CN1344270A - Functionalized heterocycles as chemokine receptor modulators - Google Patents

Abstract

The present invention relates to a novel series of functionalized heterocycles as chemokine receptor modulators of formula useful as modulators of chemokine receptor activity. These compounds are useful in the treatment and prevention of the AIDS virus. Intermediates useful in the preparation of the final products, pharmaceutical compositions containing these final products are also disclosed.

Description

Functionalized heterocycles as modulators of chemokine receptors

Background of the invention

The present invention relates to chemokine receptors (including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR1, CXCR2, CXCR-3 and/or Functionalized heterocycles of CXCR4) modulators and pharmaceutical compositions comprising these compounds and pharmaceutically acceptable carriers. More specifically, the invention relates to methods of inhibiting HIV infectivity.

Chemokines mediate a range of proinflammatory responses acting on leukocytes, such as chemotaxis, degranulation, and intigran activation (Baggiolini et al., Adv. Immunol., 1994; 55:97-179; Oppenheim et al., Annu.Rev. Immunol. ., 1991; 9: 617-48; Miller et al., Crit. Rev. Immunol., 1992; 12: 17-46). These effects are mediated by binding to seven-transmembrane-passing G protein-coupled receptors (Baggiolini et al., Adv. Immunol., 1994; 55:97-179; Murphy, Annu. Rev. Immunol., 1994; 12:593-633; Schall et al., Curr. Opin. Immunol., 1994; 6:865-73; Gerard et al., Curr. Opin. Immunol., 1994; 6; 140-5; Mackay, Curr. Bio., In press). Chemokine receptors also serve as co-receptors for HIV-1 entry into cells. This conclusion comes from the observation that RANTES, MIP-1α and MIP-1β inhibit the infection of susceptible cells in vitro by primary macrophage-tropic 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 a laboratory engineered T-cell-tropic HIV-1 cell line (Feng et al., Science (Wash.DC), 1996; 272:872-7 ). CCR-5, a RANTES, MIP-1α, and MIP-1β receptors were successively identified as major coreceptors of primary macrophage-tropic cell lines (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 observation that certain individuals who have multiple exposures to HIV-1 but remain uninfected lack expression of CCR-5 highlights the importance of CCR-5 for HIV-1 transmission (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; 1240-3). These uninfected individuals were found to be homozygous for the defective CCR-5 allele, containing an internal 32-pair deletion (CCR-5Δ32). The shortened protein encoded by this gene is apparently not expressed on the cell surface. CCR-5Δ32 homozygous individuals comprise about 1% of the Caucasian population and heterozygous individuals comprise about 20%. In a study of approximately 2700 HIV-1-infected individuals, no Δ32 homozygotes were found. Compared with wild-type homozygous individuals, individuals heterozygous for the Δ32CCR-5 allele show very slow progression to AIDS (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 identification of CCR-5 as the primary coreceptor for primary HIV isolates provides an opportunity to understand pathogenesis and, more importantly, identify new avenues for the treatment of HIV-1 infection.

The present invention is a series of functionalized heterocycles which block the interaction of CD-4/GP-120 with the CCR-5 receptor and thus can be used in the treatment of HIV infection as manifested in AIDS.

Summary of the invention

A compound of the invention is used in a method of modulating chemokine receptor activity in a patient in need of such modulation, the method comprising administering an effective amount of the compound.

The present invention relates to the use of the above substituted heterocycles as modulators of chemokine receptor activity. Specifically, these compounds are used as compounds including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR1, CXCR2 and/or CXCR-4 Modulators of chemokine receptors. In particular, the invention is preferred as a modulator of the chemokine receptor CCR-5.

The compound of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, which may exist in a closed or open ring form,

in:

A is O, S, and when X is CR ₉ , A can also be NR ₁ ;

X is N when A is NR ₁ , or

X is CR ₉ , wherein R ₉ is halogen, hydrogen atom, alkyl, -CF ₃ , CH ₂ F, CHF ₂ , -(CH ₂ ) _m -OR ₁ , aryl, aralkyl, -(CH ₂ ) _m -NR ₇ R ₈ or wherein m is an integer from 0 to 2, and in each occurrence, m is independently an integer from 0 to 2, q is an integer from 0 to 1, and r is an integer from 0 to 3;

其中s是1至3的整数，t是0至3的整数，u是0至3的整数，v是1至3的整数，而w是0至2的整数；Y is a hydrogen atom, an alkyl group, an aralkyl group, an aryl group, (CH ₂ ) _m -NR ₇ R ₈ , -N(R ₁ )-(CH ₂ ) _v -C(R ₇ R ₈ )-aryl group, or OR ₁₀ , where R ₁₀ is a hydrogen atom, alkyl, cycloalkyl, cycloalkyl fused to an aromatic ring, aryl, (CH ₂ ) _s aryl, -CH ₂ CF ₃ , (CH ₂ ) _t C(R ₇ R ₈ )-(CH ₂ ) _uaryl ,

Wherein s is an integer from 1 to 3, t is an integer from 0 to 3, u is an integer from 0 to 3, v is an integer from 1 to 3, and w is an integer from 0 to 2;

Z is CR or N;

R ₁ is a hydrogen atom or an alkyl group, and each occurrence of R ₁ is independently a hydrogen atom or an alkyl group;

R and _R are independently selected from each other:

A hydrogen atom,

alkyl,

halogen,

-CN,

-NO ₂ ,

-(CH ₂ ) _m -NR ₇ R ₈ ,

-(CH ₂ ) _m -COOR ₇ ,

-(CH ₂ ) _m -CONR ₇ R ₈ ,

-(CH ₂ ) _m -OR ₇ ,

-(CH ₂ ) _m -SO ₂ NR ₇ R ₈ , and

-(CH ₂ ) _m -S(O) _p R ₇ , wherein each occurrence of R ₇ and R ₈ is independently a hydrogen atom, alkyl, aryl, aralkyl, -CF ₃ , or R ₇ and R ₈ can together form a ring of 3 to 7 atoms, which can contain O, S or NR ₁ , and p is an integer from 0 to 2;

R ₃ is a hydrogen atom or an alkyl group;

R ₄ is a hydrogen atom, an alkyl group, an aryl group or an aralkyl group;

_R is alkyl, aryl, aralkyl, acyl; or

R and _R together with the atoms to which they are attached form a _ring of 5 to 7 atoms;

R ₆ is a hydrogen atom or an alkyl group;

When not together with R ₄ , R ₅ can form a ring of 5 to 7 atoms with R ₆ together with the atoms connected to them;

NR ₅ is also the corresponding N-oxide;

R ₁₁ is a hydrogen atom or an alkyl group;

n is an integer from 1 to 3; j is an integer from 1 to 2, and when Y is a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, j is an integer 0;

With the proviso that pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12 , 13, 14, 14a, 15-Decahydro-2-methyl-, ethyl ester.

Preferred compounds are those of formula 1 above, wherein

R ₁ is a hydrogen atom.

Other preferred compounds are compounds of formula 1 above, wherein

_R1 is a hydrogen atom, while

X is _CR9 .

Other preferred compounds are the following compounds, wherein

_R1 is a hydrogen atom, while

X is CR ₉ , wherein R ₉ is alkyl.

Other preferred compounds are the following compounds, wherein

_R1 is a hydrogen atom,

X is CR ₉ , wherein R ₉ is alkyl;

R ₄ and R ₅ form a ring of 5-7 atoms together with the atoms connected to them; and

Y is OR ₁₀ .

Other preferred compounds are the following compounds, wherein

_R1 is a hydrogen atom,

X is CR ₉ , wherein R ₉ is alkyl;

R ₄ and R ₅ together form a 6-membered ring; and

Y is OR ₁₀ , wherein R ₁₀ is alkyl, aryl or -(CH ₂ ) _s aryl, -(CH ₂ ) _t -C(R ₇ R ₈ )-(CH ₂ ) _u -aryl.

Other preferred compounds are the following compounds, wherein

_R1 is a hydrogen atom,

X is CR ₉ , wherein R ₉ is Me;

R ₄ and R ₅ together form a 6-membered ring;

R ₆ is a hydrogen atom;

n is 2; and

Y is OR ₁₀ , where R ₁₀ is alkyl, aryl, or R ₁₀ is -(CH ₂ ) _t -C(R ₇ R ₈ )-(CH ₂ ) _u -aryl, where t is O, R ₇ and _R8 can independently of each other be

H,

alkyl,

-(CH ₂ ) _v OH or (CH ₂ ) _u COOR ₇ and -(CH ₂ ) _v NR ₁ R ₂ ,

where u and v are defined as above.

More preferred compounds are those of formula 1 and are selected from the group consisting of:

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

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

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

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

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

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-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]quinazine-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]quinazine-1-carboxylic acid, 2-cyclopropyl-3,7,8,9,10 , 12, 13, 14, 14a, 15-decahydro-, ethyl ester;

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-(2-methylpropyl)-, ethyl ester;

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

2,6a,7-Trimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene-1- ethyl formate;

7-Ethyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a] Ethyl anthracene-1-carboxylate;

6a-Ethyl-2,7-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a] Ethyl anthracene-1-carboxylate;

6a,7-diethyl-2-methyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a] Ethyl anthracene-1-carboxylate;

7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a] Ethyl anthracene-1-carboxylate;

2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a] Ethyl anthracene-1-carboxylate;

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;

3H,7H-Pyrrolizino (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-8,9,10,10a,11,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopenta [h] ethyl anthracene-1-carboxylate;

3H-pyrido[1″,2″:1′2′]azepine[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]quinazine-1-carboxamide, 8, 9, 11, 12, 13, 13a, 14, 14a-Octahydro-2-methyl-N-(phenylmethyl)-;

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxamide, N-ethyl-8,9,11,12,13 , 13a, 14, 14a-octahydro-2-methyl-;

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carbaldehyde, 8, 9, 11, 12, 13, 13a, 14, 14a -Octahydro-2-methyl-;

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxamide, 8, 9, 11, 12, 13, 13a, 14, 14a-Octahydro-N,2-dimethyl-;

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

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

12H-furo (Furo) [3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 4,5-difluoro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester;

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethyl ester;

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

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

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

1-propylammonium, N,N,N-trimethyl-, 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]quinazine-1-carboxylate (1:1) salt formation;

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

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

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

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

1-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-1H-indol-4-ylmethyl]-1,2,3,4,6,7,8 , 9-octahydro-quinazinium; chloride;

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

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

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

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, with (3-carboxyphenyl)methyl 3,7,8,9,10,12,13,14,14a,15-decahydro -2-methylpyrrolo[3',2':5,6][1]-benzopyrano[3,2-i]quinazine-1-carboxylate (1:1) salt formation;

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

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

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

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

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

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

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

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

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 1-pyrazinyl ethyl ester;

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

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

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

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

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

Quinazinium, 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, (4-nitrophenyl) methyl ester;

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, bicyclo[2.2.1]heptane-2-yl ester;

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

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

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

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

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

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

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, with (6-carboxy-2-pyridyl)methyl 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15 -Decahydro-2-methylpyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylate (1:1) into Salt;

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

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

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, with (5-carboxy 3-pyridyl)methyl 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15- Decahydro-2-methylpyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylate (1:1) salt formation ;

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

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, (1R)-2,3-dihydro-1H-inden-1-yl ester;

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

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

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a,15-Decahydro-2-methyl-,10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl ester;

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 3,4-dihydro-2H-1-benzothiopyran-4-yl ester;

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

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

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

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

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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-isoquinoline ester;

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-pyrazinyl ethyl ester;

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

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

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

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

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-thioxoic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,S-(phenylmethyl)ester;

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, (1S)-1-(2-furyl) ethyl ester;

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester;

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, 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]quinazine-1-carboxylate (1:1) into Salt;

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, (R)-carboxy(phenyl)methyl ester;

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, with (R) carboxy(phenyl)methyl, 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15- Decahydro-2-methylpyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylate (1:1) salt formation ;

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

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

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

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 2-ethoxy-2-oxo-ethyl ester;

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

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

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

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

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

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 1-(5-carboxy-3-pyridyl) ethyl ester;

1,3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2': 5,6][1]benzopyrano[3,2-i]quinazin-1-yl)carbonyl]oxy]methyl]-, diethyl ester;

1,3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2': 5,6][1]benzopyrano[3,2-i]quinazin-1-yl)carbonyl]oxy]methyl]-;

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

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-acetic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-.α-oxo-, ethyl ester;

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2,4,5-trimethyl-, phenylmethyl ester;

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, tricyclo[3.3.1.13,7]decane-1-ester;

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidinate;

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

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

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester;

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, [5-[(dimethylamino)methyl]-2-furyl]methyl ester;

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

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

With 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3′,2′:5,6][1]-benzopyrano Malonic acid of [3,2-i]quinazine-1-carboxylic acid, an anhydride, 1,1-dimethylethyl ester;

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

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

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

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

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

Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3′,2′:5,6][ 1] Benzopyrano[3,2-i]quinazin-1-yl)carbonyl]oxy]methyl]-1-methyl-, methanesulfonate;

pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazinium, 3,7,8,9,10,12,13,14,14a, 15-Decahydro-2,11-dimethyl-1-[(S)-(1-phenylethoxy)carbonyl]-, methanesulfonate; and

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

The present invention includes pharmaceutical compositions of compounds of formula 1 and methods of modulating chemokine receptor activity using these compounds, all of which are useful in preventing or treating HIV infection, delaying the onset of AIDS, treating AIDS and treating inflammatory diseases.

Detailed description of the invention

In the present invention, the compound of formula I can exist in two forms (ring-closed and ring-opened) in the bicyclic aminal moiety. The balance between these two forms is pH dependent. At neutral or basic pH (pH ≥ 7.0), these compounds mainly exist in the closed ring form. However, in the acidic pH range (pH<7.0), these molecules can exist as a mixture of closed and open rings. The ratio of ring-closed and ring-opened forms depends on pH and solvent, as well as the identity of the substituents R, _R2 - _R6 and n.

In compounds of formula I, the term alkyl refers to straight or branched chain hydrocarbon groups having 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- Butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. The alkyl groups may be substituted by fluorine, for example, these alkyl groups may also be substituted by 1 to 3 substituents selected from the group consisting of alkoxy, carboxyl, hydroxyl, nitro, halogen, amino and substituted amino to provide other active compound. Alkyl includes cycloalkyl of 3 to 7 carbon atoms, for example, which may be substituted by 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, carboxyl, hydroxyl, nitro, halogen and amino and substituted of amino. Cycloalkyl groups can be fused with aromatic rings such as phenyl, pyridyl, etc.

，其中烷基定义如上。Alkoxy is O-alkyl, wherein alkyl is an alkyl group of 1 to 6 carbon atoms as defined above. Acyl is

, where alkyl is as defined above.

，其中烷基定义如上的

、其中烷基定义如上的

、其中n²是1至5的整数的-(CH₂)n²-NH₂、其中烷基和n²定义如上的-(CH₂)n²-NH-烷基、其中烷基和n²定义如上的-(CH₂)n²-N(烷基)₂取代的苯基。该术语还包括杂芳基，其是单或双环杂芳基，具有5至10个原子，可以含一个或多个杂原子如N、O、S，其包括，例如，2-或3-噻吩基、2-或3-呋喃基、2-或3-吡咯基、2-，3-，或4-吡啶基、2-吡嗪基、2-，4-，或5-嘧啶基、3-或4-哒嗪基或者2-，3-，4-，5-，6-或7-吲哚基。这些杂环可以如上述芳基一样未被取代或被取代。The term aryl refers to an aromatic group which is phenyl, which is selected from 1 to 4 alkyl as defined above, alkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, wherein alkyl is as defined above Alkylamino, wherein alkyl is as defined above, dialkylamino, nitro, cyano, carboxyl, SO ₃ H, CHO, wherein alkyl is as defined above

, where alkyl is defined as above

, wherein the alkyl group is as defined above

, -(CH ₂ )n ² -NH ₂ , wherein n ² is an integer from 1 to 5, wherein alkyl and n ² are as defined above -(CH ₂ )n ² -NH-alkyl, wherein alkyl and n ² -( _CH2 ) ⁿ² -N(alkyl) _2- substituted phenyl as defined above. The term also includes heteroaryl groups, which are mono- or bicyclic heteroaryl groups, having 5 to 10 atoms, which may contain one or more heteroatoms such as N, O, S, which include, for example, 2- or 3-thiophene Base, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- Or 4-pyridazinyl or 2-, 3-, 4-, 5-, 6- or 7-indolyl. These heterocyclic rings may be unsubstituted or substituted like the aryl groups described above.

The term aralkyl or arylalkyl refers to an aryl group attached to which is an alkyl group, wherein aryl and alkyl are as defined above, for example, benzyl, fluorenylmethyl, and the like.

Halogen is fluorine, chlorine, bromine or iodine.

Some compounds of ring-closed formula I can further form N-oxides and N-quaternary alkyl salts on the N-11 ring nitrogen atom. In addition, some compounds of ring-closed formula I can further form N-oxides and N-quaternary alkyl salts on any optionally present nitrogen atom in R ₁₀ . These structural forms are within the scope of the present invention.

Some compounds of formula I are further capable of forming pharmaceutically acceptable acid addition and/or base salts. All such forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of compounds of formula I include salts derived from non-toxic inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc., and those derived from Salts of non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Thus, such salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metasulfonates, pyrophosphates, Hydrochloride, Hydrobromide, Hydroiodide, Acetate, Trifluoroacetate, Propionate, Caprylate, Isobutyrate, Oxalate, Malonate, Succinate, Suberate, Sebacate, Fumarate, Maleate, Mandelate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Phthalate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, etc. Salts of amino acids such as arginine, etc., and gluconates, galacturonates may also be considered (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 in conventional manner by contacting the free base with a sufficient amount of the desired acid. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ to some extent from their corresponding salt forms in certain physical properties such as solubility in polar solvents, but on the other hand, for the purposes of the present invention, these salts and their corresponding free bases are equivalent.

Form pharmaceutically acceptable base addition salts with metals or amines such as alkali metals and alkaline earth metals or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium ions and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine Caine (see, eg, Berge supra, 1977).

The base addition salts of said acidic compounds are prepared in conventional manner by contacting the free acid form with a sufficient amount of the desired base. The free acid form can be regenerated by contacting the salt with an acid and isolating the free acid in a conventional manner. The free acid forms differ to some extent from their corresponding salt forms in certain physical properties, such as solubility in polar solvents, but on the other hand, for the purposes of the present invention, these salts and their corresponding free acids are equivalent.

Certain compounds of the present invention can exist in unsolvated 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 within the scope of the present invention.

Certain compounds of the present invention have one or more chiral centers, and each center may exist in the R or S configuration. The present invention includes all diastereoisomers, enantiomers and epimers and appropriate mixtures thereof. Furthermore, the compounds of the present invention may exist in the form of geometric isomers. The present invention includes all cis (cis, syn or Z), trans (trans, anti or E) isomers and appropriate mixtures thereof.

The compounds of the present invention can be prepared and administered in a variety of oral and parenteral dosage forms. Thus, the compounds of the present invention may be administered by injection, ie, intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally. Alternatively, the compounds of the present invention may be administered by inhalation, such as intranasally. In addition, 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 contain the compound of formula I or the corresponding pharmaceutically acceptable salt of the compound of formula I as an active ingredient.

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

In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active component.

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

Powders and granules preferably contain from 5 or 10 to about 70% active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc. . The term "preparation" refers to a formulation comprising the active compound with encapsulating material which provides a capsule as carrier, with or without other carriers, the active component being surrounded by a carrier, which is thus in association with the active component. Also, lozenges and cachets are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed uniformly therein, for example by stirring. The molten homogeneous mixture is then poured into conventional sized molds, allowed to cool, and then solidified.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or aqueous propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with the addition of thickening materials, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid dosage forms, which are 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 coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc. in addition to the active ingredient.

The pharmaceutical preparations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The amount of active ingredient in a unit dosage formulation may be varied or adjusted according to the particular application and potency of the active ingredient between 1 mg to 1000 mg, preferably 10 mg to 100 mg. The composition, if desired, can also contain other compatible therapeutic agents.

In therapeutic use as a treatment for HIV infection, the compounds used in the pharmaceutical methods of this invention may be administered at an initial dose of about 1 mg to about 100 mg per kilogram of body weight per day. A preferred daily dosage ranges from about 25 mg to about 75 mg per kilogram of body weight. However, the dosage will vary depending on the needs of the patient, the severity of the condition being treated and the compound being used. Determination of the appropriate dosage for a particular situation is within the general knowledge of the art. In general, start with a dose that is less than optimal for that compound. Thereafter, the dosage is gradually increased in small increments until the optimum effect under the circumstances is obtained. For convenience, the total daily dosage may be divided and administered in divided doses during the day if necessary.

Compounds of formula I are valuable CCR-5 chemokine receptor antagonists. Compounds that are antagonists of the CCR-5 chemokine receptor are expected to be effective in inhibiting HIV infection and thus useful in the treatment of AIDS. Compounds of the invention were evaluated in a CCR-5 receptor binding assay.

CCR-5 receptor binding assay

¹²⁵ I-gp120/sCD4/CCR-5 binding experiments were performed similarly to that described by Wu et al., Nature, 1996;384:179-183. Briefly, the envelope gp120 protein from HIV-1 JR-FL (Trkola et al., Nature, 1996; 384:184-186), an M-tropic strain, was milked with solid phase Oxidase iodide to a specific activity of 20 μCi/μg. For each binding reaction (final volume 100 μL of binding buffer [50 mM HEPES, pH 7.5, 1 mM CaCl ₂ , 5 mM MgCl ₂ and 0.5% BSA]), compound dissolved in 25 μL of DMSO (DMSO final concentration 0.5%) was present In the absence or absence, 25 μL (2.5 μg) of membranes prepared from CCR-5/L1.2 cells were mixed with 25 μL (3 nM) of sCD4, followed by the addition of 25 μL (0.1 nM) of radiolabeled gp120. The reaction was incubated at room temperature for 45 to 60 minutes, stopped by transferring this mixture to a GFB filter plate, and then washed 3 to 4 times with binding buffer containing 0.5M sodium chloride. The plate was dried and MicroScint scintillation fluid was added before counting.

The compound of the present invention represented by formula I blocks the binding of sCD-4/GP-120 to CCR-5 receptor with an affinity less than or equal to 200 μM.

Synthesis of CCR-5 analogs

Scheme 1 presents the synthesis of the final target compound. Compound II in a protic solvent, preferably ethanol, is treated with aqueous formaldehyde and dimethylamine at a temperature of 0-99°C, preferably 25-60°C, to give Mannich base III. Condensation of III with enamine at 50-100°C, preferably at 80-100°C, under nitrogen atmosphere, in an aprotic solvent such as dioxane affords compound IV. Alkylation of IV with NaH and an alkyl halide in an aprotic solvent, preferably DMF, under a nitrogen atmosphere at -10 to 25°C, preferably at 0-25°C, affords compounds I (where R _is not H ).

Scheme II shows the preparation of indole intermediates. Aminocrotonate V is obtained by reaction of bromoacetic acid with nitrile in the presence of active zinc in an aprotic solvent, preferably THF, under a nitrogen atmosphere. Alternatively, the aminocrotonate V can be obtained by reacting the corresponding β-ketoester with ammonia in ethanol. This β-ketoester can be obtained from 2,2,6-trimethyl-4H-1,3-dioxin-4-one and the corresponding alcohol. Aminocrotonate V and substituted benzoquinone in a solvent, preferably acetic acid, ethanol or nitromethane, at a temperature ranging from 25°C to reflux, yields substituted 5-oxindole VI. Hydrolysis of the indole ester VI with aqueous sodium hydroxide at 50-100°C, preferably at reflux temperature, under nitrogen atmosphere gives the corresponding acid VII. In order to suppress the decarboxylation reaction, it is important to cool the reaction mixture to 0°C in an ice-water bath after completion of the reaction and acidify with concentrated acid, preferably HCl, to generate the acid at 0°C. Esters or amides IX can be prepared from acids VIII following several standard esterification steps or standard amide synthesis steps using HBTU as coupling agent. For ester synthesis, the Mitsunobu method is preferred, using the appropriate alcohol, DEAD and _PH3P , and the reaction is carried out at room temperature. Another preferred method of preparing the ester is to treat the acid with a base, preferably DBU and an alkyl or aralkyl halide, in a polar solvent, preferably DMF or acetonitrile, at room temperature.

