL of dioxane, then 4-dimethylaminomethyl-1H indol-5-ol (250 mg, 1.31 mmol) was added, the resulting reaction mixture was 15 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 ; 1 H NMR (DMSO-d 6 ) 6 1.13-1.65 (in, 9H, aliphatic CH 2 and CH), 1.76-1.91 (m, 2H, aliphatic CH), 2.36-2.52 (in, obscured 20 by DMSO peak, 3H, aliphatic CH), 2.68-2.77 (m, 1H, aliphatic CH), 2.88-2.96 (in, IH, aliphatic CH), 3.06 (dd, J= 17.6, 6.78 Hz, 1H, aliphatic CH), 6.22-6.23 (in, 1H, ArH), 6.56 (d, J= 8.61 Hz, 1H, ArH), 7.07 (d, J= 8.61 Hz, 1H, ArH), 7.19-7.21 (in, 1H, ArH), 10.8 (bs, 1H, NH); MS(APCI+): m/z 383.1 (MH+). Analysis calculated for C 18
H
22
N
2 0-0.1H 2 0: C, 76.08; H, 7.87; N, 9.86; H 2 0, 25 0.63. Found: C, 76.09; H, 7.81; N, 9.83; H 2 0, 0.74. Example 4 (Intermediate) Pyrrolo[ 3
',
2 ':5,6][1]benzopyrano[3,2-i]quinolizine, 3
,
7 ,8, 9 ,10,1 2 ,13,14,14a,15 decahydro-2-methyl- WO 00/42045 PCT/US99/30434 -63 N O N CH H Step A: 2-Methyl-1H-indol-5-ol 5-Hydroxy-2-methyl-IH-indole-3-carboxylic acid ethyl ester (Aldrich, Milwaukee, WI, 20.0 g, 91.2 mmol) was mixed with aqueous NaOH (2N, 365 mL, 5 730 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 Na 2
SO
4 and concentrated in vacuo affording a brown solid. Recrystallization from EtOAc/CH 2
CI
2 gave 10 11.7 g (87%) of pure 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-d 6 ) 8 2.29 (s, 3H, ArCH 3 ), 5.88-5.89 (in, 1H, ArH), 6.45 (dd, J= 8.42, 2.38 Hz, I H, ArH), 6.68 (d, J= 2.38 Hz, IH, ArH), 7.00 (d, J= 8.42 Hz, IH, ArH), 8.44 (s, I H, NH), 10.5 (bs, IH, OH); MS(APCI+): n/z 148.1 (MH+). Analysis calculated for 15 C 9
H
9 NO: 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-ol 2-Methyl-1H-indol-5-ol (5.00 g, 34.0 mmol) was dissolved in 20 mL of EtOH, aqueous Me 2 NH (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 20 stirred at ambient temperature for 2 hours, then mixed with 50 mL of water, precipitate formed. Filtration and recrystallization from ethanol (<50'C) gave 3.0 g (43%) of pure titled compound as a white solid: mp 133-135'C; IR 3404, 3385, 1598, 1515, 1428, 1271, 1204, 798, 778 cm- 1 ; 1 H NMR (DMSO-d 6 ) 6 2.23 (s, 6H, N(CH 3
)
2 ), 2.30 (s, 3H, ArCH 3 ), 3.68 (s, 2H, CH 2 N), 5.98 (s, 1H, 25 ArH), 6.42 (d, J= 8.42 Hz, 1H, ArH), 6.95 (d, J= 8.79 Hz, 1H, ArH), 10.6 (bs, WO 00/42045 PCT/US99/30434 -64 1H, exchangeable proton); MS(APCI+): n/z 205.2 (MH+). Analysis calculated for
C
12
H
16
N
2 0: 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]benzopyrano[3, 2 -i]quinolizine, 3,7,8,9,10,1 2 ,13,14,14a,1 5-decahydro-2-methyl 5 To a mixture of perchlorate 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 Na 2
SO
4 and concentrated in vacuo. The 10 residual oil was dissolved in 7 mL of dioxane, then 4 -dimethylaminomethyl 2-methyl-1H-indol-5-ol (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 vacuo affording a brown solid. Trituration with EtOAc gave 1.01 g (59%) of pure titled compound as a beige 15 solid: mp 267-270'C (dec.); IR 3407, 3189, 2926, 1435, 1212, 1197, 774 cm-1; 1 H NMR (DMSO-d 6 ) 6 1.13-1.64 (m, 9H, aliphatic CH 2 and CH), 1.74-1.89 (m, 2H, aliphatic CH), 2.31 (s, 3H, CH 3 ), 2.35-2.50 (m, obscured by DMSO peak, 3H, aliphatic CH), 2.67-2.75 (m, 1H, aliphatic CH), 2.87-3.31 (m, 2H, aliphatic CH), 5.92 (m, 1H, ArH), 6.45 (d, J= 8.61 Hz, 1H, ArH), 6.94 (d, J= 8.79 Hz, 1H, 20 ArH), 10.6 (bs, IH, exchangeable proton); MS(APCI+): n/z 297.1 (MH+). Analysis calculated for C 1 9
H
2 4
N
2 0: C, 76.99; H, 8.16; N, 9.45. Found: C, 76.79; H, 8.19; N, 9.35.
WO 00/42045 PCT/US99/30434 -65 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 N0 B r N CH 3 H 5 StepA: 6 -Bromo-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3 carboxylic acid ethyl ester 6-Bromo-5-hydroxy-2-methyl -1 H-indole-3-carboxylic acid ethyl ester, prepared according to the literature procedure [Bell M.R.; Oesterlin R.; Beyler A.L.; Harding H.R.; Potts G.O., J. Med. Chem., 1967;10:264-266], (3.01 g, 10 10.1 mmol) and aqueous Me 2 NH (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 15 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 ; IH NMR (DMSO-d 6 ) 5 1.30 (t, J= 7.14 Hz, 3H, CH 2
CH
3 ), 2.26 (s, 6H, N(CH 3
)
2 ), 2.49 (s, 3H, obscured by DMSO peak, ArCH 3 ), 4.16 (s, 2H, ArCH 2 NMe 2 ), 4.23 (q, J= 6.96 Hz, 2H, CH 2
CH
3 ), 7.38 (s, 1H, ArH), 11.6 (bs, 1H, 20 exchangeable proton); MS(APCI+): m/z 355.0 (MH+). Analysis calculated for
C
15
H
1 9
N
2
O
3 Br: 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 of perchlorate salt (1.40 g, 5.90 mmol, Example 3, Step B) 25 and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory ftnnel until all solid had dissolved. Two layers WO 00/42045 PCT/US99/30434 -66 were separated, and the aqueous layer was extracted with ether (2 x 50 mL). Combined ether layer was dried over Na 2
SO
4 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 5 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, 1 6 6 2 , 1426, 1185, 1110, 1081, 869 cm- 1 ; 1 H NMR 10 (CDC 3 ) 8 1.15-2.08 (in, 1 1H, aliphatic CH 2 and CH), 1.39 (t, J= 7.14 Hz, 3H,
CH
2
CH
3 ), 2.45-2.65 (in, 2H, aliphatic CH), 2.60 (s, 3H, ArCH 3 ), 2.85-3.00 (in, 2H, aliphatic CH), 3.17-3.30 (in, 1H, aliphatic CH), 3.50 (dd, J= 18.0, 6.96 Hz, IH, aliphatic CH), 4.34 (q, J= 7.14 Hz, CH 2
CH
3 ), 7.35 (s, IH, ArH), 8.10 (bs, IH, NH); MS(APCI+): n/z 447.1 (MH+). Analysis calculated for 15 C 2 2
H
2 7
N
3 0 3 Br: 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][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, propyl ester CH NCH3 20 H Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid propyl ester 5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid propyl ester (intermediate D, 2.04 g, 7.42 mmol) was mixed with 20 mL of methanol, NaOCH 3 (1.60 g, 29.6 mmol) was then added. The resulting reaction mixture was 25 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% HCI until WO 00/42045 PCT/US99/30434 -67 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-d 6 ) 5 0.989 (t, J= 7.51 Hz, 3H, CH 2
CH
2
CH
3 ), 5 1.72 (sextet, J= 7.14 Hz, 2H, CH 2
CH
2
CH
3 ), 2.57 (s, 3H, ArCH 3 ), 4.14 (t, J= 6.41 Hz, 2H, CH 2
CH
2
CH
3 ), 6.58 (dd, J= 8.42, 2.20 Hz, 1H, ArH), 7.11 (d, J= 8.61 Hz, 1H, ArH), 7.29 (d, J= 2.20 Hz, 1H, ArH), 8.83 (s, 1H, OH), 11.5 (bs, IH, NH); MS(APCI+): m/z 234.1 (MH+). Analysis calculated for
C
13
H
1 5 NO3-0.06H 2 0: C, 66.63; H, 6.50; N, 5.98. Found: C, 66.27; H, 6.38; N, 10 5.84. StepB: 4 -Dimethylaminomethyl-5-hydroxy-2-methyl -I 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 Me 2 NH (40%, 1.50 mL, 12.0 mmol) were mixed with 15 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 vacuo to reduce the volume by half. Precipitate formed. Filtration and drying under vacuum 20 gave 0.86 g (54%) of pure titled compound as a white solid: mp 135-137 0 C (dec.); IR 3217, 2969, 1684, 1420, 1141, 1075 cm- 1 ; 1 H NMR (DMSO-d 6 ) 8 0.953 (t, J= 7.32 Hz, 3H, CH 2
CH
2
CH
3 ), 1.70 (sextet, J= 7.33 Hz, 2H, CH 2
CH
2
CH
3 ), 2.19 (s, 6H, N(CH 3
)
2 ), 2.49 (s, 3H, obscured by DMSO peak, ArCH 3 ), 4.06 (s, 2H, ArCH 2 NMe 2 ), 4.13 (t, J= 6.78 Hz, 2H, CH 2
CH
2
CH
3 ), 6.56 (d, J= 8.61 Hz, 25 1H, ArH), 7.07 (d, J= 8.42 Hz, 1H, ArH), 11.5 (bs, 1H, exchangeable proton); MS(APCI+): n/z 291.1 (MH+). Analysis calculated for C 16
H
2 2
N
2 0 3 : C, 66.19; H, 7.64; N, 9.65. Found: C, 65.94; H, 7.67; N, 9.31.
WO 00/42045 PCT/US99/30434 -68 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 5 were separated, and the aqueous layer was extracted with ether (2 x 30 mL). Combined ether layer was dried over Na 2
SO
4 and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole Mannich base (0.717 g, 2.47 mmol) was added; the resulting reaction mixture was refluxed under nitrogen for 3 hours. The reaction mixture was cooled to ambient 10 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 solid. Recrystallization from CH 3 CN 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 ; 1 H NMR (CDCl 3 ) 6 0.992 (t, J= 7.32 Hz, 3H, 15 CH 2
CH
2
CH
3 ), 1.76 (sextet, J= 7.08 Hz, 2H, CH 2
CH
2
CH
3 ), 1.29-1.86 (in, 10H, aliphatic CH 2 and CH), 2.11 (d, J= 13.43 Hz, 1H, aliphatic CH), 2.27-2.58 (in, 2H, aliphatic CH), 2.58 (s, 3H, ArCH 3 ), 2.82-2.86 (in, 2H, aliphatic CH), 3.00-3.10 (in, IH, aliphatic CH), 3.46 (dd, J= 18.1, 6.84 Hz, IH, aliphatic CH), 4.21 (t, J= 6.84 Hz, CH 2
CH
2
CH
3 ), 6.73 (d, J= 8.79 Hz, lH, ArH), 7.01 (d, 20 J= 8.79 Hz, lH, ArH), 8.06 (bs, lH, NH); MS(APCI+): mn/z 383.1 (MH+). Analysis calculated for C 2 3
H
3 0
N
2 0 3 : 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, 25 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methylpropyl ester WO 00/42045 PCTIUS99/30434 -69
CH
3 N 0 CH 0 3 0
CH
3 N H Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid isobutyl ester (intermediate H, 1.03 g, 4.17 mmol) and aqueous Me 2 NH (40%, 1.15 mL, 5 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 10 (49%) of pure titled compound as a white solid: mp 122-124'C (dec.); IR 3229, 2957, 1686, 1424, 1242, 1085, 1000 cm- 1 ; 1 H NMR (DMSO-d 6 ) 6 0.951 (d, J= 6.59 Hz, 6H, CH 2
CH(CH
3
)
2 ), 1.98 (in, J= 6.59 Hz, 1H, CH 2
CH(CH
3
)
2 ), 2.18 (s, 6H, N(CH 3
)
2 ), 2.50 (s, 3H, obscured by DMSO peak, ArCH 3 ), 3.97 (d, J= 6.59 Hz, 2H, CH 2
CH(CH
3
)
2 ), 4.07 (s, 2H, ArCH 2 NMe 2 ), 6.56 (d, 15 J= 8.61 Hz, 1H, ArH), 7.06 (d, J= 8.42 Hz, I H, ArH), 11.5 (bs, IH, exchangeable proton); MS(APCI+): m/z 305.2 (MH+). Analysis calculated for
C
1 7
H
24
N
2 03-1.03H 2 0: C, 63.23; H, 8.13; N, 8.67. Found: C, 62.84; H, 7.30; N, 8.44. Step B: 20 To a mixture of perchlorate salt (0.458 g, 1.93 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 Na 2
SO
4 and concentrated in vacuo. The 25 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 refluxed WO 00/42045 PCTIUS99/30434 -70 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 hexanes) to give 0.40 g (52%) of pure titled compound as a white solid: mp 203-204.5'C; IR 3341, 2933, 5 1700, 1673, 1434, 1236, 1082, 886, 781 cm- 1 ; IH NMR (CDCI 3 ) 6 0.984 (d, J= 6.84 Hz, 6H, CH 2
CH(CH
3
)
2 ), 1.32-1.90 (in, 1OH, aliphatic CH 2 and CH), 2.04 (m, J= 6.59 Hz, 1H, CH 2
CH(CH
3
)
2 ), 2.08-2.18 (in, 1H, aliphatic CH), 2.40-2.60 (in, 2H, aliphatic CH), 2.59 (s, 3H, ArCH 3 ), 2.84-2.88 (in, 2H, aliphatic CH), 2.97-3.10 (in, 1H, aliphatic CH), 3.46 (dd, J= 18.1, 6.84 Hz, IH, aliphatic 10 CH), 4.00-4.09 (in, 2H, CH 2
CH(CH
3
)
2 ), 6.73 (d, J= 8.79 Hz, 1H, ArH), 7.02 (d, J= 8.79 Hz, 1H, ArH), 8.05 (bs, 1H, NH); MS(APCI+): mn/z 397.2 (MH+). Analysis calculated for C 2 4
H
32
N
2 0 3 : C, 72.70; H, 8.13; N, 7.06. Found: C, 72.85; H, 8.19; N, 7.00. Example 8 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 2,2-dimethylpropyl ester CH N O / CH 3 0 O C H 3
CH
3 N H Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl propyl 20 ester (intermediate I, 1.55 g, 5.93 mmol) and aqueous Me 2 NH (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 25 was washed with water (2 x 50 mL), the organic phase was dried over Na 2
SO
4 and concentrated in vacuo affording a thick oil. The crude product was WO 00/42045 PCT/US99/30434 -71 further purified by flash chromatography (10%-20% methanol in CHC1 3 to give 0.90 g (48%) of pure titled compound as a white solid: mp 150-151*C (dec.); IR 3251, 2953, 1690, 1424, 1238, 1081, 801 cm-1; IH NMR (DMSO-d 6 ) 6 0.970 (s, 9H, CH 2
C(CH
3
)
3 ), 2.18 (s, 6H, N(CH 3
)
2 ), 2.52 (s, 3H, ArCH 3 ), 3.91 (s, 2H, 5 CH 2
C(CH
3
)
3 ), 4.08 (s, 2H, ArCH 2 NMe 2 ), 6.57 (d, J= 8.42 Hz, 1H, 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 C 1 8
H
2 6
N
2 0 3 : C, 67.90; H, 8.23; N, 8.80. Found: C, 67.53; H, 8.04; N, 8.57. Step B: 10 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 Na 2
SO
4 and concentrated in vacuo. The 15 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 in vacuo affording a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to afford a 20 white solid. Recrystallization from CH 3 CN gave 0.92 g (44%) of pure titled compound as a white solid: mp 240-243'C; IR 3187, 2934, 1700, 1433, 1235, 1077, 883, 780 cm- 1 ; 1 H NMR (DMSO-d 6 ) 6 0.96 (d, 9H, CH 2
C(CH
3
)
3 ), 1.19-1.57 (in, 9H, aliphatic CH 2 and CH), 1.70-1.80 (in, lH, aliphatic CH), 1.76-1.85 (in, 1H, aliphatic CH), 2.34-2.45 (in, 2H, obscured by DMSO peak 25 aliphatic CH), 2.53 (s, 3H, ArCH 3 ), 2.63-2.79 (in, 2H, aliphatic CH), 2.85-2.95 (in, lH, aliphatic CH), 3.25-3.35 (in, 1H, obscured by water peak aliphatic CH), 3.94 (ABq, Jab = 10.62 Hz, Vab = 24.1 Hz, 2H, CH 2
C(CH
3
)
3 ), 6.61 (d, J= 8.42 Hz, 1H, ArH), 7.04 (d, J= 8.61 Hz, 1H, ArH), 11.51 (bs, 1H, WO 00/42045 PCT/US99/30434 -72 NH); MS(APCI+): m/z 411.3 (MH+). Analysis calculated for C 2 4
H
3 2
N
2 0 3 : C, 73.14; H, 8.35; N, 6.82. Found: C, 73.16; H, 8.52; N, 6.77. Procedure G: General procedure for the Mannich reaction The 5-hydroxy indole ester of choice, (2.2-17.9 mmol, 1 eq) was dissolved 5 in EtOH by stirring while warming the solution; the solution was cooled. Aqueous HCHO (37%, 1.2 eq) and Me 2 NH (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/CHCl 3 as the eluent) to afford the desired product. 10 Example 9 Pyrrolo[3',2':5,6][]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, phenylmethyl ester N 0 00 O
OCH
3 H Step A: 15 4-Dimethylaminomethyl--5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid benzyl ester was synthesized from intermediate C according to Procedure G Yield: 3.36 g (55%); IH NMR (DMSO-d 6 ) 6 2.10 (s, 6H, CH 2
N(CH
3
)
2 ), 2.45 (s, 3H, ArCH 3 ), 3.97 (s, 2H, CH 2 NMe 2 ), 5.21 (s, 2H, CO 2
CH
2 Ph), 6.53 (d, J= 8.30 Hz, 1H, ArH), 7.04 (d, J= 8.55 Hz, 1H, ArH), 7.29-7.43 (in, 5H, ArH), 20 11.5 (s, 1H, NH). MS(APCI+): n/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 . 1 H NMR (DMSO-d 6 ) 6 1.11-1.67 (m, 1OH, aliphatic CH 2 and CH), 1.82-1.86 (m, WO 00/42045 PCT/US99/30434 -73 1H, aliphatic CH), 2.30-2.48 (in, 2H, obscured by DMSO peak, aliphatic CH), 2.48 (s, 3H, ArCH 3 ), 2.62-2.70 (in, 2H, aliphatic CH), 2.86-2.92 (in, 1H, aliphatic CH), 3.19 (dd, J= 18.3, 6.78 Hz, 1H, aliphatic CH), 5.23 (ABq, Jab = 12.1 Hz, 'ab = 16.4 Hz, 2H, CO 2
CH
2 Ph), 6.59 (d, J= 8.61 Hz, IH, ArH), 7.03 (d, 5 J= 8.61 Hz, 1H, ArH), 7.30-7.46 (in, 5H, ArH), 11.5 (bs, 1H, NH); MS(APCI+): 431.2 (MH+). Analysis calculated for C 2 7
H
3 0
N
2 0 3 : 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methylethyl ester
H
3 C CH N 0 O 0 0
CH
3 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. 15 Yield: 0.490 g (61%); IH NMR 8 1.26 (d, J= 6.35 Hz, 6H, CH(CH 3
)
2 ), 2.17 (s, 6H, CH 2
N(CH
3
)
2 ), 2.45 (s, 3H, ArCH 3 ), 4.03 (s, 2H, CH 2 NMe 2 ), 5.04 (sextet, J= 6.35, 1H, CO 2
CH(CH
3
)
2 ), 6.52 (d, J= 8.55 Hz, 1H, ArH), 7.02 (d, J= 8.55 Hz, 1H, ArH), 11.4 (s, lH, NH). MS(APCI+): m/z 291.1 (MH+). Step B: 20 By a procedure similar to that described in Example 7, Step C. Yield: 0.390 g (60.4%); mp 186-188'C; IR: 2976, 2930, 2856, 1703, 1433, 1079 cm- 1
.
1 H NMR (DMSO-d 6 ) 6 1.10-1.57 (in, 9H, aliphatic CH 2 and CH), 1.23 (d, J= 5.62 Hz, 3H, CH 3 ), 1.25 (d, J= 5.86 Hz, 3H, CH 3 ), 1.71-1.74 (in, IH, aliphatic CH), 1.85-1.88 (in, 1H, aliphatic CH), 2.32-2.44 (in, 2H, obscured by WO 00/42045 PCT/US99/30434 -74 DMSO peak, aliphatic CH), 2.44 (s, 3H, ArCH 3 ), 2.63-2.74 (in, 2H, aliphatic CH), 2.83-2.89 (m, IH, aliphatic CH), 3.21-3.28 (m, 1H, aliphatic CH, obscured by water peak), 5.01 (septet, 1H, CO 2
CH(CH
3
)
2 ), 6.56 (d, J= 8.79 Hz, 1H, ArH), 6.99 (d, J= 8.80 Hz, 1H, ArH), 11.4 (bs, 1H, NIH); MS(APCI+): 383.1 (MH+). 5 Analysis calculated for C 2 3
H
3 0
N
2 0 3 : C, 72.22; H, 7.91; N, 7.32. Found: C, 71.98; H, 7.85; N, 7.29. Example 11 Pyrrolo[3',2':5,6][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 0 00
CH
3 N 10 H Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl- 1 H-indole-3-carboxylic acid cyclopropyl methyl ester was synthesized from intermediate F according to Procedure G. Yield: 0.406 g (62.1%); 1 H NMR (DMSO-d 6 ) 6 0.309-0.346 (m, 15 2H, cyclopropyl CH 2
CH
2 ), 0.538-0.584 (m, 2H, cyclopropyl CH 2
CH
2 ), 1.16-1.24 (m, 1H, cyclopropyl CH), 2.23 (s, 6H, CH 2
N(CH
3
)
2 ), 2.52 (s, 3H, ArCH 3 ), 4.02 (d, J= 7.32, 2H, CO 2
CH
2 CH), 4.10 (s, 2H, CH 2 NMe 2 ), 6.58 (d, J= 8.55 Hz, IH, ArH), 7.09 (d, J= 8.55 Hz, 1H, ArH), 11.5 (s, IH, NH). MS(APCI+): m/z 303.1 (MH+). 20 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 . IH NMR (CDCl 3 ) 6 0.337-0.373 (m, 2H, cyclopropyl CH 2
CH
2 ), 0.596-0.641 (m, 2H, cyclopropyl CH 2
CH
2 ), 1.21-1.89 (m, 1OH, aliphatic 25 CH 2 and CH), 2.15-2.18 (in, 1H, aliphatic CH), 2.48-2.64 (m, 2H, obscured by WO 00/42045 PCTIUS99/30434 -75 ArCH 3 peak, aliphatic CH), 2.64 (s, 3H, ArCH 3 ), 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, CO 2
CH
2 ), 6.77 (d, J= 8.55 Hz, 1H, ArH), 7.06 (d, J= 8.79 Hz, 1H, ArH), 8.10 (bs, 1H, NH); MS(APCI+): 395.1 (MH+). Analysis 5 calculated for C 2 4
H
3 0
N
2 0 3 : 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][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 O N N 0 CH 3 N 10 H Step A: 5-Hydroxy-2-methyl-IH-indole-3-carboxylic acid 2-piperdin- I -yl-ethyl ester (intermediate J, 0.770 g, 2.55 mmol) and aqueous Me 2 NH (40%, 0.704 mL, 5.60 mmol) were mixed with 2 mL of EtOH, aqueous HCHO (37%, 0.248 g, 15 3.06 mmol) was then added. The resulting reaction mixture was heated with a heatgun until a clear solution was obtained. The reaction mixture was stirred at 50'C for 2 days. The reaction mixture was then diluted with EtOAc, then washed with water and dried over Na 2
SO
4 . The solution was concentrated in vacuo affording an oil. The crude product was further purified by flash chromatography 20 (10%-20% MeOH in CHCl 3 ) to give an oil (402 mg, 44% crude yield) which was the desired product with minor impurities: IH NMR (DMSO-d 6 ) 6 1.31-1.33 (m, 2H, piperidine CH 2 ), 1.40-1.45 (m, 4H, 2 x piperidine
CH
2 ), 2.16 (s, 6H,
CH
2
N(CH
2
N(CH
3
)
2 ), 2.30-2.40 (m, 4H, 2 x piperidine
CH
2 ), 2.47 (s, 3H, ArCH 3 ), 2.52-2.55 (m, 2H, OCH 2
CH
2 N), 4.01 (s, 2H, CH 2
N(CH
3
)
2 ), 4.22 (t, J= WO 00/42045 PCT/US99/30434 -76 5.86 Hz, 2H, OCH 2
CH
2 N), 6.52 (d, J = 8.55 Hz, 1H, ArH), 7.02 (d, J= 8.55 Hz, 1H, 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: 5 0.137 g (37%); mp 169-171'C; IR: 2928, 1696, 1434, 1094, 1081 cm- 1
.
1 H NMR (DMSO-d 6 ) 6 1.11-1.54 (in, 15H, aliphatic CH 2 and CH), 1.71-1.74 (in, 1H, aliphatic CH), 1.86-1.90 (in, 1H, aliphatic CH), 2.34-2.47 (in, 6H, obscured by DMSO peak, aliphatic CH), 2.47 (s, 3H, ArCH 3 ), 2.52 (t, J= 5.62 Hz, 2H,
OCH
2
CH
2 N), 2.62-2.71 (in, 2H, aliphatic CH), 2.84-2.89 (in, IH, aliphatic CH), 10 3.24-3.33 (in, lH, aliphatic CH, obscured by water peak), 4.14-4.26 (in, 2H,
OCH
2
CH
2 N), 6.56 (d, J= 8.79 Hz, 1H, ArH), 7.00 (d, J= 8.55 Hz, 1H, ArH), 11.5 (bs, 1H, Nil); MS(APCI+): m/z 452.3 (MH+). Analysis calculated for
C
2 7
H
3 7
N
3 0 3 -0.15H 2 0: C, 71.38; H, 8.28; N, 9.25; H 2 0, 0.59. Found: C, 71.08; H, 8.25; N, 9.02; H 2 0, 0.21. 15 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 20 under reduced pressure. The residue was subjected to flash column chromatography (Si0 2 , 1:1 ethyl acetate/hexane then 10:1 ethyl acetate/ethanol) to afford the desired product. Procedure I: General Procedure for the Synthesis of Ethyl 2-alkyl [(pyrano[2,3-b]quinolizidine)[5 ,6-e]]indole-3-carboxylate. To a stirred solution of 25 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 MgSO 4 and concentrated under reduced pressure to afford the enamine as a white solid. To a stirred solution of dioxane WO 00/42045 PCT/US99/30434 -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 (SiO 2 , 99:1 dichloromethane/methanol) to afford the desired 5 product. Example 13 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-(phenylmethyl)-, ethyl ester N O 0 CH 3 N H 10 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. I H NMR (250 MHz, CD 3 OD) 6 1.38 (t, J= 7.2 Hz, 3H), 4.32 (q, J= 8.5 Hz, 2H), 4.46 (s, 2H), 6.68 (dd, J= 6.8, 2.5 Hz, 15 1H), 7.17 (in, 5H) 7.47 (d, J = 2.25 Hz, IH). LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM N-H 4 0Ac/CH 3 CN, APCI+) t = 7.86 min, m/z = 353.2 (M+1). Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-(phenylmethyl)-, ethyl ester was 20 synthesized according to Procedure I. 68% yield as a white solid. IH NMR (250 MHz, CDCI 3 ) 5 1.36 (t, J= 7.2 Hz, 3H), 1.42 (m, 3H), 1.68 (m, 5H), 1.92 (in, 2H), 2.15 (d, J= 13.3 Hz, 1H), 2.53 (m, 2H), 2.85 (m, 2H), 3.09 (in, 1H), 3.48 (dd, J= 20.0, 7.5 Hz, 1H), 4.35 (q, J= 7.1 Hz, 2H), 4.40 (s, 2H), 6.75 (d, J= 8.6 Hz, IH), 6.96 (d, J= 8.7 Hz, 1H), 7.29 (m, 5H), 7.90 (s, IH). 1 3 C NMR WO 00/42045 PCT/US99/30434 -78 (62.5 MHz, CDC1 3 ) 6 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 NH 4 0Ac/CH 3 CN, APCI+) t = 10.73, m/z = 445.6 (M+1) Elemental Analysis Calculated: C, 75.64; H, 5 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-1-carboxylic acid, 2-ethyl 3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester N0 0 0O CH3 N CH3 H 10 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. 1 H NMR (250 MHz, DMSO) 6 1.23 (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), 15 4.30 (q, J= 7.1 Hz, 2H), 4.44 (s, 2H), 6.61 (d, J= 8.6 Hz, I H), 7.11 (d, J = 8.4 Hz, 1H), 9.70 (bs, 1H). 13 C NMR (62.5 MHz, DMSO) 6 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 NH 4 0Ac/CH 3 CN, APCI+) t = 6.25 min, m/z = 291.3 (M+1). 20 Step B: 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, 1 5-decahydro-, ethyl ester was synthesized according to Procedure I 43% yield as a white solid. 1 H NMR (250 MHz, CDCI 3 ) 6 1.34 (t, J= 7.6 Hz, 3H), 1.36 (t, J= 7.2 Hz, 3H), 1.63 (m, 5H), 1.88 (in, 3H), 25 2.15 (d, J= 13.3 Hz, 1H), 2.47 (m, 2H), 2.82 (m, 2H), 3.02 (q, J= 7.5 Hz, 2H), WO 00/42045 PCTIUS99/30434 -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). 13 C NMR (62.5 MHz, CDCl 3 ) 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 5 micron, 10 mM NH 4 0Ac/CH 3 CN, APCI+) t = 10.75, m/z = 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, 10 2-cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester N 0 0 CH 3 N H Step A: Ethyl 2 -cyclopropyl- 4 -(dimethylamino)methylene-5-hydroxy 3-indolecarboxylate was synthesized from intermediate R according to 15 Procedure H. 64% yield as a white solid. I H NMR (250 MHz, DMSO) 6 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). 13 C 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, 129.1, 147.3, 152.8, 165.9. 20 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, 1 5-decahydro-, ethyl ester was synthesized according to Procedure I. 60% yield as a white solid. IH NMR (250 MHz,
CDCI
3 ) 6 0.79 (m, 2H), 1.07 (d, J= 8.54, 2H), 1.37 (m, 3H), 1.40 (t, J= 7.2 Hz, 25 3H), 1.61 (m, 9H), 1.92 (m, 1H), 2.17 (d, J= 15.0 Hz, 2H), 2.60 (m, 3H), 2.83 (m, WO 00/42045 PCT/US99/30434 -80 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). 13 C NMR (62.5 MHz, CDCI 3 ) 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 5 18, 5 micron, 10 mM NH 4 0Ac/CH 3 CN, APCI+) t = 10.70 min, ni/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, 10 3 ,7,8, 9 ,10,1 2 ,1 3 ,14,14a,15-decahydro-2-propyl-, ethyl ester N0 0O O CH3 N CH H3 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, 1 5-decahydro-2-propyl-, ethyl ester was synthesized from 15 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 NH 4 0Ac/CH 3 CN, APCI+) t = 7.45 min, n/z = 305.3 (M+1). Step B: Pyrrolo[3',2':5,6][I]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-propyl-, ethyl ester was synthesized according to Procedure I. 28% yield as a white solid. 1 H NMR (250 MHz,
CDCI
3 ) 6 0.99 (t, J= 7.3 Hz, 3H), 1.40 (m, 4H), 1.44 (t, J= 7.1 Hz, 3H), 1.68 (in, 7H), 1.92 (in, IH), 2.12 (d, J= 12.0 Hz, 1H), 2.55 (in, 2H), 2.92 (m, 5H), 3.47 (dd, J= 16.7, 6.6 Hz, IH), 4.35 (q, J= 7.1 Hz, 2H), 6.77 (d, J= 8.7 Hz, 1H), 25 7.05 (d, J= 8.7 Hz, 1H), 8.12 (s, 1H). 13 C NMR (62.5 MHz, CDCl 3 ) 6 13.9, 14.4, WO 00/42045 PCTIUS99/30434 -81 19.8, 23.0, 25, 26, 27.0, 30.1, 30.5, 36.7, 49.6, 59.7, 87.1, 110, 111, 113.8, 127, 129, 146, 149, 167. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM
NH
4 0Ac/CH 3 CN, APCI+) t = 11.56 min, m/z = 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. 5 Example 17 Pyrrolo[3',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 N O 0 0O CH 3 N H H3C CH3 Step A: 10 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 NH 4 0Ac/CH 3 CN, APCI+) t = 7.86 min, m/z = 319.3 (M+ 1). Step B: 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-(2-methylpropyl)-, ethyl ester was synthesized according to Procedure I. 27% yield as a white solid. IH NMR (250 MHz, CDCl 3 ) 6 0.95 (d, J= 4.3 Hz, 3H), 0.98 (d, J= 4.3 Hz, 3H) 1.23 (m, 1H), 1.39 (t, J= 7.1 Hz, 3H), 1.42 (m, 6H), 1.63 (m, 6H), 1.88 (m, 1H), 2.00 (m, 20 1H), 2.16 (d, J= 13.3 Hz, IH), 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, 1H), 8.04 (s, IH). 13 C NMR (62.5 MHz, CDCl 3 ) 6 14.5, 19.8, 22.5, 22.6, 25.0, 25.5, 27.0, 29.4, 30.1, 31.2, 36.7, 37.5, 49.5, 59.7, 87.1, 109.3, 111.
4 ,11 3
.