The following schemes illustrate the methods used in the preparation of the final compounds. Variants known to the skilled chemist are part of the invention.

plan 1

Preparation of final target compound

Scenario 2

Preparation of Substituted Indole Derivatives

Option 3

Substituted 5-hydroxybenzofurans (C)

Substituted 5-hydroxybenzofurans (C) are prepared by condensation of 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 base (E)

5-Hydroxybenzofuran (C, D) was treated with aqueous dimethylamine and formaldehyde in ethanol at 50 °C, or with N,N,N',N'-tetramethyldiaminomethane in refluxing dihydrogen The reaction is complete in oxane. The solution was concentrated under reduced pressure and purified by recrystallization.

Benzofuran (G)

The mannich base (E) is added to a dioxane solution of the enamine (F), which is extracted into ether by treating its perchlorate salt with aqueous sodium hydroxide solution, dried and concentrated in vacuo This extract is freshly prepared. The resulting solution was heated at 80-100°C until the reaction was complete. The mixture is concentrated in vacuo and the product is purified by recrystallization or flash chromatography on silica gel.

Option 4

Synthesis of 7-azaindole analogs

method:

Starting from commercially available 3-hydroxy-2-phenylazopyridine (1), the corresponding aminopyridine was synthesized by reduction of 1 in acetic acid in the presence of hydrogen (57 bar) and Pd/C at 65 °C (Synthesis, 1990:681) afforded amine 2. Amine 2 was then converted to 2-amino-5-hydroxy-3-iodopyridine by reaction with iodine and acetic acid at room temperature (Synthesis, 1990:681). Iodopyridine 3 is then converted to azaindole 4 by palladium-catalyzed cyclization with an appropriately substituted alkyne (Tetrahedron Lett., 1998; 39:5355; Tetrahedron Lett., 1993; 34:2823). Conversion of 3 to 4 is followed by oxidation of the hydroxymethylene to the corresponding acid 5 with KMnO ₄ in the presence of potassium carbonate (Gazz. Chim. Ital., 1932; 62:844). Alternatively, a direct transformation of 3 to 5 can be accomplished with a carboxyl-substituted alkyne. Esterification of 5 to the desired ester with an imide coupling reagent and the desired alcohol (J. Org. Chem., 1995; 60:5214). Substitution of the pyridine ring with formaldehyde and dimethylamine (Tetrahedron Lett., 1966:4459) gave 7. The intermediate 7 is then reacted with quinolizidine imine in refluxing ethanol to obtain the final azaindole analog 8 (J.Het.Chem., 1970; 7:131)

Option 5

Preparation of final target compounds from novel intermediates

Compound I is treated in an aprotic solvent, preferably diethyl ether, dichloromethane or THF, with oxalyl chloride present in the same aprotic solvent at a temperature of -10 to 30°C, preferably 0 to 25°C, followed by Treatment of the selected amine in an aprotic solvent affords the desired product II. Compound I is treated with oxalyl chloride in an aprotic solvent, preferably diethyl ether, dichloromethane or THF, at a temperature of -10 to 30°C, preferably 0 to 25°C, followed by treatment of the selected alcohol in an aprotic solvent, The desired product III can be obtained. Alternatively, the desired product III can be prepared by reacting compound I with compound IV in an aprotic solvent such as diethyl ether, dichloromethane or THF.

Option 6

Preparation of mixed anhydrides

general description

Hydrogenolysis of benzyl ester I at room temperature in an aprotic polar solvent, preferably THF, affords acid II. Subsequent treatment of acid II with benzoyl chloride in the presence of an organic base such as triethylamine affords mixed anhydride III.

Option 7

Synthesis of Esters from Mixed Anhydrides

general description

The mixed anhydride I is mixed with the desired alcohol and the resulting reaction mixture is heated to 100 to 180° C. until the mixed anhydride reacts to give the corresponding ester.

The invention also relates to the combination of the compounds of the invention with one or more agents for the prophylaxis or treatment of AIDS. For example, the compounds of the present invention may be effectively administered in combination with effective amounts known to those of ordinary skill in the art of anti-HIV compounds, immunomodulators, anti-infectives, or prophylactic or therapeutic vaccines, regardless of exposure to the virus before and/or after.

antiviral drugs drug name manufacturer Indications 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitors) GW141 W94/VX478 Glaxo Wellcome HIV infection, AIDS, ARC (protease inhibitor) Amprenavir GW1592U89 Abacavir Glaxo Wellcome HIV infection, AIDS, ARC (RT inhibitors) Vinegar Mannan Carrington Labs (Irving, TX) ARC Aciclovir 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 (Los Angeles, CA) ARC, PGL HIV positive, AIDS alpha interferon Glaxo Wellcome Kaposi's sarcoma, HIV infection Alferon interferon Interferon Sciences Kaposi's sarcoma, HIV infection Ansamycin LM427 Adria Laboratories (Dublin, OH) Erbamont (Stamford, CT) ARC Antibodies that neutralize pH-labile alpha-abnormal interferon Advanced Biotherapy Concepts (Rockville, MD) AIDS, ARC AR77B-F-ddA Aronex Pharm Nat'l Cancer Institute HIV infection, AIDS, ARC AIDS-related diseases BMS-232623 (CGP-73547) Bristol-Myers Squibb/Novartis HIV infection, AIDS, ARC (protease inhibitor) BMS-234475 (CGP-61755) Bristol-Myers Squibb/Novartis HIV infection, AIDS, ARC (protease inhibitor) (-)6-Chloro-4(S)-cyclopropylethynyl-4(S)-trifluoro-methyl-1,4-dihydro 2H-3,1-benzoxazin-2-one Merck HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitors) C1-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Combivir AZT+3TC Glaxo Wellcome HIV infection, AIDS, ARC Curdlan sulfate AJI Pharma USA HIV infection cytomegalovirus immunoglobulin MedImmune CMV retinitis Cytovene Ganciclovir Syntex/Roche Vision-threatening CMV, peripheral CMV, retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitors) Dextran Sulfate Ueno Fine Chem.Ind Ltd. (Osaka, Japan) AIDS, ARC, HIV positive asymptomatic HIVID(ddc) dideoxycytidine Hoffman-La Roche HIV infection, AIDS, ARC ddI dideoxyinosine Bristol-Myers Squibb HIV infection, AIDS, ARC; in combination with AZT/d4T DMP-450 Triangle Pharmaceutical HIV infection, AIDS, ARC (protease inhibitor) Efavirenz (DMP 266) DuPont Merck HIV infection, AIDS, ARC (non-nucleoside RT inhibitors) EL10 Elan Corp, PLC (Gainesville, GA) HIV infection famciclovir Smith Kline herpes zoster, herpes simplex Foscavir/foscarnet Astra CMV, HSV1-2 FTC Triangle Pharmaceutical HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GS840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection, AIDS, ARC (non- Roussel nucleoside reverse transcriptase inhibitors) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC recombinant human beta interferon Triton Biosciences (Almeda, CA) AIDS, Kaposi's sarcoma, ARC interferon alpha-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis JE 2147 (KN1-764) protease inhibitor Japan Energy/Agouron PI HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also in combination with AZT KNI-272 Nat'l Cancer Institute HIV-related diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also in combination with AZT Lobucavir Bristol-Myers Squibb CMV infection-HBV infection Nelfinavir Agouron Pharmaceuticals HIV infection, AIDS, ARC (protease inhibitor) Navirapine Boeheringer Ingleheim HIV infection, AIDS, ARC (RT inhibitors) Novapren Novaferon Labs, Inc. (Akron, OH) HIV inhibitors Peptide T octapeptide sequence PeninsulaLabs (Belmont, CA) AIDS PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (egg white enzyme inhibitor) Probuka Vyrex HIV infection, AIDS RBD-CD4 Sheffield Med. Tech (Houston, TX) HIV infection, AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) S-1153 Agouron/Shionogi NRTI saquinavir Hoffmann-La Roche HIV infection, AIDS, ARC (protease inhibitor) Stavudine; d4T didehydrodeoxythymidine Bristol-Myers Squibb HIV infection, AIDS, ARC Valacyclovir Glaxo Wellcome Genital HSV & CMV infection Ribavirin Ribavirin Viratek/ICN (Costa Mesa, CA) Asymptomatic HIV positive, LAS, ARC Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other treatments

immunomodulator drug name manufacturer Indications AS-101 Wyeth-Ayerst AIDS brompiramine Pharmacia Upjohn exacerbated AIDS Vinegar Mannan Carrington Labs, Inc. (Irving, TX) AIDS, ARC CL246, 738 American Cyanamid Lederle Labs AIDS, Kaposi's sarcoma EL10 Elan Corp, PLC (Gainesville, GA) HIV infection FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells gamma interferon Genentech ARC, with w/TNF (tumor bad death factor) joint granulocyte macrophage colony stimulating factor Genetics InstituteSandoz AIDS granulocyte macrophage colony stimulating factor Hoeschst-Roussel Immunex AIDS granulocyte macrophage colony stimulating factor Schering-Plough AIDS, combined w/AZT HIV core particle immunostimulants Rorer seropositive HIV IL-2 interleukin-2 Cetus AIDS, in combination w/AZT IL-2 interleukin-2 Hoffman-La roche Immunex AIDS, ARC, HIV, in combination w/AZT IL-2 Interleukin-2 (aldeslukin) Chiron AIDS, increase in CD4 cell counts Intravenous immunoglobulin (human) Cutter Biological (Berkeley, CA) Pediatric AIDS, in combination w/AZT IMREG-1 Imreg (New Orleans, LA) AIDS, Kaposi's sarcoma, ARC, PGL IMREG-2 Imreg (New Orleans, LA) AIDS, Kaposi's sarcoma, ARC, PGL Imuthiol Diethyldithiocarbamate Merieux Institute AIDS, ARC alpha-2 interferon Schering Plow Kaposi's sarcoma w/AZT, AIDS methionine-enkephalin TNIPharmaceutical (Chicago, IL) AIDS, ARC MTP-PE muramyl-tripeptide Ciba-Geigy Corp. Kaposi's sarcoma granulocyte colony stimulating factor Amgen AIDS, in combination w/AZT Remune Immune Response Corp. immunity therapy rCD4 recombinant soluble human CD4 Genentech AIDS, ARC rCD4-IgG Hybrids AIDS, ARC recombinant soluble human CD4 Biogen AIDS, ARC interferon alpha 2a Hoffman-La Roche Kaposi's sarcoma AIDS, ARC, in combination w/AZT SK&F106528 Soluble T4 Smith Kline HIV infection thymopentin Immunobiology Research Institute (Annandale, NJ) HIV infection Tumor necrosis factor; TNF Genentech ARC, in combination w/ gamma interferon

Anti-infectives drug name manufacturer Indications Clindamycen vs. Primaquine Pharmacia Upjohn PCP Fluconazole Pfizer Cryptococcal meningitis, candidiasis Lozenge Nystatin Squibb Corp. Prevention of Oral Candidiasis Ornidyl Eflornithine Merrell Dow PCP Pentamidine Isethionate (IM&IV) LyphoMed (Rosemont, IL) PCP treatment trimethoprim Antibacterial agents trimethoprim/sulfa Antibacterial agents Pitrexine Burroughs Wellcome PCP treatment inhaled pentamidine isethionate Fisons Corporation PCP prevention Spiramycin Rhone-Poulenc Cryptosporidium diarrhea Intraconazole-R51211 Janssen Pharm. Histoplasmosis; Cryptococcal Meningitis Trimetrexate Warner-Lambert PCP

other drug name manufacturer Indications Daunorubicin NeXstar, Sequus Kaposi's sarcoma recombinant human erythropoietin Ortho Pharm. Corp. Severe anemia associated with AZT therapy recombinant human growth hormone Serono AIDS-related wasting, cachexia megestrol acetate Bristol-Myers Squibb Treating anorexia associated w/AIDS testosterone Alza, Smith Kline AIDS-related wasting total enteral nutrition Norwich Eaton Pharmaceuticals Diarrhea and malabsorption associated with AIDS

It should be understood that the scope of the combination of the compound of the present invention with AIDS antiviral, immunomodulator, anti-infection or vaccine is not limited to those listed in the above table, but in principle includes the combination with any pharmaceutical composition for the treatment of AIDS.

The following examples illustrate intermediate and final compounds and their preparation. They are not intended to limit the scope of the invention.

Experiment

Synthetic Intermediate Indole Derivatives

5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid (A)

5-Hydroxy-2-methyl-1-H-indole-carboxylic acid (8.54 g, 44.7 mmol) was dissolved in aqueous sodium hydroxide (2N, 45 mL). 1-Acetyl-1H-2,3-triazolo(4,5-b-)-pyridine (7.24g, 44.7mmol) was dissolved in THF (30mL), and this solution was added to 5-hydroxy-2- In a solution of methyl-1-H-indole-carboxylic acid. This mixture was stirred until little or no starting material remained, about 30 minutes; a white precipitate formed. The mixture was cooled to 0°C and concentrated hydrochloric acid 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 in vacuo to yield 6.95 g (67%); mp 233-235°C (dec); IR: 3331, 1740, 1642, 1234, 1207cm ^-1.1HNMR (DMSO-d ₆ )δ: 2.21(s, 3HCH ₃ ^CO ₂ ), 2.59(s, 1H, ArCH ₃ ), 6.79(d, J=6.84Hz, 1H, ArH), 7.27(d , J=8.55Hz, 1H, ArH), 7.53(s, 1H, ArH), 11.77(s, 1H, NH) 11.93(s, 1H, COOH).MS(APCI+): m/z234.1(MH ⁺ ). Calcd and analyzed for C ₁₂ H ₁₁ N ₁ O ₄ : C, 61.80; H, 4.75; N, 6.01. Found: C, 61.48; H, 4.66; N, 5.86.

Method A. General Method for Preparing Esters

5-Hydroxy-2-methyl-1-H-indole-carboxylic acid or 5-acetoxy-2-methyl-1H-indole-3-carboxylic acid (4-28 g) was mixed with enough THF to dissolve. Triphenylphosphine (1 eq) and advantageous alcohol (2.5-4.0 eq, depending on solubility) were added to this THF solution. Diethyl azodicarboxylate (DEAD, 1 eq) was added dropwise to this mixture over 1-1.5 hours. The mixture was stirred overnight at room temperature. The solution was concentrated in vacuo to an oily mixture; a 1:1 hexane/ethyl acetate solution was used to redissolve the oil. The desired product was purified by flash chromatography. The product was triturated with hot water to remove residual diethylhydrazine dicarboxylate; the resulting solid was dried under vacuum at 40°C. For compounds prepared with 5-acetoxy-2-methyl-1H-indole-3-carboxylic acid, the 5-acetyl group was removed in the following manner: the protected ester (1 eq) was dissolved in a small amount of MeOH. NaOMe (4eq) was added and the mixture was stirred until no starting material remained (ca. 45 min). The pH of this solution was adjusted to 1 by adding hydrochloric acid, resulting in a lot of white precipitate. 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 by addition of hydrochloric acid, and the solution was extracted with ethyl acetate (2 x 25 mL). The organic layer was dried over sodium sulfate and evaporated to a solid. This solid can be further purified by recrystallization from an appropriate solvent. Following method A, intermediates B-G were synthesized.

Benzyl 5-acetoxy-2-methylindole-3-carboxylate (B) yield: 8.32g (21.6%); mp152-154°C;

IR: 3310, 1752, 1662, 1226, 1094cm ^-1 ; ¹ HNMR

(DMSO-d ₆ )δ2.21(s, 3H, CH ₃ CO ₂ ), 2.60(s, 3H, ArCH ₃ ), 5.28(s, 2H, CH ₂ Ph),

6.82(dd, J=8.55, 2.44Hz, 1H, ArH), 7.26-7.41(m, 6H, ArH), 7.53(d,

J=2.44Hz, 1H, ArH), 11.9(s, 1H, NH). MS(APCI+): 324.1(MH ⁺ ).

Calcd for C ₁₉ H ₁₇ N ₁ O 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: 5.03g (76%); mp191-193°C;

IR: 3227, 1654, 1472, 1429, 1094cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ 2.54 (s, 3H, alkyl CH ₃ ), 5.26 (s, 2H, PhCH ₂ ), 6.55 (d , J=6.10Hz, 1H, ArH), 7.08(d, J=8.8Hz, 1H, ArH), 7.24-7.42(m, 6H, ArH), 8.82(s, 1H, aromatic OH), 11.55(s , 1H, NH). MS (APCI+): m/z 282.0 (MH ⁺ ). Calcd. Analytical value for C ₁₇ H ₁₅ N ₁ O ₃ : C, 71.71; H, 5.44; N, 4.92. Found value: C, 71.72; H, 5.49; N, 4.85.

Alternatively, Intermediate C can be synthesized from Intermediate B according to the method described in Example 9, Step A.

5-Acetoxy-2-methylindole-3-propyl carboxylate (D) yield: 2.16g (37%); mp134-136°C;

IR: 3263, 2966, 1758, 1677, 1657, 1215cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ0.99 (t, J=7.51Hz, 3H, CH ₂ CH ₂ CH ₃ ), 1.71 (sexte Peak, J=7.33Hz, 3H, _CH2CH2CH3 ), 2.26(s, 3H, _CH3CO ), 2.63 ₍ s _, 3H, _ArCH3 ), 4.17(t, J=6.41Hz, 2H, CH ₂ CH ₂ CH ₃ ), 6.86 (dd, J=8.61, 2.20Hz, 1H, ArH), 7.34 (d, J=8.61Hz, 1H, ArH), 7.55 (d, J=2.20Hz, 1H, ArH) , 11.9 (s, 1H, NH). MS (APCI+): m/z 276.0 (MH ⁺ ). Calculation and analysis for C ₁₅ H ₁₇ N ₁ O ₄ : C, 65.44; H, 6.22; N, 5.09. Measured Values: C, 65.13; H, 6.28; N, 5.10.

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-isopropyl ester (E) yield: 0.720g (12%); mp188-189℃;

IR: 3409, 3391, 1663, 1467, 1181, 1095 (cm ^-1 ). ¹ H NMR (DMSO-d ₆ ) δ1.27 (d, J=6.35Hz, 6H, CH(CH ₃ ) ₂ ), 2.52 (s, 3H, CH ₃ ), 5.04 (septet, J=6.35Hz, 1H, CH(CH ₃ ) ₂ ), 6.53 (dd, J=8.55, 2.44 Hz, 1H, ArH), 7.06(d, J =8.55Hz, 1H, ArH), 7.25(d, J=2.44Hz, 1H, ArH), 8.77(s, 1H, OH) 11.4(s, 1H, NH).MS(APCI+): m/z 234.1 (MH ⁺ ). Anal. Calcd. for C ₁₃ H ₁₅ N ₁ O ₃ : C, 66.94; H, 6.48; N, 6.00. Found: C, 66.79; H, 6.53; N, 5.88.

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid cyclopropylmethyl ester (F) yield: 0.532gmp187-188℃;

IR: 3388, 3297, 1663, 1466, 1179, 1094cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ0.00-0.04 (m, 2H, cyclopropyl CH ₂ CH ₂ ), 0.22-0.26 (m, 2H, cyclopropyl CH ₂ CH ₂ ), 0.86-0.93 (m, 1H, CH ₂ CH ), 2.27 (s, 3H, ArCH ₃ ), 3.72 (d, J=7.32 Hz, 2H, CH ₂ CH), 6.27(dd, J=8.55, 2.44Hz, 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 ⁺ ). Calculation and analysis for C ₁₄ H ₁₅ N ₁ O ₃ : C, 68.56; H, 6.16; N, 5.71. Measured Values: C, 68.50; H, 6.19; N, 5.67.

Yield of 1-phenyl-propyl 5-acetoxy-2-methylindole-3-carboxylate (G): 1.36g (23%);

mp144-145.5℃; IR: 3289, 1755, 1661, 1459, 1216, 1204, 1089cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ0.863 (t, J=7.32Hz, 3H, CH ₂ CH ₃ ) , 1.82-1.98 (m, 2H, CHCH ₂ CH ₃ ), 2.22 (s, 3H, CH ₃ CO), 2.63 (s, 3H, ArCH ₃ ), 5.80 (t, J=6.84Hz, 1H, benzyl CH ), 6.83(dd, J=8.79, 2.20Hz, 1H, ArH), 7.21-7.36(m, 6H, ArH), 7.60(d, J=2.20Hz, 1H, ArH), 11.9(s, 1H, NH ). MS (APCI-): m/z 350.1 (M-1). Anal. Calcd. for C ₂₁ H ₂₁ N ₁ O ₄ : C, 71.78; H, 6.02; N, 3.99. Found: C, 71.53; H , 6.02; N, 3.81.

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid isobutyl ester (H) 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid isobutyl ester was synthesized according to general method A and used Recrystallization from alkane/CH ₂ Cl ₂ gave 1.39 g (26.2%) of a white solid: mp 188-190°C;

IR(KBr) 385, 3272, 2963, 1655, 1630, 1464, 1174, 1094cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ0.95(d, J=6.84Hz, 6H, CH(CH ₃ ) ₂ ), 1.94(n, J=6.84Hz, 1H, CH(CH ₃ ) ₂ ), 2.54(s, 3H, CCH ₃ ), 3.95(d, J=1.95Hz, 2H, OCH ₂ ), 6.54( dd, J=8.55, 2.44Hz, 1H, ArH), 7.07(d, J=8, 1H, ArH), 7.25(s, 1H, ArH), 8.81(s, 1H, OH), 11.49(s, 1H , NH); MS (APCI+): m/z 248.1 (MH ⁺ ). Calcd. Analytical value 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.

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2,2-dimethyl-propyl ester (I)

2,2-Dimethyl-propyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate was synthesized according to general procedure A and recrystallized from dichloromethane to give 2.31 g (33.8%) of a white solid: mp195- 196°C;

IR(KBr) 3262, 2960, 1652, 1464, 1170, 1094cm ^-1 ; 1HNMR (400MHz, DMSO-d ₆ ) δ0.97(s, 9H, C(CH ₃ ) ₃ ), 2.55(s, 3H, ArCH ₃ ), 3.87(s, 2H, OCH ₂ ), 6.55(dd, J=8.55, 2.44Hz, 1H, ArCH), 7.07(d, J=8.55Hz, 1H, ArCH), 7.29(s, 1H, ArH ), 8.82 (s, 1H, OH), 11.50 (s, 1H, NH); MS (APCI+): m/z 262.1 (MH ⁺ ). Calcd. 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.

Method B: Another general method for preparing esters

Within 1 hour, 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 THF was added dropwise to a mixture of triphenylphosphine (Aldrich, 5.62 g, 21.4 mmol) and the selected alcohol (Aldrich, 2.00-4.00 g, 32.2 mmol) in 32 mL THF. After stirring at room temperature for 24 hours, the mixture was concentrated. This product was purified by flash column chromatography on silica gel (10% MeOH, _CHCl3 ) to give the corresponding ester.

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperidin-1-yl-ethyl ester (J)

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperidin-1-yl-ethyl ester was synthesized according to Procedure B and recrystallized from hexane/ethyl acetate to give 0.350 g (26.9%) of a white solid : mp210-212°C; IR(KBr) 3203, 2934, 1690, 1455, 1175, 1067cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.31 (m, 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=6.10Hz, 2H, OCH ₂ CH ₂ ), 4.22 (t, J=6.10Hz, 2H, OCH ₂ CH ₂ N), 6.54 (dd, J=8.66, 2.32Hz, 1H, ArH), 7.06 (d, J=8.55Hz, 1H, ArH ), 7.27(s, 1H, ArH), 8.77(s, 1H, OH), 11.48(s, 1H, NH); MS(APCI+): m/z 303.1(MH ⁺ ).C ₁₇ H ₂₂ N ₂ Analytical values calculated for O ₃ : C, 67.05; H, 7.28; N, 9.20. Found: C, 66.93; H, 7.28; N, 9.00.

Method C: General method for the synthesis of ethyl 3-alkyl-3-aminocrotonate (K-O)

Activation of zinc: Zn (20 g) was added to a stirred 3N HCl solution (50 mL) and stirred at room temperature for 15 minutes. The HCl solution was decanted and this process was repeated twice. The activated zinc was washed with distilled water (2x, 100 mL), ethanol (2x, 50 mL) and diethyl ether (2x, 50 mL). Then, the activated zinc was placed under reduced pressure at 40°C for 12 hours. To a stirred solution of dry THF (30 mL) and activated zinc (3.27 g, 50 mmol) in a flame-dried 100 mL round bottom flask was added 0.2 mL of ethyl bromoacetate (1) at room temperature under an inert gas atmosphere . The reaction was then heated to reflux. Immediately after the solution turned green (15-30 minutes), alkyl cyanide (10 mmol) was added, and ethyl bromoacetate (4.44 mL, 40 mmol) was added dropwise over 30 minutes, refluxed for another 30 minutes, and then cooled to room temperature . To the stirred solution was _added THF (30 mL) and _K2CO3 (13 mL, 50% w/w) and stirred vigorously for 30 min. This 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 (method repeated twice). The combined supernatants were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude ethyl 3-alkyl-3-aminocrotonate, which was directly used in the next reaction.

Ethyl 3-amino-3-benzylcrotonate (K)

¹ HNMR (250MHz, CDCl ₃ ) δ1.26(t, J=7.1Hz, 3H), 3.46(s, 2H), 4.12(q, J=7.15Hz, 2H), 4.64(s, 1H), 7.27( m, 5H).

Ethyl 3-amino-3-ethylcrotonate (L)

¹ H NMR (250MHz, CDCl ₃ ) δ1.47(t, J=7.5Hz, 3H), 1.26(t, J=7.1Hz, 3H), 2.16(q, 5.7Hz, 2H), 4.11(q, J =5.4Hz, 2H), 4.55(s, 1H). ¹³ CNMR (62.5MHz, CDCl ₃ ) δ12.0, 14.5, 29.3, 30.3, 58.5, 82.6, 164.9, 170.5.

Ethyl 3-amino-3-cyclopropylcrotonate (M)

¹ H NMR (250MHz, CDCl ₃ ) δ0.74(m, 2H), 0.86(m, 2H), 1.25(t, J=7Hz, 3H), 2.27(s, 1H), 4.10(q, J=7Hz , 2H), 4.45(s, 1H). ¹³ CNMR (62.5MHz, CDCl ₃ ) δ7.1, 14.6, 15.8, 58.5, 80.7, 165.1, 170.4. LC/MS (150mm×4.6mm, C-18, 5 Micron, 10mM NH ₄ OAc/CH ₃ CN, APCI+)t=7.24min, m/z=156(M+1).

3-Amino-3-propylethyl crotonate (N)

¹ H NMR (250MHz, CDCl ₃ ) δ0.95(t, J=7.3Hz, 3H), 1.26(t, J=7.1Hz, 3H), 1.56(s, J=7.3Hz, 2H), 2.10(d , J=7.3Hz, 2H), 4.1(q, J=7.2Hz, 2H), 4.53(s, 1H). ¹³ C NMR (62.5MHz, CDCl ₃ ) δ13.5, 14.5, 21.1, 38.4, 58.30, 84LC/MS (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=8.02min, m/z=158.4(M+1).

3-Amino-3-isobutyl ethyl crotonate (O)

¹ H NMR (250MHz, CDCl ₃ ) δ0.95(d, J=6.4Hz, 6H), 1.26(t, J=7.1Hz, 3H), 1.9(m, 1H), 1.96(d, J=7.0Hz , 2H), 4.11(q, J=7.1Hz, 2H), 4.51(s, 1H).LC/MS (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=8.69min, m/z=172.4(M+1).

Method D: Synthesis of ethyl 2-alkyl-5-hydroxy 3-indolecarboxylates (P-T)

To a stirred solution of ethyl 3-alkyl-3-aminocrotonate (15.3 mmol) in acetic acid (50 mL) was added 1,4-benzoquinone (3.3 g, 30.5 mmol). The solution was stirred overnight at room temperature and then filtered through a frit. The solid was washed with cold distilled water and dried over _P2O5 in an Abderhalden dryer to give _ethyl 2-alkyl-5-hydroxy-3-indolecarboxylate.

Ethyl 2-benzyl-5-hydroxy-3-indolecarboxylate (P) 70% yield (from starting nitrile) as white powder.

¹ H NMR (250MHz, DMSO) δ1.32(t, J=7.08Hz, 3H), 4.26(q, J=7.05Hz, 2H), 4.41(s, 2H), 6.63(dd, J=8.5, 2.2 Hz, 1H), 7.25(m, 7H), 8.88(s, 1H), 11.64(s, 1H). ¹³ C NMR (62.5MHz, DMSO) δ14.5, 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 (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=7.83, m/z =296.3(M+1).

Ethyl 2-ethyl-5-hydroxy-3-indolecarboxylate (Q) 54% yield (from starting nitrile) as white powder.

¹ H NMR (250MHz, DMSO) δ1.23(t, J=7.6Hz, 3H), 1.33(t, J=7.1Hz, 3H), 3.04(q, J=7.5Hz, 2H), 4.24(q, J=7.1Hz, 2H), 6.5(dd, J=8.7, 2.4Hz, 1H), 7.14(d, J=8.5Hz, 1H), 7.33(d, J=2.4Hz, 1H), 8.82, (s , 1H), 11.48(s, 1H). ¹³ C NMR (62.5MHz, DMSO) δ13.6, 14.4, 20.7, 58.4, 105.3, 111.3, 111.6, 127.9, 128.9, 150.0, 152.2, 165.0.LC/MS ( 150mm×4.6mm, C-18, 5 micron 10mM NH ₄ OAc/CH ₃ CN, APCI+)t=7.60min, m/z=234.3(M+1).

Ethyl 2-cyclopropyl-5-hydroxy-3-indolecarboxylate (R) 83% yield (from starting nitrile) as white powder.

¹ HNMR (250MHz, DMSO) δ0.97(m, 2H), 1.10(m, 2H), 1.35(t, J=7.1Hz, 3H), 3.00(m1H), 4.26(q, J=7.0Hz, 2H ), 6.59(dd, 8.7, 2.4Hz, 1H), 7.8(d, J=8.7Hz, 1H), 7.30(d, J=2.4Hz, 1H), 8.81(s, 1H), 10.93(s, 1H ). ¹³ CNMR (62.5MHz, DMSO) δ8.8, 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 (150mm× 4.6mm, C-18, 5 micron 10mM NH ₄ OAc/CH ₃ CN, APCI+)t=7.03min, m/z=246.3(M+1).

Ethyl 5-hydroxy-2-propyl-3-indolecarboxylate (S) 62% yield (from starting nitrile) as white powder.

¹ H NMR (250MHz, DMSO) δ0.93(t, J=7.3Hz, 3H), 1.35(t, J=7.1Hz, 3H), 1.67(m, 2H) 3.01(t, J=9.0Hz, 2H ), 4.26(q, J=7.1Hz, 2H), 6.77(dd, J=8.7, 2.2Hz, 1H), 7.16(d, J=8.6Hz, 1H), 7.35(d, J=2.2Hz, 1H ), 8.86(s, 1H), 11.51(s, 1H). ¹³ C NMR (62.5MHz, DMSO) δ13.7, 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 (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=7.21min, m/z=248.4(M+1).

Ethyl 2-isobutyl-5-hydroxy-3-indolecarboxylate (T) 68% yield (from starting nitrile) as white powder.

¹ H NMR (250MHz, DMSO) δ0.91(d, J=6.6Hz, 6H), 1.35(t, J=7.1Hz, 3H), 2.06(m, 1H), 2.91(d, J=7.2Hz, 2H), 4.25(q, J=7.1Hz, 2H), 6.62(dd, J=8.6, 2.4Hz, 1H), 7.16(d, J=8.5Hz, 1H), 7.35(d, J=2.4Hz, 1H), 8.85(s, 1H), 11.5(s, 1H). ¹³ C NMR (62.5MHz, DMSO) δ14.4, 17.2, 22.3, 28.6, 36.2, 58.4, 102.0, 105.2, 111.2, 111.4, 127.9, 128.8, 147.6, 152.1, 165.0.LC/MS (150mm×4.6mm, C-18, 5 micron, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=7.69min, m/z=262.4(M+1) .

Method E: General Method for the Preparation of Indoleamides

5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid (1.0 g, 4.3 mmol) was dissolved in 10 mL DMF, and _Et3N (0.6 mL, 1 eq) was added. This solution was stirred for 5 minutes. The solution was cooled to 0°C and HBTU (1.63 g, 4.3 mmol) was added and stirred for an additional 15 minutes. The amine (2N in THF, 4eq) was added and the solution was stirred until the starting material was consumed, about 1 hour, and water was added. The pH of the resulting mixture was adjusted to 5 with HCl (1 N), and extracted with ethyl acetate. The organic layer was dried and evaporated to give a crude product which could be further purified by flash chromatography or recrystallization.

Intermediates U-V were synthesized according to Method E.

2-Methyl-3-methylcarbamoyl-1H-indol-5-yl acetate (U) yield: 0.093g (18%); mp 201-203°C;

IR: 3402, 1748, 1609, 1218, 1170cm ^{-1 .1H} NMR (DMSO-d ₆ ) δ 2.21(s, 3H, CH ₃ CO), 2.45(s, 3H, ArCH ₃ ), 2.72(d, J =4.39Hz, 3H, NHCH ₃ ), 6.76 (dd, J=8.79, 1.46 Hz, 1H, ArH), 7.24 (d, J=8.79Hz, 1H, ArH), 7.25 (bs, 1H, CONHCH ₃ ), 7.41(s, 1H, ArH), 11.5(s, 1H, indoleNH).MS(APCI+): m/z 247.1(MH ⁺ ); Analysis calculated for C ₁₃ H ₁₄ N ₂ O ₃ ·0.9H ₂ O; C, 59.49; H, 6.07; N, 10.67. Found: C, 59.51; H, 6.12; N, 10.55.

Yield of 3-benzylcarbamoyl-2-methyl-1H-indol-5-yl acetate (V): 0.454g (33%); mp182-184°C;

IR: 3413, 3319, 3222, 3191, 1750, 1609, 1228, 1216, 1170cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ2.20(s, 3H, CH ₃ CO), 2.54(s, 3H, ArCH ₃ ), 4.42 (d, J=6.1Hz, 2H, NHCH ₂ Ph), 6.77 (dd, J=8.55, 1.95Hz, 1H, ArH), 7.15-7.19 (m, 1H, ArH), 7.25-7.34 (m, 5H, ArH), 7.45(d, J=1.71Hz, 1H, ArH), 7.89(t, J=6.10Hz, 1H, CONHCH ₂ Ph), 11.5(s, 1H, indole NH).MS (APCI+): m/z 323.2 (MH ⁺ ); Anal. Calcd. for C ₁₉ H ₁₈ N ₂ O ₃ : C, 70.79, H, 5.63, N, 8.69. Found: C, 70.62, H, 5.78, N , 8.60.

Method F: General Method for Amide Deacylation

The useful amide (1 eq) was dissolved in a small amount of MeOH. MeONa (4eq) was added and the mixture was stirred until no starting material remained, about 45 minutes. The pH of the solution was adjusted to 1 by the addition of aqueous hydrochloric acid, and the solution was extracted with 2 x 25 mL of ethyl acetate. The organic layer was dried and evaporated to a solid. Recrystallization from ethyl acetate gave a white solid.

Intermediates W-X were synthesized according to Method F.

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid methylamide (W) Yield: 0.201g (70%); mp226-227°C; IR: 3366, 1602, 1558, 1552, 1215, 1198cm ^-1 . ¹ HNMR (DMSO-d ₆ ) δ2.45 (s, 3H, ArCH ₃ . Obscured by DMSO peak), 2.70 (d, J=4.40Hz, 3H, CONHCH ₃ ), 6.51 (d, J= 8.55Hz, 1H, ArH), 7.02(d, J=8.55Hz, 1H, ArH), 7.07(s, 1H, ArH), 7.13-7.14(m, 1H, CONHCH ₃ ), 8.65(s, 1H, OH ), 11.0 (s, 1H, indole NH). MS (APCI+): m/z 205.1 (MH ⁺ ); C ₁₁ H ₁₂ N ₂ O ₂ Calculation and analysis: 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 benzylamide (X) yield: 0.228g (65.7%); mp: 194-196°C;

IR: 3392, 3246, 1610, 1528, 1465, 1214, 1188cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ: 2.48(s, 3H, ArCH ₃ ), 4.41(d, J=5.86Hz, 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 (m, 5H, ArH), 7.71-7.78 (m, 1H, CONHCH ₂ Ph), 8.68 (s, 1H, OH), 11.1 (s, 1H, indole NH). MS (APCI+): m/z 281.1 (MH ⁺ ); C ₁₇ H Calcd for ₁₆ N ₂ O ₂ : C, 72.84; H, 5.75; N, 9.99. Found: C, 72.78; H, 5.70; N, 9.87.

Example 1

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, ethyl ester

Synthesized according to the method described in J. Het. Chem., 1970; 7: 1311-1319.

Example 2

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 8,9,11,12,13,13a,14,14a -Octahydro-2-methyl-, (4-fluorophenyl)methyl ester

Step A: 4-fluoro-benzyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate

To a solution of 5-hydroxy-2-methyl-1-H-indole-carboxylic acid (4.6 g, 24.1 mmol) in DMF (100 mL) was added DBU (3.67 g, 24.1 mmol) followed by 4-fluorobenzyl Bromine (5.0 g, 26.5 mmol). Under a nitrogen atmosphere, the resulting mixture was stirred at room temperature for 3 days, then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was separated, washed with water (2 x 100 mL), then dried over sodium sulfate and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate afforded 3.4 g (47%) of the pure title compound as a white solid: mp 209-210°C;

IR3412, 3377, 3305, 1667, 1512, 1466, 1221, 1176, 1094 cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ2.53 (s, 3H, CH ₃ ), 5.23 (s, 2H, CH ₂ ) , 6.55(dd, J=8.79, 2.20Hz, 1H, ArH), 7.08(d, J=8.79Hz, 1H, ArH), 7.14-7.17(m, 2H, ArH), 7.19(d, J=2.20Hz , 1H, ArH), 7.44-7.48 (m, 2H, ArH), 8.81 (s, 1H, OH), 11.55 (s, 1H, NH); MS (APCI ⁺ ): m/z300.1 (MH ⁺ ) .C ₁₇ H ₁₄ FNO ₃ Calculation and analysis: C, 68.22; H, 4.71; N, 4.68. Found: C, 67.91; H, 4.65; N, 4.59.

Step B: 4-Fluoro-benzyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Mix 4-fluoro-benzyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (2.90 g, 9.69 mmol) and aqueous dimethylamine (40%, 2.67 mL, 21.3 mmol) with 22 mL of EtOH , then aqueous HCHO (37%, 0.940 g, 11.6 mmol) was 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 16 hours. The reaction mixture was left at 4°C for 15 hours and a white precipitate formed. Filtration and vacuum drying afforded 1.56 g (45%) of the pure title compound as a white solid: mp 131-133 °C (decomposition); IR 3376, 3214, 1693, 1686, 1513, 1424, 1259, 1227, 1085, ^{806 cm −1} ; ¹ H NMR (DMSO-d ₆ ) δ 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=8.61Hz, 1H, ArH), 7.06 (d, J=8.61Hz, 1H, ArH), 7.18-7.24 (m, 2H, ArH), 7.49 -7.54 (m, 2H, ArH), 11.5 (bs, 1H, exchangeable proton); MS (APCI ⁺ ): m/z 357.2 (MH ⁺ ).C ₂₀ H ₂₁ N ₂ O ₃ F ₁ ·0.1H Calcd for ₂ O: C, 67.06; H, 5.97; N, 7.82; F, 5.30; H ₂ O, 0.50. Found: C, 66.90; H, 5.81; N, _7.53 ; , 0.20.

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 8,9,11,12,13,13a, 14,14a-Octahydro-2-methyl-, (4-fluorophenyl)methyl ester

To a mixture of perchlorate (1.27 g, 5.36 mmol, Example 3, Step B) and 50 mL of diethyl ether was added 50 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 50 mL). The combined ether layers were dried over sodium sulfate 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 atmosphere for 5.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a brown solid. Recrystallization from _CH3CN afforded 1.63 g (88%) of the pure title compound as a brown solid: mp 209-214°C (dec);

IR2934, 1704, 1152, 1431, 1235, 1148, 1078, 827cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ1.06-1.67 (m, 10H, fatty CH ₂ and CH), 1.81-1.86 (m, 1H, fatty CH), 2.30-2.46 (m, 2H, obscured by DMSO peak, fatty CH), 2.46 (s, 3H, ArCH ₃ ), 2.60-2.70 (m, 2H, fatty CH), 2.84-2.91 (m , 1H, fatty CH), 3.17 (dd, J=18.3, 6.78Hz, 1H, fatty CH), 5.21 (AB _q , _Jab =11.9Hz, _νab =19.0Hz, 2H, CO ₂ CH ₂ Ar), 6.59(d, J=8.61Hz, 1H, ArH), 7.03(d, J=8.61Hz, 1H, ArH), 7.17-7.25(m, 2H, ArH), 7.48-7.52(m, 2H, ArH), 11.5 (bs, 1H, NH); MS (APCI ⁺ ): m/z 449.3 (MH ⁺ ).C ₂₇ H ₂₉ N ₂ O ₃ F ₁ ·0.08CH ₃ CN: Calcd.: C, 72.20; H , 6.52; N, 6.45; F, 4.20. Found values: C, 71.88; H, 6.35; N, 6.42; F, 4.15.

Embodiment 3 (intermediate)

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine, 3,7,8,9,10,12,13,14,14a,15 -Decahydro-

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, and aqueous dimethylamine (40%, 5.28 mL, 42.1 mmol) was added followed by aqueous HCHO (37%, 3.65 g, 45.9 mmol). The resulting reaction mixture was stirred at room temperature for 1.5 hours, during which time a precipitate formed. Filtration and vacuum drying afforded 4.13 g (57%) of the pure title compound as a beige solid: mp 137-139°C;

IR3316, 1625, 1592, 1523, 1450, 1239, 1198, 724cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ2.25(s, 6H, 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=8.61Hz, 1H, ArH), 7.10 (d, J=8.60Hz, 1H, ArH), 7.18 -7.20 (m, 1H, ArH), 10.8 (bs, 1H, exchangeable protons); MS (APCI ⁺ ): m/z 191.1 (MH ⁺ ).C ₁₁ H ₁₄ N ₂ O Calculated analysis: C, 69.45; H, 7.42; N, 14.72. Found: C, 69.36; H, 7.38; N, 14.71.

Step B: 1,2,3,4,6,7,8,9-octahydro-quinazinium perchlorate

The synthesis is described in David A. Evans, Synthesis of new endocyclic enamines. JACS, 1970; 92:7593-7595 and Leonard NJ, Hay AS, Fulmer RW, Gash V.W., Unsaturated Amines, III. Introduction of α,β-Unsaturation by Mercury Acetate: Δ ¹⁽¹⁰⁾ -Dehydrogenation Quinazilanes, J. Am. Chem. Suc., 1955;77:439-444.

Step C: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine, 3,7,8,9,10,12,13,14, 14a, 15-Decahydro-

To a mixture of perchlorate (406 mg, 1.71 mmol, Example 3, Step B) and 20 mL of diethyl ether was added 30 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 30 mL). The combined ether layers were dried over sodium sulfate 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, and the resulting reaction mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to room temperature and a precipitate formed. Filtration and recrystallization from ethyl acetate afforded 0.17 g (46%) of the pure title compound as a beige solid: mp > 250 °C;

IR3414, 3148, 1454, 1242, 1148, 888cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ1.13-1.65 (m, 9H, fatty CH ₂ and CH), 1.76-1.91 (m, 2H, fatty CH ), 2.36-2.52 (m, obscured by DMSO peak, 3H, fatty CH), 2.68-2.77 (m, 1H, fatty CH), 2.88-2.96 (m, 1H, fatty CH), 3.06 (dd, J=17.6 , 6.78Hz, 1H, fatty CH), 6.22-6.23 (m, 1H, ArH), 6.56 (d, J=8.61Hz, 1H, ArH), 7.07 (d, J=8.61Hz, 1H, ArH), 7.19 -7.21 (m, 1H, ArH), 10.8 (bs, 1H, NH); MS (APCI ⁺ ): m/z 383.1 (MH ⁺ ).C ₁₈ H ₂₂ N ₂ O·0.1H ₂ O Calcd. : C, 76.08; H, 7.87; N, 9.86; H ₂ O, 0.63. Found: C, 76.09; H, 7.81; N, 9.83; H ₂ O, 0.74.

Embodiment 4 (intermediate)

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine, 3,7,8,9,10,12,13,14,14a,15 -Decahydro-2-methyl-

Step A: 2-Methyl-1H-indol-5-ol

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (Aldrich, Milwaukee, WI, 20.0 g, 91.2 mmol) was mixed with aqueous sodium hydroxide (2N, 365 mL, 730 mmol), and the resulting reaction mixture was Reflux for 1 hour under nitrogen atmosphere. After cooling to 70°C, the reaction solution was treated with concentrated hydrochloric acid to pH=1. The resulting dark brown solution was extracted with ether (3 x 300 mL). The combined ether solutions were dried over sodium sulfate and concentrated in vacuo to give a brown solid. Recrystallization from EtOAc/ _CH2Cl2 afforded 11.7 g (87%) of the pure title 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 )δ2.29(s, 3H, ArCH ₃ ), 5.88-5.89(m, 1H, ArH), 6.45(dd, J=8.42, 2.38Hz, 1H, ArH), 6.68(d, J = 2.38Hz, 1H, ArH), 7.00 (d, J = 8.42Hz, 1H, ArH), 8.44 (s, 1H, NH), 10.5 (bs, 1H, OH); MS (APCI ⁺ ): m/z 148 .1(MH ⁺ ).C ₉ H ₉ NO calculation and analysis

Values: 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 EtOH, and aqueous dimethylamine (40%, 9.40 mL, 74.7 mmol) was added, followed by aqueous HCHO (37%, 3.30 g, 40.8 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then mixed with 50 ml of water, and a precipitate formed. Filtration and recrystallization from ethanol (<50°C) afforded 3.0 g (43%) of the pure title compound as a white solid: mp 133-135°C;

IR3404, 3385, 1598, 1515, 1428, 1271, 1204, 798, 778cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ2.23(s, 6H, N(CH ₃ ) ₂ ), 2.30(s, 3H , ArCH ₃ ), 3.68 (s, 2H, CH ₂ N), 5.98 (s, 1H, ArH), 6.42 (d, J=8.42Hz, 1H, ArH), 6.95 (d, J=8.79Hz, 1H, ArH), 10.6 (bs, 1H, exchangeable proton); MS (APCI ⁺ ): m/z 205.2 (MH ⁺ ). Calcd. Analytical value for C ₁₂ H ₁₆ N ₂ O: 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]quinazine, 3,7,8,9,10,12,13,14, 14a, 15-Decahydro-2-methyl-

To a mixture of perchlorate (973 mg, 4.10 mmol, Example 3, Step B) and 30 mL of diethyl ether was added 40 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 40 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The 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, and the resulting reaction mixture was Reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a brown solid. Trituration with ethyl acetate gave 1.01 g (59%) of the pure title compound as a beige solid: mp 267-270°C (dec);

IR3407, 3189, 2926, 1435, 1212, 1197, 774cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ1.13-1.64 (m, 9H, fatty CH ₂ and CH), 1.74-1.89 (m, 2H, fatty CH), 2.31(s, 3H, CH ₃ ), 2.35-2.50(m, obscured by DMSO peak, 3H, fatty CH), 2.67-2.75(m, 1H, fatty CH), 2.87-3.31(m, 2H , fatty CH), 5.92 (m, 1H, ArH), 6.45 (d, J = 8.61Hz, 1H, ArH), 6.94 (d, J = 8.79Hz, 1H, ArH), 10.6 (bs, 1H, exchangeable proton); MS (APCI ⁺ ): m/z 297.1 (MH ⁺ ). Anal. calculated for C ₁₉ H ₂₄ N ₂ O: C, 76.99; H, 8.16; N, 9.45. Found: C, 76.79; H , 8.19; N, 9.35.