8 ,1 6 6 .1. LC/MS (150 mm x 4.6 mm, C-18,5 micron, 10 mM WO 00/42045 PCTIUS99/30434 -82
NH
4 0Ac/CH 3 CN, APCI+) t = 6.43 min, m/z = 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, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1-dimethylethyl ester H C
H
3
C
3 OH N 0 l 3 00
OH
3 N H Step A: tert-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 10 15 minutes. The HCl solution was decanted, and this was repeated two times. The activated Zn was washed with distilled H 2 0 (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 15 bottom flask was added 5 drops of tert-butyl bromoacetate at room temperature. The mixture was then heated to reflux for 15 minutes. 0.60 mL (6 mmol) Acetonitrile was added at once and tert-butyl bromoacetate (1.50 mL, 10 mmol) was added dropwise over 30 minutes. The reaction mixture turned to green when about 2/3 of tert-butyl bromoacetate was added. The mixture was refluxed for an 20 additional 30 minutes and then allowed to cool to room temperature. To the stirred solution was added THF (30 mL) and K 2
CO
3 (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 25 combined supernatant was dried over MgSO 4 , 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 0 C to a light yellow solid. 1 H NMR WO 00/42045 PCTIUS99/30434 -83 (250 MHz, CDCl 3 ) 8 1.45 (s, 9H), 1.84 (s, 3H), 4.43 (s, 2H). 13 C NMR (62.5 MHz, CDCI 3 ) 6 22.3, 28.6, 78.1, 86.0, 158.9, 171.1. Step B: tert-Butyl 5-hydroxy- 2 -methyl-3-indolecarboxylate. 1, 4 -Benzoquinone 5 (3.30 g, 30 mmol) in ethanol (15 mL) was heated up until all solid was dissolved. tert-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 (A1 2 0 3 , ethyl acetate) to afford 3.57 g of title 10 compound (14.4 mmol, 48%) as a brown crystal. mp 1 14.0-116.0-C. IH NMR (250 MHz, DMSO) 6 1.57 (s, 9H ), 2.55 (s, 3H), 6.57 (dd, J= 8.6,2.3 Hz, lH), 7.09 (d, J= 8.6 Hz, 1H,), 7.28 (d, J= 2.3 Hz, 1H), 8.78 (s, 1H), 11.41 (s, lH). 13 C NMR (62.5 MHz, d 6 -MeOH) 6 14.4, 29.1, 80.6, 105.3, 106.8, 112.2, 129.9, 131.1, 145.9, 153.1, 161.7, 167.9. 15 Step C: tert-Butyl 4 -(dimethylamino)methylene-5-hydroxy-2-methyl 3-indolecarboxylate. To a stirred solution of tert-butyl 5-hydroxy-2-methyl 3-indolecarboxylate (1.48 g, 6.0 mmol) in ethanol (4.5 mL) was added formaldehyde (0.55 mL, 7.2 mmol) and dimethylamine (1.66 mL, 13.2 mmol). 20 The solution was stirred at 60'C for 10 hours, cooled and concentrated under reduced pressure. The residue was extracted with ether (30 mL), filter, 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 0 C (decompose). IH NMR (250 MHz, d 6 -MeOH) 6 1.63 (s, 9H), 1.88 (s, 3H), 2.61 (s, 3H), 2.90 (s, 6H), 25 4.76 (s, 2H), 6.81 (d, J= 8.7 Hz, 1H), 7.27 (d, J= 8.6 Hz, 1H). 13 C NMR (62.5 MHz, d 6 -MeOH) 6 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/CH 3 CN, APCI+) t = 7.75 min, n/z = 305.4 (M+1).
WO 00/42045 PCT/US99/30434 -84 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-, 1,1 -dimethylethyl ester To a stirred solution of NaOH (50% w/w, 100 mL) and ether (20 mL) was added 5 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 MgSO 4 and concentrated under reduced pressure to afford the enamine as a white solid. 1.0 mL dioxane was added to the enamine and then tert-butyl 4 -(dimethylamino)methylene-5-hydroxy 2-methyl-3-indole carboxylate (0.061 g, 0.20 mmol) followed by 0.5 mL dioxane. 10 The solution was refluxed overnight, cooled to room temperature, concentrated under reduced pressure and subjected to flash column chromatography (SiO 2 , 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). IH NMR (250 MHz, CDCI 3 ) 6 1.45 (in, 4H), 1.61 (s, 9H), 1.69 (m, 5H), 1.89 (in, IH), 2.14 (d, J= 15 Hz, 1H), 2.49 (m, 15 2H), 2.56 (s, 3H), 2.84 (d, J= 6 Hz, 2H), 3.06 (in, 1H), 3.48 (dd, J= 18, 7 Hz, 1H), 6.74 (d, J= 8.6 Hz, I H), 7.01(d, J= 8.6 Hz, 1H), 8.07 (s, 1H). 13 C NMR (62.5 MHz, CDCl 3 ) 5 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 NH 4 0Ac/CH 3 CN, APCI+) t 20 =7.98 min, m/z = 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-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza cyclopenta[a]anthracene-1-carboxylic acid ethyl ester N 0 -CH H3C C O CH N 25 H WO 00/42045 PCT/US99/30434 -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 Ann. Chem., 1898;289:216. Step B: 2,6a,7-Trimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza 5 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 N 2 was heated at 100 C for 4 hours. An additional 10 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-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza 15 cyclopenta[a]anthracene-1-carboxylic acid ethyl ester as a white powder: mp 169-173'C; 1 H NMR (400 MHz, CDCI 3 ) 6 1.34 (in, 2H), 1.36 (t, J= 7.08 Hz, 3H, CH 2
CH
3 ), 1.45 (s, 3H, CH 3 C(O)N), 1.56 (in, 2H), 1.66 (in, 1H), 1.93 (in, 1H), 2.56 (s, 3H, CH 3 ), 2.58 (s, 3H, CH 3 ), 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, CH 2
CH
3 ), 6.68 (d, 20 J= 8.79 Hz, 1H, ArH), 7.01 (d, J= 8.30 Hz, 1 H, ArH), 8.03 (bs, IH, NH!); MS (APCI+) mn/z 343.2 (MH+). Analysis calculated for C 2 0
H
2 6
N
2
O
3 -0.17 H 2 0: 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, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza 25 cyclopenta[a]anthracene-1-carboxylic acid ethyl ester
H
3 C N 0
/-CH
3 H3O 0 CH N
H
WO 00/42045 PCT/US99/30434 -86 Step A: 1-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. 5 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 10 was extracted with 4 x10 mL of Et 2 0, and the combined extracts were washed with 1 x10 mL of saturated aqueous NaCI, dried with MgSO 4 , filtered, and concentrated into the reaction flask to give 90 mg (0.724 mmol) of 1-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-1H-indole 15 3-carboxylic acid ethyl ester (0.200 g, 0.724 mmol) was added. The resulting solution was heated at reflux under N 2 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-7,8,9,10,1Oa,1 1 20 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- 1 ; 1 H NMR (300 MHz, CDCl 3 ) 6 1.16 (in, 3H, CH 3
CH
2 N), 1.37 (in, 1H), 1.40 (in, 1H), 1.48 (s, 2H), 1.56 (s, 2H), 1.64 (in, 2H), 1.97 (in, 1H), 2.61 (s, 3H, CH 3 ), 2.72 (in, 1H), 2.84 (in, 1H), 2.90 (bd, J= 19.04 Hz, 2H), 25 3.16 (in, 1H), 3.54 (dd, J= 18.31, 6.78 Hz, 1H), 4.35 (qd, J= 7.14, 1.65 Hz, 2H,
OCH
2
CH
3 ), 6.70 (d, J= 8.61 Hz, 1H, ArH), 7.03 (d, J= 8.61 Hz, ArH), 8.06 (bs, 1H, NH); MS (APCI+) n/z 357.1 (MH+). Analysis calculated for C21H28N2O3: C, 70.76; H, 7.92; N, 7.86. Found: C, 70.49; H, 7.80; N, 7.66.
WO 00/42045 PCT/US99/30434 -87 Example 21 FC CH3 3 O
CH
3 N H Isomer A: 6a-Ethyl-2,7-dimethyl-7,8,9,10,1 Ga, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza 5 cyclopenta[a]anthracene-1-carboxylic acid ethyl ester Step A: 6-Ethyl-i -methyl-2,3, 4 ,5-tetrahydropyridinium perchlorate 6-Ethyl-1-methyl- 2 ,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Leonard N.J.; Hauck, Jr., F.P., J. Am. Chem. Soc., 1957;79:5279. 10 Step B: 6a-Ethyl-2,7-dimethyl -7,8,9, 10,1 0a, 11 -hexahydro-3H,6aH-6-oxa 3
,
7 -diaza-cyclopenta[a]anthracene-1 -carboxylic acid ethyl ester 6-Ethyl-I -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 15 was extracted with 4 x 15 mL of Et 2 0, and the combined extracts were washed with I x 15 mL of saturated aqueous NaCl, dried with MgSO 4 , 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 20 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 N 2 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 25 silica gel using 20-60% ethyl acetate:hexanes to give 56 mg (7.5 %) of a single isomer A of 6a-ethyl-2,7-dimethyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa- WO 00/42045 PCT/US99/30434 -88 3 ,7-diaza-cyclopenta[a]anthracene-1-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- 1 ; iH NMR (400 MHz, CDCl 3 ) 8 0.91 (m, 3H,
CH
3
CH
2 C(O)N), 1.34 (m, 2H), 1.36 (m, 3H, OCH 2
CH
3 ), 1.54 (bs, 1H), 1.63 (m, 5 1H), 1.76 (m, IH), 1.84 (m, 1H), 2.06 (m, 1H), 2.46 (s, 3H, CH 3 ), 2.52 (m, 1H), 2.57 (2, 3H, CH 3 ), 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, OCH 2
CH
3 ), 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+) m/z 357.2 (MH+). Analysis calculated for C 2 1
H
2 8
N
2 03-0.04 H 2 0: C, 70.61; H, 7.92; N, 7.84; 10 water, 0.22. Found: C, 70.27; H, 7.92; N, 7.58; water, 0.22. Example 22 IN- CHs3
H
3 C CF3 \
H
3 N H Isomer B: 6a-Ethyl-2,7-dimethyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza 15 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 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et 2 0, and the combined extracts were washed 20 with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO 4 , 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 25 and MS as it was stirred at room temperature under N 2 for 2 hours, heated at 50'C for 24 hours, at 60'C for 3 hours, at 70 0 C for 17 hours, and between 89-90'C for WO 00/42045 PCT/US99/30434 -89 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 isomer B of 6a-ethyl-2,7-dimethyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa 5 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 ; I H NMR (400 MHz) 6 1.08 (in, 3H,
CH
3
CH
2 C(O)N), 1.20 (in, 1H), 1.37 (in, 3H, OCH 2
CH
3 ), 1.41 (in, lH), 1.52 (s, 3H, CH 3 ), 1.59 (in, 2H), 1.85 (bd, J= 13.18 Hz, 1H), 2.30 (i, 1H), 2.35 (in, 2H), 10 2.58 (s, 3H, CH 3 ), 2.91 (in, 1H), 3.11 (in, 2H), 4.32 (in, 2H, OCH 2
CH
3 ), 6.72 (d, J= 8.55 Hz, IH, ArH), 7.00 (d, J= 8.79 Hz, 1H, ArH), 8.03 (bs, IH, NH); MS (APCI+) m/z 357.2 (MH+). Analysis calculated for C 2 1
H
2 8
N
2 0 3 : C, 70.76; H, 7.92; N, 7.86. Found: C, 71.45; H, 8.44; N, 6.65. HPLC (ALLTECH/ALLTIMA C-18 1:1 H 2 0/CH 3 CN + 0.05% TFA): retention time = 4.940 min, 99.40% purity. 15 Example 23 6a,7-Diethyl-2-methyl-7,8,9, 10,1 Oa, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza cyclopenta[a]anthracene-1-carboxylic acid ethyl ester N 03 CH O0
CH
3 3CH 3 OH 3 N H Step A: 1,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate 20 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. Am. Chei. 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 25 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 WO 00/42045 PCT/US99/30434 -90 and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et 2 0, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO 4 , filtered, and concentrated into the reaction flask to give 207 mg (1.49 mmol) of 1,6-diethyl 5 1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (1.3 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.373 g, 1.35 mmol) was added. The resulting solution was heated at 100*C under N 2 for 7 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 20-100% 10 ethyl acetate:hexanes and recrystallized with ethyl acetate to give 123 mg (25%) of 6a,7-diethyl-2-methyl-7,8,9,10,1 Oa, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza cyclopenta[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- 1 ; 1 H NMR (400 MHz, CDCl 3 ) 6 0.900 (in, 2H, CH 3
CH
2 C(O)N), 1.11 (in, 2H, 15 CH 3
CH
2 N), 1.34 (m, 2H), 1.36 (in, 3H, CH 3
CH
2 0), 1.57 (m, 2H), 1.85 (in, 2H), 2.06 (in, 1H), 2.57 (s, 3H, CH 3 ), 2.70 (in, 2H), 2.79 (bd, J= 18.31 Hz, 1H), 2.84 (in, 1H), 3.00 (in, IH), 3.37 (in, 1H), 4.31 (m, 2H, CH 3
CH
2 0), 6.64 (d, J= 8.55 Hz, 1H, ArH), 6.98 (d, J= 8.55 Hz, 1 H, ArH), 8.00 (bs, 1H, NH); MS (APCI+) m/z 371.1 (MH+). Analysis calculated for C 2 2
H
3 0
N
2 0 3 : C, 71.32; 20 H, 8.16; N, 7.56. Found: C, 71.28; H, 7.77; N, 7.32. Example 24 7-Benzyl-2,6a-dimethyl-7,8,9,10,1 Oa, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza cyclopenta[a]anthracene- 1 -carboxylic acid ethyl ester N 0 CH 3 HO
CH
3 N
H
WO 00/42045 PCTIUS99/30434 -91 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 Mbhrle H.; Dwuletzki H.Z., Naturforsch., B: Anorg. Chem., Org. Chen., 1986;41b:1323. 5 Step B: 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 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 10 with 4 x 20 mL of Et 2 0, and the combined extracts were washed with 1 x 20 mL of saturated aqueous NaCl, dried with MgSO 4 , 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 -dimethylaminomethyl-5-hydroxy-2 methyl-1H-indole-3-carboxylic acid ethyl ester (0.330 g, 1.20 mmol) was added. 15 The resulting solution was heated at 80-90'C under N 2 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-dim ethyl 7,8,9,10,1 Oa, 11 -hexahydro-3H,6aH-6-oxa-3, 7 -diaza-cyclopenta[a]anthracene 20 1-carboxylic acid ethyl ester of an off-white powder: mp 196-198'C; IR (KBr) 3397, 2983, 2923, 2897, 2854, 1668, 1432, 1200, 1097 cm- 1 ; 1 H NMR (400 MHz, CDCl 3 ) 6 1.36 (m, 1H), 1.37 (m, 3H, OCH 2
CH
3 ), 1.50 (s, 3H,
CH
3 C(O)N), 1.53 (m, 3H), 2.03 (m, IH), 2.56 (m, 1H), 2.58 (s, 3H, CH 3 ), 2.71 (m, 1H), 2.94 (d, J= 18.07 Hz, 1H), 3.53 (dd, J= 18.07, 6.84 Hz, 1H), 25 3.58 (d, J = 15.14 Hz, 1H, NCH(H)Ph), 4.32 (m, 2H, OCH 2
CH
3 ), 4.47 (d, J= 14.89 Hz, I H, NCH(H)Ph), 6.71 (d, J= 8.55 Hz, 1H, ArMH, 7.01 (d, J= 8.55 Hz, IH, ArH), 7.18 (t, J= 7.08 Hz, 1H, PhH), 7.28 (m, 2H, PhH), 7.35 (d, J = 7.33 Hz, 2H, PhH), 8.06 (bs, 1H, NH); MS (APCI+) m/z 419.2 (MH+). Analysis calculated for C 2 6
H
3 0
N
2
O
3
-H
2 0: C, 74.39; H, 7.24; N, 30 6.67; water, 0.30. Found: C, 74.27; H, 7.25; N, 6.54; water, 0.31.
WO 00/42045 PCTIUS99/30434 -92 Example 25
H
3 C
H
3 CN 0 CH3 N H Isomer A: 2,7-Dimethyl-6a-phenyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza 5 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 I-methyl-6-phenyl-2,3,4,5-tetrahydro pyridinium perchlorate is published in Leonard N.J.; Hauck Jr. F.P., J. Am. Chem. Soc., 1957;79:5279. 10 Step B: 2,7-Dimethyl-6a-phenyl-7,8,9, 10,1 0a, 11 -hexahydro-3H,6aH-6-oxa 3,7-diaza-cyclopenta[a] anthracene- I -carboxylic acid ethyl ester An excess of I -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 15 with 4 x 20 mL of Et 2 0, and the combined extracts were washed with I x 20 mL of saturated aqueous NaCl, dried with MgSO 4 , filtered, and concentrated to give the enamine. 1-Methyl- 6 -phenyl-1,2,3,4,-tetrahydro-pyridine(o.428 g, 2.47 mmol) was dissolved in dioxane (1.8 mL) and 4 -dimethylaminomethyl-5-hydroxy 2-methyl-IH-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol) was 20 added. The reaction mixture was heated at 75-80'C under N 2 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 25 acetate:hexanes to give a single isomer A with a smaller Rf value, which was recrystallized with ether:hexanes to give 73 mg (15%) of 2,7-dimethyl-6a-phenyl- WO 00/42045 PCT/US99/30434 -93 7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa-3, 7 -diaza-cyclopenta[a]anthracene 1-carboxylic acid ethyl ester as an off-white powder; mp 176-177'C; IR (KBr) 3400, 2942, 2930, 2859, 1647, 1434, 1206, 1099, 1079 cm- 1 ; 1 H NMR (400 MHz, CDCI 3 ) 8 1.20 (in, 3H, OCH 2
CH
3 ), 1.48 (m, 2H), 1.67 (d, 5 J= 13.18 Hz, 1H), 1.84 (in, 1H), 2.13 (s, 3H, CH 3 ), 2.35 (in, 1H), 2.52 (s, 3H,
CH
3 ), 2.58 (m, 1H), 2.68 (in, 1H), 2.81 (d, J= 17.33 Hz, 1H), 2.90 (m, 1H), 4.17 (q, J= 7.08 Hz, 2H, OCH 2
CH
3 ), 6.89 (d, J= 8.79 Hz, 1H, ArH), 7.06 (d, J= 8.79 Hz, 1H, ArH), 7.15 (in, 3H, PhH), 7.35 (in, 2H, PhH), 8.07 (bs, lH, NH); MS (APCI+) mn/z 405.2 (MH+). Analysis calculated for C 2 5
H
2 8
N
2 0 3 : C, 74.23; 10 H, 6.98; N, 6.93. Found: C, 73.93; H, 7.11; N, 6.66. Example 26
H
3 C
H
3 C'N 0
CH
3 N H Isomer B: 2,7-Dimethyl-6a-phenyl-7,8,9,10,1 Oa, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza 15 cyclopenta[a]anthracene-1-carboxylic acid ethyl ester An excess of 1-methyl- 6 -phenyl-2,3,4,5-tetrahydro-pyridinlium 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 Et 2 0, and the combined extracts were washed with I x 20 mL 20 of saturated aqueous NaCl, dried with MgSO 4 , 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-IH-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol) was added. The reaction mixture was heated at 75-80'C under N 2 for 16 hours, 1.0 mL 25 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 0 C for WO 00/42045 PCT/US99/30434 -94 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 5 (14%) of a single isomer B of 2,7-dimethyl-6a-phenyl-7,8,9,10,1 Oa, 1-hexahydro 3H,6aH-6-oxa-3, 7 -diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester with a larger Rf value as a course peach powder: mp 184-186'C; IR (KBr) 3380, 2926, 1698, 1684, 1436, 1073 cm- 1 ; 1 H NMR (400 MHz, CDCl 3 ) 5 1.37 (t, J= 7.08 Hz, 3H, OCH 2
CH
3 ), 1.49 (in, 2H), 1.64 (in, lH), 1.76 (in, lH), 2.29 (in, 10 1H), 2.31 (s, 3H, CH 3 ), 2.59 (s, 3H, CH 3 ), 2.97 (d, J= 17.58 Hz, 1H), 3.52 (in, 1H), 3.77 (in, lH), 4.32 (in, 2H, OCH 2
CH
3 ), 4.89 (bs, lH), 6.74 (d, J= 8.55 Hz, 1H, Arl), 7.02 (d, J= 8.55 Hz, IH, ArH), 7.33 (in, 5H, PhH), 8.06 (bs, lH, NH); MS (APCI+) m/z 405.2 (MH+). Analysis calculated for C 2 5
H
2 8
N
2 0 3 : C, 74.23; H, 6.98; N, 6.93. Found: C, 74.18; H, 6.90; N, 6.72 15 Example 27. 1H, 7 H-Indolizino[8',8a':5,6]pyrano[3,2-e]indole-1-carboxylic acid, 8,9,11,12,13,13a,14,1 4 a-octahydro-2-methyl-, ethyl ester N 0 ICH3 CHa NN H Step A: 2,3,5,6,7,8-Hexahydro-1H-indolizinylium perchlorate 20 2 ,3,5,6,7,8-Hexahydro- IH-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-e]indole-1-carboxylic acid, 8,9,11,12,13,13a,14,1 4 a-octahydro-2-methyl-, ethyl ester 25 2 ,3,5,6,7,8-Hexahydro-1H-indolizinylium perchlorate (0.330 g, 1.48 mmol, Example 27, Step A) was dissolved in a minimum amount of water WO 00/42045 PCT/US99/30434 -95 and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et 2 0, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO 4 , filtered, and concentrated into the reaction flask to give 143 mg (1.16 mmol) of enamine. 5 1,2,3,5,6,7-Hexahydro-indolizine was dissolved in dioxane (1.5 mL) and 4 -dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.321 g, 1.16 mmol) was added. The resulting solution was heated at reflux under N 2 for 5 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 100% 10 acetone and recrystallized with ethyl acetate to give 129 mg (31%) of 1H,7H Indolizino[ 8 ',8a':5,6]pyrano[3,2-e]indole-1-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 cn 1 ; 1 H NMR (300 MHz, CDCI 3 ) 6 1.38 (in, 2H), 1.40 (t, J= 7.14 Hz, 3H, 15 OCH 2
CH
3 ), 1.68 (in, 3H), 1.90 (in, 3H), 2.05 (in, IH), 2.61 (s, 3H, CH 3 ), 2.74 (in, 1H), 2.84 (in, 1H), 2.97 (d, J = 17.40 Hz, 1H), 3.09 (in, 2H), 3.47 (dd, J= 17.76, 6.78 Hz, 1H), 4.36 (in, 2H, OCH 2
CH
3 ), 6.67 (d, J= 8.61 Hz, 1H, ArM), 7.03 (d, J= 8.61 Hz, I H, ArH), 8.06 (bs, 1H, NH); MS (APCI+) m/z 355.2 (MH+). Analysis calculated for C 2 1
H
2 6
N
2 03-0.23H 2 0: C, 70.34; H, 7.44; 20 N, 7.81. Found: C, 70.35; H, 7.48; N, 7.61.
WO 00/42045 PCT/US99/30434 -96 Example 28 3H,7H-Pyrrolizino[ l',8':5,6]pyrano[3,2-e]indole-1 -acetic acid, 8,9,11,12,12a,13 hexahydro-2-methyl-, ethyl ester N CH 3 0,~~0
CH
3 N H 5 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., Synthesis, 1978;9:701. Step B: 3H,7H-Pyrrolizino[ 1',8':5,6]pyrano[3,2-e]indole-1-acetic acid, 8,9,11,12,1 2a, 13-hexahydro-2-methyl-, ethyl ester 10 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 Et 2 0, and the combined extracts were washed with I x 15 mL of saturated aqueous NaCl, dried with MgSO 4 , filtered, and concentrated into the 15 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-1 H-indole-3-carboxylic acid ethyl ester (0.794 g, 2.88 mmol) was added. The resulting solution was heated at 80'C under N 2 for 17 hours, cooled to room temperature, and concentrated. The crude 20 residue was purified by flash column chromatography on silica gel using 15% MeOH:CH 2 Cl 2 and recrystallized with ether to give 105 mg (11%) of 3H,7H pyrrolizino[ l', 8 ':5,6]pyrano[3,2-e]indole- 1-acetic acid, 8,9,11,12,12a, 13 hexahydro-2-methyl-, ethyl ester as a white powder; mp 206-207'C; IR (KBr) 2972, 2901, 2864, 2828, 1694, 1429, 1196, 1087 cm- 1 ; 1 H NMR (400 MHz, 25 CDCI 3 ) 6 1.37 (t, J= 7.08 Hz, 3H, OCH 2
CH
3 ), 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, IH), 2.60 (s, 3H,
CH
3 ), 3.22 (m, IH), 3.35 (m, 1H), 3.36 (d, J= 4.88 Hz, 1H), 4.34 (m, 2H, WO 00/42045 PCT/US99/30434 -97
OCH
2
CH
3 ), 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
C
2 0
H
2 4
N
2 0 3 : C, 70.57; H, 7.11; N, 8.23. Found: C, 70.40; H, 7.27; N, 7.94. Example 29 5 2-Methyl-8,9, 10,1 0a, 11,12,12a, 1 3 -octahydro-3H,6aH,7H-6-oxa-3,6b-diaza benzo[a]cyclopenta[h]anthracene-1-carboxylic acid ethyl ester CH N O3 0~~
CH
3 N H Step A: 1,3,4,8,9, 9 a-Hexahydro-2H-quinolizine 1, 3
,
4
,
8
,
9
,
9 a-Hexahydro-2H-quinolizine was synthesized according to the 10 procedure published in Bohlmann F. et al., Chem. Ber., 1973;106:3026. Step B: 2-Methyl-8,9,10,10a,11,12,12a,1 3 -octahydro-3H,6aH,7H-6-oxa-3,6b diaza-benzo[a]cyclopenta[h]anthracene- I -carboxylic acid ethyl ester 1,3,4,8,9, 9 a-Hexahydro-2H-quinolizine (0.372 g, 2.71 mmol, Example 29, Step A) was dissolved in dioxane (2.7 mL) and 4-dimethylaminomethyl-5 15 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 N 2 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:CH 2 Cl 2 and recrystallized with cyclohexane to give 71 mg (14%) of 20 2-methyl-8,9,10,1 0a, 11,12,12a, 1 3-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza benzo[a]cyclopenta[h]anthracene-l-carboxylic acid ethyl ester as an off-white powder: mp 178-18 0 'C; IR (KBr) 3372, 2929, 2859, 1669, 1654, 1435, 1198, 1095, 1079 cm- 1 ; 1 H NMR (400 MHz, CDCI 3 ) 6 1.15 (m, 1H), 1.35 (t, J= 7.08 Hz, 3H, OCH 2
CH
3 ), 1.36 (in, 4H), 1.49 (in, 2H), 1.65 (m, 3H), 2.20 (in, 25 1H), 2.58 (s, 3H, CH 3 ), 2.68 (m, IH), 2.82 (in, IH), 2.89 (d, J= 17.58 Hz, 1H), WO 00/42045 PCT/US99/30434 -98 3.05 (in, 1H), 3.45 (in, 1H), 4.31 (in, 2H, OCH 2
CH
3 ), 4.68 (s, 1H, CH(O)N), 6.68 (d, J= 8.79 Hz, 1H, ArM), 6.99 (d, J= 8.55 Hz, 1H, ArH), 8.03 (bs, IH, NH); minor diastereomer diagnostic peaks IH NMR (400 MHz, CDCl 3 ) 8 6.75 (d, J= 8.55 Hz, 1H, ArH); MS (APCI+) m/z 369.1 (MH+). Analysis 5 calculated for C 2 2
H
2 8
N
2 0 3 : 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 H 2 0/CH 3 CN + 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 % Et 2 NH,ethanol + 0.05% 10 Et 2 NH): 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-e]indole-1 -acetic acid, 7,8,9,10,12,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester, or 15 7H-Azepino[1 ",2": 1 "2']pyrido[3',2':5,6]pyrano[3,2-e]indole-1 -acetic acid, 3,8,9,10,11,13,14,15,15a,16-decahydro-2-methyl-, ethyl ester NO H 3 Nr0 1r-CH 3 N 0 00 tI H 3 N OH 3 H H Step A: 2,3,4,6,7,8,9,10-Octahydro-pyrido[1,2-a]azepine perchlorate A synthesis of 2,3,4,6,7,8,9,1 0-octahydro-pyrido[1,2-a]azepine perchlorate 20 is published in McIntosh J.M. et al., Can. J Chem., 1983;61:2016. Step B: An excess of 2,3,4,6,7,8,9,1 0-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 25 with 4 x 20 mL of Et 2 0, and the combined extracts were washed with 1 x 20 mL WO 00/42045 PCT/US99/30434 -99 of saturated aqueous NaCl, dried with MgSO 4 , 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- 1 H-indole 3-carboxylic acid ethyl ester (0.797 g, 2.88 mmol) was added. The reaction 5 mixture was heated at 80'C under N 2 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:CH 2 Cl 2 -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-e]indole- -acetic acid, 10 7,8,9,10,12,13,14,15,15a, 1 6-decahydro-2-methyl-, ethyl ester or 7H azepino[ 1 ",2": I' 2 ']pyrido[3',2':5,6]pyrano[3,2-e]indole- I-acetic acid, 3,8,9,10,11,1 3 ,1 4 ,15,15a,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, 1073 cm- 1 ; IH NMR (400 MHz, CDC 3 ) 6 0.86 (m, 1H), 1.35 (in, 3H), 15 1.36 (in, 3H, OCH 2
CH
3 ), 1.45 (m, 3H), 1.60 (in, 3H), 1.69 (dd, J= 14.65, 10.01 Hz, 1H), 1.95 (m, 1H), 2.19 (m, 1H), 2.41 (in, IH), 2.54 (m, 1H), 2.57 (s, 3H, CH 3 ), 2.80 (d, J= 18.56 Hz, lH), 3.11 (in, 1H), 3.34 (in, IH), 3.48 (in, IH), 4.31 (in, 2H, OCH 2
CH
3 ), 6.70 (d, J= 8.55 Hz, IH, ArH), 6.98 (d, J= 8.55 Hz, 1H, ArH), 8.01 (bs, IH, NH); MS (APCI+) mn/z 383.1 (MH+). Analysis calculated 20 for C 2 3
H
3 0
N
2 0 3 : 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 aide (1.1 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 Me 2 NH (40%, 2.42 mmol, 2.2 eq) were added, and the reaction was allowed to stir. After several 25 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.
WO 00/42045 PCT/US99/30434 -100 Procedure K: General procedure for the condensation reaction: 1,2,3,4,6,7,8,9 octahydro-quinolizinylium perchlorate (17.8 mmol, 1.2 eq) was converted to the enamine in the following manner: the imine was dissolved in IN NaOH (10 mL) and the solution extracted with 2 x 20 mL of diethyl ether. The extracts were 5 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 10 precipitate. The mixture was cooled in an ice bath, and the resulting solid was collected by filtration. The solid was washed sparingly with CH 3 CN and dried under vacuum at 50 degrees for 24 hours. Example 31 8,9,11,12,13,13 a,4,14a-Octahydro-N,2-dimethyl-pyrrolo[3',2':5,6][1] 15 benzopyrano[3,2-i]quinolizine-1-carboxamide N O CH 3 CH N H Step A: 4 -Dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3 -carboxylic acid methyl amide was synthesized from Intermediate W according to Procedure J. 20 Yield: 0.186 g (63.2%); mp: decomposition at >210'C; IR: 3319, 1615, 1515, 1433, 1218, 801 cm- 1
.
1 H NMR (DMSO-d 6 ) 6: 2.14 (s, 6H, CH 2
N(CH
3
)
2 ), 2.28 (s, 3H, ArCH 3 ), 2.70 (d, J= 3.91 Hz, 3H, CONHCH 3 ), 3.69 (s, 2H,
CH
2
N(CH
3
)
2 ), 6.48 (d, J= 8.55 Hz, 1H, ArH), 6.97 (d, J= 8.55 Hz, 1H, ArH), 8.06 (s, 1H, CONHCH 3 ), 10.88 (s, 1H, indole NH). MS(APCI+): m/z 25 262.1 (MH+); Analysis calculated for C 14
H
19
N
3 0 2 : C, 64.35, H, 7.33, N, 16.08. Found: C, 64.26, H, 7.44, N, 15.87.