Example 5

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 5-bromo 3,7,8,9,10,12, 13, 14, 14a, 15-decahydro-2-methyl-, ethyl ester

Step A: 6-Bromo-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester

6-Bromo-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester, prepared according to literature methods [Bell M.R.; Oesterlin R.; Beyler A.L.; Harding H.R.; PottsG.O., J.Med .Chem., 1967; 10:264-266], (3.01g, 10.1mmol) and aqueous dimethylamine (40%, 2.79mL, 22.2mmol) were mixed with 30mL EtOH, and this mixture was heated with a heat gun until a clear solution was obtained . After cooling to room temperature, aqueous HCHO (37%, 0.982 g, 12.1 mmol) was added. The resulting reaction mixture was stirred at room temperature for 48 hours, during which time a white precipitate formed. Filtration and drying in vacuo afforded 1.91 g (53%) of the pure title compound as a white solid: mp 179-180°C (dec);

IR3339, 1700, 1688, 1426, 1092, 833cm ^-1 ; ¹ HNMR (DMSO-d ₆ ) δ1.30 (t, J=7.14Hz, 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=6.96Hz, 2H, CH ₂ CH ₃ ), 7.38 (s, 1H, ArH), 11.6 (bs, 1H, exchangeable proton); MS (APCI ⁺ ): m/z 355.0 (MH ⁺ ).C ₁₅ H ₁₉ N ₂ O ₃ Br

Calcd: 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 (1.40 g, 5.90 mmol, Example 3, Step B) and 50 mL of diethyl ether was added 50 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 50 mL). The combined ether layers were dried over sodium sulfate 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, and the resulting reaction mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to a thick oil. The crude was further purified by chromatography (50% EtOAc in hexanes) to give a white foam which was triturated with EtOAc/hexanes to give 1.42 g (54%) of the pure title compound as a white solid: mp 184-185 °C;

IR3295, 2930, 1662, 1426, 1185, 1110, 1081, 869cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ1.15-2.08 (m, 11H, fatty CH ₂ and CH), 1.39(t, J=7.14Hz , 3H, CH ₂ CH ₃ ), 2.45-2.65 (m, 2H, fatty CH), 2.60 (s, 3H, ArCH ₃ ), 2.85-3.00 (m, 2H, fatty CH), 3.17-3.30 (m, 1H , fatty CH), 3.50 (dd, J=18.0, 6.96Hz, 1H, fatty CH), 4.34 (q, J=7.14Hz, CH ₂ CH ₃ ), 7.35 (s, 1H, ArH), 8.10 (bs, 1H, NH); MS (APCI ⁺ ): m/z 447.1 (MH ⁺ ).C ₂₂ H ₂₇ N ₃ O ₃ Br

Calcd: C, 59.06; H, 6.08; N, 6.26; Br, 17.86. Found: C, 59.11; H, 6.07; N, 6.07; Br, 17.97.

Example 6

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, propyl ester

Step A: Propyl 5-Hydroxy-2-methyl-1H-indole-3-carboxylate

Propyl 5-acetoxy-2-methyl-lH-indole-3-carboxylate (Intermediate D, 2.04 g, 7.42 mmol) was mixed with 20 mL of methanol, then _NaOCH3 (1.60 g, 29.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1.5 hours. This reaction mixture was mixed with 20 mL of water and the resulting reaction mixture was treated with 5% HCl to pH = 1 to give a white precipitate. This solid was isolated by filtration and recrystallized from EtOAc/hexanes to give 1.39 g (80%) of pure title compound as a beige solid, mp 188-189°C (dec);

IR3381, 3297, 1661, 1457, 1178, 1090, 794, 783 cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ0.989 (t, J=7.51 Hz, 3H, CH ₂ CH ₂ CH ₃ ), 1.72 ( sextet, J=7.14Hz, 2H _, CH2CH2CH3), 2.57 ₍ s _, 3H _{, ArCH3} ), 4.14( _t , J=6.41Hz, 2H _, CH2CH2CH3), 6.58(dd, J=8.42, 2.20Hz, 1H, ArH), 7.11(d, J=8.61Hz, 1H, ArH), 7.29(d, J=2.20Hz, 1H, ArH), 8.83(s, 1H, OH), 11.5 (bs, 1H, NH); MS (APCI ⁺ ): m/z 234.1 (MH ⁺ ).C ₁₃ H ₁₅ NO ₃ ·0.06H ₂ O:

Calculated analysis value: C, 66.63; H, 6.50; N, 5.98. Measured value: C, 66.27; H, 6.38; N, 5.84.

Step B: Propyl 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Propyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (1.27 g, 5.43 mmol) and aqueous dimethylamine (40%, 1.50 mL, 12.0 mmol) were mixed with 10 mL of EtOH, and the mixture was washed with Heat the heat gun until a clear solution is obtained. After cooling to room temperature, aqueous HCHO (37%, 0.528 g, 6.52 mmol) was added. The resulting reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then concentrated in vacuo, reducing the volume by half. A precipitate formed. Filtration and vacuum drying afforded 0.86 g (54%) of the pure title compound as a white solid: mp 135-137 °C (dec); IR 3217, 2969, 1684, 1420, 1141, 1075 cm ⁻¹ ; ¹ H NMR (DMSO-d ₆ ) _{δ0.953 (} t, J=7.32Hz, 3H, CH2CH2CH3), 1.70(sextet, J=7.33Hz, 2H _{, CH2CH2CH3} ), 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=6.78Hz, 2H, CH ₂ CH ₂ CH ₃ ) , 6.56(d, J=8.61Hz, 1H, ArH), 7.07(d, J=8.42Hz, 1H, ArH), 11.5(bs, 1H, exchangeable proton); MS(APCI ⁺ ): m/z291. 1(MH ⁺ ). _Anal . _Calcd . for _C16H22N2O3 : C, 66.19; H, 7.64 _; N, 9.65. Found: C, 65.94; H, 7.67; N, 9.31.

Step C:

To a mixture of perchlorate (0.763 g, 3.21 mmol, Example 3, Step B) and 30 mL of diethyl ether was added 30 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 30 mL). The combined ether layers were dried over sodium sulfate 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 atmosphere for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to give a white solid. Recrystallization from _CH3CN gave 0.67 g (70%) of the pure title compound as a white solid: mp 162-164 °C;

IR3329, 2931, 1702, 1665, 1434, 1235, 1200, 1149, 1079, 948, 781 cm ^-1 ; ¹ HNMR (CDCl ₃ ) δ0.992 (t, J=7.32Hz, 3H, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.76 (sextet, J=7.08Hz, 2H _, CH2CH2CH3), 1.29-1.86 (m, _10H , _fatty CH2 _and CH), 2.11 (d, J=13.43Hz, 1H, Fatty CH), 2.27-2.58(m, 2H, Fatty CH), 2.58(s, 3H, _ArCH3 ), 2.82-2.86(m, 2H, Fatty CH), 3.00-3.10(m, 1H, Fatty CH), 3.46 (dd, J=18.1, 6.84Hz, 1H, fatty CH ₎ , 4.21 ₍ t, J=6.84Hz, _CH2CH2CH3 ), 6.73 (d, J=8.79Hz, 1H, ArH), 7.01( d, J=8.79Hz, 1H, ArH), 8.06 (bs, 1H, NH); MS (APCI ⁺ ): m/z 383.1 (MH ⁺ ).C ₂₃ H ₃₀ N ₂ O ₃ Calcd. Anal.: 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-methylpropyl ester

Step A:

Isobutyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (Intermediate H, 1.03 g, 4.17 mmol) and aqueous dimethylamine (40%, 1.15 mL, 9.17 mmol) were mixed with 4 mL of EtOH Mix and then add aqueous HCHO (37%, 0.406 g, 5.01 mmol). 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 left at 4°C for an additional 16 hours. Cotton-like white crystals formed. Filtration and drying in vacuo afforded 0.62 g (49%) of the pure title compound as a white solid: mp 122-124°C (dec);

IR3229, 2957, 1686, 1424, 1242, 1085, 1000cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ0.951 (d, J=6.59Hz, 6H, CH ₂ CH(CH ₃ ) ₂ ), 1.98( m, J=6.59Hz, 1H, _CH2CH ( _CH3 ) ₂ ), 2.18(s, 6H, N( _CH3 ) ₂ ), 2.50(s, 3H, obscured by DMSO peak, _ArCH3 ), 3.97( d, J=6.59Hz, 2H, _CH2CH ( _CH3 ) ₂ ), 4.07(s, 2H, _{ArCH2NMe2 )} , 6.56(d, J=8.61Hz, 1H, ArH), 7.06(d, J =8.42Hz, 1H, ArH), 11.5(bs, 1H,

Exchangeable protons); MS (APCI ⁺ ): m/z 305.2 (MH ⁺ ).C ₁₇ H ₂₄ N ₂ O ₃ ·1.03H ₂ O

Calcd: C, 63.23; H, 8.13; N, 8.67. Found: C, 62.84; H, 7.30; N, 8.44.

Step B:

To a mixture of perchlorate (0.458 g, 1.93 mmol, Example 3, Step B) and 30 mL of diethyl ether was added 30 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 30 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole mannich base (0.451 g, 1.48 mmol) was added and the resulting reaction mixture was refluxed under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to give 0.40 g (52%) of the pure title compound as a white solid: mp 203-204.5 °C;

IR3341, 2933, 1700, 1673, 1434, 1236, 1082, 886, 781 ^{cm -1} ; ¹ HNMR (CDCl ₃ ) δ0.984 (d, J=6.84Hz, 6H, CH ₂ CH(CH ₃ ) ₂ ), 1.32 -1.90 (m, 10H, fatty CH ₂ and CH), 2.04 (m, J=6.59Hz, 1H, CH ₂ CH(CH ₃ ) ₂ ), 2.08-2.18 (m, 1H, fatty CH), 2.40-2.60 (m, 2H, fatty CH), 2.59 (s, 3H, ArCH ₃ ), 2.84-2.88 (m, 2H, fatty CH), 2.97-3.10 (m, 1H, fatty CH), 3.46 (dd, J=18.1 , 6.84Hz, 1H, fatty CH), 4.00-4.09(m, 2H, _CH2CH ( _CH3 ) ₂ ), 6.73(d, J=8.79Hz, 1H, ArH), 7.02(d, J=8.79Hz , 1H, ArH), 8.05 (bs, 1H, NH); MS (APCI ⁺ ): m/z 397.2 (MH ⁺ ). Calcd. for C ₂₄ H ₃₂ N ₂ O ₃ : C, 72.70; H, 8.1 3; N, 7.06. Found: C, 72.85; H, 8.19; N, 7.00.

Example 8

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2,2-dimethylpropyl ester

Step A:

2,2-Dimethylpropyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (Intermediate I, 1.55 g, 5.93 mmol) and aqueous dimethylamine (40%, 1.64 mL, 13.1 mmol) was mixed with 4 mL of EtOH, then aqueous HCHO (37%, 0.406 g, 5.01 mmol) was 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 50ml ethyl acetate, the mixture was washed with water (2 x 50ml), the organic phase was dried over sodium sulfate and concentrated in vacuo to give a viscous oil. This crude product was further purified by flash chromatography (10%-20% methanol in chloroform) to give 0.90 g (48%) of the pure title compound as a white solid: mp 150-151 °C (dec);

IR3251, 2953, 1690, 1424, 1238, 1081, 801 cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ 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, CH ₂ C(CH ₃ ) ₃ ), 4.08 (s, 2H, ArCH ₂ NMe ₂ ), 6.57 (d, J =8.42Hz, 1H, ArH), 7.07(d, J=8.61Hz, 1H, ArH), 11.5(bs, 1H, exchangeable proton); MS(APCI ⁺ ): m/z319.2(MH ⁺ ). _{Anal .} Calcd _{for C18H26N2O3} : C, 67.90; H, 8.23; N, 8.80. Found: C, 67.53; H, 8.04; N, 8.57.

Step B:

To a mixture of perchlorate (0.710 g, 2.23 mmol, Example 3, Step B) and 30 mL of diethyl ether was added 30 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 30 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole Mannich base (0.690 g, 2.90 mmol) was added and the resulting reaction mixture was refluxed under nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to give a white solid. Recrystallization from _CH3CN gave 0.92 g (44%) of the pure title compound as a white solid: mp 240-243 °C;

IR3187, 2934, 1700, 1433, 1235, 1077, 883, 780cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ0.96(d, 9H, CH ₂ C(CH ₃ ) ₃ ), 1.19-1.57(m , 9H, fatty CH ₂ and CH), 1.70-1.80 (m, 1H, fatty CH), 1.76-1.85 (m, 1H, fatty CH), 2.34-2.45 (m, 2H, fatty CH obscured by DMSO peak), 2.53(s, 3H, ArCH ₃ ), 2.63-2.79(m, 2H, fatty CH), 2.85-2.95(m, 1H, fatty CH), 3.25-3.35(m, 1H, fatty CH blurred by water peak), 3.94 (AB _q , _Jab = 10.62Hz, ν _ab = 24.1Hz, 2H, CH ₂ C(CH ₃ ) ₃ ), 6.61 (d, J = 8.42Hz, 1H, ArH), 7.04 (d, J = 8.61 ^{H ,} _{_ _ _ _} 8.35; N, 6.82. Found: C, 73.16; H, 8.52; N, 6.77.

Method G: General Method for Mannich Reaction

The selected 5-hydroxyindole esters (2.2-17.9 mmol, 1 eq) were dissolved in ethanol by stirring while warming the solution; the solution was cooled. Aqueous HCHO (37%, 1.2eq) and aqueous dimethylamine (40%, 2.2eq) were added and the reaction was stirred at 50°C until the ratio of starting material to product was constant. Ethanol was removed in vacuo and the brown oil was purified by flash chromatography (MeOH/ _CHCl3 as eluent) to give the desired product.

Example 9

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, phenylmethyl ester

Step A:

Benzyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate Synthesized from intermediate C according to method G. Yield: 3.36g (55%);

¹ H NMR (DMSO-d ₆ ) δ 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=8.30Hz, 1H, ArH), 7.04 (d, J=8.55Hz, 1H, ArH), 7.29-7.43 (m, 5H, ArH) , 11.5(s, 1H, NH).MS(APCI ⁺ ): m/z 339.1(MH ⁺ ).

Step B:

Obtained by a method similar to Example 7, Step C: 3.30g (77%); mp162-164°C;

IR: 2930, 2855, 1700, 1432, 1077cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ1.11-1.67 (m, 10H, fatty CH ₂ and CH), 1.82-1.86 (m, 1H, fatty CH ), 2.30-2.48 (m, 2H, obscured by DMSO peak, fatty CH), 2.48 (s, 3H, ArCH ₃ ), 2.62-2.70 (m, 2H, fatty CH), 2.86-2.92 (m, 1H, fatty CH CH), 3.19 (dd, J = 18.3, 6.78 Hz, 1H, fat CH), 5.23 (AB _q , _Jab = 12.1 Hz, ν _ab = 16.4 Hz, 2H, CO ₂ CH ₂ Ph), 6.59 (d, J=8.61Hz, 1H, ArH), 7.03(d, J=8.61Hz, 1H, ArH), 7.30-7.46(m, 5H, ArH), 11.5(bs, 1H, NH); MS(APCI+): 431.2 (MH ⁺ ). Anal. Calcd. for C ₂₇ H ₃₀ N ₂ O 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-methylethyl ester

Step A:

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid isopropyl ester Synthesized from intermediate E according to method G. Yield: 0.490 g (61%);

¹ H NMR δ 1.26 (d, J=6.35Hz, 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=8.55Hz, 1H, ArH), 7.02(d , J=8.55Hz, 1H, ArH), 11.4 (s, 1H, NH). MS (APCI ⁺ ): m/z 291.1 (MH ⁺ ).

Step B:

Obtained by a method similar to Example 7, Step C: 0.390g (60.4%); mp186-188°C;

IR: 2976, 2930, 2856, 1703, 1433, 1079cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ1.10-1.57 (m, 9H, fatty CH ₂ and CH), 1.23 (d, J=5.62Hz , 3H, CH ₃ ), 1.25 (d, J=5.86Hz, 3H, CH ₃ ), 1.71-1.74 (m, 1H, fatty CH), 1.85-1.88 (m, 1H, fatty CH), 2.32-2.44 ( m, 2H, obscured by DMSO peak, fatty CH), 2.44 (s, 3H, ArCH ₃ ), 2.63-2.74 (m, 2H, fatty CH), 2.83-2.89 (m, 1H, fatty CH), 3.21-3.28 (m, 1H, fatty CH, obscured by water peak), 5.01 (Septet, 1H, CO ₂ CH(CH ₃ ) ₂ ), 6.56 (d, J=8.79Hz, 1H, ArH), 6.99 (d, J =8.80Hz, 1H, ArH), 11.4 (bs, 1H, NH); MS (APCI+): 383.1 (MH ⁺ ). Anal. Calcd. for C ₂₃ H ₃₀ N ₂ O ₃ : C, 72.22; H, 7.91; N , 7.32. Measured value: C, 71.98; H, 7.85; N, 7.29.

Example 11

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, cyclopropylmethyl ester

Step A:

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid cyclopropylmethyl ester Synthesized from intermediate F according to method G. Yield: 0.406g (62.1%);

¹ H NMR (DMSO-d ₆ ) δ0.309-0.346 (m, 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=8.55Hz, 1H, ArH), 7.09 (d, J=8.55Hz, 1H, ArH), 11.5 (s, 1H, NH) .MS(APCI ⁺ ): m/z303.1(MH ⁺ ).

Step B:

Obtained by a method similar to Example 7, Step C. Yield: 0.269g (50.7%); mp199-200°C;

IR: 3376, 3337, 2932, 2857, 1698, 1669, 1433, 1081cm ^-1 . ¹ H NMR (CDCl ₃ ) δ0.337-0.373 (m, 2H, cyclopropyl CH ₂ CH ₂ ), 0.596-0.641 ( m, 2H, cyclopropyl _{CH2CH2 )} , 1.21-1.89 (m, 10H, fatty _CH2 and CH), 2.15-2.18 (m, 1H, fatty CH), 2.48-2.64 (m, 2H, by: ArCH ₃ peak blurred, fatty CH), 2.64 (s, 3H, ArCH ₃ ), 2.86-2.96 (m, 2H, fatty CH), 3.00-3.10 (m, 1H, fatty CH), 3.52 (dd, J=18.1 , 6.84Hz, 1H, fatty CH), 4.07-4.17 (m, 1H, CO ₂ CH ₂ ), 6.77 (d, J=8.55Hz, 1H, ArH), 7.06 (d, J=8.79Hz, 1H, ArH ), 8.10 (bs, 1H, NH); MS (APCI+): 395.1 (MH ⁺ ).C ₂₄ H ₃₀ N ₂ O ₃ Calculated analysis: 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-(1-piperidinyl) ethyl ester

Step A:

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 2-piperidin-1-yl-ethyl ester (Intermediate J, 0.770 g, 2.55 mmol) and aqueous dimethylamine (40%, 0.704 mL , 5.60mmol) was mixed with 2mL EtOH, then aqueous HCHO (37%, 0.248g, 3.06mmol) was 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 2 days. The reaction mixture was further diluted with ethyl acetate, washed with water and dried over sodium sulfate. The solution was concentrated in vacuo to an oil. The crude product was further purified by flash chromatography (10%-20% MeOH in chloroform) to give an oil (402 mg, 44% crude yield) which was the desired product with minor impurities:

¹ H NMR (DMSO-d ₆ ) δ1.31-1.33 (m, 2H, piperidine CH ₂ ), 1.40-1.45 (m, 4H, 2×piperidine CH ₂ ), 2.16 (s, 6H, CH ₂ N (CH ₂ N(CH ₃ ) ₂ ), 2.30-2.40 (m, 4H, 2×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=5.86Hz, 2H, OCH ₂ CH ₂ N), 6.52 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 11.4 (bs, 1H, exchangeable proton); MS (APCI+): m/z 360.2 (MH ⁺ ).

Step B:

Obtained by a method similar to Example 7, Step C. Yield: 0.137g (37%); mp169-171°C;

IR: 2928, 1696, 1434, 1094, 1081cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ1.11-1.54 (m, 15H, fatty CH ₂ and CH), 1.71-1.74 (m, 1H, fatty CH ), 1.86-1.90 (m, 1H, fatty CH), 2.34-2.47 (m, 6H, blurred by DMSO peak, fatty CH), 2.47 (s, 3H, ArCH ₃ ), 2.52 (t, J=5.62Hz, 2H, _OCH2CH2N ), 2.62-2.71 (m, 2H, fatty CH), 2.84-2.89 (m, 1H, fatty CH), 3.24-3.33 (m, _1H , fatty CH, obscured by water peaks), 4.14-4.26 (m, 2H, _OCH2CH2N ), 6.56 (d, J = _8.79Hz , 1H, ArH), 7.00 (d, J = 8.55Hz, 1H, ArH), 11.5 (bs, 1H, NH ); MS (APCI+): m/z 452.3 (MH ⁺ ).C ₂₇ H ₃₇ N ₃ O ₃ ·0.15H ₂ O

Calcd: C, 71.38; H, 8.28; N, 9.25; H ₂ O, 0.59. Found: C, 71.08; H, 8.25; N, 9.02; H ₂ O, 0.21.

Method H: General procedure for the synthesis of ethyl 2-alkyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylates

To a stirred solution of ethyl 2-alkyl-5-hydroxy-3-indolecarboxylates (2.63 mmol) in ethanol (8 mL) was added formaldehyde (0.24 mL, 3.16 mmol) and dimethylamine (0.73 mL, 5.80 mmol). The solution was stirred at 45°C for 3 hours, cooled and concentrated under reduced pressure. Flash column chromatography ( _SiO2 , 1:1 ethyl acetate/hexane, then 10:1 ethyl acetate/ethanol) of this residue afforded the desired product.

Method I: General procedure for the synthesis of ethyl 2-alkyl-[(pyrano[2,3-b]quinazinane)[5,6-e]]indole-3-carboxylates

To a stirred solution of NaOH (50% w/w, 100 mL) and diethyl ether (20 mL) was added iminoammonium perchlorate (0.42 g, 1.78 mmol, Example 3, Step B). This solution was extracted with ether (10 x 100 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford the enamine as a white solid. To a stirred solution in dioxane (2.5 mL/mmol) was added this 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 ( _SiO2 , 99:1 dichloromethane/methanol) to give the desired product.

Example 13

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-(phenylmethyl)-, ethyl ester

Step A:

2-Benzyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylic acid ethyl, 84% yield as a white solid, synthesized from intermediate P according to Procedure H.

¹ H NMR (250MHz, CD ₃ OD) δ1.38(t, J=7.2Hz, 3H), 4.32(q, J=8.5Hz, 2H), 4.46(s, 2H), 6.68(dd, J=6.8 , 2.5Hz, 1H), 7.17(m, 5H) 7.47(d, J=2.25Hz, 1H).LC/MS (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+)t=7.86min, m/z=353.2(M+1).

Step B:

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-(phenylmethyl)-, ethyl ester was synthesized according to Method I. 68% yield as a white solid.

¹ H NMR (250MHz, CDCl ₃ ) δ1.36(t, J=7.2Hz, 3H), 1.42(m, 3H), 1.68(m, 5H), 1.92(m, 2H), 2.15(d, J= 13.3Hz, 1H), 2.53(m, 2H), 2.85(m, 2H), 3.09(m, 1H), 3.48(dd, J=20.0, 7.5Hz, 1H), 4.35(q, J=7.1Hz, 2H), 4.40(s, 2H), 6.75(d, J=8.6Hz, 1H), 6.96(d, J=8.7Hz, 1H), 7.29(m, 5H), 7.90(s, 1H). ¹³ C NMR (62.5MHz, CDCl ₃ ) δ14.5, 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 (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=10.73, m/z=445.6 (M+1 ) Elemental analysis calculated value: C, 75.64; H, 7.25; N, 6.30. Measured value: C, 75.71; H, 7.34; N, 6.23.

Example 14

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

Step A:

Ethyl 4-(dimethylamino)methylene-2-ethyl-5-hydroxy-3-indolecarboxylate Synthesized from intermediate Q according to Procedure H. 55% yield as a white solid.

¹ H NMR (250MHz, DMSO) δ1.23(t, J=7.4Hz, 3H), 1.32(t, J=7.0Hz, 3H), 2.46(s, 6H), 2.91(q, J=7.6Hz, 2H), 4.30(q, J=7.1Hz, 2H), 4.44(s, 2H), 6.61(d, J=8.6Hz, 1H), 7.11(d, J=84Hz, 1H), 9.70(bs, 1H ). ¹³ C NMR (62.5MHz, DMSO) δ14.1, 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 (150mm×4.6 mm, C-18, 5 microns, 10 mM NH4OAc/ _CH3CN , APCI+)t=6.25min, m/z=291.3(M ₊ 1).

Step B:

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 2-ethyl-3,7,8,9,10, 12, 13, 14, 14a, 15-decahydro-, ethyl esters were synthesized according to Method I, 43% yield, as a white solid.

¹ H NMR (250MHz, CDCl ₃ ) δ1.34(t, J=7.6Hz, 3H), 1.36(t, J=7.2Hz, 3H), 1.63(m, 5H), 1.88(m, 3H), 2.15 (d, J=13.3Hz, 1H), 2.47(m, 2H), 2.82(m, 2H), 3.02(q, J=7.5Hz, 2H), 3.48(dd, J=17.9, 6.8Hz, 1H) , 4.35(q, J=7.2Hz, 2H), 6.77(d, J=8.7Hz, 1H), 7.06(d, J=8.7Hz, 1H), 7.26(s, 1H), 8.19(s, 1H) . ¹³ C NMR (62.5MHz, CDCl ₃ ) δ13.7, 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 (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/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]quinazine-1-carboxylic acid, 2-cyclopropyl-3,7,8,9,10 , 12, 13, 14, 14a, 15-decahydro-, ethyl ester

Step A:

Ethyl 2-cyclopropyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylate Synthesized from intermediate R according to Procedure H. 64% yield as a white solid.

¹ H NMR (250MHz, DMSO) δ0.92(m, 2H), 1.04(m, 2H), 1.33(t, J=7.1Hz, 3H), 2.22(s, 6H), 3.98(s, 2H), 4.27(q, J=7.1Hz, 2H), 6.58(d, J=8.4Hz, 1H), 7.14(d, J=8.8Hz, 1H), 10.88(s, 1H). ¹³ CNMR(62.5MHz, DMSO )δ8.4, 8.9, 14.3, 1703, 43.9, 58.3, 59.2, 110.6, 111.3, 112.0, 129.1, 147.3, 152.8, 165.9.

Step B:

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 2-cyclopropyl-3,7,8,9,10 , 12, 13, 14, 14a, 15-decahydro-, ethyl ester was synthesized according to method I. 60% yield as a white solid.

¹ H NMR (250MHz, CDCl ₃ ) δ0.79(m, 2H), 1.07(d, J=8.54, 2H), 1.37(m, 3H), 1.40(t, J=7.2Hz, 3H), 1.61( m, 9H), 1.92(m, 1H), 2.17(d, J=15.0Hz, 2H), 2.60(m, 3H), 2.83(m, 2H), 3.48(dd, J=17.9, 6.8Hz, 1H ), 4.37(q, J=7.1Hz, 2H), 6.75(d, J=8.6Hz, 1H), 7.03(d, J=8.7Hz, 1H), 7.84(s, 1H). ¹³ C NMR (62.5 MHz, CDCl ₃ ) δ4.8, 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 (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=10.70min, m/z=395.5(M+1).Elemental analysis : Calculated (as hydrate) C, 69.88; H, 7.82; N, 6.79. Found C, 69.92; H, 7.87; N, 6.67.

Example 16

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-propyl-, ethyl ester

Step A:

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-propyl-, ethyl ester was synthesized from intermediate S according to Method H. 24% yield as a white solid. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH ₄ OAc/CH ₃ CN, APCI+) t = 7.45 min, m/z = 305.3 (M+1).

Step B:

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-propyl-, ethyl ester was synthesized according to Method I. 28% yield as a white solid.

¹ H NMR (250MHz, CDCl ₃ ) δ0.99(t, J=7.3Hz, 3H), 1.40(m, 4H), 1.44(t, J=7.1Hz, 3H), 1.68(m, 7H), 1.92 (m, 1H), 2.12(d, J=12.0Hz, 1H), 2.55(m, 2H), 2.92(m, 5H), 3.47(dd, J=16.7, 6.6Hz, 1H), 4.35(q, J=7.1Hz, 2H), 6.77(d, J=8.7Hz, 1H), 7.05(d, J=8.7Hz, 1H), 8.12(s, 1H). ¹³ C NMR (62.5MHz, CDCl ₃ )δ13 .9, 14.4, 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 (150mm×4.6 mm, C-18, 5 microns, 10 mM NH ₄ OAc/CH ₃ CN, APCI+) t = 11.56 min, m/z = 397.5 (M+1). Elemental analysis: calculated for C, 72.69; H, 8.13; N, 7.06. Measured value C, 72.30; H, 8.18; N, 6.79,

Example 17

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-(2-methylpropyl)-, ethyl ester

Step A:

Ethyl 2-isobutyl-4-(dimethylamino)methylene-5-hydroxy-3-indolecarboxylate 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 OAc/CH ₃ CN, APCI+) t = 7.86 min, m/z = 319.3 (M+1).

Step B:

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-(2-methylpropyl)-, ethyl ester was synthesized according to Method I. 27% yield as a white solid.

¹ H NMR (250MHz, CDCl ₃ ) δ0.95(d, J=4.3Hz, 3H), 0.98(d, J=4.3Hz, 3H), 1.23(m, 1H), 1.39(t, J=7.1Hz, 3H), 1.42(m, 6H), 1.63(m, 6H), 1.88(m, 1H), 2.00(m, 1H), 2.16(d, J=13.3Hz, 1H), 2.53(m, 2H), 2.86(m, 4H), 3.01(m, 1H), 3.47(dd, J=17.4, 7.2Hz, 1H), 4.34(q, J=7.1, 2H), 6.77(d, J=8.6Hz, 1H) , 7.06 (d, J=8.7Hz, 1H), 8.04 (s, 1H). ¹³ C NMR (62.5MHz, CDCl ₃ ) δ14.5, 19.8, 22.5, 22.6, 25.0, 25.5, 27.0, 29.4, 30.1, 31.2, 36.7, 37.5, 49.5, 59.7, 87.1, 109.3, 111.4, 113.8, 166.1. LC/MS (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=6.43min , 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1,1-dimethylethyl ester

Step A:

tert-butyl 3-amino-3-methylcrotonate

Activation of zinc: Zn (20 g) was added to a stirred 3N HCl solution (50 mL) and stirred at room temperature for 15 minutes. The HCl solution was decanted and this process was repeated twice. The activated zinc was washed with distilled water (2x, 100 mL), ethanol (2x, 50 mL) and diethyl ether (2x, 50 mL). Then, the activated zinc was placed under reduced pressure for 12 hours at room temperature. To a stirred suspension of dry THF (10 mL) and activated zinc (0.83 g, 13 mmol) in a flame-dried 100 mL round bottom flask was added 5 drops of tert-butyl bromoacetate at room temperature. The mixture was then heated to reflux for 15 minutes. Acetonitrile 0.60ml (6mmol) was added immediately, and tert-butyl bromoacetate (1.50ml, 10mmol) was added dropwise over 30 minutes. The reaction mixture turned green when about 2/3 of the tert-butyl bromoacetate was added. The mixture was refluxed for an additional 30 minutes, then cooled to room temperature. To the stirred solution was added THF (30 mL) and _K2CO3 ( ₂ g dissolved in 3 mL of water) and stirred vigorously for 30 min. This solution was then placed in a centrifuge tube and centrifuged. The supernatant was decanted and the pellet was resuspended in THF (30 mL), shaken vigorously and centrifuged (2x). The combined supernatants were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 0.78 g (83%) of tert-butyl 3-amino-3-methylcrotonate as a pale yellow liquid which solidified at 0°C to give Pale yellow solid. ¹ H NMR (250 MHz, CDCl ₃ ) δ 1.45 (s, 9H), 1.84 (s, 3H), 4.43 (s, 2H). ¹³ C NMR (62.5 MHz, CDCl ₃ ) δ 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 (3.30 g, 30 mmol) was heated in ethanol (15 mL) until all solids 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 reduced pressure concentrate. The residue was subjected to flash column chromatography (Al ₂ O ₃ , ethyl acetate) to obtain 3.57 g of the title compound (14.4 mmol, 48%) as brown crystals. mp114.0-116.0°C.

¹ H NMR (250MHz, DMSO) δ1.57(s, 9H), 2.55(s, 3H), 6.57(dd, J=8.6, 2.3Hz, 1H), 7.09(d, J=8.6Hz, 1H,) , 7.28 (d, J=2.3 Hz, 1H), 8.78 (s, 1H), 11.41 (s, 1H). ¹³ CNMR (62.5MHz, d ⁶ -MeOH) δ14.4, 29.1, 80.6, 105.3, 106.8, 112.2, 129.9, 131.1, 145.9, 153.1, 161.7.167.9.

Step C:

tert-butyl 4-(dimethylamino)methylene-5-hydroxy-2-methyl-3-indolecarboxylate

To stirred 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). The solution was stirred at 60°C for 10 hours, cooled and concentrated under reduced pressure. The residue was extracted with diethyl ether (30 mL), filtered, and the solvent was evaporated again under reduced pressure to give 1.54 g of the title compound (5.05 mmol, 84%) as brown crystals. mp151.0°C (decomposition).

¹ H NMR (250MHz, d ₆ -MeOH) δ1.63(s, 9H), 1.88(s, 3H), 2.61(s, 3H), 2.90(s, 6H), 4.76(s, 2H), 6.81( d, J=8.7Hz, 1H), 7.27 (d, J=8.6Hz, 1H). ¹³ C NMR (62.5MHz, d ₆ -MeOH) δ16.1, 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 (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+) t=7.75min, m/z=305.4 (M +1).

Step D:

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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 diethyl ether (20 mL) was added 0.082 g (0.20 mmol) of the iminoammonium salt (Example 3, Step B). This solution was extracted with ether (3 x 30 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford the enamine as a white solid. 1.0 mL of dioxane was added to the enamine followed by tert-butyl 4-(dimethylamino)methylene-5-hydroxy-2-methyl-3-indolecarboxylate (0.061 g, 0.20 mmol) , followed by the addition of 0.5 mL of dioxane. This 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 give 0.031 g of the desired product (0.08 mmol, 40%) as a white solid; mp214.0°C (decomposition).

¹ H NMR (250MHz, CDCl ₃ ) δ1.45(m, 4H), 1.61(s, 9H), 1.69(m, 5H), 1.89(m, 1H), 2.14(d, J=15Hz, 1H), 2.49(m, 2H), 2.56(s, 3H), 2.84(d, J=6Hz, 2H), 3.06(m, 1H), 3.48(dd, J=18, 7Hz, 1H), 6.74(d, J =8.6Hz, 1H), 7.01(d, J=8.6Hz, 1H), 8.07(s, 1H). ¹³ C NMR (62.5MHz, CDCl ₃ ) δ14.8, 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 (150mm×4.6mm, C-18, 5 microns, 10mM NH ₄ OAc/CH ₃ CN, APCI+)t=7.98min, m/z=397.4(M+1). Elemental analysis: calculated value C, 72.70; H, 8.13; N, 7.06. found value C, 72.28; H, 8.23; N, 6.72.

Example 19

2,6a,7-Trimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene-1- ethyl formate

Step A:

1,6-Dimethyl-1,2,3,4-tetrahydro-pyridine

1,6-Dimethyl-1,2,3,4-tetrahydro-pyridine was synthesized as described by Lipp A., Liebigs Annl. Chem., 1898;289:216.

Step B:

2,6a,7-Trimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene-1- ethyl formate

1,6-Dimethyl-1,2,3,4-tetrahydropyridine (0.100 g, 0.899 mmol, Example 19, Step A) and 4-dimethylaminomethyl-5-hydroxy-2- A solution of ethyl methyl-1H-indole-3-carboxylate (0.200 g, 0.724 mmol) in dioxane (0.800 mL) was heated at 100° C. for 4 hours under a nitrogen atmosphere. An additional 1.0 mL of dioxane was added and heating continued for 24 hours. The solution was cooled to room temperature, concentrated, and the residue was purified by flash column chromatography on silica gel, eluting with 50%-75% ethyl acetate: hexane, and recrystallized from ethyl acetate to give 12mg (4.8%) 2,6a,7-Trimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene-1- Ethyl formate, white powder; mp169-173℃;

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.34 (m, 2H), 1.36 (t, J=7.08 Hz, 3H, CH ₂ CH ₃ ), 1.45 (s, 3H, CH ₃ C(O)N), 1.56(m, 2H), 1.66(m, 1H), 1.93(m, 1H), 2.56(s, 3H, CH ₃ ), 2.58(s, 3H, CH ₃ ), 2.87(bd, J=17.58Hz, 2H), 3.50 (dd, J=18.19, 6.72Hz, 1H,), 4.31 (q, J=7.08Hz, 2H, _CH2CH3 ), 6.68 (d, J=8.79Hz, 1H, _ArH ), 7.01 (d, J=8.30Hz, 1H, ArH), 8.03 (bs, 1H, NH); MS (APCI ⁺ ) m/z 343.2 (MH ⁺ ).C ₂₀ H ₂₆ N ₂ O ₃ ·0.17H ₂ O Calculated and analyzed: C, 69.53; H, 7.68; N, 8.11. Found: C, 69.52; H, 7.33; N, 7.84.

Example 20

7-Ethyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene -Ethyl 1-formate

Step A: 1-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate

1-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate was synthesized according to the method disclosed by Ladenburg A., Liebigs Ann. Chem., 1899;304:54.

Step B: 7-Ethyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta [a] Ethyl anthracene-1-carboxylate

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 washed with 50 % sodium hydroxide aqueous solution to strong alkalinity. This aqueous solution was extracted with 4 x 10 mL of diethyl ether, and the combined extracts were washed with 1 x 10 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, 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. This residue was dissolved in dioxane (0.750 mL) and ethyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (0.200 g, 0.724 mmol ). The resulting solution was heated to reflux under a nitrogen atmosphere for 4 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 100% ethyl acetate and recrystallized from ethyl acetate to give 98 mg (38%) of 7-ethyl-2,6a-dimethyl-7 , 8, 9, 10, 10a, 11-hexahydro-3H, 6aH-6-oxa-3, 7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester, as white powder: mp173- 174°C;

IR (KBr) 3298, 2930, 2856, 1669, 1433, 1238, 1094 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ1.16 (m, 3H, CH ₃ CH ₂ N), 1.37 (m, 1H) , 1.40(m, 1H), 1.48(s, 2H), 1.56(s, 2H), 1.64(m, 2H), 1.97(m, 1H), 2.61(s, 3H, CH ₃ ), 2.72(m, 1H), 2.84(m, 1H), 2.90(bd, J=19.04Hz, 2H), 3.16(m, 1H), 3.54(dd, J=18.31, 6.78Hz, 1H), 4.35(qd, J=7.14 , 1.65Hz, 2H, OCH ₂ CH ₃ ), 6.70 (d, J=8.61Hz, 1H, ArH), 7.03 (d, J=8.61Hz, ArH), 8.06 (bs, 1H, NH); MS (APCI ⁺ ) m/z 357.1 (MH ⁺ ). Anal. Calcd. for C ₂₁ H ₂₈ N ₂ O ₃ : C, 70.76; H, 7.92; N, 7.86. Found: C, 70.49; H, 7.80; N, 7.66 .

Example 21

Isomer A:

6a-Ethyl-2,7-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene -Ethyl 1-formate

Step A: 6-Ethyl-1-methyl-2,3,4,5-tetrahydropyridinium perchlorate

6-Ethyl-1-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate according to Leonard N.J.; Hauck, Jr., F.P., J.Am.Chem.Soc., 1957; 79 :5279 synthesized by the method described.

Step B: 6a-Ethyl-2,7-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta [a] Ethyl anthracene-1-carboxylate

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 washed with 50% Treat with aqueous sodium hydroxide solution to strong alkalinity. This aqueous solution was extracted with 4 x 15 mL of diethyl ether, and the combined extracts were washed with 1 x 15 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated into the reaction flask to give 6-ethyl-1-methanol base-1,2,3,4-tetrahydro-pyridine. This residue was dissolved in dioxane (2.1 mL), and ethyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (0.581 g, 2.10 mmol ). When it was stirred at room temperature under a nitrogen atmosphere for 2 hours, heated at 50°C for 24 hours, at 60°C for 3 hours, at 70°C for 17 hours and at 89-90°C for 4.5 hours, the resulting solution was analyzed by TLC and MS monitor. The dark solution was cooled to room temperature and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 20-60% ethyl acetate:hexanes to afford 56 mg (7.5%) of 6a-ethyl-2,7-dimethyl-7, 8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester single isomer A, which has Larger Rf value, white powder: mp144-147℃;

IR(KBr) 3375, 2975, 2937, 2858, 1671, 1470, 1432, 1245, 1202cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ0.91(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, 1H), 1.76(m, 1H), 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=18.07Hz, 1H), 2.88(m, 1H ), 3.37 (dd, J=18.07, 6.59Hz, 1H), 4.31 (m, 2H, OCH ₂ CH ₃ ), 6.67 (d, J=8.79Hz, 1H, ArH), 6.99 (d, J=8.55Hz , 1H, ArH), 8.03 (bs, 1H, NH); MS (APCI ⁺ ) m/z 357.2 (MH ⁺ ).C ₂₁ H ₂₈ N ₂ O ₃ ·0.04H ₂ O Calcd. Anal: C, 70.61 H, 7.92; N, 7.84; Water, 0.22. Found: C, 70.27; H, 7.92; N, 7.58;

Example 22

Isomer B:

6a-Ethyl-2,7-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a] Ethyl anthracene-1-carboxylate

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 washed with 50% Treat with aqueous sodium hydroxide solution to strong alkalinity. This aqueous solution was extracted with 4 x 15 mL of diethyl ether, and the combined extracts were washed with 1 x 15 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated into the reaction flask to give 6-ethyl-1-methanol base-1,2,3,4-tetrahydro-pyridine. This residue was dissolved in dioxane (2.1 mL) and ethyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (0.581 g, 2.10 mmol) was added. When it was stirred at room temperature under a nitrogen atmosphere for 2 hours, heated at 50°C for 24 hours, at 60°C for 3 hours, at 70°C for 17 hours and at 89-90°C for 4.5 hours, the resulting solution was analyzed by TLC and MS monitor. The dark solution was cooled to room temperature and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 20-60% ethyl acetate:hexanes to afford 37 mg (4.9%) of 6a-ethyl-2,7-dimethyl-7, 8,9,10,10a,11-Hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylate, single isomer B, which With a small Rf value, it is a fine off-white powder: mp158-161°C;

IR(KBr) 3310, 2957, 2928, 2862, 1654, 1436, 1419, 1204cm ^-1 ; ¹ H NMR (400MHz) δ1.08(m, 3H, CH ₃ CH ₂ C(O)N), 1.20(m , 1H), 1.37(m, 3H, OCH ₂ C ₂ H ₃ ), 1.41(m, 1H), 1.52(s, 3H, CH ₃ ), 1.59(m, 2H), 1.85(bd, J=13.18Hz , 1H), 2.30(m, 1H), 2.35(m, 2H), 2.58(s, 3H, CH ₃ ), 2.91(m, 1H), 3.11(m, 2H), 4.32(m, 2H, OCH ₂ CH ₃ ), 6.72 (d, J=8.55Hz, 1H, ArH), 7.00 (d, J=8.79Hz, 1H, ArH), 8.03 (bs, 1H, NH); MS (APCI ⁺ ) m/z 357. 2(MH ⁺ ). Anal. Calcd. for C ₂₁ H ₂₈ N ₂ O ₃ : C, 70.76; H, 7.92; N, 7.86. Found: C, 71.45; H, 8.44; N, 6.65. HPLC (ALLTECH/ALLTIMAC -18 1:1 H ₂ O/CH ₃ CN+0.05%TFA): retention time=4.940min, 99.40% purity.

Example 23

6a,7-diethyl-2-methyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene -Ethyl 1-formate

Step A: 1,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate

1,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate according to Leonard N.J., Hauck, Jr., F.P., J.Am.Chem.Soc., 1957;79:5279 synthesis.

Step B: 6a,7-diethyl-2-methyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa

3,7-Ethyl diaza-cyclopenta[a]anthracene-1-carboxylate

1,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.485 g, 2.02 mmol, Example 23, Step A) was dissolved in a minimum amount of water and oxidized with 50% hydroxide Treat with aqueous sodium solution to strong alkalinity. This aqueous solution was extracted with 4 x 15 mL diethyl ether, and the combined extracts were washed with 1 x 15 mL saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated into the reaction vial to give 207 mg (1.49 mmol) of 1, 6-Diethyl-1,2,3,4-tetrahydro-pyridine. This residue was dissolved in dioxane (1.3 mL) and ethyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (0.373 g, 1.35 mmol) was added . The resulting solution was heated at 100° C. under a nitrogen atmosphere for 7 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 20-100% ethyl acetate:hexanes and recrystallized from ethyl acetate to give 123 mg (25%) of 6a,7-diethyl- 2-Methyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene-1-carboxylic acid ethyl ester, as White crystalline solid: mp162-163°C;

IR (KBr) 3390, 2972, 2929, 2859, 1654, 1432, 1201, 1097 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ0.900 (m, 2H, CH ₃ CH ₂ C(O)N), 1.11(m, 2H, CH3CH2N) _, 1.34 ₍ m, 2H), 1.36(m _{, 3H} , CH3CH2O), 1.57(m, 2H), 1.85(m, 2H), 2.06(m , 1H), 2.57(s, 3H, CH ₃ ), 2.70(m, 2H), 2.79(bd, J=18.31Hz, 1H), 2.84(m, 1H), 3.00(m, 1H), 3.37(m , 1H), 4.31(m, 2H, _CH3CH2O ), 6.64(d, J= _8.55Hz , 1H, ArH), 6.98(d, J=8.55Hz, 1H, ArH), 8.00(bs, 1H , NH); MS (APCI ⁺ ) m/z 371.1 (MH ⁺ ). Anal. calculated for C ₂₂ H ₃₀ N ₂ O ₃ : C, 71.32; H, 8.16; N, 7.56. Found: C, 71.28; H, 7.77; N, 7.32.

Example 24

7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a] Ethyl anthracene-1-carboxylate

Step A: 1-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate

1-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate according to Mhrle H.; Dwuletzki H.Z., Naturforsch., B: Anorg.Chem., Org.Chem ., 1986; 41b: 1323 described the method.

Step B: 7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa

3,7-Ethyl diaza-cyclopenta[a]anthracene-1-carboxylate

Dissolve excess 1-benzyl-6-metha-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 24, Step A) in a minimum amount of water and wash with 50% aqueous sodium hydroxide Handle to strongly alkaline. The aqueous solution was extracted with 4 x 20 mL of ether, and the combined extracts were washed with 1 x 20 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated to afford 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). The resulting solution was heated at 80-90 °C under nitrogen atmosphere for 20 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 10-20% ethyl acetate:hexanes and recrystallized from ethyl acetate to give 208 mg (42%) of 7-benzyl-2,6a- Off-white powder of ethyl dimethyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene 1-carboxylate : mp196-198℃;

IR (KBr) 3397, 2983, 2923, 2897, 2854, 1668, 1432, 1200, 1097cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ1.36(m, 1H), 1.37(m, 3H, OCH _{2 CH3} ), 1.50(s, 3H, _CH3C (O)N), 1.53(m, 3H), 2.03(m, 1H), 2.56(m, 1H), 2.58(s, 3H, _CH3 ), 2.71(m, 1H), 2.94(d, J=18.07Hz, 1H), 3.53(dd, J=18.07, 6.84Hz, 1H), 3.58(d, J=15.14Hz, 1H, NCH(H)Ph) , 4.32(m, 2H, OCH ₂ CH ₃ ), 4.47(d, J=14.89Hz, 1H, NCH(H)Ph), 6.71(d, J=8.55Hz, 1H, ArH), 7.01(d, J =8.55Hz, 1H, ArH), 7.18(t, J=7.08Hz, 1H, PhH), 7.28(m, 2H, PhH), 7.35(d, J=7.33Hz, 2H, PhH), 8.06(bs, 1 H, NH); MS (APCI ⁺ ) m/z 419.2 (MH ⁺ ). Anal. Calcd. for C ₂₆ H ₃₀ N ₂ O ₃ ·H ₂ O: C, 74.39; H, 7.24; N, 6.67; Water , 0.30. Measured value: C, 74.27; H, 7.25; N, 6.54; water, 0.31.