WO 00/42045 PCT/US99/30434 -101 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 5 at >210'C; IR: 3392,3057, 2935, 2857, 1625, 1429, 1215 cm- 1 ; 1 H NMR (DMSO-d 6 ) 8 1.08-1.54 (m, 9H, aliphatic CH 2 and CH), 1.63-1.69 (m, 1H, aliphatic CH), 1.81-1.93 (m, 1H, aliphatic CH), 2.27 (s, 3H, ArCH 3 ), 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, CONHCH 3 ), 2.87-2.95 (m, 1H, aliphatic 10 CH), 3.05 (dd, J 18.3, 5.37 Hz, 1H, aliphatic CH), 6.49 (d, J= 8.79 Hz, 1H, ArH), 6.94 (d, J= 8.79 Hz, IH, ArH), 7.70-7.75 (m, I H, CONHCH 3 ), 10.9 (s, 1H, NH); MS(APCI+): m/z 354.2 (MH+); Analysis calculated for C21H 2 7
N
3 0 2 -0.5C 4
H
8 0 2
(CH
3
CO
2 Et): C, 69.49, H, 7.86, N, 10.57. Found: C, 69.64, H, 7.75, N, 10.54. 15 Example 32 8,9,11,12,13,13a, 14,1 4 a-octahydro-2-methyl-N-(phenylmethyl) pyrrolo[3',2':5,6][I lbenzopyrano[3,2-i]quinolizine- 1 -carboxamide N / x\r N O H
CH
3 S N H Step A: 20 4 -Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl aide 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). 1 H NMR (DMSO-d 6 ) 5: 2.05 (s, 6H, CH 2
N(CH
3
)
2 ), 2.31 (s, 3H, ArCH 3 ), 3.67 (s, 2H, CH 2
N(CH
3
)
2 ), 4.40 (d, J= 5.86 Hz, 2H, CONHCH 2 ), 25 6.46 (d, J= 8.55, 1H, 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, lH, WO 00/42045 PCT/US99/30434 -102 indole NH). MS(APCI+): m/z 338.2 (MH+); Analysis calculated for
C
2 0
H
2 3
N
3 0 2 ; 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 5 (35.9%); mp: 235-237'C; IR: 3177, 2929, 1627, 1429, 1089 cm-l. 1 H NMR (DMSO-d 6 ) 8 1.08-1.17 (in, 3H, aliphatic CH 2 and CH), 1.35-1.61 (in, 7H, aliphatic CH 2 and CH), 1.85-1.88 (in, 1H, aliphatic CH), 2.26-2.45 (in, 3H, obscured by DMSO peak, aliphatic CH), 2.29 (s, 3H, ArCH 3 ), 2.61-2.67 (in, 1H, aliphatic CH), 2.82-2.88 (in, 1H, aliphatic CH), 2.97 (dd, J= 17.6, 6.59 Hz, 1H, 10 aliphatic CH), 4.33-4.43 (in, 2H, CONHCH 2 Ph), 6.49 (d, J= 8.55 Hz, 1H, ArH), 6.94 (d, J= 8.55 Hz, 1H, ArH), 7.17-7.31 (in, 5H, ArH), 8.36 (t, J= 6.10 Hz, 1H,
CONHCH
2 Ph), 10.9 (s, 1H, indole Nil); MS(APCI+): m/z 430.2 (MH+); Analysis calculated for C 2 7
H
3 1
N
3 0 2 -0.1C 4
H
8 0 2 : C, 75.07, H, 7.31, N, 9.59. Found: C, 74.99, H, 7.33, N, 9.54. 15 Example 33 Pyrrolo[3',2':5,6] [ ]benzopyrano[3,2-i]quinolizine- 1 -carboxamide, N-ethyl 8,9,11,12,13,13a,14,14a-octahydro-2-methyl N 0 CH 3 NN O H _CH3 N H Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid ethylamide 20 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 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-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.51 g, 17.2 mmol). The resulting reaction mixture was 25 stirred at that temperature for 15 minutes, gaseous ethylamine was bubbled in for WO 00/42045 PCTIUS99/30434 -103 10 minutes. After sequentially 15 minutes stirring at 0 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 Na 2
SO
4 . 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 199-201PC (dec.); IR 3372, 1609, 1523, 1464, 1246, 1216, 1193 cm- 1 ; IH NMR (DMSO-d 6 ) 8 1.11 (t, J = 7.14 Hz, 3H, CH 2
CH
3 ), 2.48 (s, 3H, ArCH 3 ), 3.25 (quintet, 10 J= 6.96 Hz, 2H, NHCH 2
CH
3 ), 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, I H, ArH), 7.23 (t, J= 5.68 Hz, 1H, NHEt), 8.70 (s, IH, NH), 11.1 (bs, 1H, OH); MS(APCI+): m/z 219.1 (MH+). Analysis calculated for C 12
H
14
N
2
O
2 -0.13H 2 0: C, 65.34; H, 6.52; N, 12.70. Found: C, 65.00; H, 6.38; N, 12.64. 15 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 Me 2 NH (40%, 0.895 mL, 7.13 mmol) was added followed by aqueous HCHO (37%, 0.315 g, 3.89 mmol). A 20 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 ; 1 H NMR (DMSO-d 6 ) 8 1.11 (t, J= 7.14 Hz, 3H, CH 2
CH
3 ), 2.18 (s, 6H, 25 N(CH 3
)
2 ), 2.32 (s, 3H, ArCH 3 ), 3.24 (quintet, J= 6.78 Hz, 2H, CH 2
CH
3 ), 3.78 (s, 2H, ArCH 2 NMe 2 ), 6.50 (d, J= 8.42 Hz, 1H, ArH), 7.01 (d, J= 8.61 Hz, IH, ArH), 10.6 (bs, 1H, exchangeable proton), 10.9 (bs, 1H, exchangeable proton); MS(APCI+): n/z 276.1 (MH+). Analysis calculated for C 1 5
H
2 1
N
3 0 2 : C, 65.43; H, 7.69; N, 15.26. Found: C, 65.24; H, 7.73; N, 14.92.
WO 00/42045 PCT/US99/30434 -104 Step C: 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 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 5 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 Na 2
SO
4 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, 10 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 CH 3 CN, and then further purified by chromatography (10% MeOH in HCCI 3 ) to give 0.070 g (17%) of pure titled compound as a yellow 15 solid: mp 264-266'C (dec.); IR 3313, 2930, 1623, 1604, 1435, 1216, 872 cm-1; 1 H NMR (DMSO-d 6 ) 6 1.08 (t, J= 7.14 Hz, 3H, CH 2
CH
3 ), 1.18-1.58 (in, 9H, aliphatic CH 2 and CH), 1.71-1.75 (in, 1H, aliphatic CH), 1.92-1.96 (in, 1H, aliphatic CH) 2.32 (s, 3H, ArCH 3 ), 2.38-2.49 (in, obscured by DMSO peak, 3H, aliphatic CH), 2.66-2.73 (in, IH, aliphatic CH and CH 2 ), 2.90-2.94 (in, 1H, 20 aliphatic CH), 3.10 (dd, J= 18.3, 6.78 Hz, 1H, aliphatic CH), 3.23 (quintet, J= 6.78 Hz, NHCH 2
CH
3 ), 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+): n/z 368.2 (MH+). Analysis calculated for C 2 2
H
2 9
N
3 0 2 : C, 71.90; H, 7.95; N, 11.43. Found: C, 71.52; H, 7.97; N, 11.25. 25 Example 34 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxaldehyde, 8,9,11,1 2 ,1 3 ,1 3 a,14,14a-octahydro-2-methyl- WO 00/42045 PCT/US99/30434 -105 N -0 0
CH
3 N H To a solution of DMF (642 pL, 8.29 mmol) in CH 2 Cl 2 was added POCl 3 (736 pL, 7.89 mmol) dropwise under nitrogen atmosphere. After stirring at ambient temperature for 10 minutes, pyrrolo[3',2':5,6][1]benzopyrano[3,2-i] 5 quinolizine, 3,7,8,9,10,12,13,14,14a, 1 5-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 NaHCO 3 solution and stirred vigorously for 10 minutes. The resulting mixture was extracted with CHCl 3 (4 x 100 mL), the combined organic phase was washed with water (1 x 10 200 mL) and brine (1 x 200 mL), dried over Na 2
SO
4 , and concentrated in vacuo affording a golden solid. The crude product was further purified by flash chromatography (25% acetone in EtOAc). Recrystallization from EtOH/Et 2 O gave 0.63 g (49%) of pure titled compound as a white solid: mp 262'C (dec.); IR 3178, 2931, 1633, 1617, 1484, 1474, 1436, 1391, 1130, 1085, 868, 772 cm- 1 ; 1 H 15 NMR (DMSO-d 6 ) 6 1.14-1.59 (m, 9H, aliphatic CH 2 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, ArCH 3 ), 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, 20 exchangeable proton); MS(APCI+): m/z 325.2 (MH+). Analysis calculated for
C
2 0
H
2 4
N
2 0 2 : C, 74.05; H, 7.46; N, 8.63. Found: C, 73.97; H, 7.48; N, 8.58.
WO 00/42045 PCT/US99/30434 -106 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,15-decahydro-2-methyl-, methyl ester N OCH 3 OH CH N H 3 H 5 Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl ester Synthetic procedure is available in: Studies on the Nenitzescu synthesis of 5-hydroxyindoles. Patrick, James B.; Saunders, Elizabeth K., Tetrahedron Lett., 1979;42:4009-4012. Step B: 4 -Dimethylaminomethyl-5-hydroxy-2-methyl 1 H-indole-3-carboxylic 10 acid methyl ester 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl ester (10.0 g, 49.0 mmol) and aqueous Me 2 NH (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 15 100 nL of water. The resulting mixture was extracted with EtOAc (3 x 100), the combined organic phase was washed with water (I x 100 mL) and brine (1 x 100 mL), dried over Na 2
SO
4 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 20 EtOAc and mixed with 100 mL of 10% aqueous K 2
CO
3 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 Na 2
SO
4 and concentrated in vacuo to give 3.22 g (25%) of light tan crystals. Recrystallization of small portion of the crude product from acetone/water gave 25 pure titled compound as white crystals: mp 145-146'C; IH NMR (CDCl 3 ) 6 2.33 (s, 6H, N(CH 3
)
2 ), 2.55 (s, 3H, ArCH 3 ), 3.84 (s, 3H, CO 2
CH
3 ), 4.19 (s, 2H, ArCH 2 NMe 2 ), 6.72 (d, J= 8.55 Hz, 1H, ArH), 7.04 (d, J= 8.55 Hz, IH, ArH); WO 00/42045 PCT/US99/30434 -107 MS(APCI+): ni/z 263,1 (MH+). Analysis calculated for C 14
H
1 8
N
2 0 3 : 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) 5 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 Na 2
SO
4 and concentrated in vacuo. The residual oil was dissolved in 8 mL of dioxane, then indole mannich base (2.00 g, 10 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 CH 3 CN gave 1.75 g (63%) of pure titled compound as a white solid: mp 205-205.5'C; IR 3242, 2938, 1696, 1441, 1236, 1079, 884 cm- 1 ; 1 H NMR 15 (CDCl 3 ) 8 1.21-1.80 (in, 9H, aliphatic CH 2 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 ArCH 3 peak, aliphatic CH), 2.77 (s, 3H, ArCH 3 ), 2.82-2.86 (in, 2H, aliphatic CH), 3.00-3.07 (in, IH, aliphatic CH), 3.44 (dd, J= 18.1, 6.59 Hz, 1H, aliphatic CH), 3.83 (s, 3H, CO 2
CH
3 ), 6.73 (d, J= 8.55 Hz, 1H, ArH), 7.01 (d, J= 8.79 Hz, 1H, 20 ArH), 8.12 (bs, 1H, NH); MS(APCI+): m/z 355.2 (MH+). Analysis calculated for
C
2 1
H
2 6
N
2 0 3 : 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 25 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, I 5-decahydro-2,10,1 0-trimethyl-, phenylmethyl ester WO 00/42045 PCT/US99/30434 -108 N N 0 or Me Me N N H H Step A: 4,4-Dimethyl- 1,2,3,4,6,7,8,9-octahydro-quinolizinylium perchlorate N 0 The synthesis of 4,4-dimethyl-1, 2
,
3
,
4 ,6,7,8,9-octahydro-quinolizinylium 5 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 VI, p 819. 1 H NMR (400 MHz, CDCl 3 ) 8 1.52 (s, 6H, C(CH 3
)
2 ), 1.75-1.86 (in, 4H, aliphatic CH), 1.88-2.00 (in, 4H, aliphatic CH), 2.80-2.87 (in, 4H, aliphatic CH), 2.65-2.75 (in, 2H, NCH 2 ); MS 10 (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, 1 5-decahydro-2,12,12-trimethyl-, phenylmethyl ester and/or 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2,1 0,1 0-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 20 and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et 2 0 and the combined extracts were washed with 1 x 20 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and WO 00/42045 PCT/US99/30434 -109 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 N 2 for 18 hours, cooled to room temperature, and concentrated. The 5 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, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,12,12-trimethyl-, phenylmethyl ester and/or pyrrolo[3',2':5,6][1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2,10,10-trimethyl-, phenylmethyl ester as a yellow foam: IR (KBr) 3383, 2932, 2857, 1675, 1432, 1090, 1072 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.07 (s, 3H, CH 3 ), 1.23 (s, 3H, CH 3 ), 1.09-1.26 (in, 5H, aliphatic CH), 1.42-1.61 (in, 6H, aliphatic CH), 1.90 (d, J=12.70 Hz, IH, aliphatic CH), 2.58 (d, J=18.56 Hz, 1H, aliphatic CH), 2.64-2.75 (in, 3H, aliphatic CH), 15 3.11-3.19 (in, 2H, aliphatic CH), 3.24-3.30 (m, 1H, aliphatic CH), 5.15-5.25 (in, 2H, OCH 2 Ar), 6.52 (d, J=8.79 Hz, 1H, ArH), 6.99 (d, J=8.55 Hz, 1H, ArH), 7.30-7.42 (in, 5H, ArM), 11.50 (s, 1H, NH); MS (APCI+) n/z 459.3 (MH+). Anal. Calcd for C 2 9
H
3 4
N
2
O
3 -0.19 H 2 0: C, 75.39; H, 7.50; N, 6.06; H 2 0, 0.74. Found: C, 75.00; H, 7.73; N, 5.79; H 2 0, 0.36. 20 Example 37 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 N O 0 0 Me F N
H
WO 00/42045 PCTIUS99/30434 -110 Step A: 6-Fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester 0 f 0 HOO H O 7:':r Me F N H 6-Fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester was synthesized according to the procedure published in Littell, R.; Allen, G.R., Jr. 5 J. Org. Chemn. 1968;33:2064. Step B: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole 3-carboxylic acid ethyl ester Me 2 N 0 0 HO I ~ Me F N H 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole 10 3-carboxylic acid ethyl ester was prepared according to Procedure G from 6-fluoro-5-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, 15 1443, 1124, 1078 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.32 (t, J=7.08 Hz, 3H, OCH 2
CH
3 ), 2.26 (s, 6H, N(CH 3
)
2 ), 2.50 (s, 3H, ArCH 3 ), 4.17 (s, 2H,
NCH
2 Ar), 4.24 (q, J=7.08 Hz, 2H, OCH 2
CH
3 ), 7.05 (d, J=10.50 Hz, 1H, ArMH, 11.56 (bs, 1H, NH); 19 F NMR (DMSO-d 6 ) 6 -141.69 (d, J=10.68 Hz); MS (APCI+) n/z 295.1 (MH+). Anal. Calcd for C 1 5
H
19
F
1
N
2 0 3 : C, 61.21; H, 6.51; 20 N, 9.52; F, 6.45. Found: C, 61.32; H, 6.55; N, 9.51; F, 6.61.
WO 00/42045 PCTIUS99/30434 -111 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, 1 5-decahydro-2-methyl-, ethyl ester was 5 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, 10 1135 cm- 1 ; IH NMR (400 MHz, CDCl 3 ) 6 1.37 (t, J=7.08 Hz, 3H, OCH 2
CH
3 ), 1.25-1.47 (in, 4H, aliphatic CH), 1.60-1.78 (in, 5H, aliphatic CH), 1.85-1.95 (in, 1H, aliphatic CH), 2.09 (bd, J=13.43 Hz, 1H, aliphatic CH), 2.43-2.49 (in, 2H, aliphatic CH), 2.57 (s, 3H, ArCH 3 ), 2.87-2.92 (m, 2H, aliphatic CH), 3.05-3.18 (m, 1H, aliphatic CH), 3.43-3.50 (in, 1H, aliphatic CH), 4.32 (q, 15 J=7.08 Hz, 2H, OCH 2
CH
3 ), 6.86 (d, J=10.01 Hz, 1H, ArH), 8.09 (bs, 1H, NH); 19 F NMR (CDCl 3 ) 8 -140.62 (d, J=10.68 Hz); MS (APCI+) m/z 387.1 (MH+). Anal. Calcd for C 2 2
H
2 7
FIN
2 0 3 : C, 68.37; H, 7.04; N, 7.25; F, 4.92. Found: C, 68.30; H, 7.11; N, 7.09; F, 4.97. Example 38 20 Pyrrolo[3',2':5,6][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 N o 0 0 Me F N
H
WO 00/42045 PCT/US99/30434 -112 Step A: 6-Fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 0 OH HO Me F N 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 5 hydroxide and heated at reflux for 1 hour. The solution was cooled to 0 0 C and carefully acidified to pH 9 with concentrated HCl. The solution was extracted with CH 2
CI
2 , the extracts were discarded and the aqueous layer was further acidified at 0 0 C to pH 4 with concentrated HCL. The precipitate was filtered off and dried in vacuo for 18 hours to afford a tannish pink solid (1.16 g, 62%): mp 10 202-204'C (dec); IR (KBr) 3584, 3358, 1649, 1471, 1109 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 2.53 (s, 3H, ArCH 3 ), 7.04 (d, J= 11.23 Hz, 1H, ArH), 7.46 (d, J=9.03 Hz, 1 H, ArH), 9.17 (s, I H, ArOH), 11.46 (s, 1 H, NH or COOH), 11.76(s, 1H, COOH or NH); 19 F NMR (DMSO-d 6 ) 8 -141.60 (t, J=10.68 Hz); MS (APCI-) m/z 208.0 (M-1). 15 Step B: 6-Fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester O 0 HO Me F N H 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 N 2 was added dropwise via syringe 1, 8 -diazabicyclo[5.4.0]undec-7-ene (4.92 mmol, 20 0.736 mL) followed by benzyl bromide (5.42 mmol, 0.644 mL). After 48 hours, water (10 mL) was added, and the precipitate was filtered off, dried, 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 ; 1 H NMR WO 00/42045 PCT/US99/30434 -113 (400 MHz, DMSO-d 6 ) 8 2.59 (s, 3H, ArCH 3 ), 5.32 (s, 2H, OCH 2
C
6
H
5 ), 7.12 (d, J=10.99 Hz, 1H, ArH), 7.31-7.49 (in, 6H, ArH), 9.29 (s, 1H, ArOH), 11.67 (s, 1H, NH); 19 F NMR (DMSO-d 6 ) 8 -140.96-141.01 (in); MS (APCI-) m/z 298.1 (M-1). Anal. Calcd for C 17
H
1 4
F
1
N
1 03-0.04 H 2 0: C, 68.06; H, 4.73; N, 4.67; F, 6.33; 5 H 2 0, 0.24. Found: C, 67.69; H, 4.63; N, 4.57; F, 6.61; H 2 0, 0.10. Step C: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole 3-carboxylic acid benzyl ester Me 2 N 0 0 HO Me F N H A solution of 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 10 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 N 2 was heated at reflux for 21 hours. An additional aliquot of 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 15 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 2.12 (s, 6H, N(CH 3
)
2 ), 2.44 (s, 3H, ArCH 3 ), 4.04 (s, 2H, NCH 2 Ar), 5.23 (s, 2H, OCH 2
C
6
H
5 ), 7.01 (d, J=1 0.50 Hz, 1H, ArH), 7.31-7.44 (in, 5H, ArH), 11.57 (s, 1H, NH); 19 F NMR (DMSO-d 6 ) 6 -141.55 (d, 20 J=10.68 Hz); MS (APCI+) m/z 357.1 (MH+). Anal. Calcd for
C
2 0
H
2 1
F
1
N
2 O3-0.07 C 4
H
8 0 2 : 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.
WO 00/42045 PCT/US99/30434 -114 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, 1 5-decahydro-2-methyl-, phenylmethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 5-fluoro-3,7,8,9,10,12,13,14,14a, 1 5-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 10 ether to give a white solid (0.169 g, 63%): mp 179-181*C; IR (KBr) 2932, 2857, 1699, 1453, 1131, 1075 cm- 1 ; IH NMR (400 MHz, CDCl 3 ) 6 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, ArCH 3 ), 2.79 (d, J=17.58 Hz, 1H, aliphatic CH), 2.85-2.92 (m, 1H, aliphatic 15 CH), 3.04-3.17 (m, 1H, aliphatic CH), 3.35 (dd, J=18.31, 6.51 Hz, 1H, aliphatic CH), 5.25-5.37 (m, 2H, OCH 2
C
6
H
5 ), 6.86 (d, J=10.25 Hz, 1H, ArH), 7.28-7.38 (in, 3H, ArH), 7.40-7.44 (m,2H, ArH), 8.07 (bs, 1H, NH); 19 F NMR (CDCl 3 ) 8 -142.0 (m); MS (APCI+) m/z 449.1 (MH+). Anal. Calcd for
C
2 7
H
2 9
F
1
N
2 0 3 : C, 72.30; H, 6.52; N, 6.25; F, 4.24. Found: C, 72.28; H, 6.45; 20 N, 6.09; F, 4.50. Example 39 12H-Furo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-fluoro 7,8,9,10,13,14,14a, 15-octahydro-2-methyl-, ethyl ester N 0 0 0 Me F 0 WO 00/42045 PCTIUS99/30434 -115 Step A: 6-Fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester 0 0 HO Me F 0 To a solution of 2 -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 5 (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, 1110 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 5 1.36 (t, J=7.08 Hz, 3H, 10 OCH 2
CH
3 ), 2.68 (s, 3H, ArCH 3 ), 4.32 (q, J=7.08 Hz, 2H, OCH 2
CH
3 ), 7.43 (d, J=8.79 Hz, IH, ArH), 7.55 (d, J=10.74 Hz, 1H, ArH), 9.82 (s, 1H, ArOH); 19 F NMR (DMSO-d 6 ) 6 -137.42 (t, J=9.16 Hz); MS (APCI-) m/z 237.1 (M-1). Anal. Calcd for C 1 2
H
1 1
F
1 0 4 : C, 60.50; H, 4.65; F, 7.98. Found: C, 60.50; H, 4.46; F, 8.20. 15 Step B: 4 -Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-benzofuran 3-carboxylic acid ethyl ester Me 2 N 0 0 HO I ~ Me F 0 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 20 (2.09 mmol, 0.285 mL) in 4 mL of dioxane under N 2 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 ; 1
H
WO 00/42045 PCT/US99/30434 -116 NMR (400 MHz, DMSO-d 6 ) 8 1.34 (t, J=7.08 Hz, 3H, OCH 2
CH
3 ), 2.21 (s, 6H,
N(CH
3
)
2 ), 2.57 (s, 3H, ArCH 3 ), 4.03 (s, 2H, NCH 2 Ar), 4.32 (q, J=7.08 Hz, 2H,
OCH
2
CH
3 ), 7.48 (d, J=10.25 Hz, 1H, ArH); 19 F NMR (DMSO-d 6 ) S -137.69 (d, J=10.68 Hz); MS (APCI+) m/z 296.1 (MH+). Anal. Calcd for C 15
H
1 8
F
1
N
1 0 4 : 5 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-1-carboxylic acid, 5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl 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, 1 5-octahydro-2-methyl-, ethyl ester was synthesized 10 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 frop ether to afford a white solid (0.210 g, 90%): mp 147-149'C; IR (KBr) 2936, 2848, 1717, 1453, 1242, 15 1125 cm- 1 ; 1 H NMR (400 MHz, CDCI 3 ) 8 1.25-1.37 (m, 2H, aliphatic CH), 1.38 (t, J=7.08 Hz, 3H, OCH 2
CH
3 ), 1.40-1.52 (m, 2H, aliphatic CH), 1.57-1.80 (m, 5H, aliphatic CH), 1.84-1.96 (m, 1H, aliphatic CH), 2.02 (d, J=13.43 Hz, 1H, aliphatic CH), 2.42-2.58 (m, 2H, aliphatic CH), 2.61 (s, 3H, ArCH 3 ), 2.83-2.91 (m, 1H, aliphatic CH), 2.90 (d, J=17.82 Hz, 1H, aliphatic CH), 20 3.06-3.16 (in, 1H, aliphatic CH), 3.34-3.40 (m, 1H, aliphatic CH), 4.34 (q, J=7.08 Hz, 2H, OCH 2
CH
3 ), 7.03 (d, J=9.77 Hz, 1H, ArH); 19 F NMR (CDCl 3 ) 8 -137.90 (d, J=9.16 Hz); MS (APCI+) m/z 388.2 (MH+). Anal. Calcd for
C
2 2
H
2 6
F
1
N
1 0 4 : 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. 25 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, 1 5-decahydro-2-methyl-, phenylmethyl ester WO 00/42045 PCT/US99/30434 -117 N 0 0 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 5 potassium persulfate nitrate following the procedure of Feiring, A.E.; Sheppard, W.A. J. Org. Chen. 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 ; IH NMR (400 MHz, 10 DMSO-d 6 ) 6 6.52 (d, J=5.37 Hz, 2H, ArH), 9.45 (s, 2H, ArOH); 19 F NMR (DMSO-d 6 ) 8 -159.78 (d, J=4.58 Hz); MS (APCI-) m/z 145.0 (M-1). Anal. Calcd for C 6
H
4
F
2 0 2 : 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 0 F F 0 15 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. Chem. 1975;40:2543 to afford a bright yellow solid (6.63 g, 94%): mp 97.0-98.5*C; IR (KBr) 3352, 1684, 1333 cm- 1 ; IH NMR (400 MHz, DMSO d 6 ) 8 6.98 (s, 2H, ArH); 19 F NMR (DMSO-d 6 ) 6 -144.85 (s); MS (APCI-) in/z WO 00/42045 PCTIUS99/30434 -118 144.0 (M-). Anal. Calcd for C 6
H
2
F
2 0 2 : 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-I H-indole-3-carboxylic acid benzyl ester O 0 HO I | Me F N H 5 F To a solution of 2
,
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 10 with glacial acetic acid and dried in vacuo to give clean product. The filtrate was neutralized, water (20 mL) was added, and the solution was extracted with ethyl acetate (4 x 20 mL). The extracts were dried over MgSO 4 , filtered, concentrated and the residue purified by silica gel flash column chromatography (20% ethyl acetate/hexanes). The pure portions were combined to give 0.174 mg (52%) of 15 off-white solid, which was recrystallized from acetonitrile: mp 215-217 0 C; IR (KBr) 3457, 3243, 1658, 1480, 1338, 1150 cm- 1 ; 1 H NMR (400 MHz, DMSO d 6 ) 8 2.58 (s, 3H, ArCH 3 ), 5.31 (s, 2H, OCH 2
C
6
H
5 ), 7.29-7.45 (in, 6H, ArH), 9.75 (s, 1H, ArOH), 12.13 (s, 1H, NH); MS (APCI+) m/z 318.0 (MH+). Anal. Calcd for C 1 7
H
1 3
F
2
N
1 0 3 -0.04 C 2
H
4 0 2 : C, 64.17; H, 4.15; N, 4.38; F, 11.89. 20 Found: C, 63.80; H, 4.15; N, 4.05; F, 12.18.
WO 00/42045 PCT/US99/30434 -119 Step D: 4-Dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-1H-indole 3-carboxylic acid benzyl ester Me 2 N 0 0 HO 1 ~ Me F N H F 4 -Dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl- 1 H-indole 5 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, 10 1123, 1083 cm- 1 ; IH NMR (400 MHz, DMSO-d 6 ) 6 2.13 (s, 6H, N(CH 3
)
2 ), 2.46 (s, 3H, ArCH 3 ), 4.00 (s, 2H, ArCH 2 N), 5.24 (s, 2H, OCH 2
C
6
H
5 ), 7.27-7.38 (m, 3H, ArH), 7.41-7.44 (m, 2H, ArH), 12.08 (s, IH, NH); 1 9 F NMR (DMSO-d 6 ) 6 -168.26 (d, J=21.4 Hz), -159.68 (d, J=21.4 Hz); MS (APCI+) m/z 375.0 (MH+). Anal. Calcd for C 2 0
H
2 0
F
2
N
2 0 3 : C, 64.16; H, 5.38; N, 7.48; F, 15 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-1-carboxylic acid, 4,5-difluoro-3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, phenylmethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 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 -1 H-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 25 (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, WO 00/42045 PCT/US99/30434 -120 1704, 1455, 1141, 1124 cm- 1 ; 1 H NMR (400 MHz, CDCl 3 ) 6 1.17-1.36 (m, 3H, aliphatic CH), 1.43-1.49 (m, 1H, aliphatic CH), 1.57-1.78 (m, 6H, aliphatic CH), 2.00 (d, J=13.7 Hz, 1H, aliphatic CH), 2.46 (d, J=9.77 Hz, 1H, aliphatic CH), 2.53-2.57 (in, 1H, aliphatic CH), 2.57 (s, 3H, ArCH 3 ), 2.71 (d,J=18.31 Hz, 1H, 5 aliphatic CH), 2.83-2.88 (m, 1H, aliphatic CH), 3.06-3.16 (m, IH, aliphatic CH), 3.24-3.30 (in, 1H, aliphatic CH), 5.24-5.36 (m, 2H, OCH 2
C
6
H
5 ), 7.32-7.38 (m, 3H, ArH), 7.42 (d, J=6.84 Hz, 2H, ArH), 8.21 (s, 1H, NH); 19 F NMR (CDCI 3 ) 6 -166.80 (d, J=19.84 Hz), -162.52 (d, J=21.36 Hz); MS (APCI+) m/z 467.1 (MH+). Anal. Called for C 2 7
H
2 8
F
2
N
2 0 3 : C, 69.51; H, 6.05; N, 6.00; F, 8.14. Found: C, 10 69.36; H, 5.99; N, 5.88; F, 8.37. Example 41 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 N O 0 0 Me Cl N H Cl 15 Step A: 6 ,7-Dichloro-5-hydroxy-2-methyl-1 IH-indole-3-carboxylic acid benzyl ester O 0 HO Me C1 N H Cl 6,7-Dichloro-5-hydroxy-2-methyl- 1H-indole-3-carboxylic acid benzyl ester was prepared from 2
,
3 -dichloro-[1,4]benzoquinone (16.8 mmol, 2.98 g) and 20 3-amino-but-2-enoic acid benzyl ester (25.3 mmol, 4.83 g) following the procedure for the corresponding ethyl ester reported by Grinev, A.N.; Zaitsev, WO 00/42045 PCT/US99/30434 -121 I.A.; Shvedov, V.I.; Terent'ev, A.P. J Org. Chem. USSR (English) ;28:439. Yield 0.649 g (11%): mp 235-236 0 C; IR (KBr) 3421, 3281, 1651, 1098 cm- 1 ; IH NMR (400 MHz, DMSO-d 6 ) 6 2.59 (s, 3H, ArCH 3 ), 5.29 (s, 2H, OCH 2
C
6
H
5 ), 7.30 (t, J=7.08 Hz, 1H, ArH), 7.34-7.38 (m, 2H, ArH), 7.42 (d, J=7.32 Hz, 2H, ArH), 5 7.51 (s, 1H, ArH); MS (APCI-) m/z 348.0 (M-1). HPLC (ALLTECH/ALLTIMA C-18, 1:1-2:98 H 2 0/CH 3 CN + 0.05% TFA): retention time=6.573 min, 98.4 1% purity. Step B: 4 -Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-IH-indole 3-carboxylic acid benzyl ester Me 2 N 0 0 HO I ~ Me Cl N H 10 Cl 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- 1 H-indole-3-carboxylic acid benzyl ester (3.06 mmol, 1.07 g). The reaction was heated at 50'C for 22.5 hours, concentrated 15 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, 1409,1330,1281,1107 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 2.18 (s, 6H, N(CH 3
)
2 ), 2.52 (s, 3H, ArCH 3 ), 4.06 (s, 2H, ArCH 2 N), 5.27 (s, 2H,
OCH
2
C
6
H
5 ), 7.30-7.39 (m, 3H, ArH), 7.41-7.47 (m, 2H, ArH), 11.84 (s, 1H, 20 NH); MS (APCI+) n/z 407.1 (M+). Anal. Called for C 2 0
H
2 0 Cl 2
N
2 0 3 : 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.
WO 00/42045 PCTIUS99/30434 -122 Step C: 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, 1 5-decahydro-2-methyl-, phenylmethyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 4,5-dichloro-3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, phenylmethyl ester was synthesized according to Procedure I (80'C, 18 hours) from 4-dimethylaminomethyl-6,7-dichloro-5-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 10 (75%) peach colored foam: mp 100-105'C; IR (KBr) 3424, 2932, 2853, 1685, 1430, 1125, 1076 cm-1; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.00-1.30 (in, 3H, aliphatic CH), 1.37-1.76 (in, 8H, aliphatic CH), 2.37-2.40 (in, 1H, aliphatic CH), 2.46-2.49 (in, 1H, aliphatic CH), 2.50 (s, 3H, ArCH 3 ), 2.63-2.69 (in, 2H, aliphatic CH), 2.95-2.99 (in, 1H, aliphatic CH), 3.17 (dd, J=18.31, 6.74 Hz, 1H, aliphatic 15 CH), 5.23 (dd, J=28.08, 12.21 Hz, 2H, OCH 2
C
6
H
5 ), 7.31-7.39 (in, 3H, ArH), 7.42-7.44 (in, 2H, ArH), 11.85 (s, 1H, NH); MS (APCI+) m/z 499.1 (MH+). Anal. Calcd for C 2 7
H
2 8 Cl 2
N
2 03-0.07 H 2 0: C, 64.77; H, 5.66; N, 5.59; Cl, 14.16;
H
2 0, 0.25. Found: C, 64.37; H, 5.64; N, 5.51; Cl, 13.96; H 2 0, 0.32. Example 42 20 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-4,5-dimethoxy-2-methyl-, phenylmethyl ester N o 0 0 Me MeO N H OMe WO 00/42045 PCT/US99/30434 -123 Step A: 6
,
7 -Dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester 0 HO Me MeO N H OMe 2
,
3 -Dimethoxy-[1,4]benzoquinone (10.4 mmol, 1.74 g) was added to a 5 solution of 3-amino-but-2-enoic acid benzyl ester (8.62 mmol, 1.65 g) in ethanol (25 mL) at 0 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 10 154-156'C; IR (KBr) 3336, 3267, 1660, 1468, 1327, 1146, 1081 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 2.56 (s, 3H, ArCH 3 ), 3.73 (s, 3H, OCH 3 ), 3.89 (s, 3H,
OCH
3 ), 5.29 (s, 2H, OCH 2
C
6
H
5 ), 7.11 (s, 1H, ArH), 7.29-7.43 (m, 5H, ArH), 8.79 (s, 1H, ArOH), 11.59 (s, 1H, NH); MS (APCI-) n/z 340.0 (M-1). Anal. Calcd for C 19
H
19 NI0 5 : C, 66.85; H, 5.61; N, 4.10. Found: C, 66.69; H, 5.55; N, 3.79. 15 Step B: 4 -Dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl 1 H1-indole 3-carboxylic acid benzyl ester Me 2 N 0 0 HO Me MeO 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 20 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 WO 00/42045 PCT/US99/30434 -124 acetate) and recrystallized from cyclohexane to afford a lemon yellow solid (0.274 g, 41%): mp 132-134'C; IR (KBr) 3312, 1698, 1440, 1415, 1290, 1129 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 2.10 (s, 6H, N(CH 3
)
2 ), 2.44 (s, 3H, ArCH 3 ), 3.73 (s, 3H, ArOCH 3 ), 3.86 (s, 3H, ArOCH 3 ), 3.94 (s, 2H, 5 ArCH 2 N), 5.21 (s, 2H, OCH 2
C
6
H
5 ), 7.29-7.38 (in, 3H, ArH), 7.41-7.43 (m, 2H, ArH), 11.48 (s, 1H, NH); MS (APCI+) m/z 399.0 (MH+). Anal. Called for
C
2 2
H
2 6
N
2 0 5 : 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-4,5-dimethoxy-2-methyl-, 10 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 was synthesized according to Procedure I (90'C, 21 hours) from 4 -dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-1H-indole 15 3-carboxylic acid benzyl 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, 1137, 1123 cm- 1 ; I H NMR (400 MHz, CDCl 3 ) 6 1.24-1.38 (m, 4H, aliphatic 20 CH), 1.44-1.55 (in, IH, aliphatic CH), 1.59-1.80 (in, 6H, aliphatic CH), 2.09 (d, J=13.98 Hz, 1H, aliphatic CH), 2.51 (d, J=10.37 Hz, 1H, aliphatic CH), 2.58 (s, 3H, ArCH 3 ), 2.78 (d, J=18.08 Hz, 1H, aliphatic CH), 2.85-2.91 (in, 1H, aliphatic CH), 3.08-3.14 (m, 1H, aliphatic CH), 3.29-3.36 (m, 1H, aliphatic CH), 3.96 (s, 3H, OCH 3 ), 4.05 (s, 3H, OCH 3 ), 5.26-5.37 (in, 2H, OCH 2
C
6
H
5 ), 7.31-7.40 (in, 25 3H, ArM), 7.44 (d, J=6.99 Hz, 2H, ArM), 8.29 (s, 1H, NH); MS (APCI+) m/z 491.1 (MH+). HPLC (ALLTECH/ALLTIMA C-18, 1:1-2:98 H 2 0/CH 3 CN + 0.05 % TFA): retention time=4.527 min, 100.00% purity.