Example 25

Isomer A:

2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a] Ethyl anthracene-1-carboxylate

Step A: 1-Methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate

The method for the synthesis of 1-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate is described in Leonard N.J.; Hauck Jr.F.P., J.Am.Chem.Soc., 1957 ;79:5279.

Step B: 2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta [a] Ethyl anthracene-1-carboxylate

Dissolve excess 1-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 25, Step A) in a minimum amount of water and wash with 50% NaOH Aqueous treatment to strong alkaline. The aqueous solution was extracted with 4 x 20 mL of ether, and the combined extracts were washed with 1 x 20 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated to afford the enamine. 1-Methyl-6-phenyl-1,2,3,4,-tetrahydro-pyridine (0.428 g, 2.47 mmol) was dissolved in dioxane (1.8 mL) and 4-dimethylaminomethyl- 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol). The reaction mixture was heated at 75-80°C under nitrogen atmosphere for 16 hours, 1.0 mL of dioxane was added and heating was continued at 90°C for 5 hours. Dry toluene (1.0 mL) was added to this 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 eluting with 10-50% ethyl acetate: hexanes to give single isomer A with a lower Rf value, which was purified with diethyl ether: hexanes Recrystallization afforded 73 mg (15%) of 2,7-dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7- Ethyl diaza-cyclopenta[a]anthracene-1-carboxylate, off-white powder; mp176-177℃;

IR (KBr) 3400, 2942, 2930, 2859, 1647, 1434, 1206, 1099, 1079 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.20 (m, 3H, OCH ₂ CH ₃ ), 1.48 (m , 2H), 1.67(d, J=13.18Hz, 1H), 1.84(m, 1H), 2.13(s, 3H, CH ₃ ), 2.35(m, 1H), 2.52(s, 3H, CH ₃ ), 2.58(m, 1H), _2.68 (m, 1H), 2.81(d, J=17.33Hz, 1H), 2.90(m, 1H), 4.17(q, J=7.08Hz, 2H, _OCH2CH3 ), 6.89(d, J=8.79Hz, 1H, ArH), 7.06(d, J=8.79Hz, 1H, ArH), 7.15(m, 3H, PhH), 7.35(m, 2H, PhH), 8.07(bs, 1H, NH); MS (APCI ⁺ ) m/z 405.2 (MH ⁺ ). Anal. Calcd. for C ₂₅ H ₂₈ N ₂ O ₃ : C, 74.23; H, 6.98; N, 6.93. Found: C, 73.93 ; H, 7.11; N.6.66.

Example 26

Isomer B:

2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6-oxa-3,7-diazacyclopenta[a]anthracene -Ethyl 1-formate

Dissolve excess 1-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 25, Step A) in a minimum amount of water and wash with 50% NaOH Aqueous treatment to strong alkaline. The aqueous solution was extracted with 4 x 20 mL of ether, and the combined extracts were washed with 1 x 20 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated to afford the enamine. 1-Methyl-6-phenyl-1,2,3,4,-tetrahydro-pyridine (0.428 g, 2.47 mmol) was dissolved in dioxane (1.8 mL) and 4-dimethylaminomethyl - 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol). The reaction mixture was heated at 75-80°C under nitrogen atmosphere for 16 hours, 1.0 mL of dioxane was added and heating was continued at 90°C for 5 hours. Dry 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, eluting with 10-50% ethyl acetate: hexane, recrystallized from diethyl ether: hexane and the filtrate was further purified by silica gel chromatography, using 1-10 Elution with % ethyl acetate:hexanes gave 70 mg (14%) of 2,7-dimethyl-6a-phenyl-7,8,9,10,10a,11-hexahydro-3H,6aH-6- Oxa-3,7-diaza-cyclopenta[a]anthracene-1-carboxylic acid ethyl ester single isomer B, which has a large Rf value peach-colored powder: mp184-186 °C;

IR(KBr) 3380, 2926, 1698, 1684, 1436, 1073cm ^-1 ; 1H NMR (400MHz, CDCl ₃ ) δ1.37(t, J=7.08Hz, 3H, OCH ₂ CH ₃ ), 1.49(m, 2H ), 1.64(m, 1H), 1.76(m, 1H), 2.29(m, 1H), 2.31(s, 3H, CH ₃ ), 2.59(s, 3H, CH ₃ ), 2.97(d, J=17.58 Hz, 1H), 3.52(m, 1H), 3.77(m, 1H), 4.32(m, 2H, OCH ₂ CH ₃ ), 4.89(bs, 1H), 6.74(d, J=8.55Hz, 1H, ArH ), 7.02 (d, J=8.55Hz, 1H, ArH), 7.33 (m, 5H, PhH), 8.06 (bs, 1H, NH); MS (APCI ⁺ ) m/z 405.2 (MH ⁺ ).C Anal. Calcd _{for 25} H ₂₈ N ₂ O ₃ : C, 74.23; H, 6.98; N, 6.93. Found: C, 74.18; H, 6.90; N, 6.72

Example 27

1H,7H-Indoleazino[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

Step A: 2,3,5,6,7,8-Hexahydro-1H-indoxazinium perchlorate

2,3,5,6,7,8-Hexahydro-1H-indolazinium perchlorate was synthesized as described by Reinecke M.G.; Kray L.R., J.Org. Chem., 1964;29:1736.

Step B: 1H,7H-Indoleazino[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

2,3,5,6,7,8-Hexahydro-1H-indolazinium perchlorate (0.330 g, 1.48 mmol, Example 27, Step A) was dissolved in a minimum amount of water and washed with 50% hydrogen Aqueous sodium oxide treatment to strong alkalinity. This aqueous solution was extracted with 4 x 15 mL diethyl ether, and the combined extracts were washed with 1 x 15 mL saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated into the reaction flask to give 143 mg (1.16 mmol) of the enamine . Dissolve 1,2,3,5,6,7-hexahydro-indolezine in dioxane (1.5 mL) and add 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H - Ethyl indole-3-carboxylate (0.321 g, 1.16 mmol). The resulting solution was heated to reflux under a nitrogen atmosphere for 5 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 100% acetone and recrystallized from ethyl acetate to give 129 mg (31%) of 1H,7H-indoleazino[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, off-white Powder: mp170-172℃;

IR (KBr) 3396, 3353, 2929, 2853, 1668, 1434, 1156, 1096, 1075cm ^-1 ; ¹ H NMR (300MHz, CDCl ₃ ) δ1.38(m, 2H), 1.40(t, J=7.14Hz , 3H, OCH ₂ CH ₃ ), 1.68(m, 3H), 1.90(m, 3H), 2.05(m, 1H), 2.61(s, 3H, CH ₃ ), 2.74(m, 1H), 2.84(m , 1H), 2.97(d, J=17.40Hz, 1H), 3.09(m, 2H), 3.47(dd, J=17.76, 6.78Hz, 1H), 4.36(m, 2H, OCH ₂ CH ₃ ), 6.67 (d, J=8.61Hz, 1H, ArH), 7.03 (d, J=8.61Hz, 1H, ArH), 8.06(bs, 1H, NH); MS(APCI ⁺ ) m/z 355.2 (MH ⁺ ) .C ₂₁ H ₂₆ N ₂ O ₃ 0.23H ₂ O Calcd. Analytical value: C, 70.34; H, 7.44; N, 7.81. Found: C, 70.35; H, 7.48; N, 7.61.

Example 28 3H,7H-Pyrrolizino[1',8':5,6]pyrano[3,2-e]indole-1-acetic acid, 8,9,11,12,12a , 13 Hexahydro-2-methyl-, ethyl ester

Step A: 1,2,3,5,6,7-Hexahydro-pyrrolidinium perchlorate

1,2,3,5,6,7-Hexahydro-pyrrolidinium perchlorate was synthesized as described in Miyano S. et al., Synthesis, 1978;9:701.

Step B: 3H,7H-Pyrrolazino[1',8':5,6]pyrano[3,2-e]indole-1-acetic acid, 8,9,11,12,12a,13- Hexahydro-2-methyl-, ethyl ester

1,2,3,5,6,7-Hexahydro-pyrrolidinium perchlorate (0.904 g, 4.31 mmol, Example 28, Step A) was dissolved in a minimum amount of water and washed with 50% aqueous sodium hydroxide Handle to strongly alkaline. The aqueous solution was extracted with 4 x 15 mL of ether, and the combined extracts were washed with 1 x 15 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated into the reaction flask to give 325 mg (2.98 mmol) of the alkene Amine, 2,3,5,6-tetrahydro-1H-pyrrolizine. This residue was dissolved in dioxane (2.8 mL) and ethyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (0.794 g, 2.88 mmol) was added . The resulting solution was heated at 80 °C under a nitrogen atmosphere for 17 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 15% MeOH: _CH2Cl2 and recrystallized from diethyl ether to _give 105 mg (11%) of 3H,7H-pyrrolidazino[1',8 ': 5,6]pyrano[3,2-e]indole-1-acetic acid, 8,9,11,12,12a,13-hexahydro-2-methyl-, ethyl ester, as white powder ;mp206-207℃;

IR (KBr) 2972, 2901, 2864, 2828, 1694, 1429, 1196, 1087 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.37 (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, 1H), 2.60 (s, 3H, CH ₃ ), 3.22 (m, 1H), 3.35 (m, 1H), 3.36 (d, J=4.88Hz, 1H), 4.34 (m, 2H, OCH ₂ CH ₃ ), 6.76 (d , J=8.55Hz, 1H, ArH), 7.00(d, J=8.55Hz, 1H, ArH, 8.26(m, 1H, NH); MS(APCI ⁺ ) m/z 341.1(MH ⁺ ).C ₂₀ Calcd for H ₂₄ N ₂ O ₃ : C, 70.57; H, 7.11; N, 8.23. Found: C, 70.40; H, 7.27; N, 7.94.

Example 29

2-methyl-8,9,10,10a,11,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a]cyclopenta [h]Ethyl anthracene-1-carboxylate

Step A: 1,3,4,8,9,9a-Hexahydro-2H-quinolazine

1,3,4,8,9,9a-Hexahydro-2H-quinolazine was synthesized according to the method described by Bohlmann F. et al., Chem. Ber., 1973;106:3026.

Step B: 2-Methyl-8,9,10,10a,11,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza-benzo[a Ethyl cyclopenta[h]anthracene-1-carboxylate

1,3,4,8,9,9a-Hexahydro-2H-quinolazine (0.372 g, 2.71 mmol, Example 29, Step A) was dissolved in dioxane (2.7 mL) and 4-dimethyl Ethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (0.374 g, 1.36 mmol). The resulting solution was heated at 80° C. under a nitrogen atmosphere for 17 hours, refluxed for 24 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 10-20% ethyl acetate: _CH2Cl2 and _{recrystallized} from cyclohexane to give 71 mg (14%) of 2-methyl-8 , 9, 10, 10a, 11, 12, 12a, 13-octahydro-3H, 6aH, 7H-6-oxa-3, 6b-diazabenzo[a]cyclopenta[h]anthracene-1- Ethyl formate, off-white powder: mp178-180°C;

IR(KBr) 3372, 2929, 2859, 1669, 1654, 1435, 1198, 1095, 1079cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ1.15(m, 1H), 1.35(t, J=7.08Hz , 3H, OCH ₂ CH ₃ ), 1.36(m, 4H), 1.49(m, 2H), 1.65(m, 3H), 2.20(m, 1H), 2.58(s, 3H, CH ₃ ), 2.68(m , 1H), 2.82(m, 1H), 2.89(d, J=17.58Hz, 1H), 3.05(m, 1H), 3.45(m, 1H), 4.31(m, 2H, OCH ₂ CH ₃ ), 4.68 (s, 1H, CH(O)N), 6.68(d, J=8.79Hz, 1H, ArH), 6.99(d, J=8.55Hz, 1H, ArH), 8.03(bs, 1H, NH); times To diastereomer identification peak ¹ H NMR (400MHz, CDCl ₃ ) δ6.75 (d, J=8.55Hz, 1H, ArH); MS (APCI ⁺ ) m/z369.1 (MH ⁺ ).C ₂₂ H ₂₈ N ₂ O ₃ Calculated analysis value: C, 71.71; H, 7.66; N, 7.60. Found value: C, 71.96; H, 7.92; N, 7.09. HPLC (ALLTECH/ALLTIMA C-18 150mm×4.6mm Column, 1:1 H ₂ O/CH ₃ CN+0.5% TFA): retention time = 3.526 min (11.26%), 3.882 min (85.82%) (diastereoisomers), 97.08% purity. HPLC (Alltima Silica5 microns, 150mm×4.5mm column, 95:5 hexane+0.05%Et ₂ NH, ethanol+0.05%Et ₂ NH): retention time=5.19min (84.08%), 5.87min (8.63%) (diastereo isomers), 92.71% purity.

Example 30

3H-pyrido[1″,2″:1′2′]azepine[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-azepine[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

Step A: 2,3,4,6,7,8,9,10-Octahydro-pyrido[1,2-a]azepine perchlorate

A method for the synthesis of 2,3,4,6,7,8,9,10-octahydro-pyrido[1,2-a]azepine perchlorate is described in McIntosh J.M. et al., Can.J.Chem. , 1983;61:2016.

Step B:

Dissolve excess 2,3,4,6,7,8,9,10-octahydro-pyrido[1,2-a]azepine perchlorate (Example 30, step A) in a minimum water and treated with 50% aqueous sodium hydroxide until strongly basic. This aqueous solution was extracted with 4 x 20 mL of diethyl ether, and the combined extracts were washed with 1 x 20 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 582 mg (3.85 mmol) of the crude enamine. This residue was dissolved in dioxane (3.8 mL) and ethyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (0.797 g, 2.88 mmol) was added . The reaction mixture was heated at 80°C under a nitrogen atmosphere for 6 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate: _CH2Cl2-100 % ethyl acetate and recrystallized from isooctane to give 18 mg (2%) _of the single compound , 3H-pyrido[1″,2″:1′2′]azepine[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-azepine[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 are fine white powder: mp118-121℃;

IR (KBr) 3379, 3306, 2926, 2853, 1671, 1435, 1151, 1094, 1073cm ^-1 ; 1H NMR (400MHz, CDCl3) δ0.86(m, 1H), 1.35(m, 3H), 1.36(m , 3H, OCH ₂ CH ₃ ), 1.45(m, 3H), 1.60(m, 3H), 1.69(dd, J=14.65, 10.01Hz, 1H), 1.95(m, 1H), 2.19(m, 1H) , 2.41(m, 1H), 2.54(m, 1H), 2.57(s, 3H, CH ₃ ), 2.80(d, J=18.56Hz, 1H), 3.11(m, 1H), 3.34(m, 1H) , 3.48(m, 1H), 4.31(m, 2H, OCH ₂ CH ₃ ), 6.70(d, J=8.55Hz, 1H, ArH), 6.98(d, J=8.55Hz, 1H, ArH), 8.01( bs, 1H, NH); MS (APCI ⁺ ) m/z 383.1 (MH ⁺ ). rC ₂₃ H ₃₀ N ₂ O ₃ Calculated analysis: C, 72.22; H, 7.91; N, 7.32. Found: C , 72.14; H, 7.95; N, 6.97.

Method J: General method for Mannich reactions:

The amide (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 dimethylamine (40%, 2.42 mmol, 2.2 eq) were added and the reaction was stirred. After several hours, a white precipitate begins to form in the solution; the reaction can be accelerated by heating to 5°C. At the end of the reaction, little or no starting material is present. Water was added to the solution, and the mixture was cooled in an ice bath. The resulting white solid was collected by filtration and dried in vacuo.

Method K: General method for condensation reactions:

1,2,3,4,6,7,8,9-Octahydro-quinazinium perchlorate (17.8 mmol, 1.2 eq) was converted to the enamine by dissolving the imine in 1 N NaOH ( 10 mL) and this solution was extracted with 2 x 20 mL ether. The combined extracts were dried and evaporated in vacuo to give a white solid. This solid was dissolved in dioxane (10 mL). 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methyl or benzylamide (14.8 mmol, 1 eq) was dissolved in dioxane (10 mL) and added to In this enamine. The solution was refluxed for 19 hours and a white precipitate formed. This mixture was cooled in an ice bath, and the resulting solid was collected by filtration. The solid was washed with a small amount of _CH3CN and dried under vacuum at 50°C for 24 hours.

Example 31

8,9,11,12,13,13a,14,14a-octahydro-N,2-dimethyl-pyrrolo[3',2':5,6][1]-benzopyrano[ 3,2-i]quinolazine-1-carboxamide

Step A:

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid methylamide was synthesized from intermediate W according to Method J. Yield: 0.186g (63.2%); mp: decomposed at >210°C;

IR: 3319, 1615, 1515, 1433, 1218, 801cm ^-1 .1H NMR (DMSO-d ₆ ) δ: 2.14(s, 6H, CH ₂ N(CH ₃ ) ₂ ), 2.28(s, 3H, ArCH ₃ ), 2.70(d, J=3.91Hz, 3H, CONHCH ₃ ), 3.69(s, 2H, CH ₂ N(CH ₃ ) ₂ ), 6.48(d, J=8.55Hz, 1H, ArH), 6.97(d , J=8.55Hz, 1H, ArH), 8.06(s, 1H, CONHCH ₃ ), 10.88(s, 1H, indole NH). MS (APCI+): m/z 262.1 (MH ⁺ ); C ₁₄ H Anal. Calcd. _{for 19} N ₃ O ₂ : C, 64.35, H, 7.33, N, 16.08. Found: C, 64.26, H, 7.44, N, 15.87.

Step B:

8,9,11,12,13,13a,14,14a-octahydro-N,2-dimethylpyrrolo[3',2':5,6][1]benzopyrano[3, 2-i] Quinazine-1-carboxamide Synthesized according to Method K. Yield: 0.057g (9.8%); mp: decomposed at >210°C;

IR: 3392, 3057, 2935, 2857, 1625, 1429, 1215cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ1.08-1.54 (m, 9H, fatty CH ₂ and CH), 1.63-1.69 (m, 1H, fatty CH), 1.81-1.93 (m, 1H, fatty CH), 2.27 (s, 3H, ArCH ₃ ), 2.31-2.45 (m, 3H, obscured by DMSO peak, fatty CH), 2.63-2.69 (m , 1H, fatty CH), 2.68 (d, J=3.91Hz, 3H, CONHCH ₃ ), 2.87-2.95 (m, 1H, fatty CH), 3.05 (dd, J=18.3, 5.37Hz, 1H, fatty CH) , 6.49(d, J=8.79Hz, 1H, ArH), 6.94(d, J=8.79Hz, 1H, ArH), 7.70-7.75(m, 1H, CONHCH ₃ ), 10.9(s, 1H, NH); MS (APCI+): m/z 354.2 (MH ⁺ ); C ₂₁ H ₂₇ N ₃ O ₂ ·0.5C ₄ H ₈ O ₂ (CH ₃ CO ₂ Et)

Calcd: C, 69.49, H, 7.86, N, 10.57. Found: C, 69.64, H, 7.75, N, 10.54.

Example 32

8,9,11,12,13,13a,14,14a-octahydro-2-methyl-N-(phenylmethyl)-pyrrolo[3',2':5,6][1]benzene Pyrano[3,2-i]quinazine-1-carboxamide

Step A:

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzylamide Synthesized from intermediate X according to Method J.

Yield: 0.582g (69.2%); mp: 208-210°C;

IR: 3312, 1610, 1510, 1437, 1207, 747, 697 (cm ^-1 ). ¹ H NMR (DMSO-d ₆ ) δ: 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=5.86Hz, 2H, CONHCH ₂ ), 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, CONHCH ₂ ), 10.76 (s, 1H, aromatic OH) , 10.91 (s, 1H, indole NH). MS (APCI+): m/z 338.2 (MH ⁺ ); C ₂₀ H ₂₃ N ₃ O ₂ Calculated analysis value; C, 71.19, H, 6.87, N, 12.45 .Measured values: C, 70.82, H, 6.86, N, 12.24.

Step B:

Example 32 was synthesized according to Method K. Yield: 0.228g (35.9%); mp: 235-237°C;

IR: 3177, 2929, 1627, 1429, 1089cm ^-1 . ¹ H NMR (DMSO-d ₆ ) δ 1.08-1.17 (m, 3H, fatty CH ₂ and CH), 1.35-1.61 (m, 7H, fatty CH ₂ and CH), 1.85-1.88 (m, 1H, fatty CH), 2.26-2.45 (m, 3H, obscured by DMSO peak, fatty CH), 2.29 (s, 3H, ArCH ₃ ), 2.61-2.67 (m, 1H, fatty CH), 2.82-2.88 (m, 1H, fatty CH), 2.97 (dd, J = 17.6, 6.59 Hz, 1H, fatty CH), 4.33-4.43 (m, 2H, CONHCH ₂ Ph), 6.49 ( d, J=8.55Hz, 1H, ArH), 6.94(d, J=8.55Hz, 1H, ArH), 7.17-7.31(m, 5H, ArH), 8.36(t, J=6.10Hz, 1H, CONHCH ₂ Ph), 10.9 (s, 1H, indole NH); MS (APCI+): m/z 430.2 (MH ⁺ ); Analysis for C ₂₇ H ₃₁ N ₃ O ₂ ·0.1C ₄ H ₈ O ₂ Calcd: C , 75.07, H, 7.31, N, 9.59. Found: C, 74.99, H, 7.33, N, 9.54.

Example 33

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxamide, N-ethyl-8,9,11,12,13 , 13a, 14, 14a-octahydro-2-methyl-

Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid ethylamide

Under a nitrogen atmosphere, 5-hydroxy-2-methyl-1-H-indolecarboxylic acid (3.28 g, 17.2 mmol) was dissolved in dry DMF (20 mL) and cooled to 0 °C in an ice-water bath. To this solution was added triethylamine (2.39 mL, 17.2 mmol) followed by solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphoric acid Salt (6.51 g, 17.2 mmol). The resulting reaction mixture was stirred at room temperature for 15 minutes and gaseous ethylamine was bubbled through for 10 minutes. After stirring at 0 °C for 15 min and then at room temperature for 15 min, the reaction mixture was mixed with 60 mL of EtOAc, and the resulting mixture was washed sequentially with 1N aqueous HCl (2×60 mL), brine (2×60 mL), and dried over sodium sulfate. The solution was concentrated in vacuo to give a solid. The crude product was further purified by flash chromatography (100% EtOAc) followed by recrystallization from ethyl acetate to give 0.81 g (18%) of the pure title compound as a white solid: mp 199-201 °C (dec);

IR3372, 1609, 1523, 1464, 1246, 1216, 1193cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ1.11 (t, J=7.14Hz, 3H, CH ₂ CH ₃ ), 2.48(s, 3H, ArCH ₃ ), 3.25 (quintet, J=6.96Hz, 2H, NHCH ₂ CH ₃ ), 6.54 (dd, J=8.61, 2.20Hz, 1H, ArH), 7.06 (d, J=8.42Hz, 1H, ArH), 7.09(d, J=2.01Hz, 1H, ArH), 7.23(t, J=5.68Hz, 1H, NHEt), 8.70(s, 1H, NH), 11.1(bs, 1H, OH); MS (APCI ⁺ ): m/z 219.1 (MH ⁺ ).C ₁₂ H ₁₄ N ₂ O ₂ 0.13H ₂ O Calcd. Analytical value: C, 65.34; H, 6.52; N, 12.70. Found: C, 65.00 ; H, 6.38; N, 12.64.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid acetamide

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid acetamide (0.708 g, 3.24 mmol) was mixed with 7 mL of EtOH, aqueous dimethylamine (40%, 0.895 mL, 7.13 mmol) was added, followed by Aqueous HCHO (37%, 0.315 g, 3.89 mmol). A clear reaction solution was obtained. The resulting reaction mixture was stirred at room temperature for 2 hours, during which time a precipitate formed. Filtration and vacuum drying afforded 0.298 g (33%) of the pure title compound as a white solid: mp 198-200°C (dec);

IR3346, 3189, 2986, 1615, 1436, 1215, 801cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ1.11 (t, J=7.14Hz, 3H, CH ₂ CH ₃ ), 2.18(s, 6H, N(CH ₃ ) ₂ ), 2.32 (s, 3H, ArCH ₃ ), 3.24 (quintet, J=6.78Hz, 2H, CH ₂ CH ₃ ), 3.78 (s, 2H, ArCH ₂ NMe ₂ ), 6.50 MS (APCI ⁺ ): m/z 276.1 (MH ⁺ ). Anal. Calcd. for C ₁₅ H ₂₁ N ₃ O ₂ : C, 65.43; H, 7.69; N, 15.26. Found: C, 65.24; H, 7.73; N, 14.92.

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxamide, N-ethyl-8,9,11, 12, 13, 13a, 14, 14a-octahydro-2-methyl-

To a mixture of perchlorate (263 mg, 1.11 mmol, Example 3, Step B) and 30 mL of diethyl ether was added 40 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 40 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 20 mL of dioxane, then 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethylamide (234 mg, 0.851 mmol) was added, The resulting reaction mixture was refluxed for 16 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a brown solid. The crude product was recrystallized from acetonitrile followed by further purification by chromatography (10% MeOH in chloroform) to give 0.070 g (17%) of the pure title compound as a yellow solid: mp 264-266 °C (dec);

IR3313, 2930, 1623, 1604, 1435, 1216, 872cm ^-1 ; ¹ H NMR (DMSO-d ₆ ) δ1.08 (t, J=7.14Hz, 3H, CH ₂ CH ₃ ), 1.18-1.58 (m, 9H, fatty CH ₂ and CH), 1.71-1.75 (m, 1H, fatty CH), 1.92-1.96 (m, 1H, fatty CH), 2.32 (s, 3H, ArCH ₃ ), 2.38-2.49 (m, DMSO Peak blur, 3H, fatty CH), 2.66-2.73 (m, 1H, fatty CH and CH ₂ ), 2.90-2.94 (m, 1H, fatty CH), 3.10 (dd, J=18.3, 6.78Hz, 1H, fatty CH), 3.23 (quintet, J=6.78Hz, NHCH ₂ CH ₃ ), 6.53 (d, J=8.79Hz, 1H, ArH), 6.98 (d, J=8.61Hz, 1H, ArH), 7.87( t, J=5.68Hz, 1H, NHEt), 10.9 (bs, 1H, exchangeable protons); MS (APCI ⁺ ): m/z 368.2 (MH ⁺ ).C ₂₂ H ₂₉ N ₃ O ₂ Calcd. : C, 71.90; H, 7.95; N, 11.43. Found: C, 71.52; H, 7.97; N, 11.25.

Example 34

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carbaldehyde, 8, 9, 11, 12, 13, 13a, 14, 14a -Octahydro-2-methyl-

To a solution of DMF (642 μL, 8.29 mmol) in _{CH2Cl2 , POCl3} (736 μL, 7.89 mmol) was added dropwise under nitrogen atmosphere. After stirring at room temperature for 10 minutes, add pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine, 3,7,8,9,10,12 , 13, 14, 14a, 15-Decahydro-2-methyl- (Example 4, 1.17g, 3.95mmol). When the reaction was shown to be complete by TLC, the reaction mixture was poured into 300 mL of saturated aqueous sodium bicarbonate and stirred vigorously for 10 minutes. The resulting mixture was extracted with _CHCl3 (4 x 100 mL), the combined organic phases were washed with water (1 x 200 mL) and brine (1 x 200 mL), dried over sodium sulfate, and concentrated in vacuo to give a golden solid. The crude product was further purified by flash chromatography (25% acetone in EtOAc). Recrystallization from EtOH/ _Et2O afforded 0.63 g (49%) of the pure title compound as a white solid: mp 262°C (dec);

IR3178, 2931, 1633, 1617, 1484, 1474, 1436, 1391, 1130, 1085, 868, 772cm ^-1 ; ¹ HNMR (DMSO-d ₆ ) δ1.14-1.59 (m, 9H, fatty CH ₂ and CH) , 1.75-1.87 (m, 2H, fatty CH), 2.34-2.54 (m, obscured by DMSO peak, 2H, fatty CH), 2.56 (s, 3H, ArCH ₃ ), 2.63-2.70 (m, 1H, fatty CH ), 2.83-2.90 (m, 2H, fatty CH), 3.22-3.29 (m, 1H, blurred by water peak, fatty CH), 6.60 (d, J=8.55Hz, 1H, ArH), 7.04 (d, J = 8.55Hz, 1H, ArH), 10.0 (s, 1H, ArCHO), 11.9 (bs, 1H, exchangeable protons); MS (APCI ⁺ ): m/z 325.2 (MH ⁺ ).C ₂₀ H ₂₄ N Calcd. for ₂ O ₂ : C, 74.05; H, 7.46; N, 8.63. Found: C, 73.97; H, 7.48; N, 8.58.

Example 35

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, methyl ester

Step A: Methyl 5-Hydroxy-2-methyl-1H-indole-3-carboxylate

For synthetic methods, see Nenitzescu Synthesis of 5-Hydroxyindole, Patrick, James B.; Saunders, Elizabeth K., Tetrahedron Lett., 1979; 42:4009-4012.

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

Methyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (10.0 g, 49.0 mmol) and aqueous dimethylamine (40%, 12.0 mL, 107 mmol) were mixed with 32 mL of EtOH, then aqueous HCHO was added (37%, 4.75 mL, 58 mmol). After stirring at room temperature for 16 hours, the reaction mixture was mixed with 100 mL of water. The resulting mixture was extracted with EtOAc (3 x 100), the combined organic phases were washed with water (1 x 100 mL) and brine (1 x 100 mL), dried over sodium sulfate and filtered. The filtrate was treated with hydrogen chloride gas and a precipitate formed which was isolated by filtration. Trituration with hot acetone (150 mL) gave 3.88 g of a white solid. The white solid was suspended in 150 mL of EtOAc and mixed with 100 mL of 10% aqueous potassium carbonate, the mixture was stirred until a clear solution was obtained which separated into two layers, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give 3.22 g (25%) of light brown crystals. A small batch of crude product was recrystallized from acetone/water to give the pure title compound as white crystals: mp 145-146°C;

¹ H NMR (CDCl ₃ ) δ2.33(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=8.55Hz, 1H, ArH), 7.04 (d, J=8.55Hz, 1H, ArH); MS (APCI ⁺ ): m/z 263.1 (MH ⁺ ) .Calc. for C ₁₄ H ₁₈ N ₂ O 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 (2.17 g, 9.10 mmol, Example 3, Step B) and 50 mL of diethyl ether was added 50 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 50 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 8 mL of dioxane, then indole mannich base (2.00 g, 7.60 mmol) was added, and the resulting reaction mixture was refluxed under nitrogen for 2.5 hours, then stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to a viscous oil. Recrystallization from acetonitrile afforded 1.75 g (63%) of the pure title compound as a white solid: mp 205-205.5°C;

IR3242, 2938, 1696, 1441, 1236, 1079, 884cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ1.21-1.80 (m, 9H, fatty CH ₂ and CH), 1.82-1.95 (m, 1H, fatty CH ), 2.09-2.13 (m, 1H, fatty CH), 2.41-2.77 (m, 2H, obscured by ArCH ₃ peak, fatty CH), 2.77 (s, 3H, ArCH ₃ ), 2.82-2.86 (m, 2H, Fat CH), 3.00-3.07(m, 1H, Fat CH), 3.44(dd, J=18.1, 6.59Hz, 1H, Fat CH), 3.83(s, 3H, CO ₂ CH ₃ ), 6.73(d, J = 8.55Hz, 1H, ArH), 7.01 (d, J = 8.79Hz, 1H, ArH), 8.12 (bs, 1H, NH); MS (APCI ⁺ ): m/z 355.2 (MH ⁺ ).C ₂₁ Calcd _{for H26N2O3} : 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2, 12, 12-trimethyl-, phenylmethyl ester

and / or

步骤A：4，4-二甲基-1，2，3，4，6，7，8，9-八氢-喹嗪鎓高氯酸盐

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2, 10, 10-trimethyl-, phenylmethyl ester

Step A: 4,4-Dimethyl-1,2,3,4,6,7,8,9-octahydro-quinazinium perchlorate

Synthesized from 1-chloro-3-iodopropane and 2,3,4,5-tetrahydro-2,2,6 collidine using the method described in Evans, DA; Domeier, LAOrg Synth Coll Vol VI, p819 4,4-Dimethyl-1,2,3,4,6,7,8,9-octahydro-quinazinium perchlorate. ¹ H NMR (400MHz, CDCl ₃ ) δ1.52 (s, 6H, °C (CH ₃ ) ₂ ), 1.75-1.86 (m, 4H, aliphatic CH), 1.88-2.00 (m, 4H, aliphatic CH) , 2.80-2.87 (m, 4H, aliphatic CH), 2.65-2.75 (m, 2H, NCH ₂ ); MS (APCI ⁺ ) m/z 166.1 (mother MH ⁺ ).

Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2, 10, 10-trimethyl-, phenylmethyl ester

One equivalent of 4,4-dimethyl-1,2,3,4,6,7,8,9-octahydro-quinazinium perchlorate (1.45 mmol, 0.385 g) was dissolved in a minimum amount of water And treated with 50% aqueous sodium hydroxide to strongly basic. The aqueous solution was extracted with 4 x 20 mL of _Et2O and the combined extracts were washed with 1 x 20 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated to afford the enamine. This residue was dissolved in dioxane (14 mL) and benzyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (1.45 mmol, 0.490 g) was added. The reaction mixture was heated at 90°C under nitrogen for 18 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting with 100% ethyl acetate and trituration with diethyl ether to afford 90 mg (14%) of pyrrolo[3',2':5,6][1]benzene Pyrano[3,2-i]quinolazine-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]quinazine-1-carboxylic acid, 3,7,8, 9, 10, 12, 13, 14, 14a, 15-Decahydro-2, 10, 10-trimethyl-, phenylmethyl ester as yellow foam:

IR (KBr) 3383, 2932, 2857, 1675, 1432, 1090, 1072 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.07 (s, 3H, CH ₃ ), 1.23 (s, 3H, CH ₃ ), 1.09-1.26 (m, 5H, fat CH), 1.42-1.61 (m, 6H, fat CH), 1.90 (d, J=12.70Hz, 1H, fat CH), 2.58 (d, J=18.56Hz , 1H, fat CH), 2.64-2.75 (m, 3H, fat CH), 3.11-3.19 (m, 2H, fat CH), 3.24-3.30 (m, 1H, fat CH), 5.15-5.25 (m, 2H , OCH ₂ Ar), 6.52(d, J=8.79Hz, 1H, ArH), 6.99(d, J=8.55Hz, 1H, ArH), 7.30-7.42(m, 5H, ArH), 11.50(s, 1H , NH); MS (APCI ⁺ ) m/z 459.3 (MH ⁺ ). Anal. Calcd. for C ₂₉ H ₃₄ N ₂ O ₃ ·0.19H ₂ O: C, 75.39; H, 7.50; N, 6.06; H ₂ O, 0.74. Found: C, 75.00; H, 7.73; N, 5.79; H ₂ O, 0.36.

Example 37

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12 , 13, 14, 14a, 15-decahydro-2-methyl-, ethyl ester Step A: 6-Fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester

6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester was synthesized according to the method published by Littell, R.; Allen, G.R., Jr.J.Org.Chem.1968;33:2064 .

Step B: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester was prepared from 6-fluoro-5-hydroxy-2-methyl-1H according to Method G - Preparation of ethyl indole-3-carboxylate (4.51 mmol, 1.07 g). The product was precipitated from the reaction solution by reducing the volume by one-third and recrystallized from acetonitrile to give an orange solid (0.510 g, 38%): mp 174-176°C (dec);

IR (KBr) 3278, 2975, 1692, 1443, 1124, 1078 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.32 (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=7.08Hz, 2H, OCH ₂ CH ₃ ), 7.05 (d, J = 10.50Hz, 1H, ArH), 11.56 (bs, 1H, NH); 19F NMR (DMSO-d ₆ ) δ-141.69 (d, J = 10.68Hz); MS (APCI ⁺ ) m/ z295.1(MH ⁺ ).Anal. Calcd. for C ₁₅ H ₁₉ F ₁ N ₂ O ₃ : C, 61.21; H, 6.51; N, 9.52; F, 6.45. Found: C, 61.32; H, 6.55; N , 9.51; F, 6.61.

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12 , 13, 14, 14a, 15-decahydro-2-methyl-, ethyl ester from 4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole according to method I -Synthesis of ethyl 3-carboxylate (1.66mmol, 0.488g). The compound was purified by flash column chromatography on silica gel (50:50 ethyl acetate:hexane) and recrystallized from ethyl acetate to give a white solid (32%): mp 184-186°C;

IR (KBr) 3367, 2932, 2858, 1670, 1456, 1437, 1135 ^{cm -1} ; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.37 (t, J=7.08 Hz, 3H, OCH ₂ CH ₃ ), 1.25- 1.47 (m, 4H, fat CH), 1.60-1.78 (m, 5H, fat CH), 1.85-1.95 (m, 1H, fat CH), 2.09 (bd, J=13.43Hz, 1H, fat CH), 2.43 -2.49 (m, 2H, fatty CH), 2.57 (s, 3H, ArCH ₃ ), 2.87-2.92 (m, 2H, fatty CH), 3.05-3.18 (m, 1H, fatty CH), 3.43-3.50 (m , 1H, fatty CH), 4.32 (q, J=7.08Hz, 2H, OCH ₂ CH ₃ ), 6.86 (d, J=10.01Hz, 1H, ArH), 8.09 (bs, 1H, NH); ¹⁹ F NMR (CDCl ₃ )δ-140.62 (d, J=10.68Hz); MS (APCI ⁺ ) m/z 387.1 (MH ⁺ ).Calc. for C ₂₂ H ₂₇ F ₁ N ₂ O 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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12 , 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester Step A: 6-Fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid

Dissolve ethyl 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylate (Example 37, Step A, 9.02 mmol, 2.14 g) in 40 mL of 2N NaOH and heat to reflux for 1 hour . The solution was cooled to 0°C and carefully acidified to pH 9 with concentrated hydrochloric acid. This solution was extracted with dichloromethane, the extract was removed and the aqueous layer was further acidified to pH 4 with concentrated hydrochloric acid at 0°C. The precipitate was filtered off and dried under vacuum for 18 hours to give a dark pink solid (1.16 g, 62%): mp 202-204°C (decomposition);

IR(KBr) 3584, 3358, 1649, 1471, 1109cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.53(s, 3H, ArCH ₃ ), 7.04(d, J=11.23Hz, 1H, ¹⁹ F NMR (DMSO-d ₆ ) δ-141.60 (t, J=10.68Hz); MS (APCI-) m/z 208.0 (M-1).

Step B: Benzyl 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Under a nitrogen atmosphere at room temperature, 1,8 - Diazabicyclo[5.4.0]undec-7-ene (4.92 mmol, 0.736 mL), followed by benzyl bromide (5.42 mmol, 0.644 mL). After 48 hours, water (10 mL) was added, and the precipitate was filtered, dried, and recrystallized from chloroform to give a white, cotton-like solid (0.677 g, 46%): mp 191-193°C; IR (KBr) 3384, 3254, 1662, 1475, 1327, 1129, 1098cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.59(s, 3H, ArCH ₃ ), 5.32(s, 2H, OCH ₂ C ₆ H ₅ ), 7.12(d , J=10.99Hz, 1H, ArH), 7.31-7.49 (m, 6H, ArH), 9.29 (s, 1H, ArOH), 11.67 (s, 1H, NH); ¹⁹ F NMR (DMSO-d ₆ ) δ -140.96-141.01(m); MS(APCI-)m/z298.1(M-1).·C ₁₇ H ₁₄ F ₁ N ₁ O ₃ ·0.04H ₂ O Calcd. Analysis: C, 68.06; H, 4.73; N, 4.67; F, 6.33; H ₂ O, 0.24. Found: C, 67.69; H, 4.63; N, 4.57; F, 6.61; H ₂ O, 0.10.

Step C: Benzyl 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Benzyl 6-fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylate (2.26mmol, 0.677g) and N,N,N',N'-tetramethyldiaminomethane (2.49 A solution of mmol, 0.34 mL) in 5 mL of dioxane was heated to reflux for 21 hours under a nitrogen atmosphere. Another aliquot of N,N,N',N'-tetramethyldiaminomethane (2.49 mmol, 0.34 mL) was added and the reaction was continued to reflux for 24 hours, cooled to room temperature, and concentrated. The residue was recrystallized from ethyl acetate to give a light yellow solid (0.260 g, 32%): mp 167-169°C;

IR(KBr) 3280, 2951, 1692, 1443, 1123, 1081cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.12(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=10.50Hz, 1H, ArH), 7.31-7.44 (m, 5H, ArH), 11.57 (s, 1H, NH); ¹⁹ F NMR (DMSO-d ₆ ) δ-141.55 (d, J=10.68Hz); MS (APCI ⁺ ) m/z 357.1 (MH ⁺ ). C ₂₀ H ₂₁ F ₁ N ₂ O ₃ ·0.07C ₄ H ₈ O ₂

Calculated and analyzed: C, 67.18; H, 5.99; N, 7.73; F, 5.24. Found: C, 66.81; H, 6.20; N, 7.74; F, 5.49.

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 5-fluoro-3,7,8,9,10,12 , 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester according to method I from 4-dimethylaminomethyl-6-fluoro-5-hydroxyl-2-methyl-1H- Benzyl indole-3-carboxylate (0.601mmol, 0.214g) was synthesized by heating at 80°C for 40 hours. This product was purified by flash column chromatography on silica gel (30-50% ethyl acetate/hexane) and recrystallized from ether to give a white solid (0.169 g, 63%): mp 179-181°C;

IR(KBr) 2932, 2857, 1699, 1453, 1131, 1075cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ1.17-1.38(m, 3H, fatty CH), 1.41-1.48(m, 1H, fatty CH), 1.55-1.85(m, 6H, fatty CH), 2.03(bd, J=12.94Hz, 1H, fatty CH), 2.42-2.48(m, 2H, fatty CH), 2.55(s, 3H, _ArCH3 ), 2.79 (d, J=17.58Hz, 1H, fat CH), 2.85-2.92 (m, 1H, fat CH), 3.04-3.17 (m, 1H, fat CH), 3.35 (dd, J=18.31, 6.51 Hz, 1H, fatty CH), 5.25-5.37 (m, 2H, OCH ₂ C ₆ H ₅ ), 6.86 (d, J=10.25Hz, 1H, ArH), 7.28-7.38 (m, 3H, ArH), 7.40 -7.44 (m, 2H, ArH), 8.07 (bs, 1H, NH); ¹⁹ F NMR (CDCl ₃ ) δ -142.0 (m); MS (APCI ⁺ ) m/z 449.1 (MH ⁺ ).C ₂₇ Calcd for H ₂₉ F ₁ N ₂ O ₃ Analysis: C, 72.30; H, 6.52; N, 6.25; F, 4.24. Found: C, 72.28; H, 6.45; N, 6.09; F, 4.50.

Example 39

步骤A：6-氟-5-羟基-2-甲基-苯并呋喃-3-甲酸乙酯

12H-furo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 5-fluoro 7,8,9,10,13, 14, 14a, 15-octahydro-2-methyl-, ethyl ester

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

To a solution of 2-fluoro-[1,4]benzoquinone (38.3 mmol, 4.82 g) in 300 mL of glacial acetic acid was added ethyl 3-amino-but-2-enoate (31.9 mmol, 4.12 g). The solution was heated to reflux for 1.5 hours, cooled to room temperature, and concentrated. The product was separated by silica gel flash column chromatography (30-50% ethyl acetate/hexane) to give a yellow solid (0.456g, 6%): mp138-139°C;

IR (KBr) 3284, 2991, 1680, 1469, 1422, 1326, 1110 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.36 (t, J=7.08 Hz, 3H, OCH ₂ CH ₃ ), 2.68 (s, 3H, ArCH ₃ ), 4.32 (q, J=7.08Hz, 2H, OCH ₂ CH ₃ ), 7.43 (d, J=8.79Hz, 1H, ArH), 7.55 (d, J=10.74Hz, 1H, ArH), 9.82 (s, 1H, ArOH); ¹⁹ FNMR (DMSO-d ₆ ) δ-137.42 (t, J=9.16Hz); MS (APCI-) m/z 237.1 (M-1). Calcd for C ₁₂ H ₁₁ F ₁ O ₄ : C, 60.50; H, 4.65; F, 7.98. Found: C, 60.50; H, 4.46; F, 8.20

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

Ethyl 6-fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylate (1.90mmol, 0.452g) and N,N,N',N'-tetramethyldiaminomethane (2.09mmol , 0.285 mL) in 4 mL of dioxane was heated to reflux for 4.5 hours under a nitrogen atmosphere, cooled to room temperature, and concentrated. Water (10 mL) was added to this residue, and the resulting precipitate was filtered off, dried, and recrystallized from tert-butyl methyl ether to give a pale yellow solid (0.225 g, 40%): mp 120-122°C; IR (KBr) 2989, 1706, 1446, 1384, 1322, 1120cm ^-1 ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ1.34 (t, J=7.08Hz, 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=7.08Hz, 2H, OCH ₂ CH ₃ ), 7.48 (d, J=10.25 Hz, 1H, ArH); ¹⁹ F NMR (DMSO-d ₆ ) δ-137.69 (d, J=10.68 Hz); MS (APCI ⁺ ) m/z 296.1 (MH ⁺ ).C ₁₅ H ₁₈ F ₁ N Calculation and analysis of ₁ O ₄ : C, 61.01; H, 6.14; N, 4.74; F, 6.43. Measured values: 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]quinazine-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]quinazine-1-carboxylic acid, 5-fluoro-7,8,9,10,13 , 14, 14a, 15-octahydro-2-methyl-, ethyl ester from 4-dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl according to method I (90°C, 21 hours) - Synthesis of ethyl benzofuran-3-carboxylate (0.603 mmol, 0.178 g). This product was purified by flash column chromatography on silica gel (30% ethyl acetate/hexane) and recrystallized from ether to give a white solid (0.210 g, 90%): mp 147-149°C;

IR(KBr) 2936, 2848, 1717, 1453, 1242, 1125cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ1.25-1.37(m, 2H, fatty CH), 1.38(t, J=7.08Hz, 3H, OCH ₂ CH ₃ ), 1.40-1.52 (m, 2H, fatty CH), 1.57-1.80 (m, 5H, fatty CH), 1.84-1.96 (m, 1H, fatty CH), 2.02 (d, J= 13.43Hz, 1H, fatty CH), 2.42-2.58(m, 2H, fatty CH), 2.61(s, 3H, _ArCH3 ), 2.83-2.91(m, 1H, fatty CH), 2.90(d, J=17.82 Hz, 1H, fatty CH), 3.06-3.16 (m, 1H, fatty CH) _, 3.34-3.40 (m, 1H, fatty CH), 4.34 (q, J=7.08Hz, 2H, _OCH2CH3 ), 7.03 (d, J=9.77Hz, 1H, ArH); ¹⁹ F NMR (CDCl ₃ ) δ-137.90 (d, J=9.16Hz); MS (APCI ⁺ ) m/z 388.2 (MH ⁺ ).C ₂₂ H Calcd and analyzed for ₂₆ F ₁ N ₁ O 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.

Example 40

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 4,5-difluoro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester Step A: 2,3-Difluoro-benzene-1,4-diol

2,3-Difluorophenol (Aldrich, 183.2 mmol, 24.32 g) was oxidized with potassium nitrate persulfate according to the following method: Feiring, AE; Sheppard, WAJ Org. Chem. 1975;40:2543. The crude product was purified by flash column chromatography on silica gel (10% acetonitrile/chloroform) and recrystallized from chloroform to give a pale yellow solid (7.32 g, 27%): mp 156-158 °C; IR (KBr) 3343 (br), 1514, 1505, 1259 , 1199, 1041cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.52 (d, J=5.37Hz, 2H, ArH), 9.45 (s, 2H, ArOH); ¹⁹ F NMR (DMSO-d ₆ ) δ-159.78 (d, J=4.58Hz); MS (APCI-) m/z 145.0 (M-1). Calculation and analysis for C ₆ H ₄ F ₂ O ₂ : C, 49.33; H, 2.76; F, 26.01. Measured value: C, 49.09; H, 2.73; F, 26.37.