WO 00/42045 PCT/US99/30434 -125 Example 43 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-2,5-dimethyl-, phenylmethyl ester N 0 0 1 \\ Me Me N H 5 Step A: 6 -Methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester 0 O Me Me N H 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 10 the procedure for the corresponding ethyl ester reported by Allen, G.R., Jr.; Pidacks, C.; Weiss, M.J. J. Am. Chem. Soc. 1966;88:2536. The crude 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 15 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 acetate/hexanes) was 6 -methyl-5-hydroxy-2-methyl 20 1H-indole-3-carboxylic acid benzyl ester: mp 196-197'C; IR (KBr) 3399, 3314, 1655, 1469, 1438, 1086 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 2.14 (s, 3H, ArCH 3 ), 2.53 (s, 3H, ArCH 3 ), 5.28 (s, 2H, OCH 2
C
6
H
5 ), 6.99 (s, IH, ArH), 7.28-7.42 (m, 6H, ArH), 8.81 (s, IH, ArOH), 11.42 (s, 1H, NH); MS (APCI+) m/z WO 00/42045 PCT/US99/30434 -126 296.0 (MH+). Anal. Called for C 18
H
17
N
1 03-0.25 H 2 0: C, 72.10; H, 5.88; N, 4.67. Found: C, 71.72; H, 5.54; N, 4.74. Step B: 4 -Dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-1H-indole 3-carboxylic acid benzyl ester Me 2 N 0 0 HO I ~ Me Me N 5 H 4 -Dimethylaminomethyl-6-methyl-5-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 10 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, 1688, 1432, 1227, 1119, 1075 cm- 1 ; IH NMR (400 MHz, DMSO 15 d 6 ) 8 2.13 (s, 9H, N(CH 3
)
2 and ArCH 3 ), 2.44 (s, 3H, ArCH 3 ), 4.01 (s, 2H, ArCH 2 N), 5.22 (s, 2H, OCH 2
C
6
H
5 ), 6.95 (s, IH, ArH), 7.29-7.44 (in, 5H, ArH), 11.40 (s, 1H, NH); MS (APCI+) m/z 353.1 (MH+). Anal. Calcd for
C
2 1
H
2 4
N
2 0 3 : 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, 20 3,7,8,9,10,12,13,14,14a, 1 5-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, 1 5-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-1H-indole-3-carboxylic 25 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 WO 00/42045 PCT/US99/30434 -127 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.05-1.16 (in, 2H, aliphatic CH), 1.21-1.25 (in, 1H, aliphatic CH), 1.33-1.42 (in, 2H, aliphatic CH), 1.45-1.66 (in, 5H, aliphatic CH), 1.78 (d, 5 J=13.67 Hz, 1H, aliphatic CH), 2.18 (s, 3H, ArCH 3 ), 2.34 (d, J=9.28 Hz, 1H, aliphatic CH), 2.44 (s, 3H, ArCH 3 ), 2.41-2.46 (in, 1H, aliphatic CH), 2.62-2.70 (m, 2H, aliphatic CH), 2.87-2.95 (in, 1H, aliphatic CH), 3.16 (dd, J=18.07, 6.59 Hz, 1H, aliphatic CH), 5.19 (dd, J=25.15, 12.21 Hz, 2H,
OCH
2
C
6
H
5 ), 6.90 (s, 1H, ArH), 7.28-7.37 (in, 3H, ArH), 7.41 (d, J=6.84 Hz, 2H, 10 ArH), 11.37 (s, 1H, NH); MS (APCI+) m/z 445.3 (MH+). Anal. Called for
C
2 8
H
3 2
N
2
O
3 -0.16 H 2 0: C, 75.16; H, 7.28; N, 6.26; H 2 0, 0.64. Found: C, 74.76; H, 7.35; N, 6.07; H 2 0, 0.34. Example 44 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, phenylmethyl ester N 0 '0 Me N H Me Step A: 7-Methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester 0 HO Me N H Me 7-Methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester 20 (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 WO 00/42045 PCTIUS99/30434 -128 (79.5 mmol, 15.2 g) as in Example 43, Step A. Single crystal X-ray analysis indicated that the lower Rf 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 ; 1 H NMR 5 (400 MHz, DMSO-d 6 ) 6 2.32 (s, 3H, ArCH 3 ), 2.58 (s, 3H, ArCH 3 ), 5.27 (s, 2H,
OCH
2
C
6
H
5 ), 6.39 (d, J=1.22 Hz, 1H, ArH), 7.10 (d, J=1.71 Hz, lH, 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+) n/z 296.0 (MH+). Anal. Calcd for C 1 8
H
1 7
N
1 0 3 : C, 73.20; H, 5.80; N, 4.74. Found: C, 73.02; H, 5.70; N, 10 4.40. Step B: 4-Dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-1H-indole 3-carboxylic acid benzyl ester Me 2 N 0 0 HO Me N H Me 4-Dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl- I H-indole 15 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 50'C for 46 hours, concentrated, purified by silica gel flash column chromatography (0-5% triethylamine/ethyl 20 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-d 6 ) 6 2.08 (s, 6H, N(CH 3
)
2 ), 2.30 (s, 3H, ArCH 3 ), 2.47 (s, 3H, ArCH 3 ), 3.89 (s, 2H, ArCH 2 N), 5.22 (s, 2H, OCH 2
C
6
H
5 ), 6.37 (s, IH, ArH), 7.28-7.38 (m, 3H, ArH), 7.43 (d, J=7.08 Hz, 2H, ArH), 11.28 (s, 1H, NH); MS WO 00/42045 PCTIUS99/30434 -129 (APCI+) m/z 353.2 (MH+). Anal. Calcd for C 2 1
H
2 4
N
2 0 3 : 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 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2,4-dimethyl-, phenylmethyl ester was synthesized according to Procedure I (80*C, 39 hours) from 4 -dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (2.55 mmol, 0.900 g). The product was purified by silica gel 10 flash column chromatography (30% ethyl acetate/hexanes then 20-50% ethyl acetate/dichloromethane) to give 0.569 g (50%) off-white solid: mp 183-187'C; IR (KBr) 3325, 2929, 1664, 1431, 1279, 1221, 1107, 1075 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.06-1.15 (m, 2H, aliphatic CH), 1.19-1.22 (m, 1H, aliphatic CH), 1.31-1.62 (m, 8H, aliphatic CH), 1.81 (d, J=12.94 Hz, 1H, aliphatic 15 CH), 2.30 (s, 3H, ArCH 3 ), 2.33-2.42 (m, IH, aliphatic CH), 2.45 (s, 3H, ArCH 3 ), 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 CH), 3.09-3.15 (in, 1H, aliphatic CH), 5.20 (dd, J=24.90, 12.21 Hz, 2H, OCH 2
C
6
H
5 ), 6.41 (s, I H, ArH), 7.28-7.43 (m, 5H, ArR), 11.31 (s, IH, NH); MS (APCI+) n/z 445.3 (MH+). Anal. Calcd for 20 C 2 8
H
3 2
N
2 0 3 : 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 N Me -~ F N o 0 0 I 'Me Me N 25
H
WO 00/42045 PCTIUS99/30434 -130 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 0 N o 0 Me Me M H 5 To a solution of pyrrolo[3',2':5,6][1 ]benzopyrano[3,2-i]quinolizine 1-carboxylic acid, 3,7,8,9,10,12,13,14,1 4a,15-decahydro-2,5-dimethyl-, phenylmethyl ester (1.88 mmol, 0.837 g) and triethylamine (1.88 mmol, 0.262 mL) in 18 mL of tetrahydrofuran was added 20% Pd(OH) 2 /C (0.200 g, 24 wt%). The mixture was stirred under a hydrogen atmosphere (balloon) at room 10 temperature for 20 minutes and filtered through celite, rinsing with tetrahydrofuran, to give the carboxylic acid: MS (APCI+) n/z 355.2 (MH+). To the filtrate under N 2 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 15 to afford a light peach solid (0.517 g, 60%): 1 H NMR (400 MHz, DMSO-d 6 ) selected diagnostic peaks 6 2.23 (s, 3H, ArCH 3 ), 2.48 (s, 3H, ArCH 3 ), 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, 2H, ArH), 11.94 (s, 1H, NH); MS (APCI+) n/z 459.2 (MH+). Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 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-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2,5-dimethyl-, anhydride with benzoic acid (1.13 mmol, 0.517 g) was added to 4-fluoro-ca-methylbenzyl alcohol (3.38 mmol, 25 0.427 mL) and heated with stirring at 150'C for 2 minutes. A homogeneous solution formed, was cooled to room temperature, dissolved with ethyl acetate WO 00/42045 PCT/US99/30434 -131 (10 mL), and stirred with a saturated aqueous solution of NaHCO 3 . 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 (10-15% acetone/hexanes) to 5 give a shiny beige powder (0.256 g, 48%): mp 124-128'C; IR (KBr) 3378, 2933, 1675, 1425, 1228, 1127, 1059 cm- 1 ; IH NMR (400 MHz, DMSO-d 6 ) 6 1.07-1.28 (in, 3H, aliphatic CH), 1.42-1.65 (in, 6H, aliphatic CH), 1.57 (d, J=6.75 Hz, 3H, OCH(CH 3 )Ar), 1.71-1.74 (in, 1H, aliphatic CH), 1.79-1.87 (in, IH, aliphatic CH), 2.21 & 2.22 (s, 3H, ArCH 3 , diastereomers), 2.38 (d, 10 J=11.09 Hz, 1H, aliphatic CH), 2.46-2.49 (in, 1H, aliphatic CH), 2.50 & 2.52 (s, 3H, ArCH 3 , diastercomers), 2.64-2.72 (in, 2H, aliphatic CH), 2.92-2.98 (in, lH, aliphatic CH), 3.10-3.29 (in, 1H, aliphatic CH), 5.94-6.00 (in, lH, OCH(CH 3 )Ar), 6.92 & 6.93 (s, 1H, ArH, diastereomers), 7.16-7.22 (in, 2H, ArH), 7.45-7.51 (in, 2H, ArH), 11.40 (s, 1H, NH); 19 F NMR (DMSO-d 6 ) -115.13 & -114.94 (s, 15 diastereomers); MS (APCI+) m/z 477.3 (MH+). Anal. Calcd for C 2 9
H
3 3
FIN
2 0 3 : C, 73.09; H, 6.98; N, 5.88; F, 3.99. Found: C, 72.84; H, 7.02; N, 5.78; F, 3.89. Example 46 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, 1 -(4-fluorophenyl)ethyl 20 ester N OMe F NN I "Me N H Me WO 00/42045 PCT/US99/30434 -132 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, 1 5-decahydro-2,4-dimethyl-, anhydride with benzoic acid 0 N O 0 I Me N H Me 5 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, 1 5-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+). 10 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-2,4-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, 1 5-decahydro-2,4-dimethyl-, 1-(4-fluorophenyl)ethyl 15 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 20 (0.227 g, 43%): mp 105-108 0 C; IR (KBr) 3325, 2931, 1674, 1512, 1433, 1222, 1109, 1059 cm- 1 ; I H NMR (400 MHz, DMSO-d 6 ) 6 1.12-1.26 (in, 3H, aliphatic CH), 1.39-1.72 (in, 7H, aliphatic CH), 1.57 (d, J=6.51 Hz, 3H, OCH(CH 3 )Ar), 1.82-1.91 (in, 1H, aliphatic CH), 2.31-2.36 (in, IH, aliphatic CH), 2.33 & 2.34 (s, 3H, ArCH 3 , diastereomers), 2.43-2.47 (in, 1H, aliphatic CH), 2.54 & 2.56 (s, 3H, 25 ArCH 3 , diastereomers), 2.58-2.70 (in, 2H, aliphatic CH), 2.86-2.91 (in, 1H, aliphatic CH), 3.06-3.25 (in, 1H, aliphatic CH), 5.94-6.01 (in, 1H, OCH(CH 3 )Ar), WO 00/42045 PCTIUS99/30434 -133 6.43 & 6.45 (s, 1H, ArH, diastereomers), 7.16-7.22 (in, 2H, ArH), 7.45-7.51 (m, 2H, ArH), 11.31 & 11.32 (s, 1H, NH, diastereomers); 19 F NMR (DMSO-d 6 ) -(115.13-115.08) & -(114.92-114.91) (in, diastereomers); MS (APCI+) m/z 477.3 (MH+). Anal. Calcd for C 2 9
H
3 3
F
1
N
2
O
3 -0.12 H 2 0: C, 72.75; H, 7.00; N, 5 5.85; F, 3.97; H 2 0, 0.45. Found: C, 72.38; H, 7.13; N, 5.73; F, 3.61; H 2 0, 0.31. Example 47 Pyrrolo[3',2':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
CO
2 Me N 0 Me, 0 0 Me N 10 H Step A: 3-(1-Hydroxyethyl)benzoic acid methyl ester HO
CO
2 Me A 500 mL stainless steel reactor was purged with N 2 and charged successively with 1-(3-bromophenyl)ethanol (0.126 mol, 25.4 g), DMSO 15 (150 mL), methanol (3.70 mol, 150 mL), triethylamine (0.143 mol, 20.0 mL), Pd(OAc) 2 (2.78 mmol, 0.625 g), and 1, 3 -bis(diphenylphosphino)propane (2.62 mmol, 1.08 g). The reactor was sealed, purged with N 2 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 1 00 0 C for 20 70 hours. The reaction was cooled to room temperature, filtered through celite, concentrated, and partitioned between H 2 0 and CH 2 Cl 2 . The aqueous phase was extracted with CH 2 Cl 2 (3 x 100 mL), and the extracts were washed with water (3 x 100 mL), dried over MgSO 4 , and concentrated to an oil. The product was WO 00/42045 PCT/US99/30434 -134 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%): 1H NMR (400 MHz, CDCl 3 ) 6 1.50 (d, J=6.59 Hz, 3H, CH(CH 3 )OH), 1.86 (d, J=3.66 Hz, 1H, CH(CH 3 )OH), 3.90 (s, 3H, CO 2
CH
3 ), 4.92-4.97 (in, IH, 5 CH(CH 3 )OH), 7.39-7.43 (in, 1H, ArH), 7.57 (d, J=7.57 Hz, 1H, ArH), 7.92 (d, J=7.57 Hz, 1H, ArH), 8.02 (s, 1H, ArH). 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 5-decahydro-2-methyl-, 1- [3 -(methoxycarbonyl)phenyl] ethyl ester 10 A 100 mL flask was charged with 3 -(1-hydroxyethyl)benzoic 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 15 solution was cooled to room temperature, dissolved in ethyl acetate and stirred with a saturated aqueous solution of NaHCO 3 . 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 20 column chromatography (20% acetone/hexanes) to give a white solid (0.776 g, 34%): mp 100-103, 155-156'C (diastereomers); IR (K1Br) 3375, 2931, 2855, 1725, 1704, 1432, 1200, 1078, 1065 cm- 1 ; 1 H NMR (400 MHz, CDCI 3 ) 6 1.20-1.29 (in, 1H, aliphatic CH), 1.32-1.34 (in, 2H, aliphatic CH), 1.38-1.47 (m, 1H, aliphatic CH), 1.53-1.58 (in, 2H, aliphatic CH), 1.62-1.82 (m, 4H, aliphatic CH), 1.68 (d, 25 J=6.59 Hz, 3H, OCH(CH 3 )Ar), 2.01-2.12 (m, 1H, aliphatic CH), 2.41-2.45 (in, 1H, aliphatic CH), 2.50-2.53 (in, 1H, aliphatic CH), 2.60 & 2.62 (s, 3H, ArCH 3 , diastereomers), 2.69-2.85 (m, 2H, aliphatic CH), 2.98-3.04 (m, 1H, aliphatic CH), 3.29-3.43 (in, 1H, aliphatic CH), 3.89 (s, 3H, CO 2
CH
3 ), 6.09-6.17 (in, IH,
OCH(CH
3 )Ar), 6.73 & 6.74 (d, J=8.55 Hz, 1H, ArH, diastereomers), 7.01 & 30 7.02 (d, J=8.79 & 8.55 Hz, 1H, ArH, diastereomers), 7.41 & 7.42 (t, J=7.81 & WO 00/42045 PCT/US99/30434 -135 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 (in, 1H, ArH, diastereomers), 8.06 (bs, 1H, NH), 8.10 & 8.13 (s, 1H, ArH, diastereomers); MS (APCI+) m/z 503.1 (MH+). Anal. Calcd for C 3 0
H
34
N
2 0 5 : C, 71.69; H, 6.82; N, 5.57. Found: C, 71.58; H, 5 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 CO 2 H Me N 0o 0 0 I 'Me 6 0 N H 10 A solution of pyrrolo[3 ',2':5,6] [1 ]benzopyrano[3 ,2-i]quinlolizine 1 -carboxylic acid, 3,7,8,9,10,12,13,1 4,14a,1 5-decahydro-2-rnethyl-, 1 -[3 (methoxycarbonyl)phenyl] ethyl ester (1.43 mmol, 0.717 g) in methanol (18 mL) and IN NaOH (5.71 mmol, 5.71 mL) was heated at 55-60'C for 1 hour. The solution was cooled to room temperature, the methanol was removed by rotary 15 evaporation, and the aqueous phase was neutralized with IN HCI. A precipitate formed and was filtered off and purified by silica gel flash column chromatography (10- 15 % MeOH/CHCI 3 ) to afford a cream colored powder (0.522 g, 75%): mp 244-250'C (dcc); JR (KBr) 3413-3229 (b), 2931, 1685, 1432, 1195, 1150, 1078, 1063 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.03-1.22 (in, 20 3H, aliphatic ClH), 1.38-1.72 (in, 7H, aliphatic CH!), 1.57 (d, J=6.35 Hz, 3H,
OCH(CH
3 )Ar), 1.78-1.88 (in, 1H, aliphatic CH, 2.28-2.38 (in, 1H, aliphatic ClH), 2.40-2.47 (in, 1H, aliphatic ClH), 2.51 & 2.55 (s, 3H, ArCH 3 , diastereoiners), 2.56-2.69 (in, 2H, aliphatic ClH), 2.8 1-2.92 (in, 1H, aliphatic CH!), 3.06-3.23 (in, I1H, aliphatic CT!), 5.96-6.04 (in, I1H, OCH(CH 3 )Ar), 6.5 7 & 6.5 8 (d, J=8.5 5 & 25 8.30 Hz, IH, ArH, diastereomers), 7.01 & 7.02 (d, J=8.30 Hz, 1H, ArH, WO 00/42045 PCT/US99/30434 -136 diastereomers), 7.45-7.50 (in, 1H, 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, CO 2 H); MS (APCI+) n/z 489.1 (MH+). Anal. Calcd for 5 C 2 9
H
3 2
N
2 05-0.50H 2 00.20 SiO 2 : C, 68.35; H, 6.53; N, 5.50; H 2 0, 1.77. Found: C, 67.96; H, 6.81; N, 5.22; H 2 0, 1.81. HPLC (ALLTECH/ALLTIMA C-18, 60:40-20:80 H 2 0/CH 3 CN + 0.05% TFA): retention time=4.843 & 4.970 min (diastereomers), 95.53% purity. Example 49 10 1 -Propanaminium, N,N,N-trimethyl-, salt with 1 -(3-carboxyphenyl)ethyl 3,7,8,9,10,12,1 3 ,1 4 ,1 4 a,15-decahydro-2-methylpyrrolo[3',2':5,6][1] benzopyrano[3,2-i]quinolizine-1-carboxylate (1:1)
CO
2 00 N Me / NMe 3 0 OH \1Me O N H An aqueous solution of choline bicarbonate (0.935 mmol, 0.165 mL, 15 5.66 M) was added to a suspension of pyrrolo[3',2':5,6][1]benzopyrano[3,2 i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(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 20 ether and filtered to give a light yellow solid. The solid was dissolved in hot
CHCI
3 , filtered, concentrated, and dried at 60'C in vacuo to give a yellow powder (0.233 g, 42%): mp 210-216'C; IR (KBr) 3428-3211 (b), 2930, 1684, 1566, 1432, 1878, 1870, 1079, 1063 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.03-1.26 (in, 3H, aliphatic CH), 1.36-1.72 (in, 6H, aliphatic CH), 1.55 (d, J=6.35 Hz, 3H, 25 OCH(CH 3 )Ar), 1.80-1.88 (in, 1H, aliphatic CH), 2.30-2.42 (in, 2H, aliphatic CH), WO 00/42045 PCT/US99/30434 -137 2.51 & 2.52 (s, 3H, ArCH 3 , diastereomers), 2.61-2.70 (in, 2H, aliphatic CH), 2.81-2.92 (m, 1H, aliphatic CH), 3.07 (s, 9H, N(CH 3
)
3 ), 3.11-3.23 (m, 1H, aliphatic CH), 3.26-3.35 (m, 2H, CH 2 OH & aliphatic CH), 3.36 (t, J=4.88 Hz, 2H,
OCH
2
CH
2
N(CH
3
)
3 ), 3.77-3.83 (in, 2H, OCH 2
CH
2
N(CH
3
)
3 ), 5.91-5.99 (in, 1H, 5 OCH(CH 3 )Ar), 6.54-6.58 (in, 1H, ArH), 7.01-7.04 (m, 1H, ArH), 7.21-7.28 (m, 1H, ArH), 7.32-7.38 (in, 1H, ArH), 7.71-7.79 (m, 1H, ArH), 7.91 & 7.93 (s, 1H, ArH, diastereomers), 11.70 (s, 1H, NH); MS (APCI-) mn/z 487.1 (parent M-1). Anal. Calcd for C 2 9
H
3 1
N
2 05-0.88 C 5
H
14 NO-0.50 H 2 0-0.50 CHC1 3 : C, 62.84; H, 6.97; N, 6.23; H 2 0, 1.39. Found: C, 62.92; H, 6.17; N, 6.93; H 2 0, 1.72. 10 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
NO
2 N O 0 0 Me N H Following the procedure from Example 47, Step B, 3-nitrobenzyl alcohol 15 (18.0 mmol, 2.81 g) and 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-, anhydride with benzoic acid (Example 86, 4.50 mmol, 2.00 g) were converted to pyrrolo[3',2':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. The 20 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- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.02-1.16 (in, 2H, aliphatic CH), 1.19-1.24 (in, 1H, aliphatic CH), 1.32-1.62 (in, 25 7H, aliphatic CH), 1.82 (d, J=13.18 Hz, 1H, aliphatic CH), 2.33 (d, J=9.76 Hz, WO 00/42045 PCT/US99/30434 -138 1H, aliphatic CH), 2.41 (d, J=11.23 Hz, 1H, aliphatic CH), 2.48 (s, 3H, ArCH 3 ), 2.60-2.67 (m, 2H, aliphatic CH), 2.84-2.89 (m, 1H, aliphatic CH), 3.15-3.21 (m, 1H, aliphatic CH), 5.32-5.40 (m, 2H, OCH 2 Ar), 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, J=7.57 Hz, 1H, 5 ArH), 8.18 (d, J=8.06 Hz, 1H, ArH), 8.29 (s, 1H, ArH), 11.58 (s, 1H, NH); MS (APCI+) n/z 476.1 (MH+). Anal. Calcd for C 2 7
H
2 9
N
3 0 5 : 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, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-cyanophenyl)ethyl ester CN N 0 OM Me I Me N H Step A: 3-(1-Hydroxyethyl)benzonitrile HO CN To a solution of 3-acetylbenzonitrile (68.9 mmol, 10.0 g) in MeOH 15 (230 mL) at 0 0 C under N 2 was added NaBH 4 (68.9 mmol, 2.61 g) in portions. After 2 hours of gradual warming to room temperature, 1N 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 CH 2 Cl 2 (50 mL). The combined extracts were washed with 20 NaHCO 3 (1 x 50 mL), saturated NaCl (1 x 50 mL), dried over MgSO 4 , and concentrated under vacuum to give pure product as a yellow oil (10.0 g, 98%): 1 H NMR (400 MHz, CDCl 3 ) 6 1.47 (d, J=6.35 Hz, 3H, ArCH(CH 3 )OH), 1.99 (bs, 1H, OH), 4.92 (q, J=6.35 Hz, 1H, ArCH(CH 3 )OH), 7.43 (t, J=7.81 Hz, WO 00/42045 PCT/US99/30434 -139 1H, ArH), 7.53 (d, J=7.57 Hz, 1H, ArH), 7.59 (d, J=7.81 Hz, 1H, ArH), 7.66 (s, 1H, ArH). 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-, 5 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, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 3.37 mmol, 1.50 g) were converted 10 pyrrolo[3',2':5,6][1]-benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(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, 15 1432, 1148, 1077, 1066 cm- 1 ; I H NMR (400 MHz, DMSO-d 6 ) 6 1.02-1.25 (m, 3H, aliphatic CH), 1.31-1.72 (in, 7H, aliphatic CH), 1.57 (d, J=6.35 Hz, 3H,
OCH(CH
3 )Ar), 1.79-1.88 (in, IH, aliphatic CI), 2.32-2.44 (in, 2H, aliphatic CH), 2.46 (s, 3H, ArCH 3 ), 2.56-2.69 (in, 2H, aliphatic CH), 2.80-2.91 (m, I H, aliphatic CH), 3.02-3.28 (m, 1H, aliphatic CH), 5.93-6.01 (in, IH, OCH(CH 3 )Ar), 20 6.56-6.60 (m, 1H, ArH), 7.00-7.04 (m, 1H, ArH), 7.51-7.59 (m, 1H, ArH), 7.71-7.80 (in, 2H, ArH), 7.86 & 7.90 (s, 1H, ArH, diastereomers), 11.56 (s, 1H, NH); MS (APCI+) n/z 470.1 (MH+). Anal. Called for C 2 9
H
3 1
N
3 0 3 -0.25 H 2 0: C, 73.47; H, 6.70; N, 8.86; H 2 0, 0.95. Found: C, 73.18; H, 6.73; N, 8.56, H 2 0, 0.58. 25 Example 52 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 1-[3-[(dimethylamino)carbonyl]phenyl]ethyl ester WO 00/42045 PCTIUS99/30434 -140 0 NMe 2 Me N o 0 0 Me N H Step A: 3-(1-Hydroxyethyl)benzoic acid OH 0 OH A mixture of 3-(1-hydroxyethyl)benzonitrile (Example 51, Step A, 5 6.79 mmol, 1.00 g) in 10% aqueous NaOH (68 mL) was heated at reflux for 4.5 hours, cooled to room temperature, and extracted with ether (2 x 50 mL). The extracts were discarded. The aqueous phase was acidified with concentrated HCl, extracted with ether (3 x 50 mL), and the combined extracts were washed with brine, dried over MgSO4, and concentrated to give a white solid (0.98 g, 87%): 10 mp 107-1 10'C; IH NMR (400 MHz, DMSO-d 6 ) 8 1.29 (d, J=6.35 Hz, 3H, ArCH(CH 3 )OH), 4.71-4.78 (m, 1 H, ArCH(CH 3 )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, ArT!), 7.91 (s, 1H, ArH), 12.87 (s, 1H, COOH); MS (APCI-) n/z 165.1 (M-1). 15 Step B: 3-(1-Hydroxyethyl)-NN-dimethylbenzamide OH 0 -IV 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 iPr 2 NEt (109 mmol, 19.1 mL) in 55 mL of DMF at 0 0 C under N 2 was added HBTU 20 (54.8 mmol, 20.8 g) in two portions. After 45 minutes, IN HCl (50 mL) and ether (50 mL) were added, and the layers were separated. The aqueous phase was WO 00/42045 PCT/US99/30434 -141 further acidified with IN HCl and extracted with ether (4 x 50 mL). The extracts were combined and concentrated. The aqueous phase was concentrated also. The concentrates were combined, dissolved in CH 2 Cl 2 , washed with 10% HCl (1 x 20 mL), saturated NaHCO 3 (1 x 20 mL), brine (1 x 20 mL), dried over 5 MgSO 4 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, iPr 2 NEt, and NN,N',N' tetramethylurea. The yield based on IH NMR was 6.56 g (62%). A small portion was rechromatographed to give pure product as a clear, colorless oil: IH NMR 10 (400 MHz, DMSO-d 6 ) 6 1.28 (d, J=6.59 Hz, 3H, ArCH(CH 3 )OH), 2.86 (s, 3H,
NCH
3 ), 2.93 (s, 3H, NCH 3 ), 4.67-4.73 (in, lH, ArCH(CH 3 )OH), 5.20 (d, J=4.15 Hz, 1H, OH), 7.18-7.20 (in, lH, ArH), 7.31-7.37 (in, 3H, ArH); MS (APCI+) n/z 194.0 (MH+). Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 3
,
7
,
8
,
9 ,10,1 2 ,13,14,14a,15-decahydro-2-methyl-, I 1[3-[(dimethylamino)carbonyl]phenyl] ethyl ester Following the procedure from Example 47, Step B, 3-(l-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 20 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 25 chromatography (0-5% Et 3 N/ethyl acetate), dissolved in ether/ethyl acetate and washed with water (15 x 20 mL) to remove unreacted 3-(1-hydroxyethyl)-NN 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, 30 1146, 1091, 1062 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.02-1.28 (in, 3H, WO 00/42045 PCT/US99/30434 -142 aliphatic CH), 1.32-1.70 (m, 7H, aliphatic CH), 1.57 (d, J=6.84 Hz, 3H,
OCH(CH
3 )Ar), 1.76-1.88 (m, 1H, aliphatic CH), 2.32-2.43 (m, 2H, aliphatic CH), 2.50 & 2.51 (s, 3H, ArCH 3 , diastereomers), 2.52-2.689 (m, 2H, aliphatic CH), 2.84 (s, 3H, NCH 3 ), 2.84-2.89 (m, 1H, aliphatic CH), 2.92 (s, 3H, NCH 3 ), 5 3.06-3.30 (m, 1H, aliphatic CH), 5.94-6.01 (m, 1H, OCH(CH 3 )Ar), 6.57 & 6.58 (d, J=8.55 Hz, 1H, ArH, diastereomers), 7.01 & 7.02 (d, J=8.55 Hz, 1H, ArH, diastereomers), 7.29 (t, J=7.33 Hz, 1H, ArH), 7.37-7.50 (m, 3H, ArH), 11.53 (s, IH, NH); MS (APCI+) n/z 516.3 (MH+). Anal. Called for
C
3 1
H
3 7
N
3 0 4 : C, 72.21; H, 7.23; N, 8.15. Found: C, 71.96; H, 7.25; N, 8.22. 10 Example 53 Pyrrolo[3',2':5,6][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 NMe 2 Me N 0 0 0 Me N H 15 Step A: 1-(3-Dimethylaminomethylphenyl)ethanol OH NMe 2 To a suspension of LiAIH 4 (23.3 mmol, 0.931 g/95 %) in THF (40 mL) at 0*C under N 2 was added a solution of 3-(1-hydroxyethyl)-NN dimethylbenzamide (Example 52, Step B, 15.5 mmol, 3.00 g) in 10 mL of THF. 20 After the evolution of H 2 had ceased, the reaction was warmed to room temperature. After 4 hours at room temperature, the mixture was cooled to 0 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, MgSO 4 and celite WO 00/42045 PCT/US99/30434 -143 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: IH NMR (400 MHz, DMSO-d 6 ) 6 1.26 (d, J=6.59 Hz, 3H, ArCH(CH 3 )OH), 2.09 (s, 6H, N(CH 3
)
2 ), 3.31 (s, 2H, 5 ArCH 2 N), 4.64-4.67 (in, 1H, ArCH(CH 3 )OH), 5.08 (d, J=4.15 Hz, 1H, OH), 7.07 (d, J=7.08 Hz, 1H, ArH), 7.15-7.25 (in, 3H, ArH); MS (APCI+) m/z 180.0 (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-, 10 1-[3-[(dimethylamino)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, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, anhydride with benzoic acid 15 (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-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-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 20 acetone and the inorganic salts filtered off. The filtrate was concentrated. The organic and aqueous residues were combined, mixed with 15 mL of CH 2
CI
2 at room temperature under N 2 and treated with 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). 25 The aqueous washes were concentrated and the product was purified by silica gel flash column chromatography (0-5% Et 3 N/ethyl acetate) to give a yellow solid (0.160 g, 8.4%): mp 95-100'C; JR (KBr) 2931, 2857, 1678, 1430, 1237, 1195, 1147, 1062 cm- 1 . IH NMR (400 MHz, DMSO-d 6 ) 6 1.09-1.27 (in, 3H, aliphatic CH), 1.32-1.68 (in, 7H, aliphatic CH), 1.54 (d, J=6.35 Hz, 3H, OCH(CH 3 )Ar), 30 1.79-1.84 (in, IH, aliphatic CH), 2.07 & 2.08 (s, 6H, N(CH 3
)
2 , diastereomers), WO 00/42045 PCT/US99/30434 -144 2.29-2.43 (in, 2H, aliphatic CH), 2.49 & 2.50 (s, 3H, ArCH 3 , diastereomers), 2.59-2.69 (in, 2H, aliphatic CH), 2.81-2.92 (in, 1H, aliphatic CH), 3.02-3.17 (in, 1H, aliphatic CH), 3.33 & 3.34 (s, 2H, ArCH 2 N, diastereomers), 5.90-5.98 (in, 1H, OCH(CH 3 )Ar), 6.56-6.59 (in, 1H, ArH), 7.00-7.03 (in, 1H, ArH), 5 7.12-7.21 (in, 1H, ArH), 7.26-7.33 (in, 3H, ArH), 11.50 & 11.51 (s, 1H, NH, diastereomers); MS (APCI+) m/z 502.2 (MH+). Anal. Called for
C
3 1
H
3 9
N
3 03-0.27 C 4
H
8 0 2 : C, 73.33; H, 7.90; N, 8.00. Found: C, 72.94; H, 7.90; N, 8.10. General Procedure J. 10 Diethyl azodicarboxylate (Aldrich, 1 eq.) was 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 15 silica gel (45% ethyl acetate:hexanes) to give the corresponding ester. General Procedure K. Under a nitrogen atmosphere, DBU (Aldrich, I 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 20 (Aldrich, 1.1 eq.) in DMF was added. After stirring at room temperature for 24 hours, the reaction mixture was diluted with CH 2
CI
2 which induced precipitation of the desired product. The solid product was filtered off and washed with
H
2 0. General Procedure L. 25 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 -145 was purified by flash column chromatography on silica gel (30% MeOH:CH 2
CI
2 ). General Procedure M. 1, 2
,
3
,
4
,
6
,
7
,
8
,
9 -Octahydroquinolizinylium perchlorate (1.7 eq.) was dissolved in 5 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 10 0 C 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 10 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 150'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 15 with saturated NaHCO 3 . 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 0. To a solution of a ester (1 eq.) in methanol was added 2N NaOH (4 eq.). After 20 heating at 55'C for 1 hour, the reaction became clear. The reaction mixture was cooled to 0 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. 25 To a suspension of Mannich base of choice (1 eq.) in anhydrous THF was added slowly solid LiBH 4 (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, IN HCI was added to neutralize the reaction. The product precipitated out of solution as a white solid. The mother liquor was extracted with CH 2
CI
2 . The WO 00/42045 PCT/US99/30434 -146 combined organic layers were dried with MgSO 4 , and solvent was removed to yield more product. Example 54 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,1,13,14,14a,15-decahydro-2-methyl-,2-phenylethyl ester N O 0 H Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid phenylethyl ester 0 HO N H 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid phenylethyl ester was 10 synthesized according to Procedure J from 2-phenyl-ethanol (6.39 g, 52.3 mmol) and recrystallized from hexane/ethyl acetate to give 2.40 g (3 1.1%) of fine white powder: mp 186-188'C; IR (KBr) 3231, 2978, 1644, 1463, 1173, 1101 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 2.49 (s, 3H, CCH 3 ), 3.03 (t, J=6.99 Hz, 2H,
OCH
2
CH
2 ), 4.40 (t, J=6.75 Hz, 2H, OCH 2
CH
2 ), 6.57 (dd, J=8.60, 2.29 Hz, 1H, 15 ArH), 7.09 (d, J=8.68 Hz, 1H, ArH), 7.20 (d, J=6.99 Hz, 1H, ArH), 7.26-7.33 (in, 5H, ArH), 8.81 (s, 1H, OH), 11.49 (s, 1H, NH); MS(APCI+): n/z 326.1 (MH+). Anal. Calcd for C 18
H
17
N
1 03: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.23; H, 5.74; N, 4.67.
WO 00/42045 PCT/US99/30434 -147 Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenylethyl ester 0 O HO N H 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 5 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 2.34 (s, 3H, CCH 3 ) 2.68 (s, 6H, N(CH 3
)
2 ), 3.00 (t, 10 J=6.59 Hz, 2H, OCH 2
CH
2 ), 4.43 (t, J=6.59 Hz, 2H, OCH 2
CH
2 ), 4.67 (s, 2H,
NCH
2 Ar), 6.81 (d, J=8.79 Hz, 1H, ArH), 7.17-7.20 (m, 1H, ArH), 7.23-7.28 (in, 5H, ArH), 11.93 (s, IH, NH); MS(APCI+): m/z 353.2 (MH+). Anal. Called for
C
2 1
H
24
N
2 0 3 : 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, 15 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, 1 5-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 20 recrystallized from ethyl acetate/hexanes to give 0.170 g (54.0%) of a white solid: mp 185-186*C; IR (KBr) 3297, 2931, 2856, 1673, 1432, 1199, 1080 cm- 1 ; IH NMR (400 MHz, CDC 3 ) 6 1.20-1.81 (m, I0H, aliphatic CH), 2.07 (d, J=13.92 Hz, IH, aliphatic CH), 2.41 (s, 3H, CCH 3 ), 2.44-2.53 (m, 2H, aliphatic CH), 2.73-2.84 (m, 2H, aliphatic CH), 2.98-3.04 (in, 1H, aliphatic CH), WO 00/42045 PCT/US99/30434 -148 3.05-3.08 (in, 2H, OCH 2
CH
2 ), 3.38 (dd, J=17.95, 6.71 Hz, 1H, aliphatic CH), 4.50-4.53 (in, 2H, OCH 2
CH
2 ), 6.72 (d, J=8.79 Hz, 1H, ArH), 6.99 (d, J=8.79 Hz, 1H, ArH), 7.17-7.29 (in, 5H, ArH), 7.99 (s, 1H, NH); MS(APCI+): m/z 445.3 (MH+). Anal. Calcd for C 2 8
H
3 2
N
2 0 3 : C, 75.56; H, 7.26; N, 6.30. Found: 5 C, 75.36; H, 7.28; N, 6.13. Example 55 Pyrrolo[3',2':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 0 N O0'~ O O N 10 H Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl benzyl ester 0 0 HO N H 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl 15 benzyl ester was synthesized according to Procedure K from 4-bromomethyl benzoic acid methyl ester (6.64 g, 29.0 mmol) and precipitated out of 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 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 2.57 (s, 3H, CCH 3 ), 3.80 (s, 3H, OCH 3 ), 5.34 (s, 2H, OCH 2 Ar), 6.55 (dd, J=8.67, 20 2.32 Hz, IH, ArH), 7.09 (d, J=8.55 Hz, 1H, ArH), 7.24 (d, J=2.20 Hz, I H, ArH), 7.54 (d, J=8.06 Hz, 2H, ArH), 7.94 (d, J=8.30 Hz, 2H, ArH), 8.83 (s, 1H, OH), WO 00/42045 PCTIUS99/30434 -149 11.59 (s, 1H, NH); MS(APCI+): n/z 340.1 (MH+). Anal. Called for
C
1 9
H
1 7
N
1 0 5 : C, 67.25; H, 5.05; N, 4.13. Found: C, 66.88; H, 5.06; N, 4.05. Step B: 4 -Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester 0 N 0 0-/ 0 HO N 5 H 4 -Dimethylaminomethyl-5-hydroxy-2-nethyl-1 H-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 10 white solids: mp 125-126'C; IR (KBr) 3142, 2959, 1672, 1585, 1434, 1285, 1095 cm- 1 ; I H NMR (400 MHz, DMSO-d 6 ) 8 2.12 (s, 6H, N(CH 3
)
2 ), 2.49 (s, 3H, CCH 3 ), 3.84 (s, 3H, OCH 3 ), 4.02 (s, 2H, NCH 2 Ar), 5.34 (s, 2H, OCH 2 Ar), 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+): m/z 15 397.2 (MH+). Anal. Calcd for C 2 2
H
2 4
N
2 0 5 : C, 66.41; H, 6.12; N, 7.04. Found: C, 66.41; H, 6.01; N, 6.97. Step C: Pyrrolo[3',2':5,6][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 20 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15 -decahydro-2-methyl-,[4-(methoxycarbonyl) phenyl]methyl ester was synthesized according to Procedure M from 4 -dimethylaminomethyl-5-hydroxy-2-methyl- I H-indole-3-carboxylic acid 4 -methoxycarbonyl-benzyl ester (0.200 g, 0.505 mmol) and recrystallized from 25 t-butyl methyl ether to give 0.090 g (23.0%) of granular off-white solids: mp WO 00/42045 PCT/US99/30434 -150 179-180'C; IR (KBr) 3173, 2930, 2856, 1725, 1615, 1433, 1275, 1079 cm- 1 ; 1 H NMR (400 MHz, CDCl 3 ) 6 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, 1H, aliphatic CH), 2.50-2.53 (in, 1H, aliphatic CH), 2.55 (s, 3H, CCH 3 ), 2.73-2.84 (in, 2H, aliphatic CH), 5 2.96-3.05 (m, IH, aliphatic CH), 3.38 (dd, J=17.70, 7.20 Hz, IH, aliphatic CH), 3.89 (s, 3H, OCH 3 ), 5.34 (dd, J=16.36, 12.70 Hz, 2H, OCH 2 Ar), 6.73 (d, J=8.79 Hz, 1H, ArH), 7.01 (d, J= 8.79 Hz, 1H, 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+): m/z 489.3 (MH+). Anal. Called for C 2 9
H
3 2
N
2 0 5 : C, 71.29; H, 6.60; N, 5.73. Found: 10 C, 70.94; H, 6.26; N, 5.57. Example 56 Pyrrolo[3',2':5,6] [1 ]benzopyrano[3, 2 -i]quinolizine- I -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2,-methyl-, (4-carboxyphenyl)methyl ester 0 N O / OH 0 0 N H 15 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (4-carboxyphenyl)methyl ester was synthesized according to Procedure 0 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.05-1.26 (in, 20 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 (in, 1H, aliphatic CH), 2.48 (s, 3H, CCH 3 ), 2.63-2.69 (in, 2H, aliphatic CH), 2.85-2.91 (in, 1H, aliphatic CH), 3.19 (dd, J=18.07, 6.84 Hz, 1H, aliphatic CH), 3.41-3.43 (in, IH, aliphatic CH), 5.31 (dd, J=20.02, 12.94 Hz, 2H, OCH 2 Ar), 6.60 (d, J=8.55 Hz, 25 1H, ArH), 7.04 (d, J=8.55 Hz, 1H, ArH), 7.54 (d, J=8.30 Hz, 2H, ArH), 7.94 (d, WO 00/42045 PCT/US99/30434 -151 J= 8.30 Hz, 2H, ArH), 11.57 (s, 1H, NH), 12.98 (s, 1H, C02H); MS(APCI+): m/z 475.3 (MH+). Anal. Calcd for C 2 8
H
3 0
N
2 0 5 : C, 70.17; H, 6.42; N, 5.85. Found: C, 69.78; H, 6.50; N, 5.62. Example 57 5 1-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-1H-indol-4-ylmethyl] 1,2,3,4,6,7,8,9-octahydro-quinolizinylium; chloride Cl® ®N OH HO N H 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-, 10 [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 0 C and concentrated HCI was added slowly until pH 3. The aqueous layer was extracted with ethyl acetate (5 x 50 mL), and the 15 combined organic layers were dried with MgSO 4 , 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 ; IH NMR (400 MHz, DMSO-d 6 ) 6 1.20-1.30 (m, IH, aliphatic CH) 1.43-1.51 (m, 4H, aliphatic CH), 1.69-2.30 (m, 5H, aliphatic CH), 2.48 & 2.49 (s, 20 3H, CCH 3 , opened and closed forms) , 2.48-2.55 (m, 2H, aliphatic CH), 2.85-3.30 (m, 2H, aliphatic CH), 3.40-3.80 (m, 3H, aliphatic CH), 5.33-5.36 (m, 2H,
OCH
2 Ar), 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 & 25 11.85 (s, 1H, NH, opened & closed forms), 13.00 (s, 1H, C02H); MS(APCI+): WO 00/42045 PCTIUS99/30434 -152 n/z 475.3 (MH+). Anal. Called for C 2 8
H
3 1
N
2 0 5 C1 1 : 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][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl ester OH O0 N H Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester IOH HO N 10 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- 1 H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (Example 56, Step B, 2.32 g, 5.84 mmol) and 15 triturated with acetone to give 0.993 g (47.0%) of a white solid: mp 140-143'C; IR (KBr) 3140, 2777, 1686, 1583, 1435, 1092 cm- 1 ; IH NMR (400 MHz, DMSO d 6 ) 8 2.51 (s, 3H, CH 3 ), 2.71 (s, 6H, N(CH 3
)
2 ), 4.47 (d, J=5.13 Hz, 2H, ArCH 2 OH), 4.73 (s, 2H, NCH 2 Ar), 5.18 (t, J=5.62 Hz, 1H, ArCH 2 OH), 5.25 (s, 2H, OCH 2 Ar), 6.84 (d, J=8.55 Hz, lH, ArH), 7.28 (d, J=8.55 Hz, 1H, ArH), 20 7.31 (d, J=7.81 Hz, 2H, ArH), 7.40 (d, J=7.81 Hz, 2H, ArH), 8.60 (s, 1H, OH), 11.97 (s, 1H, NH); MS(APCI+): i/z 369.2 (MH+). HPLC (ALLTCH/ALLTIMA WO 00/42045 PCT/US99/30434 -153 C-18 1:1-2:98 H 2 0/CH 3 CN + 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,15-decahydro-2-methyl-, 5 [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 10 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.11-1.27 (m, 3H, aliphatic CH),1.39-1.70 (in, 7H, 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, IH, aliphatic 15 CH), 2.47 (s, 3H, CCH 3 ), 2.65-2.69 (m, 2H, aliphatic CH), 2.86-2.92 (in, 1H, aliphatic CH), 3.23 (dd, J=16.64, 9.64 Hz, 1H, aliphatic CH), 4.48 (d, J=5.78 Hz, 2H, ArCH 2 OH), 5.17 (t, J=5.55 Hz, IH, ArCH 2 OH), 5.21 (dd, J=22.42, 12.06, Hz, 2H, OCH 2 Ar), 6.59 (d, J=8.44 Hz, 1H, ArH), 7.03 (d, J=8.68 Hz, IH, ArH), 7.31 (d, J= 7.72 Hz, 2H, ArH), 7.39 (d, J=7.96 Hz, 2H, ArH), 11.52 (s, 1H, NH); 20 MS(APCI+): mn/z 461.2 (MH+). Anal. Called for C 2 8
H
3 2
N
2 0 4 : 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]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmethyl ester N 0 0 0 N 25 H WO 00/42045 PCT/US99/30434 -154 Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen 2-ylmethyl ester 0 rC 0 HO N H 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl 5 ester was synthesized according to Procedure K from 2-bromomethyl-naphthalene (7.63 g, 34.5 mmol) and precipitated out of CH 2 Cl 2 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- 1 ; I H NMR (400 MHz, DMSO-d 6 ) 8 2.59 (s, 3H, CCH 3 ), 5.46 (s, 2H, OCH 2 Ar), 6.59 (dd, J=8.44, 2.41 Hz, 1H, ArtH), 7.12 (d, J=8.44 Hz, 1H, 10 ArH), 7.30 (d, J=2.41 Hz, IH, ArH), 7.51 (dd, J=6.03, 3.38 Hz, 1H, ArH), 7.59 (d, J=1.69 Hz, 1H, ArH), 7.61 (d, J=1.69 Hz, 1H, ArH), 7.90-7.96 (in, 4H, ArH), 8.83 (s, 1H, OH), 11.58 (s, 1H, NH); MS(APCI+): mn/z 332.2 (MH+). HPLC (ALLTCH/ALLTIMA C-18 35:65-2:98 H 2 0/CH 3 CN + 0.05% TFA): rentention time=3.70 min, 95.81% purity. 15 Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester 0 HO N H 4-Dimethylaminomethyl-5 -hydroxy-2-methyl- 1 H-indole-3 -carboxylic acid naphthalen-2-ylmethyl ester synthesized according to the Procedure L from 20 5-hydroxy-2-methyl- 1 H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester (Example 57, Step A, 3.38 g, 10.2 mmol) and recrystallized from CH 2 Cl 2 to give WO 00/42045 PCT/US99/30434 -155 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 2.11 (s, 6H, N(CH 3
)
2 ), 2.49 (s, 3H, CCH 3 ), 4.03 (s, 2H, NCH 2 Ar), 5.43 (s, 2H,
OCH
2 Ar), 6.57 (d, J=8.68 Hz, 1H, ArH), 7.08 (d, J=8.44 Hz, 1H, ArH), 5 7.51-7.53 (in, 2H, ArH), 7.60 (d, J=8.44 Hz, 1H, ArH), 7.91-7.99 (m, 4H, ArH), 11.55 (s, 1H, NH); MS(APCI+): mn/z 389.2 (MH+). HPLC (ALLTCH/ALLTIMA C-18 55:45-15:85 H 2 0/CH 3 CN + 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, 10 3,78,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, 2-naphthalenylmethyl 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 was synthesized according to Procedure M from 4 -dimethylaminomethyl-5-hydroxy 15 2-methyl-iH-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 ; 1 H NMR (400 MHz, CDCl 3 ) 5 1.19-1.45 (m, 4H, aliphatic CH) 1.55-1.78 (in, 6H, aliphatic CH), 2.07 (d, J=13.99 Hz, 1H, aliphatic CH), 20 2.43-2.46 (in, 1H, aliphatic CH), 2.52-2.55 (m, 1H, aliphatic CH), 2.58 (s, 3H,
CCH
3 ), 2.77-2.86 (m, 2H, aliphatic CH), 3.01-3.07 (in, IH, aliphatic CH), 3.41 (dd, J=18.08, 6.75 Hz, IH, aliphatic CH), 5.48 (dd, J=19.53, 10.61 Hz, 2H,
OCH
2 Ar), 6.75 (d, J=8.68 Hz, 1H, ArH), 7.03 (d, J=8.68 Hz, IH, ArH), 7.48-7.50 (m, 2H, ArH), 7.55-7.57 (in, IH, ArH), 7.82-7.86 (m, 3H, ArH), 8.11 (s, 25 1H, NH); MS(APCI+): m/z 481.3 (MH+). Anal. Calcd for C 3 1
H
3 2
N
2 0 3 : C, 77.47; H, 6.71; N, 5.83. Found: C, 77.13; H, 6.84; N, 5.51.
WO 00/42045 PCT/US99/30434 -156 Example 60 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester o / 0 N O 6 N 5 H Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl benzyl ester o / 0 0Z0 0 HO N H 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl 10 benzyl ester was synthesized according to Procedure K from 3-bromomethyl benzoic acid methyl ester (5.49 g, 24.0 mmol) and triturated with ethyl acetate 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; I H NMR (400 MHz, DMSO-d 6 ) 6 2.56 (s, 3H, CCH 3 ), 3.81 (s, 3H, OCH 3 ), 5.35 (s, 2H, OCH 2 Ar), 6.57 (dd, J=8.55, 15 2.20 Hz, 1H, 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, 1H, ArH), 7.70 (d, J=7.81 Hz , 1H, ArH), 7.89 (d, J=7.57 Hz, 1H, ArH), 8.01 (s, IH, ArH), 8.82 (s, 1H, OH), 11.58 (s, 1H, NH); MS(APCI+): m/z 340.1 (MH+). Anal. Calcd for C 19
H
1 7
N
1 0 5 : C, 67.25; H, 5.05; N, 4.13. Found: C, 67.22; H, 4.75; N, 4.05.
WO 00/42045 PCT/US99/30434 -157 Step B: 4 -Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester o / 0 00 ,N O HO N H 4 -Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 5 3-methoxycarbonyl-benzyl ester was synthesized according to Procedure L from 5-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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 2.10 (s, 6H, N(CH 3
)
2 ), 2.49 (s, 10 3H, CCH 3 ), 3.81 (s, 3H, OCH 3 ), 3.96 (s, 2H, NCH 2 Ar), 5.31 (s, 2H, OCH 2 Ar), 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, IH, ArH), 7.90 (d, J=7.81 Hz, 1H, ArH), 8.03 (s, 1H, ArH), 11.54 (s, 1H, NH); MS(APCI+): m/z 397.0 (MH+). HPLC (ALLTCH/ALLTIMA C-18 65:35-15:85 H 2 0/CH 3 CN + 0.05% TFA): rentention 15 time=4.91 min, 92.97% purity. 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-(methoxycarbonyl)phenyl]methyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(methoxycarbonyl) phenyl]methyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-IH-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; 25 IR (KBr) 3380, 2931, 2855, 1721, 1433, 1289, 1076 cm-1; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.03-1.21 (in, 3H, aliphatic CH) 1.36-1.63 (in, 7H, aliphatic CH), WO 00/42045 PCT/US99/30434 -158 1.81 (d, J=13.43 Hz, 1H, aliphatic CH), 2.33 (d, J=10.50 Hz, IH, aliphatic CH), 2.40-2.42 (m, 1H, aliphatic CH), 2.46 (s, 3H, CCH 3 ), 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, 1H, aliphatic CH), 3.81 (s, 3H, OCH 3 ), 5.29 (dd, J=25.15, 12.45 Hz, 2H, OCH 2 Ar), 6.57 (d, 5 J=8.79 Hz, 1H, ArH), 7.02 (d, J= 8.79 Hz, 1H, ArH), 7.52 (t, J=7.57 Hz, 1H, 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
C
2 9
H
3 2
N
2 0 5 : C, 71.29; H, 6.60; N, 5.73. Found: C, 71.22; H, 6.91; N, 5.43. Example 61 10 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]methyl ester N 0 OH 0 0 N H Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-IH-indole-3-carboxylic 15 acid 3-hydroxymethyl-benzyl ester OH 0 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 20 3-methoxycarbonyl-benzyl ester (Example 60, Step B, 2.21 g, 5.58 mmol) and triturated with CH 2
CI
2 to give 1.11 g (54.0%) of white powder: mp 199-201 C; IR (KBr) 3065, 2884, 1681, 1586, 1432, 1090 cm- 1 ; 1 H NMR (400 MHz, DMSO- WO 00/42045 PCT/US99/30434 -159 d 6 ) 8 2.25 (s, 3H, CCH 3 ) 2.72 (s, 6H, N(CH 3
)
2 ), 4.48 (d, J=5.37 Hz, 2H, ArCH 2 OH), 4.75 (s, 2H, NCH 2 Ar), 5.22 (t, J=5.62 Hz, 1H, ArCH 2 OH), 5.28 (s, 2H, OCH 2 Ar), 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 5 369.2 (MH+). HPLC (ALLTCH/ALLTIMA C-18 98:2-75:25 H 2 0/CH 3 CN + 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, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]methyl ester 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl) phenyl]methyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester (0.980 g, 2.66 mmol) and triturated with t-butyl 15 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 ; IH NMR (400 MHz, DMSO-d 6 ) 5 1.06-1.37 (in, 3H, aliphatic CH) 1.40-1.65 (in, 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 (in, 1H, aliphatic CH), 2.46 (s, 3H, CCH 3 ), 2.61-2.68 (in, 20 2H, aliphatic CH), 2.83-2.89 (in, 1H, aliphatic CH), 3.12-3.16 (in, 1H, aliphatic CH), 3.18 (dd, J=18.31, 6.84 Hz, 1H, aliphatic CH), 4.46 (d, J=5.62 Hz, 2H, ArCH 2 OH), 5.18 (t, J=6.10 Hz, 1H, ArCH 2 OH), 5.21 (dd, J=20.27, 12.21 Hz, 2H, OCH 2 Ar), 6.58 (d, J=8.79 Hz, 1H, ArH), 7.01 (d, J=8.55 Hz, 1H, ArH), 7.23-7.32 (in, 3H, ArH), 7.36 (s, 1H, ArH), 11.51 (s, 1H, NH); MS(APCI+): m1/z 25 461.1 (MH+). Anal. Calcd for C 2 8
H
3 2
N
2 0 4 : C, 73.02; H, 7.00; N, 6.08. Found: C, 72.84; H, 7.07; N, 5.91.
WO 00/42045 PCTIUS99/30434 -160 Example 62 Pyrrolo[3',2':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) 0 OH N 0 00 N H 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-carboxyphenyl)methyl ester was synthesized according to Procedure 0 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-, [3-(methoxycarbonyl)phenyl]methy ester (Example 60, 10 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- I; IH NMR (400 MHz, DMSO-d 6 ) 6 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, 1H, aliphatic CH), 2.47 (s, 15 3H, CCH 3 ), 2.56-2.67 (m, 2H, aliphatic CH), 2.84-2.88 (m, 1H, aliphatic CH), 3.15 (dd, J=17.82, 6.35 Hz, 1H, aliphatic CH), 5.28 (dd, J=24.17, 12.45 Hz, 2H,
OCH
2 Ar), 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, I H, ArH), 8.00 (s, 1H, ArH), 11.55 (s, 1H, NH); MS(APCI+): m/z 475.1 (MH+). Anal. 20 Calcd for C 2 8
H
3 0
N
2 0 5 : 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] 25 benzopyrano[3,2-i]quinolizine-1-carboxylate (1:1) WO 00/42045 PCT/US99/30434 -161 O0 N 0 0 OH N 0 00 N H To a suspension of pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1 carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-carboxyphenyl)methyl ester (Example 62, 0.100 g, 0.211 mmol) in 5 mL of 5 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 ; 1 H NMR 10 (400 MHz, DMSO-d 6 ) 6 1.09-1.28 (in, 3H, aliphatic CH) 1.39-1.70 (in, 7H, aliphatic CH), 1.86 (d, J=13.50 Hz, 1H, aliphatic CH), 2.35 (d, J=10.37 Hz, 1H, aliphatic CH), 2.42-2.45 (in, 1H, aliphatic CH), 2.47 (s, 3H, CCH 3 ), 2.65-2.72 (in, 2H, aliphatic CH), 2.87-2.91 (in, IH, aliphatic CH), 3.09 (s, 9H, N(CH 3
)
3 ), 3.23 (dd, J=15.19, 8.44 Hz, IH, aliphatic CH), 3.35-3.40 (in, 2H, NCH 2
CH
2 OH), 15 3.81-3.85 (in, 2H, NCH 2
CH
2 OH), 5.20 (dd, J=23.63, 12.30 Hz, 2H, OCH 2 Ar), 6.55 (d, J=8.44 Hz, 1 H, ArH), 7.03 (d, J= 8.44 Hz, 1H, ArH), 7.22 (t, J=7.47 Hz, 1H, ArH), 7.29 (d, J=7.23 Hz, IH, ArH), 7.75 (d, J=7.48 Hz, 1H, ArH), 7.89 (s, 1H, ArH), 11.55 (s, 1H, NH); MS(APCI+): n/z 475.1 (MH+). Anal. Calcd for
C
3 3
H
4 3
N
3 0 6 : C, 65.23; H, 7.68; N, 6.92. Found: C, 64.95; H, 7.68; N, 6.92. 20 Example 64 Pyrrolo[3',2':5,6][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]imethyl ester WO 00/42045 PCT/US99/30434 -162 N N 0 0 0 N H To a stirred solution of Ph 3 P (0.161 g, 0.616 mmol) 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-, [3-(hydroxymethyl)phenyl] 5 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 10 purified by flash column chromatography on silica gel (20% MeOH:CH 2 Cl 2 ) and recrystallized from CH 2 C1 2 to give 1.21 g (40.3%) of coarse off-white powder: mp 87-90*C; IR (KBr) 2930, 2854, 1700, 1589, 1432, 1077 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.06-1.36 (in, 3H, aliphatic CH) 1.39-1.63 (in, 7H, aliphatic CH), 1.82 (d, J=13.18 Hz, 1H, aliphatic CH), 2.11 (s, 6H, N(CH 3
)
2 ) 15 2.34 (d, J=10.74 Hz, 1H, aliphatic CH), 2.40-2.46 (in, 1H, aliphatic CH), 2.45 (s, 3H, CCH 3 ), 2.59-2.67 (in, 2H, aliphatic CH), 2.83-2.89 (i, 1H, aliphatic CH), 3.15 (dd, J=18.31, 6.84 Hz, 1H, aliphatic CH), 3.37 (s, 2H, ArCH 2
N(CH
3
)
2 ), 5.20 (dd, J=23.93, 12.21 Hz, 2H, OCH 2 Ar), 6.57 (d, J=8.79 Hz, 1H, ArH), 7.02 (d, J=8.79 Hz, 1H, ArH), 7.22-7.31 (in, 3H, ArH), 7.34 (s, 1H, ArH), 20 11.53 (s, 1H, NM); MS(APCI+): m/z 488.1 (MH+). Anal. Calcd for
C
3 0
H
3 7
N
3 0 3 : C, 71.89; H, 7.65; N, 8.62. Found: C, 71.89; H, 7.65; N, 8.20. Example 65 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 25 [3-[(dimethylamino)carbonyl]phenyl]methyl ester WO 00/42045 PCT/US99/30434 -163 o / N 00 N 0 N H Step A: 3-Hydroxymethyl-N,N-dimethyl-benzamide 0 HO To a mixture of 3-(hydroxymethyl)benzoic acid (9.87 g, 64.9 mmol), 5 dimethylamine (2 M in THF, 32.4 mL, 64.9 mmol), 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 0 C. After 5 minutes, the yellow solution turned orange. After stirring at 0 0 C for 1 hour, the reaction mixture was diluted with diethyl ether, washed with 10% HCI, saturated NaHCO 3 , brine, dried with 10 MgSO 4 , and concentrated to give a brown oil. The product was purified by flash column chromatography on silica gel (3% MeOH:CH 2
CI
2 ) to afford 7.5 g (64.5%) of a yellow oil: 1 H NMR (400 MHz, DMSO-d 6 ) 6 2.88 (s, 3H, NCH 3 ), 2.96 (s, 3H, NCH 3 ), 4.51 (d, J=5.55 Hz, 2H, OCH 2 Ar), 5.25 (t, J=5.79 Hz, 1H, OH), 7.21-7.25 (in, 1H, ArH), 7.31-7.47 (m, 3H, ArH); MS(APCI+): n/z 15 180.1 (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, 1 5-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]phenyl]methyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 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 ; 1 H NMR (400 MHz, DMSO- WO 00/42045 PCTIUS99/30434 -164 d 6 ) 8 1.09-1.62 (in, I0H, aliphatic CH), 1.82 (d, J=14.16 Hz, 1H, aliphatic CH), 2.33 (d, J=10.25 Hz,1H, aliphatic CH), 2.40-2.43 (in, 1H, aliphatic CH), 2.45 (s, 3H, CCH 3 ), 2.46 (s, 6H, N(CH 3
)
2 ), 2.59-2.67 (in, 2H, aliphatic CH), 2.86-2.93 (in, IH, aliphatic CH), 3.16 (dd, J=18.80, 7.81 Hz, 1H, aliphatic CH), 5 5.24 (dd, J=20.75, 12.45 Hz, 2H, OCH 2 Ar), 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 (in, 2H, ArH), 7.49 (d, J=7.57 Hz, 1H, ArH), 11.54 (s, 1H, NH); MS(APCI+): m/z 502.2 (MH+). Anal. Calcd for C 3 0
H
3 5
N
3 0 4 : C, 71.83; H, 7.03; N, 8.38. Found: C, 71.44; H, 7.05; N, 8.21. 10 Example 66 Pyrrolo[3',2':5,6][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 N N 0 0 0 N H Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a, 1 5-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 CH 2 Cl 2 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.14-1.75 (in, 1OH, aliphatic CH), 1.90 (d, 20 J=13.18 Hz, 1H, aliphatic CH), 2.34-2.46 (in, 2H, aliphatic CH), 2.46 (s, 4H,
N(CH
2
CH
2
)
2 0), 2.49 (s, 3H, CCH 3 ), 2.59 (t, J=5.62 Hz, 2H, CO 2
CH
2
CH
2 ), 2.64-2.73 (in, 2H, aliphatic CH), 2.86-2.91 (in, 1H, aliphatic CH), 3.29 (dd, J=19.29, 10.25 Hz, IH, aliphatic CH), 3.52 (s, 4H, N(CH 2
CH
2
)
2 0), 4.18-4.30 (in, 2H, CO 2
CH
2
CH
2 ), 6.58 (d, J= 8.55 Hz, 1H, ArH), 7.02 (d, J=8.55 Hz, 1H, WO 00/42045 PCT/US99/30434 -165 ArH), 11.48 (s, 1H, NH); MS(APCI+): m/z 454.1 (MH+). Anal. Calcd for
C
2 6
H
3 5
N
3 0 4 : C, 68.60; H, 7.79; N, 9.23. Found: C, 68.23; H, 7.80; N, 9.02. Example 67 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-[1,1'-biphenyl]-4-ylethyl ester N O 0 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-[1,1'-biphenyl]-4-ylethyl ester was synthesized according to Procedure N from 1-biphenyl-4-yl-ethanol (2.68 g, 10 13.5 mmol) and triturated with diethyl ether to give 0.619 g (35.4%) of white powder: mp 132-135'C; IR (KBr) 2929, 2855, 1677, 1432, 1078 cm- 1 ; 1H NMR (400 MHz, DMSO-d 6 ) 6 1.11-1.67 (in, 1OH, aliphatic CH), 1.59 (d, J=6.59 Hz, 2H, OCHCH 3 ), 1.79-1.89 (in, 2H, aliphatic CH), 2.33-2.47 (m, 1H, aliphatic CH), 2.53 & 2.54 (s, 3H, CCH 3 , diastereomers), 2.60-2.67 (in, 2H, aliphatic CH), 15 2.79-2.95 (in, 1H, aliphatic CH), 3.14 (dd, J=28.08, 10.12 Hz, 1H, aliphatic CH), 5.96-6.03 (in, IH, OCHCH 3 ), 6.55-6.59 (in, 1H, ArH), 7.00-7.03 (m, 1H, ArH), 7.31-7.34 (in, 1H, ArH), 7.40-7.51 (in, 4H, ArH), 7.60-7.64 (in, 4H, ArH), 11.53 (s, 1H, NH); MS(APCI+): mn/z 521.1 (MH+). Anal. Calcd for
C
3 4
H
3 6
N
2 0 3 : C, 78.25; H, 7.36; N, 5.14. Found: C, 78.20; H, 7.76; N, 4.85. 20 Example 68 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (2,6-difluorophenyl)methyl ester WO 00/42045 PCT/US99/30434 -166 F N 0 0 o\ F 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-,(2,6-difluorophenyl)methyl ester was synthesized according to Procedure N from (2,6-difluoro-phenyl)-methanol 5 (1.50 mL, 13.5 mmol) and triturated with diethyl ether to give 1.07 g (68.0%) of fluffy white powder: mp 219-220 0 C; IR (KBr) 3330, 2928, 1664, 1473, 1059 cm- 1 ; IH NMR (400 MHz, DMSO-d 6 ) 5 1.03-1.35 (in, 3H, aliphatic CH), 1.38-1.56 (in, 7H, cylic CH), 1.78 (d, J=13.18 Hz, 2H, aliphatic CH), 2.32-2.34 (in, 2H, aliphatic CH), 2.41 (s, 3H, CCH 3 ), 2.55-2.66 (in, 2H, aliphatic CH), 10 2.83-2.88 (in, 1H, aliphatic CH), 3.08 (dd, J=18.31, 7.08 Hz, 1H, aliphatic CH), 5.20 (d, J=1 1.96 Hz, 1H, OCH 2 Ar), 6.57 (d, J=8.55 Hz, 1H, ArH), 7.01 (d, J=8.55 Hz, 1H, ArH), 7.16 (t, J=7.81 Hz, 2H, ArH), 7.48-7.53 (in, 1H, ArH), 11.57 (s, 1H, NH); MS(APCI+): m/z 467.1 (MH+). Anal. Calcd for
C
2 7
H
2 8
N
2 0 3
F
2 : C, 69.32; H, 6.19; N, 5.80. Found: C, 69.51; H, 6.05; N, 6.00. 15 Example 69 Pyrrolo[3',2':5,6][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 F N 0 0 0 N H 20 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (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 WO 00/42045 PCT/US99/30434 -167 0.356 g (31.8%) of fluffy white powder: mp 115-117"C; IR (KBr) 3382, 2931, 1718, 1432, 1067 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.07-1.68 (in, IOH, aliphatic CH), 1.87-1.90 (m, 2H, aliphatic CH), 2.35-2.46 (in, 2H, aliphatic CH), 2.58-2.62 (m, 1H, aliphatic CH), 2.61 & 2.62 (s, 3H, CCH 3 , diastereomers), 5 2.62-2.90 (in, 1H, aliphatic CH), 3.18 (dd, J=17.82, 6.84 Hz, IH, aliphatic CH), 6.52-6.57 (in, 1H, OCHCF 3 ), 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+): n/z 499.1 (MH+). Anal. Calcd for C 2 8
H
2 9
N
2 0 3
F
3 : C, 67.46; H, 5.86; N, 5.62. Found: C, 67.40; H, 6.03; N, 5.44. 10 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, 1 5-decahydro-2-methyl-, 1-[3-(tri fluoromethyl)phenyl] ethyl ester F F N 0 0 1\ N H 15 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[ 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%) of white solid: mp 102-105*C; IR (KBr) 3380, 2931, 1680, 1432, 20 1075 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.05-1.59 (in, 1OH, aliphatic CH), 1.59 (d, J=6.59 Hz, 3H, OCHCH 3 ), 1.77-1.88 (in, 1H, aliphatic CH), 2.33 (d, J=9.03 Hz, IH, aliphatic CH), 2.41 (d, J=8.55 Hz, 1H, aliphatic CH), 2.51 & 2.52 (s, 3H, CCH 3 , diastereomers), 2.51-2.67 (in, 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 25 (m, 1H, OCHCH 3 ), 6.58-6.60 (in, 1H, ArH), 7.01-7.04 (in, IH, ArH), 7.57-7.67 WO 00/42045 PCTIUS99/30434 -168 (in, 2H, ArH), 7.71-7.75 (m, 2H, ArH), 11.56 (s, 1H, NH); MS(APCI+): m/z 513.1 (MH+). Anal. Calcd for C2 9
H
3 1
N
2 0 3
F
3 : C, 67.69; H, 6.08; N, 5.44. Found: C, 67.34; H, 6.35; N, 5.24. Example 71 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester
N-
N 0 0 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, 1 5-decahydro-2-methyl-, 2 -(dimethylamino)ethyl ester 10 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- 1 ; I H NMR (400 MHz, DMSO-d 6 ) 6 1.13-1.59 (m, 1OH, aliphatic CH), 1.71-1.76 (in, IH, aliphatic CH), 1.90 (d, J=13.43 Hz, IH, aliphatic CH), 2.05 (s, 15 6H, N(CH 3
)
2 ), 2.35 (d, J=10.25 Hz, 1H, aliphatic CH), 2.48 (s, 3H, CCH 3 ), 2.52 (t, J=5.86 Hz, 2H, OCH 2
CH
2 ), 2.64-2.74 (in, 2H, aliphatic CH), 2.85-2.89 (in, 1H, aliphatic CH), 3.31 (dd, J=18.56, 7.08 Hz, IH, aliphatic CH), 4.14-4.27 (m, 2H, OCH 2
CH
2 ), 6.58 (d, J=8.55 Hz, 1H, ArH), 7.02 (d, J=8.79 Hz, 1H, ArH), 11.56 (s, IH, NH); MS(APCI+): m/z 412.2 (MH+). Anal. Calcd for 20 C 2 4
H
33
N
3 0 3 : C, 70.04; H, 8.08; N, 10.21. Found: C, 70.01; H, 8.20; N, 9.98. Example 72 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(I-pyrrolidinyl)ethyl ester WO 00/42045 PCT/US99/30434 -169 q N 0 0 0 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, 1 5-decahydro-2-methyl-, 2-(1 -pyrrolidinyl)ethyl ester was synthesized according to Procedure N from 2-pyrrolidin-1-yl-ethanol (1.02 g, 5 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- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.12-1.78 (m, I0H, aliphatic CH), 1.61-1.69 (m, 8H, cyclic CH 2 ), 1.92 (d, J=13.26 Hz, 1H, aliphatic CH), 2.37 (d, J=10.61 Hz, 1H, aliphatic CH), 2.47-2.49 (m, 1H, aliphatic CH), 2.50 (s, 3H, CH 3 ), 2.66-2.76 10 (m, 2H, aliphatic CH), 2.72 (t, J=6.51 Hz, 2H, OCH 2
CH
2 ), 2.87-2.93 (m, 1H, aliphatic CH), 3.32 (dd, J=19.05, 13.02 Hz, 1H, aliphatic CH), 4.19-4.30 (m, 2H,
OCH
2
CH
2 ), 6.60 (d, J=8.68 Hz, 1H, ArH), 7.04 (d, J=8.68 Hz, IH, ArH), 11.49 (s, 1H, NH); MS(APCI+): ni/z 438.2 (MH+). Anal. Calcd for C 2 6
H
3 5
N
3 0 3 : C, 71.37; H, 8.06; N, 9.60. Found: C, 70.99; H, 8.13; N, 9.49. 15 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, I 5-decahydro-2-methyl-, 1 -(1 -naphthalenyl)ethyl ester N 0 00 0 N H Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -(1 -naphthalenyl)ethyl ester was synthesized according to Procedure N from 1-naphthalen-1-yl-ethanol WO 00/42045 PCT/US99/30434 -170 (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- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 0.94-1.72 (m, 1OH, aliphatic CH), 1.72 (d, J=2.69 Hz, 3H, OCHCH 3 ), 1.83 (d, J=12.94 Hz, 1H, aliphatic CH), 2.30-2.63 (in, 5 3H, aliphatic CH), 2.50 & 2.52 (s, 3H, CCH 3 , diastereomers), 2.83-2.88 (in, 2H, aliphatic CH), 3.21 (dd, J=32.72, 26.12 Hz, 1H, aliphatic CH), 6.52-6.58 (m, IH, ArH), 6.74-6.75 (in, IH, OCHCH 3 ), 6.98-7.03 (m, 1H, ArH), 7.46-7.65 (m, 4H, ArH), 7.84-7.89 (in, 1H, ArH), 7.93-7.96 (in, IH, ArH), 8.12-8.14 (m, 1H, ArH), 11.54 (s, 1H, NH); MS(APCI+): m/z 513.1 (MH+). Anal. Calcd for 10 C 3 2
H
3 4
N
2 0 3 : 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][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 N 0 0 N H 15 Step A: 1-Phenyl-cyclobutanol OH To a solution of phenylmagnesium bromide (1 M in THF, 148 mL, 148 mmol) in 87 mL of anhydrous diethyl ether was added cyclobutanone (10.0 g, 143 mmol) in 15 mL of ether at 0 0 C. The reaction mixture was stirred in an ice 20 bath for 1 hour. Saturated ammonium chloride was added and stirred for 10 minutes. The reaction mixture was washed with H 2 0 (2 x 250 mL), dried with MgSO 4 , 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 WO 00/42045 PCT/US99/30434 -171 (47.7%) of a yellow oil: 1 H NMR (400 MHz, CDCI 3 ) 8 1.62-1.73 (m, 1H,
CCH
2
CH
2 ), 1.94-2.09 (m, 1H, CCH 2
CH
2 ), 2.29-2.38 (m, 2H, CCH 2 ), 2.50-2.57 (m, 2H, CCH 2 ), 2.68 (s, 1H, OH), 7.21-7.29 (m, lH, ArH), 7.31-7.38 (m, 2H, ArH), 7.38-7.50 (m, 2H, ArH); MS(APCI+): mn/z 171.5 (MH+). 5 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-, 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, 1 5-decahydro-2-methyl-, I -phenylcyclobutyl ester was 10 synthesized according to Procedure N from 1-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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.09-1.84 (m, 1OH, aliphatic CH), 1.94-2.00 (m, IH, aliphatic CH), 2.33 (d, J=9.03 Hz, 1H, aliphatic CH), 2.40-2.46 (m, 1H, aliphatic 15 CH), 2.46 (s, 3H, CCH 3 ), 2.56 (s, 6H, cyclic C(CH 2
)
3 Ar), 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, 1H, aliphatic CH), 6.56 (d, J=8.55 Hz, IH, ArH), 7.00 (d, J=8.55 Hz, I H, ArH), 7.22 (t, J=7.08 Hz, 1H, ArH), 7.33 (t, J=7.57 Hz, 2H, ArH), 7.47 (d, J=7.32 Hz, 2H, ArH), 11.48 (s, 1H, NH); MS(APCI+): m/z 671.1 (MH+). Anal. Calcd for 20 C 3 0
H
3 5
N
2 0 3 : 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-phenyleylopropyl ester N 0 0 0 N
H
WO 00/42045 PCT/US99/30434 -172 Step A: 1 -Phenyl-cyclopropanol OH 1 -Phenyl-cyclopropanol was synthesized according to the procedure published in Kulinkovich, O.G.; Sviridov, S.V.; Vasilevskii, D.A.; Savchenko, 5 A.I.; 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-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, I-phenylcylopropyl ester Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, I -phenylcylopropyl ester was 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; IR (KBr) 3384, 2929, 1690, 1431, 1069 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.06-1.69 (m, IOH, aliphatic CH), 1.86 (d, 15 J=13.43 Hz, 1H, aliphatic CH), 2.34 (d, J=10.01 Hz, 1H, aliphatic CH), 2.41-2.44 (in, IH, aliphatic CH), 2.46 (s, 3H, CCH 3 ), 2.52 (s, 4H, cyclic
C(CH
2
)
2 Ar), 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, IH, aliphatic CH), 6.59 (d, J=8.55 Hz, IH, ArH), 7.03 (d, J=8.55 Hz, 1H, ArH), 7.15-7.19 (m, 3H, ArH), 7.26-7.30 (m, 2H, ArH), 20 11.57 (s, 1H, NH); MS(APCI+): m/z 457.1 (MH+). Anal. Calcd for
C
2 9
H
3 2
N
2 0 3 : 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][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 N 0 00 0 N 25
H
WO 00/42045 PCT/US99/30434 -173 Step A: 1 -Pyrazin-2-yl-ethanol V< OH N1) To a solution of 1-pyrazin-2-yl-ethanone (5.00 g, 40.9 mmol) in 100 mL of MeOH at 0*C was added NaBH 4 (0.774 g, 20.5 mmol) in portions. After stirring 5 at room temperature for 24 hours, the reaction mixture was quenched with IN HCl and extracted with CH 2 Cl 2 (3 x 100 mL). The organic layers were dried with Na 2
SO
4 and concentrated to give 2.60 g (51.2%) of a yellow oil: 1 H NMR (400 MHz, CDCl 3 ) 6 1.54 (d, J=6.59 Hz, 3H, CHCH 3 ), 3.54 (s, IH, OH), 4.97 (q, J=6.59 Hz, IH, CH 3 CH), 8.49 (s, 2H, NCHCHN), 8.65 (s, 1H, CCHN); 10 MS(APCI+): m/z 125.1 (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-, I-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, 1 5-decahydro-2-methyl-, 1 -pyrazinylethyl ester was 15 synthesized according to Procedure N from l-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 ; IH NMR (400 MHz, DMSO-d 6 ) 6 1.06-1.63 (in, 1OH, aliphatic CH), 1.61 (d, J=3.17 Hz, 3H, OCHCH 3 ), 1.77-1.98 (in, 1H, aliphatic CH), 2.34 (d, J=10.25 Hz, 20 1H, aliphatic CH), 2.40-2.43 (in, 1H, aliphatic CH), 2.52 & 2.53 (s, 3H, CCH 3 , diastereomers), 2.62-2.68 (in, 1H, aliphatic CH), 2.84-2.87 (in, 1H, aliphatic CH), 3.12 (dd, J=19.04, 6.84 Hz, 1H, aliphatic CH), 5.99 (q, J=7.08 Hz, IH,
OCHCH
3 ), 6.56-6.60 (in, 1H, ArH), 7.01-7.04 (in, 1H, ArH), 8.57 (s, 1H, ArH), 8.62 (s, IH, ArH), 8.71 & 8.73 (s, 1H, ArH, diastereomers), 11.56 (s, 1H, NH); 25 MS(APCI+): i/z 447.1 (MH+). Anal. Calcd for C 2 6
H
3 0
N
4 0 3 : C, 69.90; H, 6.79; N, 12.50. Found: C, 69.51; H, 6.78; N, 12.35.
WO 00/42045 PCTIUS99/30434 -174 Example 77 Pyrrolo[3',2':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 N N 0 0 0 N H 5 Step A: 1-Quinolin-4-yl-ethanol N I 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 stirring for 5 hours, the reaction mixture was quenched with 10 saturated NH 4 Cl and extracted with ethyl acetate (5 x 100 mL). The organic layers were washed with brine, dried with Na 2
SO
4 , and concentrated to give a purple solid. The solid was triturated with acetone to yield 4.52 g (82.2%) of light purple solid: 1 H NMR (400 MHz, CDCI 3 ) 6 1.60 (d, J=6.35 Hz, 3H, CHCH 3 ), 3.70 (s, 1H, OH), 5.62 (q, J=6.35 Hz, 1H, CHCH 3 ), 7.50 (t, J=7.57 Hz, 1H, 15 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, IH, CCCHCH), 8.05 (d, J=8.30 Hz, 1H, NCCHCH), 8.73 (d, J=4.39 Hz, 1H, NCHCH), MS(APCI+): n/z 174.1 (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-, 1-(4-quinolinyl)ethyl 20 ester Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-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 WO 00/42045 PCT/US99/30434 -175 powder: mp 165-168'C; IR (KBr) 2930, 2853, 1690, 1429, 1074 cm- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.00-1.46 (m, I0H, aliphatic CH), 1.70 (d, J=6.35 Hz, 3H, OCHCH 3 ), 1.85 (d, J=13.18 Hz, 1H, aliphatic CH), 2.32-2.63 (m, 3H, aliphatic CH), 2.57 & 2.58 (s, 3H, CCH 3 , diastereomers), 2.83-2.86 (m, 2H, 5 aliphatic CH), 3.20 (dd, J=18.31, 6.84 Hz, I H, aliphatic CH), 6.55-6.58 (m, 1H, ArH), 6.65 (q, J=6.59 Hz, 1H, OCHCH 3 ), 7.01-7.05 (m, 1H, ArH), 7.50-7.54 (m, 1H, ArH), 7.63-7.67 (m,.IH, ArH), 7.75-7.79 (in, 1H, ArH), 8.04-8.06 (m, 1H, ArH), 8.21-8.23 (m, 1H, ArH), 8.84-8.88 (m, IH, ArI), 11.61 (s, 1H, NH); MS(APCI+): n/z 496.2 (MH+). Anal. Called for C 3 1
H
3 3
N
3 0 3 : C, 74.12; H, 7.00; 10 N, 7.83. Found: C, 73.73; H, 7.09; N, 7.44. Example 78 Pyrrolo[3',2':5,6][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 ND N N N H 15 Step A: I-Pyrimidin-2-yl-ethanone 0 N '~N 1-Pyrimidin-2-yl-ethanone was synthesized according to the procedure published in Naumenko, I. I.; Mikhaleva, M. A.; Mamaev, V. P. Chem. Het. Cmpds. 1981;17:710-714. 20 Step B: 1-Pyrimidin-2-yl-ethanol N 0 OH
KN
WO 00/42045 PCTIUS99/30434 -176 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 NaBH 4 (0.726 g, 19.2 mmol) in portions. After stirring at room temperature for 4 hours, the reaction mixture was quenched with IN HCI and extracted with CH 2 Cl 2 (3 x 100 mL). The organic layers were dried 5 with Na 2
SO
4 and concentrated to afford 0.984 g (41.3%) of a yellow oil: 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.36 (d, J=6.59 Hz, 3H, CHCH 3 ), 4.73 (q, J=6.59 Hz, 1H, CH 3 CH), 5.21 (s, 1H, OH), 7.33-7.36 (in, 1H, NCHCH), 8.73-8.77 (in, 2H, NCHCH); MS(APCI+): n/z 125.1 (MH+). Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 10 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, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(2-pyrirmidinyl)ethyl ester was synthesized according to Procedure N from I-pyrimidein-2-yl-ethanol (1.01 g, 15 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 ; 1 H NMR (400 MHz, DMSO-d 6 ) 6 1.06-1.54 (in, I0H, aliphatic CH), 1.59 (d, J=6.59 Hz, 3H, OCHCH 3 ), 1.84 (d, J=13.92 Hz, 1H, aliphatic CH), 2.34-2.55 (m, 2H, aliphatic CH), 2.58 (s, 3H, CCH 3 ), 2.64-2.69 (in, 2H, aliphatic CH), 2.81-2.86 (m, 20 1H, aliphatic CH), 3.17 (dd, J=18.31, 6.59 Hz, IH, aliphatic CH), 5.84 (q, J=6.84 Hz, 1H, OCHCH 3 ), 6.57 (d, J=8.79 Hz, 1H, ArH), 7.02 (d, J=9.03 Hz, IH, ArH), 7.37-7.38 (in, 1H, ArH), 8.76-8.77 (in, 2H, ArH), 11.53 (s, IH, NH); MS(APCI+): n/z 447.1 (MH+). Anal. Calcd for C 2 6
H
3 0
N
4 0 3 : C, 69.86; H, 7.04; N, 12.07. Found: C, 69.50; H, 6.94; N, 11.71. 25 Example 79 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 WO 00/42045 PCTIUS99/30434 -177 N 0 0 0 ci N H Step A: 6-Chloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester 0 / 0 HO ci N H To a solution of 3-amino-but-2-enoic acid benzyl ester (10.1 g, 52.9 mmol) 5 in 211 mL of EtOH was added 2-chloro-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: mp 221-224'C; IR 10 (KBr) 3409, 3226, 1642, 1461, 1181 cm- 1 ; IH NMR (400 MHz, DMSO-d 6 ) 6 2.55 (s, 3H, CCH 3 ), 5.29 (s, 2H, OCH 2 Ar), 7.27 (s, 1H, ArH), 7.30 (d, J=6.84 Hz, 1H, ArH), 7.36 (t, J=8.30 Hz, 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/z 316.1 (MH+). HPLC (ALLTCH/ALLTIMA C-18 50:50-2:98 H 2 0/CH 3 CN + 0.05% TFA): 15 rentention time=5.47 min, 95.86% purity. Step B: 6-Chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl- I H-indole 3-carboxylic acid benzyl ester N o r 0 HO c1 N H 6-Chloro-4-dimethylaminomethyl-5 -hydroxy-2-methyl- 1 H-indole 20 3-carboxylic acid benzyl ester was synthesized according to Procedure L from WO 00/42045 PCT/US99/30434 -178 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 6.77g (73.8%) of a white solid: mp 178-180*C; IR (KBr) 3298, 2951, 1687, 1425, 1437, 1264, 1078 cm- 1 ; IH NMR (400 MHz, DMSO-d 6 ) 8 2.14 (s, 6H, N(CH 3
)
2 ) 4.06 (s, 2H, NCH 2 Ar), 5 5.23 (s, 2H, OCH 2 Ar), 7.22 (s, 1H, ArH), 7.31-7.39 (m, 3H, ArH), 7.44 (d, J=6.84 Hz, 2H, ArH), 11.85 (s, 1H, NH); MS(APCI+): m/z 373.1 (MH+). HPLC (ALLTCH/ALLTIMA C-18 50:50-2:98 H 2 0/CH 3 CN + 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, 10 5-chloro-3,7,8,9,10,12,13,14,14a, 1 5-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-2methyl-, phenylmethyl ester was synthesized according to Procedure M from 6 -chloro-4-dimethylaminomethyl 15 5-hydroxy-2-methyl-IH-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 ; iH NMR (400 MHz, DMSO-d 6 ) 5 1.01-1.71 (in, 1OH, aliphatic CH), 1.75 (d, J=13.43 Hz, 1H, aliphatic CH), 2.37 (d, J=10.50 Hz, 1H, aliphatic CH), 2.45-2.46 (m, IH, 20 aliphatic CH), 2.46 (s, 3H, CCH 3 ), 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, IH, aliphatic CH), 5.21 (dd, J=26.12, 12.21 Hz, 2H, OCH 2 Ar), 7.18 (s, 1H, ArH), 7.29-7.43 (in, 5H, ArH), 11.62 (s, 1H, NH); MS(APCI+): n/z 465.2 (MH+). Anal. Calcd for
C
2 7
H
2 9
N
2 0 3 Cl: C, 69.74; H, 6.29; N, 6.02. Found: C, 69.45; H, 6.68; N, 5.82. 25 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, I 5-decahydro-2-methyl, I -(4-fluorophenyl)ethyl ester WO 00/42045 PCTIUS99/30434 -179 F N 0 0 c H Step A: 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, anhydride with benzoic acid 0 N 0 O 0 0 CI N 5 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, 1 5-decahydro-2methyl-, phenylmethyl ester (Example 79, Step C, 5.44 g, 11.7 mmol), THF (58.6 mL, 0.2 M), Et 3 N (1.63 mL, 11.7 mmol), 10 and 10% Pd(OH) 2 /C (1.26 g) sequentially. The mixture was stirred under a
H
2 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 15 to give a brown oil. Trituration with acetone afforded 3.50 g (62.4%) of yellow powder: mp 160-165'C; IH NMR (400 MHz, DMSO-d 6 ) 6 1.10-1.58 (in, 1OH, aliphatic CH), 1.83 (d, J=12.94 Hz, 1H, aliphatic CH), 2.41-2.46 (in, 2H, aliphatic CH), 2.51 (s, 3H, CCH 3 ), 2.66-2.71 (in, 1H, aliphatic CH), 2.98-3.01 (in, 2H, aliphatic CH), 3.38 (dd, J=17.82, 6.59 Hz, 1H, aliphatic CH), 7.29 (s, 1H, ArH), 20 7.58 (t, J=7.57 Hz, 2H, ArH), 7.74 (t, J=7.57 Hz, 1H, ArH), 8.07 (d, J=7.08 Hz, 2H, ArH), 12.14 (s, 1H, NH); MS(APCI+): n/z 479.1 (MH+). Step B: 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 WO 00/42045 PCTIUS99/30434 -180 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-, 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][1 ]-benzopyrano[3,2-i]quinolizine- 1 5 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- 1 ; 1 H NMR (400 MHz, DMSO-d 6 ) 8 1.06-1.81 (m, 11H, aliphatic CH), 1.55 (d, J=6.59 Hz, 3H, 10 OCHCH 3 ), 2.37 (d, J=10.25 Hz, 1H, aliphatic CH), 2.44-2.46 (m, 1H, aliphatic CH), 2.46 (s, 3H, CCH 3 ), 2.63-2.75 (m, 2H, aliphatic CH), 2.97-3.14 (m, 1H, aliphatic CH), 3.20 (dd, J=13.18, 6.59 Hz, 1H, aliphatic CH), 5.95 (q, J=6.59 Hz, 1H, OCHCH 3 ), 7.15-7.19 (m, 3H, ArH), 7.43-7.49 (m, 2H, ArH), 11.62 (s, 1H, NH); MS(APCI+): m/z 497.2 (MH+). Anal. Called for C 2 8
H
3 0
N
2 0 3
F
1 ClI: C, 15 66.82; H, 6.15; N, 5.57. Found: C, 66.96; H, 6.39; N, 5.46. Example 81 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 00 HO N H 20 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-, (4-fluorophenyl)methyl ester (0.500 g, 1.11 mmol) in 125 mL of CH 2 Cl 2 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 25 (61.0%) of white powder: mp 179-185'C; IR (KBr) 3408, 3193, 2934, 1697, 1431, 1152 cm- 1 ; 1 H NMR (400 MHz, CDCl 3 ) 8 1.37-1.52 (m, 1H, aliphatic CH), 1.52-1.77 (in, 8H, aliphatic CH), 2.07-2.15 (m, 1H, aliphatic CH), 2.26 (d, WO 00/42045 PCTIUS99/30434 -181 J=14.65 Hz, 1H, aliphatic CH), 2.40-2.54 (in, 2H, aliphatic CH), 2.58 (s, 3H,
CCH
3 ), 3.10-3.18 (m, 2H, aliphatic CH), 3.34-3.48 (in, 2H, aliphatic CH), 5.28 (dd, J=14.65, 12.45 Hz, 2H, OCH 2 Ar), 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, 1H, ArH), 7.41 (t, J=5.37 Hz, 5 1H, ArH), 8.58 (s, 1H, OH), 12.52 (s, 1H, NH); MS(APCI+): n/z 449.3 (MH+). Anal. Calcd for C 2 7
H
3 0
N
2 0 3
F
1 Cli: 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, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-1,2-dimethyl-, (4-fluorophenyl)methyl ester N 0 F 0 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-, (4-fluorophenyl)methyl ester (0.500 g, 1.11 mol) in 20 mL of DMF was added to NaH (60% dispersion in 15 mineral oil, 0.049 g, 1.23 mmol, washed with hexanes) and was stirred at room temperature for 1 hour. 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
H
2 0 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 20 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, CDCl 3 ) 6 1.06-1.21 (m, 3H, aliphatic CH), 1.36-1.58 (m, 7H, aliphatic CH), 1.79 (d, J=14.20 Hz, 1H, aliphatic CH), 2.34 (d, J=10.74 Hz, 1H, aliphatic CH), 2.42-2.49 (m, 2H, aliphatic CH), 2.49 (s, 3H, CCH 3 ), 2.64 (t, J=10.74 Hz, 1H, aliphatic CH), 2.86 (t, J=l 1.48 Hz, 1H, 25 aliphatic CH), 3.10 (dd, J.=18.31, 6.84 Hz, 1H, aliphatic CH), 3.59 (s, 3H, NCH 3 ), 5.21 (dd, J=29.05, 11.96 Hz, 2H, OCH 2 Ar), 6.64 (d, J=8.79 Hz, 1H, ArH), WO 00/42045 PCT/US99/30434 -182 7.16-7.22 (in, 3H, ArH), 7.48 (t, J=7.81 Hz, 1H, ArH); MS(APCI+): n/z 463.1 (MH+). Anal. Called for C 2 8
H
3 1
N
2 0 3
F
1 : C, 72.71; H, 6.76; N, 6.06. Found: C, 72.89; H, 6.72; N, 5.92. Example 83 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylpropyl ester NO 00 H Step A: 5-Acetoxy-2-methyl-1IH-indole-3-carboxylic acid 1 -phenyl-propyl ester 0 N H 10 This compound was made according to Procedure A. White solid, mp 144-145.5'C; MS(APCI-): m/z 350.1 (M-H). Step B: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 1-phenyl-propyl ester O/ 0 N 5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester 15 (1.36 g, 3.86 mmol) was mixed with 10 mL of methanol, NaOCH 3 (0.834 g, WO 00/42045 PCT/US99/30434 -183 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 5 extracted with EtOAc (2 x 60 mL). The combined organic mixture was dried over Na 2
SO
4 and concentrated in vacuo to give a black thick oil which was further purified by chromatography using 10% MeOH in HCCl 3 as the eluant to give 1.13 g (98%) of the desired product as a brown solid: IH NMR (DMSO-d 6 ) 6 0.917 (t, J= 7.33 Hz, 3H, CHCH 2
CH
3 ), 1.84-2.03 (in, 2H, CHCH 2
CH
3 ), 2.59 (s, 10 3H, ArCH 3 ), 5.84 (t, J= 5.68 Hz, 2H, CHCH 2
CH
3 ), 6.59 (dd, J= 8.61, 2.38 Hz, 1H, ArH), 7.12 (d, J= 8.61 Hz, 1H, ArH), 7.23-7.41 (in, 6H, ArH), 8.87 (s, IH, 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 N O H~ N 15 H 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester (1.07 g, 3.60 mmol) and aqueous Me 2 NH (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 20 (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 raction mixture was diluted with EtOAc (30 mL), washed with water (2 x 30 mL), and dried over Na 2
SO
4 . Concentration in vacuo followed by chromatography using 100% EtOAc, then 10% MeOH in HCCl 3 as the eluants gave 0.50 g (38%) of pure titled 25 compound as a yellow foam: mp 50-62'C (dec.); MS(APCI+): m/z 367.2 (MH+).
WO 00/42045 PCT/US99/30434 -184 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 -phenylpropyl ester N O O N H To a mixture of perchlorate salt (0.38 g, 1.6 mmol, Example 3, Step B) and 5 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 Na 2
SO
4 and concentrated in vacuo. The residual oil was dissolved in 10 mL of dioxane, then indole mannich base (0.45 g, 1.2 mmol) 10 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 0 C; MS(APCI+): mn/z 459.3 (MH+). 15 Example 84 Quinolizinium, 1,2,3,4,6,7,8,9-octahydro-l-[[5-hydroxy-2-methyl 3-[(phenylmethoxy)carbonyl]-1H-indol-4-yl]methyl]-, chloride Cl H 0% 0 HO >N H To a solution of pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1 20 carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester (0.209 g, 0.485 mmol) in CH 2
CI
2 was added etheral HCl. After stirring at WO 00/42045 PCT/US99/30434 -185 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+): mn/z 431.3 (MH+). Anal. Calcd for C 2 7
H
3 0
N
2 O3-1.0 HCl-0.3H 2 0: C, 68.65; H, 5 6.74; N, 5.93; Cl, 7.50; H 2 0, 1.14. Found: C, 68.62; H, 6.80; N, 6.00; Cl, 7.54;
H
2 0, 0.93. Example 85 Pyrrolo[3',2':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 N 00 0\ O N O 10 H 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-methyl-, phenylmethyl ester (0.149 g, 0.341 mmol) was dissolved in 15 mL of THF, to the solution was added NN dimethylacetamide dimethyl acetal (0.5 mL), and Pd(OH) 2 /C (20%, 0.125 g). The 15 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 vacuo at ambient temperature and used in the next step without further purification. To a solution of crude product of debenzylation reaction in DMF were 20 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 NaHCO 3 (3 x 50 mL) and water (3 x 50 mL). After drying over Na2SO4, the solution was concentrated in vacuo and purified by chromatography twice using 10% MeOH in WO 00/42045 PCT/US99/30434 -186
HCCL
3 and 50% EtOAc in hexanes to give 28 mg (17%) of desired product as a yellow solid: mp 240-242*C; MS(APCI+): n/z 476.3 (MH+). Example 86 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, anhydride with benzoic acid N O _ O0 N C H Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, phenylmethyl ester (10.15 g, 23.58 mmol) was dissolved in 110 mL of THF, and the solution was transferred to 10 a round bottom flask equipped with a stir bar and a three-way stopcock 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 15 consumed (2 hours in this case). The catalyst was removed by filtration, and the filtrate was used in the next step. To the filtrate was added benzoyl chloride (2.737 mL, 23.58 mmol). The resulting reaction solution was stirred at ambient temperature for 16 hours under nitrogen. White precipitate formed was removed by filtration. The filtrate was concentrated 20 in vacuo affording thick oil; trituration with Et 2 0 gave 9.18g (88% over two steps) the desired product as a white solid: mp 159-160'C; MS(APCI+): m/z 443.3 (MH+).
WO 00/42045 PCT/US99/30434 -187 General procedure Q: ester synthesis from the mixed anhydride The mixed anhydride (1 eq.) was mixed with the corresponding alcohol (>2 eq.), the resulting slurry was heated at 120-150'C until a clear solution was obtained. After cooling down to ambient temperature, the solution was diluted 5 with EtOAC, then mixed with aqueous NaHCO 3 (saturated). The mixture was for 5 minutes. Two layers were separated, and the organic layer was washed with brine and water, then dried over MgSO 4 . Purification with flash chromatography or recrystallization gave the desired product. Example 87 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1 -phenylethyl ester N 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-, (I R)- 1 -phenylethyl ester was 15 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 100-1 12'C; MS(APCI+): m/z 445.3 (MH+). Example 88 20 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 1-(4-fluorophenyl)ethyl ester WO 00/42045 PCT/US99/30434 -188 1 F N O0 O O qN 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)ethyl ester was synthesized according to procedure Q from 1 -(para-fluorophenyl)ethanol. The 5 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 98-1 10 C; MS(APCI+): m/z 463.1 (MH+). General procedure R: parallel synthesis of 6 esters from the mixed anhydride 10 The mixed anhydride (I 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 Na 2
SO
4 were added to the tube. The mixture was stirred for 1 minute, then the ether layer was transferred into a new 15 tube with MgSO 4 . After 10 minutes, the MgSO 4 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 20 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][l]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 25 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester WO 00/42045 PCTIUS99/30434 -189 N O9 0 0O H Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, phenyl ester was synthesized according to procedure R from phenol. The crude product was not further 5 purified: white solid; MS(APCI+): n/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, 15-decahydro-2-methyl-, 2,2,2-trifluoro-1 -phenyl 1-(trifluoromethyl)ethyl ester FF F N FF0 O N 10 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-, 2,2,2-trifluoro-1-phenyl I -(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 15 purified: white solid; MS(APCI-): mn/z 565.1 (M-H). Example 91 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, bicyclo[2.2.1 ]hept-2-yl ester WO 00/42045 PCT/US99/30434 -190 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, 1 5-decahydro-2-methyl-, bicyclo[2.2. 1 ]hept-2-yl ester was synthesized according to procedure R from exo-norborneol. The crude 5 product was not further purified: white solid; MS(APCI-): ni/z 433.2 (M-H). Example 92 Pyrrolo[3',2':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 N 0 0 \ 0 N 10 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 -fluorophenyl)-2-propanol. The crude product was chromatographed on a 15 silica gel column (50-70% of ether in hexanes as eluant) to give 0.15 g (9%) of the desired product as a white solid mp 110-1 12 0 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,15-decahydro-2-methyl-, I-phenylcyclopentyl ester WO 00/42045 PCTIUS99/30434 -191 N 0 00 / 0 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 5 product was chromatographed on a silica gel column (50% of ether in hexanes as eluant) to give 0.15 g (6%) of the desired product as a white solid: mp 205-206'C; MS(APCI+): m/z 483.1 (MH+). Example 94 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylcyclohexyl ester N 0 0 - 0 / \ 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-phenylcyclohexyl ester was synthesized according to procedure Q from 1 -phenylcyclohexanol. The crude 15 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, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester WO 00/42045 PCTIUS99/30434 -192 N O0 OH N C 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 -(hydroxymethyl)phenyl ester was synthesized according to procedure Q from 3-hydroxybenzyl alcohol. The 5 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-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester OH N 0 00 0 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-, (3-hydroxyphenyl)methyl ester was synthesized according to procedure Q from 3-hydroxybenzyl alcohol. The 15 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+): m/z 447.1 (MH+). Example 97 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1 S)- 1 -(4-pyridinyl)ethyl ester WO 00/42045 PCT/US99/30434 -193 N O0 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 5 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 105-115'C; MS(APCI+): n/z 447.2 (MH+). Example 98 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl) 2-pyridinyl]methyl ester 0 N 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) 15 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 separative 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 20 dried over Na 2
SO
4 . 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+): n/z 490.1 (MH+).
WO 00/42045 PCT/US99/30434 -194 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, 1 5-decahydro-2-methyl-, 2-pyridinylmethyl ester N O r, 1 O O 6 N H 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 2-pyridinylmethyl ester was synthesized according to procedure Q from 2-pyridylmethanol. The EtOAc solution (40 mL) of the crude product was mixed with 40 mL of 0.5N HCI solution in a separative funnel and shaken well, then the aqueous phase was 10 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 Na 2
SO
4 . 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+): mn/z 432.2 (MH+). 15 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 0 N O N OH N H 20 To a solution of 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-, [6-(methoxycarbonyl)-2-pyridinyl]methyl ester (797.4 mg, 1.629 mmol) in MeOH WO 00/42045 PCT/US99/30434 -195 (20 mL) was added IN NaOH (6.5 mL, 6.5 mmol). The resulting reaction mixture was refluxed for 15 minutes, then concentrated in vacuo. The residue was purified by chromatography (10-30% MeOH in HCC1 3 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 5 MeOH/HCCl3, then mixed with 0.64 mL of IN HCL. The mixture was concentrated in vacuo, the residue was purified by chromatography (10-30% MeOH in HCCl 3 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 10 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- I -carboxylate (1:1) 0 N 0 0 00 N H N To a suspension of Pyrrolo[3',2':5,6][ 1]benzopyrano[3,2-i]quinolizine 15 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,1 5-decahydro-2-methyl-, (6-carboxy 2-pyridinyl)methyl 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 in vacuo, and the residue was dissolved in 2 mL of ethanol and then 20 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-): n/z 474.1 (M-H). Anal. Called for
C
2 7
H
2 8
N
3 05- .0C 5
H
14
N
1 0 1 -0.2C 5
H
1 5
N
1 02-1.8H 2 0: C, 62.38; H, 7.71; N, 9.26. Found: C, 62.40; H, 7.58; N, 9.03.
WO 00/42045 PCT/US99/30434 -196 Example 102 Pyrrolo[3',2':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 0 N 00 0 0 \-e N NN 5 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 10 crude product was mixed with 40 mL of 0.5 N HCI solution in a separative 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 MgSO 4 . Chromatography on a silica gel column (50-100% of EtOAc in hexanes as eluant) 15 followed by crystallization from ether gave 0.4254 g (25%) of the desired product as a yellow solid: mp 195-197'C; MS(APCI+): n/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 20 ester 0 N O OH d 0 N H 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-, WO 00/42045 PCTIUS99/30434 -197 [5-(methoxycarbonyl)-3-pyridinyl]methy 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 in vacuo. 5 The residue was purified by chromatography (10-30% MeOH in HCC1 3 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-): m/z 474.1 (M-H). Example 104 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (5-carboxy 10 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) 0 N o 0o N N H /N 0 To a suspension of Pyrrolo[3',2':5,6] [1 ]benzopyrano[3,2-i]quinolizine 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (5-carboxy 15 3-pyridinyl)methyl ester (170.3 mg, 0.3580 mmol) in ethanol was added aqueous choline bicarbonate (5.66 M, 0.0569 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 20 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
C
2 7
H
2 8
N
3 0 5 -1.0C 5
HI
4
N
1 01 -0.28C 4
H
1 0 0-1.2Sil0 2 1.4H 2 0: C, 57.09; H, 6.89; N, 8.04. Found: C, 57.09; H, 6.70; N, 7.77.
WO 00/42045 PCT/US99/30434 -198 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 N O N 5 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[1,1'-biphenyl] 3-yl)ethyl ester was synthesized according to procedure Q from 1-(4'-methyl biphenyl-3-yl)-ethanol. The crude product was chromatographed on a silica gel 10 column (40% of EtOAc in hexanes as eluant) to give 0.67 g (36%) of the desired product as a white foam: mp 105-115'C; MS(APCI+): n/z 535 (MH+). Example 106 Pyrrolo[3',2':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 15 ester N0 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-dimethylphenyl)ethyl ester was synthesized according to procedure Q from 1-(2,6-dimethyl-phenyl) 20 ethanol. The crude product was chromatographed on a silica gel column (30-50% WO 00/42045 PCT/US99/30434 -199 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+): n/z 473.3 (MH+). Procedure S: procedure for the array synthesis: The mixed anhydride (1 eq.) and the corresponding alcohol (2-4 eq.) were 5 mixed in a VWR 60826-202 tube. The tube was loosely capped and submerged 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 Na 2
SO
4 were added to the tube. The mixture was shaken and stirred for 1 minute, then the organic layer was pipeted out and filtered through a pack of MgSO 4 10 (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 15 in a parallel fashion: Example 107 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S, 2 R)-2-(dimethylamino) I -phenylpropyl ester NI N O O O N 20 H MS(APCI+): in/z 502 (MH+).
WO 00/42045 PCTIUS99/30434 -200 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-, (1 R,2S)-2-(dimethylamino) 1 -phenylpropyl ester N 0 N N 5 H 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-naphthalenyl ester 100 N0 O 10 H MS(APCI+): m/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 WO 00/42045 PCT/US99/30434 -201 N H MS(APCI+): m/z 507 (MH+). Example 111 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R)-2,3-dihydro-1H-inden-1 -yl ester o N H MS(APCI+): mn/z 457 (MH+). Example 112 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-dihydro-1-acenaphthylenyl ester WO 00/42045 PCTIUS99/30434 -202 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, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, cyclohexyl(phenyl)methyl ester NI O0 H MS(APCI+): m/z 513 (MH+). Example 114 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 9H-fluoren-9-yl ester N H MS(APCI+): m/z 505 (MH+).
WO 00/42045 PCT/US99/30434 -203 Example 115 Pyrrolo[3',2':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 N O0 O O 5 H MS(APCI+): m/z 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) 10 3-phenyloxiranyl]methyl ester 0 N 0 O0 O0 N I H MS(APCI+): m/z 473 (MH+). Example 117 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-oxo- 1,2-diphenylethyl ester WO 00/42045 PCTIUS99/30434 -204 N O O 'N H MS(APCI+): m/z 535 (MH+). Example 118 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 10,11 -dihydro-5H dibenzo[a,d]cyclohepten-5-yl ester H MS(APCI+): m/z 533 (MH+). Example 119 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15 -decahydro-2-methyl-,
(
2 -methylphenyl)phenylmethyl ester WO 00/42045 PCT/US99/30434 -205 N H MS(APCI+): n/z 521 (MH+). Example 120 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclopropyl(4-fluorophenyl)methyl ester NO F O 0 N H MS(APCI+): m/z 489 (MH+). Example 121 10 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, 3,4-dihydro-2H 1-benzothiopyran-4-yl ester S N
O
WO 00/42045 PCT/US99/30434 -206 MS(APCI+): mn/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-, (1 S)- 1 -(2-bromophenyl)ethyl 5 ester Br N O O O N H MS(APCI+): m/z 524 (MH+). Example 123 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2,2,2-trifluoroethyl ester F F N 1 H MS(APCI+): m/z 423 (MH+). Example 124 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [(2S,3S) 3-phenyloxiranyl]methyl ester WO 00/42045 PCT/US99/30434 -207 0 N O 0/ O N H MS(APCI+): m/z 475 (MH+). Example 125 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro-1-methyl 1-(trifluoromethyl)ethyl ester F F F F N O F O F N H MS(APCI+): m/z 505 (MH+). Example 126 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2,2,2-trifluoro 1-(4-fluorophenyl)-1-(trifluoromethyl)ethyl ester WO 00/42045 PCT/US99/30434 -208 F F NF F N F F OF N H MS(APCI+): i/z 585 (MH+). Example 127 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -cyclopentyl-1 -phenylethyl ester d;- N H MS(APCI+): m/z 513 (MH+). Example 128 10 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-[1,1'-biphenyl]-4-yl I -methylethyl ester WO 00/42045 PCT/US99/3043 4 -209 N O N H MS(APCI+): m/z 535 (MH+). Example 129 Pyrrolo[3', 2 ':5, 6 ][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methyl-1-phenyl-2-propynyl ester N H MS(APCI+): m/z 469 (MH+). Example 130 10 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-, 1,1 -diphenylethyl ester N O N H MS(APCI+): m/z 521 (MH+).
WO 00/42045 PCTIUS99/30 4 3 4 -210 Example 131 Pyrrolo[3', 2 ':5, 6 ][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methyl-1,2-diphenylethyl ester N H 5 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 10 ester N O O -F 0 0N H MS(APCI+): n/z 517 (MH+). Example 133 Pyrrolo[3', 2 ':5, 6 ][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-diphenylethyl ester WO 00/42045 PCTIUS99/30 4 3 4 -211 0N H MS(APCI+): m/z 521 (MH+). Example 134 Pyrrolo[3', 2 ':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -phenyl-2-propyn yl ester kN H MS(APCI+): m/z 455 (MH+). Example 135 Pyrrolo[3', 2 ':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [1,1'-biphenyl]-4-ylmethyl ester N O N H MS(APCI+): m/lz 507 (MH+) WO 00/42045 PCT/US99/3043 4 -212 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-pyridinylmethyl ester N O0 O N H 5 MS(APCI+): n/z 432 (MH+). Example 137 Pyrrolo[3',2':5,6][1lbenzopyrano[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 0 N ~~0 N O N 10 H MS(APCI+): m/z 546 (MH+). Example 138 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 15 1-[3-(dimethylamino)phenyl] ethyl ester WO 00/42045 PCTIUS99/30 43 4 -213 N N O O O 0N H MS(APCI+): n/z 488 (MH+). Example 139 Pyrrolo[3', 2 ':5, 6 ][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -dimethyl-2-pyrazinylethyl ester N N O O O N H MS(APCI+): m/z 475 (MH+). Example 140 10 Pyrrolo[3', 2 ':5, 6 ][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 4-(dipropylamino) 1,1-dimethyl-2-butynyl ester WO 00/42045 PCT/US99/3043 4 -214 N O 0O N NN H MS(APCI+): ni/z 520 (MH+). Example 141 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)-2,3-dihydro-1H-inden-1-yl ester d; 0N H MS(APCI+): m/z 457 (MH+). Example 142 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, (1 S,2S)-2-(dimethylamino) 1 -phenylpropyl ester N H MS(APCI+): n/z 502 (MH+).
WO 00/42045 PCTIUS99/30434 -215 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,15-decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]methyl ester
CF
3 N O0~ O N 5 Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-trifluoromethylbenzyl ester /: CF 3 0 HO N To a mixture of 5-hydroxy-2-methyl-IH-indole-3-carboxylic acid (4.5 g, 10 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 Na 2
SO
4 and concentrated in vacuo to give a residue, which was 15 recrystallized from ethyl acetate to give 4.26 g (52%) of the desired product as a white solid: mp 224-225*C; MS(APCI+): n/z 350.1 (MH+); Anal. Calcd for
C
18
H
14
F
3 NlO 3 : C, 61.89; H, 4.04; N, 4.01. Found: C, 61.87; H, 4.00; N, 3.98. Step B: 4-Dimethylaminomethyl-5 -hydroxy-2-methyl- 1 H-indole-3 -carboxylic acid 4-trifluoro-methylbenzyl ester WO 00/42045 PCT/US99/30434 -216
CF
3 NO 0 0 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 5 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 in vacuo to half volume to give a solid, which was filtered. The solid was washed with ethanol water and dried in vacuo to give 1.8 g (52%) of pure titled compound as an off 10 white foam: MS(APCI+): m/z 407.2 (MH+). Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-nethyl-, [4-(trifluoromethyl)phenyl]methyl ester
/OCF
3 N 15 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 Na 2
SO
4 and concentrated in vacuo. 20 The residual oil was dissolved in 25 mL of dioxane, then indole mannich base WO 00/42045 PCT/US99/30434 -217 (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 (55%) of 5 titled compound as a white foam: mp 97-99'C; MS(APCI+): mn/z 499.2 (MH+); Anal. Calcd for C 2 8
H
2 9
F
3
N
2 0 3 : 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, 10 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, (4-chlorophenyl)methyl ester N CI 0 0 0 0 HO N To a mixture of 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (5.0 g, 15 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 Na 2
SO
4 and concentrated in vacuo to give a residue, which was 20 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-): i/z 314.1 (M-H).
WO 00/42045 PCTIUS99/30434 -218 Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1 H-indole-3-carboxylic acid 4-chlorobenzyl ester CI N O0 O HO N 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-chlorobenzyl ester 5 (4.0 g, 12.7 mmol) and aqueous dimethylamine (40%, 3.5 mL, 27.8 mmol) were mixed with 10.4 mL of 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 vacuo to give a residue, 10 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: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 15 (4-chlorophenyl)methyl ester N OC 0O 6 0N 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 20 separated and the aqueous layer was extracted with ether (2 x 100 mL). Combined WO 00/42045 PCT/US99/30434 -219 ether layer was dried over Na 2
SO
4 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 5 in vacuo to give a thick oil. The crude product was further purified by chromatography (20%-25% ethyl acetate in hexanes) to give 1.7 g (59%) of 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, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-, phenylmethyl ester N O r O0 0 -o 0 HO N To a mixture of 5-hydroxy-IH-indole-3-carboxylic acid (4.5 g, 25.4 mmol) 15 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 Na 2
SO
4 and concentrated in vacuo to give a residue, which was recrystallized from ethyl 20 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).
WO 00/42045 PCTIUS99/30434 -220 Step B: 4 -Dimethylaminomethyl-5-hydroxy-1H-indole-3-carboxylic acid benzyl ester N O0-~ O HO N 5-Hydroxy-1H-indole-3-carboxylic acid benzyl ester (2.3 g, 8.6 mmol) and 5 aqueous dimethylamine (40%, 2.37 mL, 18.9 mmol) were mixed with 6.67 mL 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 0 C overnight. The reaction mixture was concentrated in vacuo to give a residue, 10 which was chromatographed using 50%-l00% 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, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-, phenylmethyl ester N O r 15 N To a mixture of perchlorate 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 20 100 mL). Combined ether layer was dried over Na 2
SO
4 and concentrated WO 00/42045 PCT/US99/30434 -221 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 5 recrystallized from acetonitrile to give 1.2 g (47%) of titled compound as an off white solid: mp 255-257"C; MS(APCI+): m/z 417.3 (MH+). Example 146 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3
,
7
,
8
,
9 ,10,12,13,14,14a,15-decahydro-, ethyl ester N O O 0 p AoN H O 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 15 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 Na 2
SO
4 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: 20 MS(APCI+): m/z 206.2 (MH+). Step B: 4 -Dimethylaminomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester WO 00/42045 PCT/US99/30434 -222 N 0 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 5 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 50%-100% ethyl acetate in hexanes as eluant to give 2.1 g (78%) of pure titled compound as a gum: MS(APCI+): n/z 10 263.1 (MH+). Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3
,
7
,
8
,
9 ,10,1 2 ,1 3 ,14,14a,15-decahydro-, ethyl ester N O O 0N To a mixture of perchlorate salt (2.36 g, 9.9 mmol, Example 3, Step B) and 15 150 mL of ether was added 250 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until 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 Na 2
SO
4 and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannich base (2.0 g, 7.6 mmol) 20 was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated WO 00/42045 PCT/US99/30434 -223 in vacuo 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 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 2-hydroxyethyl ester OH N O OH 0 00 HO N Step A: 5-Hydroxy- 2 -methyl-1H-indole-3-carboxylic acid hydroxyethyl ester OH H O N 10 To a mixture of 5 -hydroxy-2-m ethyl -1H-indole-3-carboxylic acid (5.0 g 26.15 mmol) and 1, 8 -diazabicyclo[5.4.0]undec-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 15 Na 2
SO
4 and concentrated in vacuo to give a residue, which was choromatographed using 30%-100% ethyl acetate in hexanes as eluant to give 2.4 g (39%) of the desired product as a gum: MS(APCI+): n/z 236.1 (MH+). Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid hydroxyethyl ester WO 00/42045 PCT/US99/30434 -224 OH 0 NO 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 5 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 10 gum: MS(APCI+): ni/z 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 N O 0O 60 0N To a mixture of perchlorate salt (2.1 g, 8.9 mmol, Example 3, step B) and 15 150 mL of ether was added 250 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until 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 Na 2
SO
4 and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 6.84 mmol) 20 was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated WO 00/42045 PCT/US99/30434 -225 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 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-methylphenyl)methyl ester 00 HOO N 10 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 15 Na 2
SO
4 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 0 C; MS(APCI+): m/z 296.2 (MH+). Step B: 4 -Dimethylaminomethyl-5-hydroxy-2-methyl- 1 H-indole-3-carboxylic acid 3-methylbenzyl ester WO 00/42045 PCT/US99/30434 -226 N 0 HO N 5-Hydroxy-2-methyl-IH-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 5 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 10 353.3 (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, 1 5-decahydro-2-methyl-, (3-methylphenyl)methyl ester N O --~ / N 15 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 Na 2
SO
4 and concentrated in vacuo. The 20 residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, WO 00/42045 PCT/US99/30434 -227 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 5 titled compound as a white solid: mp 80-82 0 C; MS(APCI+): m/z 445.4 (MH+). Example 149 Pyrrolo[3',2':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 0/ N O N 10 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-, (1 S)- I -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+): 15 m/z 445.2 (MH+). Example 150 Pyrrolo[3',2':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
N
WO 00/42045 PCT/US99/30434 -228 Pyrrolo[3',2':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 was synthesized according to procedure Q from 1-phenylethanol. The crude product was chromatographed using 40% ether in hexanes followed by 50% ethyl acetate 5 in hexanes as eluant to give 480 mg of the desired product as a white solid: mp 89-90 0 C; MS(APCI+): m/z 445.2 (MH+). Example 151 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 N O O/ 10 N 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 15 desired product as a white solid: MS(A1PCI+): m/z 447.1 (MH+). Example 152 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester N O N
N
WO 00/42045 PCTIUS99/30434 -229 Pyrrolo[3',2':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 was synthesized according to procedure Q from 3-pyridylcarbinol. The crude product was chromatographed using 50% ethyl acetate in hexanes followed by 10% 5 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, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, 10 1- [4-(trifluoromethyl)phenyl] ethyl ester N_/ C F 3 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-u 15 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-): n/z 511.1 (M-H). Example 154 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -(pentafluorophenyl)ethyl ester WO 00/42045 PCT/US99/30434 -230 F F F N O O F 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-, 1-(pentafluorophenyl)ethyl ester was synthesized according to procedure Q from pentafluoro-a-methylbenzyl 5 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 93-95'C; MS(APCI+): m/z 535.1 (MH+). Example 155 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2,6-difluorophenyl)ethyl ester F N O F 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-(2,6-difluorophenyl)ethyl 15 ester was synthesized according to procedure Q from 2,6-difluoro-u-methylbenzyl alcohol. The crude product was chromatographed using 40% ether in hexanes as eluant to give 180 mg of the desired product as a white solid: mp 85-87 0 C; MS(APCI+): n/z 481.1 (MH+).
WO 00/42045 PCT/US99/30434 -231 Example 156 Pyrrolo[3',2':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 ester 0 N O O N 5 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-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 eluant to give 300 mg of the desired product as a white solid: mp 84-86'C; MS(APCI+): m/z 10 435.1 (MH+). Example 157 Pyrrolo[3',2':5,6][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 0 N 0/ 15 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-(4-morpholinyl) 1-phenylethyl ester was synthesized according to procedure Q from cx-phenyl- WO 00/42045 PCT/US99/30434 -232 4-morpholineethanol. The crude product was chromatographed using 40%-60% ether in hexanes as eluant to give 130 mg of the desired product as a white solid: mp 251-252*C; MS(APCI-): m/z 528.2 (M-H). Example 158 5 Pyrrolo[3',2':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)- 1 -(2-furanyl)ethyl ester 0 0 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-, (1 R)- 1 -(2-furanyl)ethyl ester 10 was synthesized according to procedure Q from R(+)-1-(2-furyl)ethanol. The crude 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+): m/z 435.1 (MH+). Example 159 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-methoxy-2-oxo-1-phenylethyl ester N O 0
N/
WO 00/42045 PCT/US99/30434 -233 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxy-2-oxo- 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 5 eluant to give 309 mg of the desired product as a white solid: mp 103-105'C; MS(APCI+): m/z 489.2 (MH+). Example 160 Pyrrolo[3',2':5,6][I]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 N O 100 10 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 5-decahydro-2-methyl-, 1-(3-pyridinyl)ethyl ester was synthesized according to procedure Q from I-(3-pyridyl)ethanol. The crude product was chromatographed using 50% ether in hexanes followed by 10% 15 methanol in methylene chloride as eluant to give 300 mg of the desired product as a white solid: mp 78-80'C; MS(APCI+): m/z 446.2 (MH+). Example 161 Pyrrolo[3',2':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 WO 00/42045 PCTIUS99/30434 -234 OH N O 0/ N To a solution of pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine 1-carboxylic acid, 3,7,8,9,10,12,13,1 4 ,14a,15-decahydro-2-methyl-, 2-methoxy 2-oxo-1-phenylethyl ester (650 mg, 1.33 mmol) in methanol (60 mL) was added 5 IN NaOH solution (5.32 mL, 5.32 mmol). The resulting reaction mixture was stirred at 50'C for 1 hour, then concentrated in vacuo. 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 IN HCl. The mixture was 10 concentrated in vacuo, the residue was purified by chromatography (10-30% methanol in chloroform as eluant) followed by recrystallization from methanol to give 0.35 g of the desired product as a white solid: mp 250-251 0 C; MS(APCI-): n/z 473.1 (M-H), Anal. Calcd for C 2 8
H
3 0
N
2 0 5 -0.36H 2 0: C, 69.91; H, 6.44; N, 5.82. Found: C, 69.96; H, 6.33; N, 5.59. 15 Example 162 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, 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) 0 N O 0/ CH O H 3 C /. H 3C N OH
N
WO 00/42045 PCT/US99/30434 -235 To a suspension of pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,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 5 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+): n/z 475.2 (MH+). Anal. Calcd for 10 C 2 8
H
2 9
N
2 05-C 5
H
14 NO-1.2H 2 0: 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, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R)-2-methoxy-2-oxo 15 1 -phenylethyl ester 00~ 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-, (1R)-2-methoxy-2-oxo I -phenylethyl ester was synthesized according to procedure Q from (R)-(-)-methyl 20 mandelate. The crude 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+): mn/z 489.2 (MH+).
WO 00/42045 PCT/US99/30434 -236 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, 1 5-decahydro-2-methyl-, (R)-carboxy(phenyl)methyl ester OH 0/ N O O O 5 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 IN NaOH (5.5 mL, 5.5 mmol). The resulting reaction mixture was 10 stirred at 50*C for 1 hour and IN HCl (5.5 mL) was added. The mixture was concentrated in vacuo to give a residue, which was purified by chromatography (10-30% methanol in chlorofonrm 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-): m/z 473.1 (M-H). 15 Example 165 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (R) carboxy(phenyl)methyl, 3,7,8,9,10,1 2 ,1 3 ,1 4 ,14a,15-decahydro 2-methylpyrrolo[3',2':5,6] [1 ]benzopyrano[3, 2 -i]quinolizine- 1 -carboxylate (1:1) 0 0/ N O O CH O
H
3 Cs / O H 3C N OH
N
WO 00/42045 PCT/US99/30434 -237 To a suspension of pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,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 5 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 10 C 2 8
H
2 9
N
2
O
5
-C
5
H
14 NO-1.8H 2 0: 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][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester NN 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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 20 acetate as eluant to give 260 mg of the desired product as a white solid: mp 199-201'C; MS(APCI+): mn/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 WO 00/42045 PCT/US99/30434 -238 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-, I -(4-pyridinyl)ethyl ester was synthesized according to procedure Q from 1-(4-pyridyl)ethanol. The crude 5 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][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(2-pyridinyl)ethyl ester 0 ~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 5-decahydro-2-methyl-, 1-(2-pyridinyl)ethyl ester was synthesized according to procedure Q from 1 -(2-pyridyl)ethanol. The crude 15 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+): m/z 446.2 (MH+).
WO 00/42045 PCTIUS99/30434 -239 Example 169 Pyrrolo[3',2':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 N O OS 0N 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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+): n/z 10 437.5 (MH+). Example 170 Pyrrolo[3',2':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 F 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, (1 S)- 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% 20 ether in hexanes as eluant to give 300 mg of the desired product as a white solid: mp 108-1 10*C; MS(APCI+): n/z 463.3 (MH+).
WO 00/42045 PCT/US99/30434 -240 Example 171 Pyrrolo[3',2':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)- 1 -(4-fluorophenyl)ethyl ester F O/ 5 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-, (1R)-1-(4-fluorophenyl)ethyl ester was synthesized according to procedure Q from R(+)-1-(4 florophenyl)ethanol. The crude product was chromatographed using 30%-50% 10 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 rN 15 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 5-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 20 product as a solid: mp 73-80'C; MS(APCI +): m/z 432.6 (MH+).
WO 00/42045 PCTIUS99/30434 -241 Example 173 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester N 0 0 0 N 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester was synthesized according to procedure Q from ethyl glycolate. The crude product was chromatographed (1:1 hexane/EtOAc) to give 0.5287g (36.8%) of desired product as a solid: mp 60-70 0 C; MS(APCI +): m/z 427.2 (MH+). 10 Example 174 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 N O N NN 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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 86mg 20 (41.2%) of pure desired product as crystals: mp 228-232'C; MS(APCI +): m/z 446.2 (M+).
WO 00/42045 PCTIUS99/30434 -242 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 1. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quatemary alkyl salts with nitrogen atoms 5 optionally present in R 10 . These structural forms are within the scope of the present invention. Example 175 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizinium, 3,7,8,9,10,12,13,14,14a,15 decahydro-2, 11 -dimethyl- 1 -[(S)-(1 -phenylethoxy)carbonyl]-, methanesulfonate N+ O 100 10 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 5-decahydro-2-methyl-, (1 S)-1 -phenylethyl ester (0.6 g, 1.349 mmol) and methyl methanesulfonate (1.089 g, 10.7964 mmol) were mixed together in 1,2 dichloroethane (8ml) and refluxed at 88'C for 18 hours. The 15 reaction mixture was concentrated in vacuo. The crude product was chromatographed (2:10 MeOH/CH 2
CI
2 ) to give 0.41 g (61.5%) 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 20 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 R 10 . These structural forms are within the scope of the present invention.
WO 00/42045 PCTIUS99/30434 -243 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 CO 0N 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-furanylmethyl ester was synthesized according to procedure Q from furan-3-yl-methanol. The crude product was chromatographed (1:1 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+). 10 Example 177 Pyrrolo[3',2':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 0 l. N O O N Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a, 1 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(APCI +): m/z 476.5 (MH+).
WO 00/42045 PCT/US99/30434 -244 Example 178 Pyrrolo[3',2':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 N O OI O N 5 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-furanylmethyl ester was synthesized according to procedure Q from furan-2-yl-methanol. The crude product was chromatographed (1:1 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+). 10 Example 179 Pyrrolo[3',2':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 CI N Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-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/ether) to give 80 mg (5.0%) of desired product as a solid: mp 95-105'C; MS(APCI +): m/z 479.2 (MH+).
WO 00/42045 PCT/US99/30434 -245 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 0 N O rO 0N 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester (0.47 g, 0.96 mmol) was mixed with IN 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 IN HCl to neutralize. The reaction 10 mixture was concentrated in vacuo, and the crude product was chromatographed (initially 1:1 hexane/ether, then 10% MeOH in CHCl 3 ) to give 0.374g of crude solid. The crude solid was redissolved in CHCl 3 and filtered to get 78 mg (20.6%) of desired product as a solid: MS(APCI +): mp 260'C; m/z 399.1 (MH+). Example 181 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(2,6-dichlorophenyl)ethyl ester CI N O CI N Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 20 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, I -(2,6-dichlorophenyl)ethyl ester was synthesized according to procedure Q from 1-(2,2-dichloro phenyl) WO 00/42045 PCT/US99/30434 -246 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 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1--carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 1-(2-methoxyphenyl)ethyl ester 0 0 N O O/ 0N Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 1 -(2-methoxyphenyl)ethyl ester 10 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 115-125'C; MS(APCI +): m/z 475.2 (MH+). Example 183 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 15 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)-1-phenylethyl ester, 11-oxide 6N Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1 S)- 1 -phenylethyl ester (0.3 g) WO 00/42045 PCT/US99/30434 -247 was mixed with 50% H 2 0 2 in MeOH and the mixture was stirred at room temperature for 3 hours. Then excess H 2 0 2 was destroyed using Pd/C. The reaction solution was filtered and concentrated in vacuo. The crude product was chromatographed (10% MeOH in CH 2
CI
2 ) to give 52 mg (48.2%) of pure desired 5 product as a solid: mp 180-190*C; MS(APCI +): m/z 461.2 (MH+). Some of the compounds of ring close Formula I are capable of further forming N-oxides and N-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 10 optionally present in R 10 . These structural forms are within the scope of the present invention. Example 184 Pyrrolo[3',2':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 15 ester 0 0 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 H 2
SO
4 and the mixture was refluxed for 24 hours. 20 The reaction solution was then neutralized with solid NaHCO 3 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+).
WO 00/42045 PCT/US99/30434 -248 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 NaBH 4 (1.104 g, 29.19 mmol) was added slowly. The reaction was monitored by TLC. When the starting material was 5 completely consumed mixture was neutralized by NaHCO 3 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 10 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 100-1 10 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, 15 the filtrate and the solid were collected. The solid was dissolved in NaHCO 3 and extracted with EtOAc. The extracts and the filtrate were combined together and dried over Na 2
SO
4 . 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+). 20 Step D: Pyrrolo[3',2':5,6][I]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 1 -[5-(methoxycarbonyl)-3 -pyridinyl]ethyl ester 0 / 0 N O N
N
WO 00/42045 PCT/US99/30434 -249 Pyrrolo[3',2':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 was synthesized according to procedure Q from 5-(1-hydroxy-ethyl)-nicotinic acid methyl ester. The crude product was 5 chromatographed (1:1 hexane/EtOAc) to give 0.81 g (37%) of desired product as a solid: MS(APCI +): m/z 504.3 (MH+). Step E: Pyrrolo[3',2':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 10 Example 184, 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 (0.2202 g, 0.4378 mmol) was mixed with IN NaOH (1.75 mmol, 1.75 mL) in MeOH (10 mL). The reaction flask was kept in an oil bath at 50'C for 1 hour. Then the reaction mixture was 15 cooled to ambient temperature followed by addition of IN HCI (2 mL) to neutralize the reaction mixture. Mixture was concentrated in vacuo to give the crude product which was chromatographed (20:10, MeOH/CH 2 C1 2 ) to give 0.2665 g (100%) of the desired product as a solid: MS(APCI +): m/z 490.2 (MH+). 20 Example 185 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 N O0 N 0 0 0 0 N0 H 0 WO 00/42045 PCTIUS99/30434 -250 Pyrrolo[3',2':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) (0.502 g, 1.13 mmol) is combined with diethyl-5 (hydroxymethyl)isophthalate (0.859 g, 3.40 mmol) and placed in a 150'C oil bath 5 for 6 minutes. The reaction is allowed to cool to room temperature, diluted with EtOAc and saturated NaHCO 3 and stirred until all residue is dissolved. The layers are separated and the organic layer is washed with water and brine, dried (MgSO 4 ) and evaporated. The product is purified by column chromatography eluting with a gradient of ether/hexanes (30% yield). 1 H NMR (CDCI3, 10 300 MHz): 5 8.64 (s, 1H), 8.31 (s, 2H), 8.11 (s, 1H), 7.03 (d, 1H) 6.76 (d, 1H), 5.40 (d, 2H), 4.44 (q, 4H), 3.38-3.44 (dd, 1H), 3.04 (m, 1H), 2.76-2.82 (m, 2H), 2.61 (s, 3H), 2.44-2.56 (m, 2H), 1.40 (t, 6H), 1.23-1.78 (m, 11H). MS (APCI, m/z, M+1): 575.2
C
33
H
3 8
N
2 0 7 -0.67 H 2 0. Calcd: C, 67.50; H, 6.70; N, 4.77. Found: C, 67.19; H 15 6.54; N, 4.37. Example 186 1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro 2-methylpyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizin I -yl)carbonyl]oxy]methyl] 0 N O OH 0 0 N o 20 H HO 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 (0.4787 g, 0.83 mmol) in 10 mL THF, 2 mL MeOH and 0.83 mL (1.66 mmol) of 2 M NaOH were combined and heated 25 to 50-60*C. Two 0.83 mL portions of 2 M NaOH were added until reaction complete by MS. The reaction was cooled to room temperature and washed with Et 2 0. The aqueous layer was neutralized and concentrated. The residue was WO 00/42045 PCT/US99/30434 -251 dissolved in hot MeOH and filtered to remove NaCl. The filtrate was concentrated and dissolved in MeOH at room temperature and again filtered. The filtrate was dried over MgSO 4 , filtered and concentrated. The product was lyophilized to give 362.2 mg (83%). LCMS: 88.17% 5 Example 187 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 -chloro-5-nitrophenyl)methyl ester Cl N O o 0 N 0 H 10 Step A: 2-Chloro-5-nitrobenzyl alcohol An oven dried 3 neck flask, fitted with 2 septa and a reflux condenser is charged with 2-chloro-5-nitrobenzoic acid (5.53 g, 27.43 mmol), 14 mL THF and
BF
3 -OEt 2 (3.5 mL, 27.62 mmol) is added dropwise. The solution is heated to reflux for 2 hours at which point borane methyl sulfide complex (2M/THF, 15 18 mL, 36 mmol) is added dropwise over 30 minutes. The refluxing is continued for another 2 hours until the reaction is complete by TLC. The reaction is cooled to room temperature and 4 mL 1:1 THF/H 2 0 is slowly added followed by 20.5 mL 5 M NaOH. The reaction is heated to reflux for 16 hours and filtered through a coarse sintered glass funnel while hot, washing solids with THF (2x). 20 The filtrate is dried (MgSO 4 ), filtered, concentrated and purified by column chromatography eluting with a EtOAc/hexane gradient. The product is triturated with hexanes and filtered to obtain the product in 79% yield. IH NMR (CDCI 3 , 300 MHz): 8 8.45 (d, 1H). 8.11 (dd, 1H), 7.52 (d, IH), 8.86 (d, 2H), 2.18 (t, 1H) MS (APCI, AP-) 186.9 WO 00/42045 PCTIUS99/30434 -252 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-, (2-chloro 5-nitrophenyl)methyl ester 2 -Chloro-5-nitrobenzyl alcohol (1.0879 g, 5.80 mmol) and 5 pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, anhydride with benzoic acid (Example 86) (0.512 g, 1.15 mmol) are combined and placed in a 150'C oil bath for 6 minutes. The reaction is cooled to ambient temperature and diluted with EtOAc. The mixture is washed with saturated NaHCO 3 , water and brine, dried 10 (MgSO 4 ), filtered, concentrated and purified by column chromatography eluting with a gradient of EtOAc/hexanes to obtain the product in 57% yield. I H NMR (DMSO, 300 MHz): 6 11.65 (s, 1H), 8.39 (s, 1H), 8.24 (dd, IH), 7.85 (d, 1H), 7.07 (d, 1H), 6.63 (d, 1H), 5.42 (d, 2H), 3.23 (m, 1H), 2.8-3.0 (m, 1H), 2.60-2.70 (m, 2H), 2.30-2.60 (m, 3H), 2.37 (s, 3H), 1.82-1.87 (m, 1H), 15 1.0-1.75 (in, 11H) MS (APCI, AP+): 510.1 LCMS: 98.23 % retention time: 7.627 minutes Example 188 Pyrrolo[3',2':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 20 2 -chlorophenyl)methyl ester CI N O0 O0
NH
2 N H Step A: 5-Amino-2-chlorobenzoic acid Raney-Nickel (3 gm) was added to a methanolic solution of 5-nitro 2 -chlorobenzoic acid (10 gm,150 mL), this mixture was then connected to a 25 H 2 source, after 4 hours, the reaction was completed by TLC (30% WO 00/42045 PCT/US99/30434 -253 MeOH/CH 2
CI
2 ). The catalyst was removed by filtration and the filtrate was evaporated to dryness, collected 8 g of product and it was used in the next step without further purification. MS (APCI, AP+): 172.0 Step B: 5-Amino-2-chlorobenzyl alcohol 5 An oven dried two neck flask fitted with a septum and a reflux condenser is charged with 5-amino-2-chlorobenzoic acid (2.611 g, 15.22 mmol) and 7.5 mL THF. BF3-OEt2 is added dropwise and the reaction is heated to reflux for 2 hours. Borane methyl sulfide complex (2M/THF, 10 mL, 20 mmol) is added dropwise. The reaction is refluxed for 3 hours, and an additional 3.8 mL of borane methyl 10 sulfide complex (7.2 mmol) is added. The refluxing is continued for 1 hour, cooled to ambient temperature and 3 mL 1:1 THF/H 2 0 is added slowly, followed by 11.2 mL 5 M NaOH. The reaction is heated to reflux for 16 hours and filtered hot through a coarse sintered glass funnel, rinsing the solids with THF (2x). The filtrate is concentrated and the residue partitioned between CH 2
CI
2
/H
2 0. The 15 product is extracted three times into CH 2 Cl 2 . The tan solid in the organic layer is collected by filtration and dried in a 40'C vacuum oven overnight to give 0.6374 g of product. The organic filtrate is dried (MgSO 4 ), filtered, concentrated and purified by column chromatography eluting with a MeOH/CH 2
CI
2 gradient to give 0.56 g of product. 1 H NMR (DMSO, 300 MHz): 6 6.93 (d, I H), 6.75 (d, lH), 20 6.39 (dd, IH), 5.16 (s, 2H), 4.38 (d, 2H). MS (APCI, AP+): 158.0 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-, (5-amino 2-chlorophenyl)methyl ester 25 5-Amino-2-chlorobenzyl alcohol (1.055 g, 6.70 mmol) 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) (0.7023 g, 1.58 mmol) are combined and placed in a 150'C oil bath for 6 minutes. The reaction is cooled, diluted with EtOAc and saturated NaHCO3 30 and stirred until all residue is dissolved. The organic layer is washed with water WO 00/42045 PCT/US99/30434 -254 and brine, dried (MgSO 4 ), filtered and concentrated. The product is purified by column chromatography eluting with 5% MeOH/CH 2 C1 2 . The product is placed under high vacuum for two days to yield 0.260 g (34%) of a light pink solid. 1H NMR (DMSO, 300 MHz): 5 11.16 (s, 1H), 10.13 (s, 1H), 8.02 (d, 1H), 7.60 (dd, 5 1H), 7.29 (d, 1H), 7.05 (d, 1H), 6.60 (d, 1H), 5.37 (t, 1H), 4.51 (d, 2H), 3.14-3.18 (m, 1H), 2.90-3.00 (m, 1H), 2.65-2.72 (m, 1H), 2.30-3.20 (in, 3H), 2.39 (s, 3H), 1.10-1.75 (m, 11H). MS (APCI, AP+): 480.1 LCMS: 91.44% retention time: 4.623 minutes Example 189 10 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 N 0 0 o_' N H 2-Methyl-pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine (0.296 gm, 1 mm) and ethyl oxylate (0.123 mL, 1.1 mm) were mixed in 20 mL of THF and 15 this mixture was stirred at ambient temperature for 48 hours. THF was evaporated and residue was redissolved in EtOAc, the organic layer was washed with bicarbonate, brine, and evaporated to dryness. The pure product was isolated by column chromatography eluted with hexanes/EtOAc = 1:1 (50 mg, 12.4%) MS (APCI, AP+): 397.1. 1 H NMR (CDCl 3 , 300 MHz): 8 8.3 (s, NH), 7.05 (d, 20 1H), 6.8 (d, 1H), 4.4 (q, 2H), 2.4-3.6 (m, 6H), 2.75 (s, 3H), 1.22-2.15 (m, 11H), 1.4 (t, 3H), C 23
H
2 8
N
2 0 4 -1/3 H 2 0. Calc'd: C, 68.69; H, 7.19; N, 6.96. Found: C, 68.85; H 6.98; N, 6.51. MP: 200 0
C
WO 00/42045 PCTIUS99/30434 -255 Example 190 Pyrrolo[3',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 N0 O N 0H 5 Step A: 2,3-Dimethyquinone To a solution of NaOAc (16.4 gm, 60 mm) in 200 mL of water was added 2 ,3-dimethyl-4-hydroxyphenol (5.526 gm, 20 mm) and a solution of benzyltrimethylammonium tribromide (17.6 gm, 22 mm). The mixture was stirred until the color of the solution was faded (3 hours). The organic layer was 10 separated and washed with brine, dried and evaporated, total weight 5 gm, This material was used for the next step without further purification. Step B: 5-Hydroxy-2,6,7-trimethyl-1H-indole-3-carboxylic acid ethyl ester To a solution of 2 ,3-dimethylquinone (3.5 gm, 25.7 mm) in 60 mL of EtOH, was added a solution of 3-amino-but-2-enoic acid, benzyl ester (5.41 gm, 15 28.3 mm) under nitrogen. White solid was filtered, and the filtrate was concentrated and the product was purified by column chromatography eluted with hexanes/EtOAc = 1:1 (0.5 gm, 6.3%) MS (APCI, AP+): 367.1. Step C: 4 -Dimethylaminomethyl-5-hydroxy-2,6,7-trimethyl-1H-indole-3 20 carboxylic acid ethyl ester 37.5% formaldehyde solution (0.157 mL, 1.94 mm) and 40% dimethylamine solution were added to a solution of 5-hydroxy-2,6,7-trimethyl IH-indole-3-carboxylic acid ethyl ester in 11 mL of EtOH. The reaction mixture was stirred at 55'C for 48 hours. The solvent was removed, the pure product was 25 isolated by column chromatography eluted with MeOH/EtOAc = 1:4 (0.22 gm, 37.3%) WO 00/42045 PCTIUS99/30434 -256 MS (APCI, AP+): 367.1. 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-2,4,5-trimethyl-, phenylmethyl ester 5 The perchlorate salt 1,2,3,4,6,7, 8
,
9 -octahydro-quinolizinylium perchlorate (0.204 gm, 0.855 mm) was dissolved in 10 mL IN NaOH and extracted with 3 x 35 mL ether. The ether was concentrated and the residue was redissolved in 4 mL dioxane. The mine solution solution was added to the 4 -dimethylaminomethyl-5 hydroxy- 2 ,6,7-trimethyl-1H-indole-3-carboxylic acid ethyl ester in 8 mL of 10 dioxone. The reaction was refluxed at 11 0"C for 18 hours. The solvent was evaporated and the pure product was isolated by column chromatography eluted with MeOH/EtOAc = 1:4 (0.117 gm, 44.5%) MS (APCI, AP+): 459.2. MP: 75-80'C
C
2 3
H
2 8
N
2 0 4 -2/3 H 2 0. Calc'd: C, 74.11; H, 7.52; N, 5.966.96. Found: C, 74.12; 15 H 7.37; N, 5.77. Example 191 Pyrrolo[ 3
',
2 ':5, 6 ][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester N O O N H 20 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester was synthesized according to procedure Q from 2-methyl-but-3-yn-2-ol. MS: in/z 407.52 (MH+).
WO 00/42045 PCT/US99/30434 -257 Example 192 Pyrrolo[3',2':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 N Cl 0 0 oj "Cl N 5 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-, 2,2,2-trichloro-1,1 dimethylethyl ester was synthesized according to procedure Q from 1,1,1-trichloro-2-methyl-propan-2-ol. MS: m/z 500.86 (MH+). 10 Example 193 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, tricyclo[3.3.1.13, 7 ]dec-1-yl ester 0 K 0" N H 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, tricyclo[3.3.1.13, 7 ]dec-1-yl ester was synthesized according to procedure Q from adamantan-1 -ol. MS: m/z 474.63 (MH+).
WO 00/42045 PCT/US99/30434 -258 Example 194 Pyrrolo[3',2':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-i -phenylethyl ester N O N H 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl-i -phenylethyl ester was synthesized according to procedure Q from 2-phenyl-propan-2-ol. MS: n/z 459.59 (MH+). Example 195 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methylcyclohexyl ester - N 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, I 5-decahydro-2-methyl-, I -methylcyclohexyl ester was 15 synthesized according to procedure Q. MS: m/z 437.59 (MH+). Example 196 Pyrrolo[3',2':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 WO 00/42045 PCT/US99/30434 -259 NOO 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-, 1,1,2-trimethylpropyl ester was synthesized according to procedure Q. MS: mn/z 425.58 (MH+). 5 Example 197 Pyrrolo[3',2':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 N O N H Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methylcyclopentyl ester was synthesized according to procedure Q. MS: m/z 423.56 (MH+). Example 198 Pyrrolo[3',2':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 15 ester WO 00/42045 PCT/US99/30434 -260 N O O NO 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-cyclohexyl-1-methylethyl ester was synthesized according to procedure Q. MS: mn/z 465.64 (MH+). 5 Example 199 Pyrrolo[3',2':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 N O O N N H Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 10 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidinyl ester was synthesized according to procedure Q. MS: n/z 452.60 (MH+). Example 200 Pyrrolo[3',2':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 N OF N 15
H
WO 00/42045 PCT/US99/30434 -261 Pyrrolo[3',2':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 was synthesized according to procedure Q. MS: m/z 435.50 (MH+). Example 201 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-methylphenyl ester N 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, 1 5-decahydro-2-methyl-, 3-methylphenyl ester was 10 synthesized according to procedure Q. MS: mn/z 431.54 (MH+). Example 202 Pyrrolo[3',2':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 N N H 15 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, phenyl ester was synthesized according to procedure Q. MS: n/z 417.51 (MH+).
WO 00/42045 PCT/US99/30434 -262 Example 203 Pyrrolo[3',2':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 N 00 0> 0 N 5 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-(methoxycarbonyl)phenyl ester was synthesized according to procedure Q. MS: mn/z 475.55 (MH+). Example 204 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinyl ester 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, 1 5-decahydro-2-methyl-, 3-pyridinyl ester was 15 synthesized according to procedure Q. MS: m/z 417.50 (MH+). Example 205 Pyrrolo[3',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 WO 00/42045 PCT/US99/30434 -263 N 0O O0 O F N H F F Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-(trifluoromethyl)-, ethyl ester was synthesized according to procedure Q. MS: n/z 423.44 (MH+). 5 Example 206 Pyrrolo[3',2':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 N O O0 NN H 10 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [5-[(dimethylamino)methyl] 2-furanyl]methyl ester was synthesized according to procedure Q. MS: n/z 478.60 (MH+). Example 207 15 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2 -carboxy-2-methylpropyl ester WO 00/42045 PCT/US99/30434 -264 N O O O O OH 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-carboxy-2-methylpropyl ester was synthesized according to procedure Q. MS: m/z 441.53 (MH+). 5 Example 208 Pyrrolo[3',2':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 10 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(dimethylamino) 2,2-dimethylpropyl ester was synthesized according to procedure Q. MS: m/z 454.62 (MH+). Example 209 15 Propanedioic acid, monoanhydride with 3,7,8,9,10,12,13,14,14a, 1 5-decahydro 2-methylpyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 1,1 -dimethylethyl ester WO 00/42045 PCT/US99/30434 -265 o 0 XI 0)-~ r H 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 was synthesized according to procedure Q. MS: n/z 5 483.57 (MH+). Example 210 Pyrrolo[3',2':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 0 N 10 H PyTolo[3',2':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 was synthesized according to procedure Q. MS: n/z 440.59 (MH+). 15 Example 211 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(1H-imidazol-1-yl)ethyl ester o n 1, IN
H
WO 00/42045 PCT/US99/30434 -266 Pyrrolo[3',2':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 was synthesized according to procedure Q. MS: m/z 435.53 (MH+). Example 212 5 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2 -benzofuranylmethyl ester O N O O NH Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 2-benzofuranylmethyl ester was 10 synthesized according to procedure Q from benzofuran-2-yl-methanol. MS(APCI+): m/z 471.2 (MH+). Example 213 Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR,2S)-2-(dimethylamino)-1 15 phenylpropyl ester N N 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 R,2S)-2-(dimethylamino)- 1 phenylpropyl ester was synthesized according to procedure Q from (IR, 2S) 20 dimethylamino-phenyl-propan-l-ol. MS(APCI+): m/z 502.1 (MH+).
WO 00/42045 PCTIUS99/30434 -267 Example 214 Pyrrolo[3',2':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 O00O N 5 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-, (I S, 2 R)-2-(dimethylamino)- 1 phenylpropyl ester was synthesized according to procedure Q from (IS, 2R)-2 (dimethylamino-phenyl-propan-1-ol. MS(APCI+): n/z 502.1 (MH+). 10 Example 215 Pyrrolo[3',2':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 N F N o 0 0 Me N H 15 Step A: 1-( 4 -Fluorophenyl)cyclopropanol HO Following the procedure reported by Kulinkovich, O.G.; Sviridov, S.V.; Vasilevskii, D.A.; Savchenko, A.I.; and Pritytskaya, T.S. in J. Org. Ciem. USSR (Engl) 1991;27(2):250 for the preparation of 1-phenylcyclopropanol, 20 4-fluorobenzoic acid ethyl ester (65.72 mmol, 11.05 g) was converted to 1-(4 fluorophenyl)cyclopropanol (5.34 g, 53%) as a yellow liquid; 1H NMR WO 00/42045 PCT/US99/30434 -268 (400 MHz, CDCl 3 ) 8 0.99-1.02 (in, 2H, cyclopropyl CH 2 ), 1.23-1.26 (in, 2H, cyclopropyl CH 2 ), 2.22 (bs, 1H, OH), 6.98-7.05 (m, 2H, ArH), 7.26-7.32 (in, 2H, ArH); 1 9 F NMR (CDCl 3 ) 6 -117.09 (d, J=15.43 Hz); MS (APCI+) m/z 152.9 (MH+). 5 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-, 1-(4 fluorophenyl)cyclopropyl ester Following the procedure from Example 47, Step B, 1-(4-fluorophenyl) cyclopropanol (35.1 mmol, 5.34 g) and pyrrolo[3',2':5,6][1]benzopyrano[3,2 10 i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, anhydride with benzoic acid (Example 86), (8.77 mmol, 3.90 g) were converted to pyrrolo[3',2':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. The product was purified by silica gel flash column chromatography 15 (25-50% ethyl acetate/hexanes, then 30-50% ether/hexanes) and recrystallized from 2,2,4-trimethylpentane to afford a light yellow solid (0.364 g, 9%): mp 130 135'C; IR (KBr) 3302, 29.31, 2857, 1689, 1515, 1429, 1221, 1194, 1147, 1068 cm- 1 ; IH NMR (400 MHz, DMSO-d 6 ) 6 1.13-1.60 (in, 13H, aliphatic CH), 1.71 1.74 (in, 1H, aliphatic CH), 1.88 (d, J=13.18 Hz, 1H, aliphatic CH), 2.36 (d, 20 J=10.74 Hz, IH, aliphatic CH), 2.43-2.49 (in, 1H, aliphatic CH), 2.53 (s, 3H, ArCH 3 ), 2.66-2.71 (m, 2H, aliphatic CH), 2.87-2.90 (in, 1H, aliphatic CH), 3.22 (dd, J=18.31, 6.84 Hz, 1H, aliphatic CH), 6.61 (d, J=8.79 Hz, 1H, ArH), 7.04 (d, J=8.55 Hz, 1H, ArH), 7.11-7.15 (in, 2H, ArH), 7.28-7.32 (in, 2H, ArH), 11.57 (s, 1H, NH); 19 F NMR (DMSO-d 6 ) 6 -117.03; MS (APCI+) m/z 475.2 (MH+). Anal. 25 Calcd for C 2 9
H
3 1
F
1
N
2 0 3 : C, 73.40; H, 6.58; F, 4.00; N, 5.90. Found: C, 73.58; H, 6.79; F, 3.93; N, 5.52.

Claims (10)

1. A compound of Formula I R 6 ",R6 T (CH2)n 6 (CH2)n SR 3 Y N R 3 0 y 40 R5 RR - R X A ring close ring open or a pharmaceutically acceptable salt thereof wherein: 5 A is 0, S, and additionally A is NR 1 when X is C-R 9 ; X is N when A is NRI or X is C-R 9 wherein R 9 is halogen, hydrogen, alkyl, -CF 3 , CH 2 F, CHF 2 , -(CH2)m-ORl, aryl, arylalkyl, -(CH2)m-NR 7 R 8 , or C )r (CH2)q -r wherein m is an integer of from 0 to 2 and 10 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-NR 7 R 8 , -N(R )-(CH 2 )v C(R 7 R 8 )-aryl, or OR 10 wherein R 10 is hydrogen, alkyl, cycloalkyl, cycloalkyl fused to an aryl ring, aryl, (CH 2 )saryl, 15 -CH 2 CF 3 , (CH2)tC(R7R 8 )-(CH 2 )uaryl, 0 R (CH2m C-NR 7 R 8 Aryl WO 00/42045 PCT/US99/30434 -270 0 2 )m N 7 R 8 Rm(CH 2 ) OC- R 7 VX alkyl alkyl 0 R CH2m C-NR 7 R 8 alkyl 0 R (CH 2 ) 7 m NR 7 R 8 (CH 2 )m C-OR 7 cycloalkyl cycloalkyl 0 R I (CH 2 )-m C 7-NR 7 R 8 cycloalkyl CC3 CH 3 5 C=N , C=CH , ,or 5 R2 CH2)w wherein s is an integer of from I to 3, t is an integer of from 0 to 3, u 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; 10 RI is hydrogen or alkyl and each occurrence of RI is independently hydrogen or alkyl; R and R 2 are each independently selected from: hydrogen, alkyl, 15 halogen, -CN, -NO 2 , -(CH 2 )m-NR 7 R 8 , WO 00/42045 PCT/US99/30434 -271 -(CH2)m-COOR 7 , -(CH2)m-CONR 7 R 8 , 0 (CH 2 ) m N R7 0 5 11 -(CH2)mN-S-R 7 , II -(CH2)m-OR 7 , 10 -(CH2)m-SO 2 NR 7 R 8 , and (CH2)m-S(O)pR 7 wherein each occurrence of R 7 and R 8 are each independently hydrogen, alkyl, aryl, arylalkyl, -CF 3 , or R7 and R 8 may be taken together to form a cyclic ring of from 3 to 7 atoms which ring may have 0, S, or NR 1 and p is an 15 integer of from 0 to 2; R 3 is hydrogen or alkyl; R 4 is hydrogen, alkyl, aryl, or aralkyl; R 5 is alkyl, aryl, arylalkyl, acyl; or R 4 and R 5 are taken together with the atoms to which they are attached to 20 form a cyclic ring of from 5 to 7 atoms; R 6 is hydrogen or alkyl; R 5 when not taken together with R 4 can be taken together with R 6 with the atoms to which they are attached to form a ring of from 5 to 7 atoms; 25 N-R 5 is also the corresponding N-oxide; R 1 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; WO 00/42045 PCTIUS99/30434 -272 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 5 R 1 is hydrogen.
3. A compound according to Claim 1 wherein: R 1 is hydrogen and X is C-R 9 .
4. A compound according to Claim 1 wherein: 10 R 1 is hydrogen and X is C-R 9 , wherein R 9 is alkyl.
5. A compound according to Claim 1 wherein: R 1 is hydrogen, X is C-R 9 , wherein R 9 is alkyl; 15 R 4 and R 5 are taken together with the atoms to which they are attached to form a ring of from 5 to 7 atoms; and Y is OR 10 .
6. A compound according to Claim 1 wherein: R 1 is hydrogen, 20 X is C-R 9 , wherein R 9 is alkyl; R 4 and R 5 are taken together to form a 6-membered ring; and Y is OR 10 wherein R 10 is alkyl, aryl or -(CH 2 )saryl, -(CH2)t-C(R 7 R 8 )-(CH 2 )u-aryl.
7. A compound according to Claim 1 wherein: 25 R 1 is hydrogen, WO 00/42045 PCTIUS99/30434 -273 X is C-R 9 , wherein R 9 is Me; R 4 and R 5 are taken together to form a 6-membered ring; R 6 is hydrogen; n is 2; and 5 Y is OR 10 wherein R 10 is alkyl, aryl or R 10 is -(CH2)t-C(R 7 R 8 )-(CH 2 )u aryl wherein t is 0, R 7 and R 8 can each independently be H, alkyl, -(CH2)vOH or (CH2)uCOOR 7 , and -(CH 2 )vNRIR 2 where u and v are as defined above. 10 8. A compound according to Claim I 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, 1 5-decahydro-2-methyl-, methyl ester; Pyrrolo[3',2':5,6][1 ]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 5-bromo-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl 15 ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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 20 ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, 2,2-dimethylpropyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 25 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 30 acid, 3,7,8,9,10,12,13,14,14a,15 -decahydro-2-methyl-, cyclopropylmethyl ester; WO 00/42045 PCT/US99/30434 -274 Pyrrolo[3',2':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 5 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; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-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, 1 5-decahydro-2-(2-methylpropyl)-, ethyl ester; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1 -dimethylethyl ester; 2,6a,7-Trimethyl-7,8,9,10,1 Oa, 11 -hexahydro-3H,6aH-6-oxa 3,7-diaza-cyclopenta[a]anthracene- I -carboxylic acid ethyl ester; 20 7-Ethyl-2,6a-dimethyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa 3,7-diaza-cyclopenta[a]anthracene- 1 -carboxylic acid ethyl ester; 6a-Ethyl-2,7-dimethyl-7,8,9,10,1 0a, 11 -hexahydro-3H,6aH-6-oxa 3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester; 6a,7-Diethyl-2-methyl-7,8,9,10,1 Ga, 11 -hexahydro-3H,6aH-6-oxa 25 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, 10,1 0a, 11 -hexahydro-3H,6aH 6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester; 30 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-e]indole-1-carboxylic acid, 8,9,11,12,13,13a,14,14a-octahydro-2-methyl-, ethyl ester; WO 00/42045 PCT/US99/30434 -275 3H,7H-Pyrrolizino[1',8':5, 6 ]pyrano[3,2-e]indole-1-acetic acid, 8,9,11,12,12a,13-hexahydro-2-methyl-, ethyl ester; 2-Methyl-8,9, 10,1 Oa, 11,12,12a, 1 3-octahydro-3H,6aH,7H-6-oxa 3,6b-diaza-benzo[a]cyclopenta[h]anthracene-1-carboxylic acid ethyl ester; 5 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-e]indole- 1-acetic acid, 3,8,9,10,11,13,1 4 ,15,15a,16-decahydro-2-methyl-, ethyl ester; Pyrrolo[3',2':5,6] [1 ]benzopyrano[3,2-i]quinolizine- I -carboxamide, 10 8,9,11,12,13,13a, 14,1 4 a-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, 1 4 ,1 4 a-octahydro-2-methyl-; Pyrrolo[3',2':5,6][1 ]benzopyrano[3, 2 -i]quinolizine- 1 carboxaldehyde, 8,9,11,12,13,13a,14,1 4 a-octahydro-2-methyl-; 15 Pyrrolo[3',2':5,6][1 ]benzopyrano[3,2-i]quinolizine- 1 carboxamide,8,9,11,12,13,13a, 14,1 4 a-octahydro-N,2-dimethyl-; Pyrrolo[3',2':5,6][1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 8,9,11,12,13,13a,14,1 4 a-octahydro-2-methyl-, (4-fluorophenyl) methyl ester; 20 Indazolo[ 4 ',5':5,6]pyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,1 3 ,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; 25 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,1 2 ,13,14,14a,1 5-decahydro-2,10,1 0-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 30 ester; WO 00/42045 PCTIUS99/30434 -276 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 5 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-3,7,8,9,10,12,13,14,1 4 a,15-decahydro-2-methyl-, phenylmethyl ester; Pyrrolo[3',2':5,6][]benzopyrano[3, 2 -i]quinolizine-1-carboxylic 10 acid, 4,5-dichloro-3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, phenylmethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethyl ester; 15 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-2,5-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, 1 5-decahydro-2,4-dimethyl-, phenylmethyl 20 ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2,4-dimethyl-, I -(4-fluorophenyl)ethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 25 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; 30 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); WO 00/42045 PCT/US99/30434 -277 Pyrrolo[3',2':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 5 acid, 3,7,8,9,10,12,13,14,14a, I 5-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, 1 5-decahydro-2-methyl-, 1-[3-[(dimethylamino)carbonyl]phenyl] ethyl ester; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-[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; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [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, 1 5-decahydro-2,-methyl-, 20 (4-carboxyphenyl)methyl ester; 1-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-1 H 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, I 5-decahydro-2-methyl-, 25 [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 30 acid, 3 , 7 ,8, 9 ,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester; WO 00/42045 PCT/US99/30434 -278 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-methyl-, [3-(hydroxymethyl)phenyl]methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3, 2 -i]quinolizine-1-carboxylic 5 acid, 3,7,8,9,10,12,13,14,14a, 1 5-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, 1 5-decahydro 2-methylpyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylate 10 (1:1); 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 -[(dimethylamino)methyl]phenyl]mcthyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 15 acid, 3 , 7 , 8 , 9 ,10,12,13,14,14a,1 5-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, I 5-decahydro-2-methyl-, [2-(4-morpholinyl)ethyl ester; 20 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 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, I 5-decahydro-2-methyl-, 25 (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 30 acid, 3,7,8,9,10,12,13,14,14a,15 -decahydro-2-methyl-, 1-[ 3 -(trifluoromethyl)phenyl]ethyl ester; WO 00/42045 PCT/US99/30434 -279 Pyrrolo[3',2':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 5 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,1 5-decahydro-2-methyl-, 1 -(1 -naphthalenyl)ethyl ester; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, I-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 15 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 20 acid, 3,7,8,9,10,12,13,14,14a,1 5-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, 1 5-decahydro-2-methyl-, 1-(2-pyrimidinyl)ethyl ester; 25 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, 30 1-(4-fluorophenyl)ethyl ester; Quinolizinium, 1-[[(4-fluorophenyl)methoxy]carbonyl]-5-hydroxy 2-methyl-iH-indol-4-yl]methyl]-1,2,3,4,6,7,8,9-octahydro-, chloride; WO 00/42045 PCT/US99/30434 -280 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-1,2-dimethyl-, (4-fluorophenyl)methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 5 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 10 acid, 3,7,8,9,10,12,13,14,14a,1 5-decahydro-2-methyl-, (4-nitrophenyl)methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R)-1-phenylethyl ester; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-(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; 20 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-, 2,2,2-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, 1 5-decahydro-2-methyl-, bicyclo[2.2.1 ]hept 25 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) I -methylethyl ester; Pyrrolo[3',2': 5,6] [1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic 30 acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, I -phenylcyclopentyl ester; WO 00/42045 PCT/US99/30434 -281 Pyrrolo[3',2':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 5 acid, 3 , 7 , 8 , 9 ,10,1 2 ,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; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (IS) 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-, 15 [ 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, 1 5-decahydro-2-methyl-, 2-pyridinylmethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 20 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 25 (1:1); Pyrrolo[3',2':5,6] [1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3 , 7 , 8 , 9 ,10,1 2 ,1 3 ,1 4 ,14a,15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridinyl]methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 30 acid, 3,7,8,9,10,12,13,14,14a, 1 5-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- WO 00/42045 PCT/US99/30434 -282 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, 1 5-decahydro-2-methyl-, 1-(4'-methyl[ 1,1' 5 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 10 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][l]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; 15 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-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 20 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-, (1R)-2,3-dihydro 1 H-inden-1-yl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 25 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, 3,7,8,9,10,1 2 ,1 3 ,14,14a,15-decahydro-2-methyl-, cyclohexyl(phenyl)methyl ester; 30 Pyrrolo[3',2':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; WO 00/42045 PCT/US99/30434 -283 Pyrrolo[3',2':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 5 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; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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-, 15 (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 20 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-, (IS) 1-(2-bromophenyl)ethyl ester; 25 Pyrrolo[3',2':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) 30 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; WO 00/42045 PCT/US99/30434 -284 Pyrrolo[3',2':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 5 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; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-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 15 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 20 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; 25 Pyrrolo[3',2':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] 30 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; WO 00/42045 PCT/US99/30434 -285 Pyrrolo[3',2':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 5 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, 1 5-decahydro-2-methyl-, 1,1 -dimethyl 2-pyrazinylethyl ester; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 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 15 1 H-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)- I -phenylpropyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 20 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 ,10,1 2 ,1 3 ,14,14a,15-decahydro-2-methyl-, (4-chlorophenyl)methyl ester; 25 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-, phenylmethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3 ,7,8, 9 ,10,1 2 ,1 3 ,14,14a,15-decahydro-, ethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 30 acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, 2-hydroxyethyl ester; WO 00/42045 PCT/US99/30434 -286 Pyrrolo[3',2':5,6] [1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic acid, 3,7,8,9,10,1 2 ,13,14,14a,1 5-decahydro-2-methyl-, (3-methylphenyl)methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 5 acid, 3,7,8,9,10,12,13,14,14a, I 5-decahydro-2-methyl-, (1 S)- 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- I -carbothioic 10 acid, 3,7,8,9,10,12,13,14,14a, 1 5-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; 15 Pyrrolo[3',2':5,6] [1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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-, 20 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 25 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, I 5-decahydro-2-methyl-, 2-(4-morpholinyl) 1 -phenylethyl ester; 30 Pyrrolo[3',2':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; WO 00/42045 PCTIUS99/30434 -287 Pyrrolo[3',2':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 I -phenylethyl ester; Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine- I -carboxylic 5 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; 10 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- I -carboxylate (1:1); Pyrrolo[3',2':5,6] [1 ]benzopyrano[3,2-i]quinolizine-1 -carboxylic 15 acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2-methoxy 2-oxo- I -phenylethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, (R) carboxy(phenyl)methyl ester; 20 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (R) carboxy(phenyl)methyl, 3,7,8,9,10,12,13,14,14a, 1 5-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 25 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; 30 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-pyridinyl)ethyl ester; WO 00/42045 PCT/US99/30434 -288 Pyrrolo[3',2':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 5 acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (IS) 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; 10 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 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 15 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 20 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; 25 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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 30 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; WO 00/42045 PCT/US99/30434 -289 Pyrrolo[3',2':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 5 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; 10 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, 1 5-decahydro-2-methyl-, (2-chloro 15 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, 1 5-decahydro-2-methyl-, (2-chloro 5-nitrophenyl)methyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 20 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 25 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; 30 Pyrrolo[3',2':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; WO 00/42045 PCT/US99/30434 -290 Pyrrolo[3',2':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 5 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, 3,7,8,9,10,1 2 ,1 3 ,14,14a,15-decahydro-2-methyl-, 1-methylcyclohexyl ester; 10 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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-, 15 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, 1 5-decahydro-2-methyl-, 1 -cyclohexyl 1-methylethyl ester; Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic 20 acid, 3,7,8,9,10,12,13,14,14a, I 5-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; 25 Pyrrolo[3',2':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; 30 Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinolizine-1-carboxylic acid, 3 , 7 , 8 , 9 ,10,1 2 ,13,14,14a,15-decahydro-2-methyl-, 3-(methoxycarbonyl)phenyl ester; WO 00/42045 PCT/US99/30434 -291 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-pyridinyl ester; Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine- I -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-(trifluoromethyl)-, ethyl 5 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 10 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; 15 Propanedioic acid, monoanhydride with 3 , 7 , 8 , 9 ,10,1 2 ,1 3 ,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) 20 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 25 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; 30 Pyrrolo[3',2':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 WO 00/42045 PCT/US99/30434 -292 Pyrrolo[3',2':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, 5 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 10 carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-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 15 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, 1 5-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 20 according to Claim I 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 25 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. WO 00/42045 PCTIUS99/30434 -293 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 5 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 10 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,1 5-decahydro-2,1 1-dimethyl-l -[(S)-(l phenylethoxy)carbonyl]-, methanesulfonate; and 15 Pyrrolo[3',2':5,6] [1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 1 5-decahydro-2-methyl-, (I S)-I -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-, 20 anhydride with benzoic acid.
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