Step B: 2,3-Difluoro-[1,4]benzoquinone

2,3-Difluoro-benzene-1,4-diol (49.1 mmol, 7.17 g) was treated with cerium(IV) ammonium nitrate according to the following method: Feiring, AE; Sheppard, WAJ Org. Chem.1975; 40:2543 Oxidation gave a bright yellow solid (6.63g, 94%): mp97.0-98.5°C; IR (KBr) 3352, 1684, 1333cm ^-1 ; ¹ H NMR (400MHz, DMSOd6) δ6.98 (s, 2H, ArH ); ¹⁹ F NMR (DMSO-d ₆ ) δ-144.85 (s); MS (APCI-) m/z 144.0 (M-). Anal. Anal. _{for C6H2F2O2} : C, 50.02; _H , 1.40; F _, 26.37. Found: C, 49.89; H, 1.31; F, 26.19.

Step C: Benzyl 6,7-difluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylate

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 benzyl 3-amino-but-2-enoate (1.05 mmol, 0.200 g) . The mixture was heated at 50°C for 18 hours, cooled to room temperature, and the precipitate was filtered off. The beige solid was washed with glacial acetic acid and dried in vacuo to give a clean product. The filtrate was neutralized, water (20 mL) was added, and the solution was extracted with ethyl acetate (4 x 20 mL). The residue was dried over magnesium sulfate, filtered, concentrated and the residue was purified by flash column chromatography on silica gel (20% ethyl acetate/hexanes). The pure fractions were combined to give 0.174 mg (52%) of an off-white solid, which was recrystallized from acetonitrile: mp 215-217°C; IR (KBr) 3457, 3243, 1658, 1480, 1338, 1150cm ^-1 ; ¹ H NMR (400MHz, DMSO -d ₆ ) δ2.58 (s, 3H, ArCH ₃ ), 5.31 (s, 2H, OCH ₂ C ₆ H ₅ ), 7.29-7.45 (m, 6H, ArH), 9.75 (s, 1H, ArOH), 12.13 (s, 1H, NH); MS (APCI ⁺ ) m/z 318.0 (MH ⁺ ). Anal. Calcd. for C ₁₇ H ₁₃ F ₂ N ₁ O ₃ 0.04C ₂ H ₄ O ₂ : C, 64.17; H, 4.15; N, 4.38; F, 11.89. Found: C, 63.80; H, 4.15; N, 4.05; F, 12.18.

Step D: Benzyl 4-Dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylate

4-Dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-1H-indole 3-carboxylate benzyl ester was prepared from 6,7-difluoro-5-hydroxy-2 - Prepared from benzyl methyl-1H-indole-3-carboxylate (8.08mmol, 2.56g). The reaction was heated at 50 °C for 21 hours, the precipitate was filtered off, washed with ethanol, and dried to give a light yellow solid (1.49 g, 49%): mp 159-160 °C (dec);

IR(KBr) 3235, 1688, 1438, 1365, 1301, 1123, 1083cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.13(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, 1H, NH); ¹⁹ F NMR (DMSO-d ₆ ) δ-168.26 (d, J=21.4Hz), -159.68 (d, J=21.4Hz); MS (APCI ⁺ ) m/z 375.0 (MH ⁺ ). Anal. Calcd. for C ₂₀ H ₂₀ F ₂ N ₂ O ₃ : C, 64.16; H, 5.38; N, 7.48; F, 10.15. Found: C, 64.00; H, 5.44 ; N, 7.36; F, 10.15.

Step E: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 4,5-difluoro-3,7,8 , 9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 4,5-difluoro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenyl methyl ester was synthesized from 4-dimethylaminomethyl-6,7-di Synthesis of benzyl fluoro-5-hydroxy-2-methyl-1H-indole-3-carboxylate (3.82mmol, 1.43g). This product was purified by flash column chromatography on silica gel (5-10% ethyl acetate/dichloromethane) to give 1.37 g (77%) of a cream solid. Part of it was recrystallized with tert-butyl methyl ether/hexane to give a white solid: mp159-160°C; IR (KBr) 3297, 2933, 2857, 1704, 1455, 1141, 1124cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ )δ1 .17-1.36 (m, 3H, fat CH), 1.43-1.49 (m, 1H, fat CH), 1.57-1.78 (m, 6H, fat CH), 2.00 (d, J=13.7Hz, 1H, fat CH ), 2.46(d, J=9.77Hz, 1H, fatty CH), 2.53-2.57(m, 1H, fatty CH), 2.57(s, 3H, ArCH ₃ ), 2.71(d, J=18.31Hz, 1H, Fat CH), 2.83-2.88(m, 1H, Fat CH), 3.06-3.16(m, 1H, Fat CH), 3.24-3.30(m, 1H, Fat CH), 5.24-5.36(m, 2H, OCH ₂ C ₆ H ₅ ), 7.32-7.38 (m, 3H, ArH), 7.42 (d, J=6.84Hz, 2H, ArH), 8.21 (s, 1H, NH); ¹⁹ F NMR (CDCl ₃ ) δ-166.80 (d, J=19.84Hz), -162.52 (d, J=21.36Hz); MS (APCI ⁺ ) m/z 467.1 (MH ⁺ ).C ₂₇ H ₂₈ F ₂ N ₂ O ₃ Calcd. Analytical value: C , 69.51; H, 6.05; N, 6.00; F, 8.14. Found: C, 69.36; H, 5.99; N, 5.88; F, 8.37.

Example 41

步骤A：6，7-二氯-5-羟基-2-甲基-1H-吲哚-3-甲酸苄酯

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 4,5-dichloro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester

Step A: Benzyl 6,7-dichloro-5-hydroxy-2-methyl-1H-indole-3-carboxylate

6,7-Dichloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester was prepared from 2,3-dichloro-[1,4]benzoquinone (16.8mmol, 2.98g) and 3 -Amino-but-2-enoic acid benzyl ester (25.3 mmol, 4.83 g) as reported by Grinev, A.N.; Zaitsev, I.A.; Shvedov, V.I.; Terent'ev, A.P.J.Org.Chem.USSR (English); 28:439 The corresponding ethyl ester was prepared by the method. Yield 0.649g (11%): mp235-236°C;

IR (KBr) 3421, 3281, 1651, 1098cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.59 (s, 3H, ArCH ₃ ), 5.29 (s, 2H, OCH ₂ C ₆ H ₅ ) , 7.30(t, J=7.08Hz, 1H, ArH), 7.34-7.38(m, 2H, ArH), 7.42(d, J=7.32Hz, 2H, ArH), 7.51(s, 1H, ArH); MS (APCI-)m/z348.0(M-1).HPLC (ALLTECH/ALLTIMAC-18, 1:1-2:98 H ₂ O/CH ₃ CN+0.05%TFA): retention time: =6.573min, 98.41% pure.

Step B: Benzyl 4-Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-1H-indole-3-carboxylate

4-Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester was synthesized from 6,7-dichloro-5-hydroxy- Preparation of benzyl 2-methyl-1H-indole-3-carboxylate (3.06 mmol, 1.07 g). The reaction was heated at 50°C for 22.5 hours, concentrated and purified by flash column chromatography on silica gel (30-50% acetone/hexanes) to give a golden yellow solid (0.830 g, 67%): mp 167-170°C;

IR(KBr) 3328, 1695, 1438, 1409, 1330, 1281, 1107cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.18(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, NH); MS (APCI ⁺ ) m/z 407.1 (M ⁺ ). Analytical values calculated for C ₂₀ H ₂₀ Cl ₂ N ₂ O 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.

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 4,5-dichloro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester was synthesized from 4-dimethylaminomethyl-6,7-dichloro - Synthesis of benzyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (1.82mmol, 0.742g). This product was purified by flash column chromatography on silica gel (10% acetone/hexane) to give 0.684 g (75%) of a pink foam: mp 100-105°C;

IR (KBr) 3424, 2932, 2853, 1685, 1430, 1125, 1076cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.00-1.30(m, 3H, fatty CH), 1.37-1.76(m , 8H, fatty CH), 2.37-2.40 (m, 1H, fatty CH), 2.46-2.49 (m, 1H, fatty CH), 2.50 (s, 3H, ArCH ₃ ), 2.63-2.69 (m, 2H, fatty CH), 2.95-2.99 (m, 1H, fatty CH), _3.17 (dd, J=18.31, 6.74Hz, 1H, fatty CH), 5.23 (dd, J=28.08, 12.21Hz, 2H, _{OCH2C6H 5} ), 7.31-7.39 (m, 3H, ArH), 7.42-7.44 (m, 2H, ArH), 11.85 (s, 1H, NH); MS (APCI ⁺ ) m/z 499.1 (MH ⁺ ).C ₂₇ H ₂₈ Cl ₂ N ₂ O ₃ 0.07 H ₂ O Calcd. Anal.: C, 64.77; H, 5.66; N, 5.59; Cl, 14.16; H ₂ O, 0.25. Found: C, 64.37; H, 5.64 ; N, 5.51; Cl, 13.96; H ₂ O, 0.32.

Example 42

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-4, 5-dimethoxy-2-methyl-, phenylmethyl ester Step A: Benzyl 6,7-dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylate

2,3-Dimethoxy-[1,4]benzoquinone (10.4mmol, 1.74g) was added to 3-amino-but-2-enoic acid benzyl ester (8.62mmol, 1.65g) at 0°C ethanol (25mL) solution. The reaction was warmed to room temperature, then heated to reflux for 18 hours. The solvent was removed and the product was purified by flash column chromatography on silica gel (30-50% ethyl acetate/hexanes) and recrystallized from toluene to give a pink solid (0.621 g, 21%): mp 154-156°C;

IR (KBr) 3336, 3267, 1660, 1468, 1327, 1146, 1081 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ2.56 (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-) m/z 340.0 (M-1). Anal. Calcd. for C ₁₉ H ₁₉ N ₁ O ₅ : C, 66.85; H, 5.61 ; N, 4.10 Found: C, 66.69; H, 5.55; N, 3.79.

Step B: Benzyl 4-dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylate

4-Dimethylaminomethyl-6,7-methoxy-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester was synthesized from 6,7-dimethoxy-5 -Prepared from benzyl hydroxy-2-methyl-1H-indole-3-carboxylate (1.69 mmol, 0.577 g). The reaction was heated at 50°C for 18 hours, concentrated and purified by flash column chromatography on silica gel (0-3% triethylamine/ethyl acetate) and recrystallized from cyclohexane to give a lemon yellow solid (0.274 g, 41%): mp132-134°C;

IR(KBr) 3312, 1698, 1440, 1415, 1290, 1129cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.10(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, ArCH ₂ N), 5.21 (s, 2H, OCH ₂ C ₆ H ₅ ), 7.29-7.38 (m, 3H, ArH), 7.41-7.43 (m, 2H, ArH), 11.48 (s, 1H, NH); MS (APCI ⁺ ) m/z 399.0 (MH ⁺ ).C ₂₂ H ₂₆ N ₂ O ₅ Calcd: 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-4,5-dimethoxy-2-methyl-,phenylmethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-4, 5-dimethoxy-2-methyl-, phenyl methyl ester according to method I (90 ℃, 21 hours) from 4-dimethylaminomethyl-6,7 - Synthesis of benzyl dimethoxy-5-hydroxy-2-methyl-1H-indole 3-carboxylate (0.595 mmol, 0.237 g). The product was purified by flash column chromatography on silica gel (50% ethyl acetate/hexane) and recrystallized from 2,2,4-trimethylpentane to give 0.089 g (30%) of a white solid: mp 130-136°C;

IR (KBr) 3307, 2931, 2856, 1833, 1700, 1684, 1448, 1418, 1282, 1137, 1123cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ1.24-1.38 (m, 4H, fatty CH) , 1.44-1.55 (m, 1H, fat CH), 1.59-1.80 (m, 6H, fat CH), 2.09 (d, J=13.98Hz, 1H, fat CH), 2.51 (d, J=10.37Hz, 1H , fatty CH), 2.58 (s, 3H, ArCH ₃ ), 2.78 (d, J=18.08Hz, 1H, fatty CH), 2.85-2.91 (m, 1H, fatty CH), 3.08-3.14 (m, 1H, fatty CH), 3.29-3.36 (m, 1H, fatty CH), 3.96 (s, 3H, OCH ₃ ), 4.05 (s, 3H, OCH ₃ ), 5.26-5.37 (m, 2H, OCH ₂ C ₆ H ₅ ), 7.31-7.40 (m, 3H, ArH), 7.44 (d, J=6.99Hz, 2H, ArH), 8.29 (s, 1H, NH); MS (APCI ⁺ ) m/z 491.1 (MH ⁺ ) .HPLC (ALLTECH/ALLTIMA C-18, 1:1-2:98 H ₂ O/CH ₃ CN+0.05% TFA): retention time = 4.527 min, 100.00% purity.

Example 43

步骤A：6-甲基-5-羟基-2-甲基-1H-吲哚-3-甲酸苄酯

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2,5-dimethyl-, phenylmethyl ester

Step A: Benzyl 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

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 (79.5mmol, 15.2g), the reaction method is according to Allen, G.R., Jr.; Pidacks, C.; Weiss, M.J.J.Am.Chem.Soc.1966; 88 :2536 reported in the corresponding ethyl ester method. The crude reaction product consists of the desired benzyl 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate and the regioisomer 7-methyl-5-hydroxy-2-methyl-1H - Mixture of benzyl indole-3-carboxylates. These regioisomers were separated by the method of the corresponding ethyl esters reported in Poletto, J.F.; Allen, G.R., Jr.; Sloboda, A.E.; Weiss, M.J.J. Med. Chem. 1973;16:757. Each isomer was recrystallized separately from acetone to give X-ray quality crystals. Single-crystal X-ray analysis indicated the higher Rf isomer (silica gel, 50% ethyl acetate/hexane) as 6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid Benzyl ester: mp196-197℃;

IR(KBr) 3399, 3314, 1655, 1469, 1438, 1086cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.14(s, 3H, ArCH ₃ ), 2.53(s, 3H, ArCH ₃ ) , 5.28(s, 2H, OCH ₂ C ₆ H ₅ ), 6.99(s, 1H, ArH), 7.28-7.42(m, 6H, ArH), 8.81(s, 1H, ArOH), 11.42(s, 1H, NH); MS (APCI ⁺ ) m/z 296.0 (MH ⁺ ). Calcd. Analytical value for C ₁₈ H ₁₇ N ₁ O ₃ 0.25H ₂ O: C, 72.10; H, 5.88; N, 4.67. Found: C, 71.72; H, 5.54; N, 4.74.

Step B: Benzyl 4-Dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Benzyl 4-dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate was prepared from 6-methyl-5-hydroxy-2-methyl - Benzyl 1H-indole-3-carboxylate (7.48mmol, 2.21g) was prepared by adding 49.4mmol of dimethylamine and 26.9mmol of formaldehyde. The reaction was heated at 50°C for 70 hours, concentrated and purified by flash column chromatography on silica gel (0-5% triethylamine/ethyl acetate) to give a tan solid (1.67 g, 63%). Part of it was recrystallized from ethyl acetate to obtain a light yellow solid: mp162-164°C;

IR(KBr) 3313, 1688, 1432, 1227, 1119, 1075cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.13(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, 1H, ArH), 7.29-7.44 (m, 5H, ArH), 11.40 (s, 1H, NH); MS (APCI ⁺ ) m/z 353.1 (MH ⁺ ). Analytical values calculated for C ₂₁ H ₂₄ N ₂ O ₃ : C, 71.57; H, 6.86; N, 7.95 .Measured values: C, 71.30; H, 6.92; N, 7.87.

Step C: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2,5-dimethyl-, phenylmethyl ester was synthesized from 4-dimethylaminomethyl-6-methyl-5-hydroxy- Benzyl 2-methyl-1H-indole-3-carboxylate (4.45mmol, 1.57g) was synthesized. This product was purified by flash column chromatography on silica gel (20-50% acetone/hexanes then 20-40% ethyl acetate/dichloromethane) to give 0.953 g (48%) of a yellow solid: mp 110-115°C; IR (KBr) 3379, 2931, 2857, 1673, 1425, 1123, 1071cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.05-1.16 (m, 2H, fat CH), 1.21-1.25 (m, 1H, fat CH), 1.33-1.42 (m, 2H, fatty CH), 1.45-1.66 (m, 5H, fatty CH), 1.78 (d, J=13.67Hz, 1H, fatty CH), 2.18 (s, 3H, ArCH ₃ ), 2.34 (d, J=9.28Hz, 1H, fatty CH), 2.44 (s, 3H, ArCH ₃ ), 2.41-2.46 (m, 1H, fatty CH), 2.62-2.70 (m, 2H, fatty CH) , 2.87-2.95 (m, 1H, fatty CH), 3.16 (dd, J=18.07, 6.59Hz, 1H, fatty CH), 5.19 (dd, J=25.15, 12.21Hz, 2H, OCH ₂ C ₆ H ₅ ) , 6.90(s, 1H, ArH), 7.28-7.37(m, 3H, ArH), 7.41(d, J=6.84Hz, 2H, ArH), 11.37(s, 1H, NH); MS(APCI ⁺ )m /z445.3(MH ⁺ ).C ₂₈ H ₃₂ N ₂ O ₃ ·0.16H ₂ O

Calcd: C, 75.16; H, 7.28; N, 6.26; _{H 2 O} , 0.64. Found: C, 74.76; H, 7.35; N, 6.07;

Example 44

步骤A：7-甲基-5-羟基-2-甲基-1H-吲哚-3-甲酸苄酯

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2,4-dimethyl-, phenylmethyl ester

Step A: Benzyl 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

As in Example 43, in Step A, 7- Benzyl methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate (2.04 g, 8.7% yield) was an off-white powder. Single crystal X-ray analysis indicated the lower Rf isomer (silica gel, 50% ethyl acetate/hexanes) as benzyl 7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate: mp188-189°C;

IR(KBr) 3430, 3286, 1641, 1446, 1294, 1153, 1098cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.32(s, 3H, ArCH ₃ ), 2.58(s, 3H, ArCH ₃ ), 5.27(s, 2H, OCH ₂ C ₆ H ₅ ), 6.39(d, J=1.22Hz, 1H, ArH), 7.10(d, J=1.71Hz, 1H, ArH), 7.26-7.31(m MS (APCI ⁺ ) m/z 296.0 (MH ⁺ ). Anal. Calcd. for C ₁₈ H ₁₇ N ₁ O ₃ : C, 73.20; H, 5.80; N, 4.74. Found: C, 73.02; H, 5.70; N , 4.40.

Step B: Benzyl 4-Dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Benzyl 4-dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate was prepared from 7-methyl-5-hydroxy-2-methyl - Preparation of benzyl 1H-indole-3-carboxylate (6.62mmol, 1.85g), 41.3mmol of dimethylamine and 22.5mmol of formaldehyde. The reaction was heated at 50°C for 46 hours, concentrated, purified by flash column chromatography on silica gel (0-5% triethylamine/ethyl acetate) and recrystallized from ethyl acetate to give a pale tan solid (0.900 g, 41%) : mp161-164℃;

IR(KBr) 3307, 1684, 1292, 1220, 1070cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.08(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, 1H, ArH), 7.28-7.38 (m, 3H, ArH), 7.43 (d, J=7.08Hz, 2H, ArH), 11.28 (s, 1H, NH); MS (APCI ⁺ ) m/z 353.2 (MH ⁺ ).C ₂₁ H ₂₄ Calcd for N ₂ O 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2,4-dimethyl-,phenylmethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2,4-.dimethyl-, phenylmethyl ester according to method I (80 ℃ 39 hours) from 4-dimethylaminomethyl-7-methyl-5-hydroxy- Synthesis of 2-methyl-1H-indole-3-carboxylic acid benzyl ester (2.55mmol, 0.900g). This product was purified by flash column chromatography on silica gel (30% ethyl acetate/hexane, then 20-50% ethyl acetate/dichloromethane) to give 0.569 g (50%) of an off-white solid: mp 183-187°C; IR (KBr )3325, 2929, 1664, 1431, 1279, 1221, 1107, 1075cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.06-1.15 (m, 2H, fatty CH), 1.19-1.22 (m, 1H, fatty CH), 1.31-1.62 (m, 8H, fatty CH), 1.81 (d, J=12.94Hz, 1H, fatty CH), 2.30 (s, 3H, ArCH ₃ ), 2.33-2.42 (m, 1H , fatty CH), 2.45 (s, 3H, ArCH ₃ ), 2.55 (d, J=17.82Hz, 1H, fatty CH), 2.61-2.66 (m, 1H, fatty CH), 2.82-2.88 (m, 1H, fatty CH), 3.09-3.15 (m, 1H, fatty CH), 5.20 (dd, J=24.90, 12.21Hz, 2H, OCH ₂ C ₆ H ₅ ), 6.41 (s, 1H, ArH), 7.28-7.43 ( m, 5H, ArH), 11.31 (s, 1H, NH); MS (APCI ⁺ ) m/z 445.3 (MH ⁺ ). Anal. Calcd. for C ₂₈ H ₃₂ N ₂ O 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2,5-dimethyl-, 1-(4-fluorophenyl) ethyl ester

Step A: Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid with benzoic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,5-dimethyl-, anhydride

To pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2,5-dimethyl-, phenylmethyl ester (1.88mmol, 0.837g) and triethylamine (1.88mmol, 0.262mL) in 18mL THF solution, add 20% Pd(OH) ₂ /C (0.200 g, 24 wt%). The mixture was stirred at room temperature under a hydrogen atmosphere (balloon) for 20 min and filtered through Celite, washing with THF to give the carboxylic acid: MS (APCI+) m/z 355.2 (MH ⁺ ). To this filtrate was added dropwise benzoyl chloride (1.88 mmol, 0.218 mL) at room temperature under a nitrogen atmosphere. After 60 hours at room temperature, the precipitate was filtered off, the filtrate was concentrated, and the residue was triturated with diethyl ether to give a pale pink solid (0.517 g, 60%): the selected identification peak by ¹ H NMR (400 MHz, DMSO-d ₆ ) δ2.23(s, 3H, ArCH ₃ ), 2.48(s, 3H, ArCH ₃ ), 7.00(s, 1H, ArH), 7.57(t, J=7.81Hz, 2H, ArH), 7.73(t, J = 7.57Hz, 1H, ArH), 8.06 (d, J = 7.32Hz, 2H, ArH), 11.94 (s, 1H, NH); MS (APCI ⁺ ) m/z 459.2 (MH ⁺ ).

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid with benzoic acid, 3,7,8,9,10,12 , 13, 14, 14a, 15-Decahydro-2,5-dimethyl-, anhydride (1.13 mmol, 0.517 g) was added to 4-fluoro-α-methylbenzyl alcohol (3.38 mmol, 0.427 mL), And heated and stirred at 150° C. for 2 minutes. A homogeneous solution formed, cooled to room temperature, dissolved in ethyl acetate (10 mL), and stirred with saturated aqueous sodium bicarbonate. 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 flash column chromatography on silica gel (10-15% acetone/hexanes) to give a shiny beige powder (0.256 g, 48%): mp 124-128°C;

IR(KBr) 3378, 2933, 1675, 1425, 1228, 1127, 1059cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.07-1.28(m, 3H, fatty CH), 1.42-1.65(m , 6H, fatty CH), 1.57 (d, J=6.75Hz, 3H, OCH( _CH3 )Ar), 1.71-1.74 (m, 1H, fatty CH), 1.79-1.87 (m, 1H, fatty CH), 2.21 & 2.22 (s, 3H, ArCH ₃ , diastereomers) 2.38 (d, J = 11.09Hz, 1H, fatty CH), 2.46-2.49 (m, 1H, fatty CH), 2.50 & 2.52 (s, 3H, ArCH ₃ , diastereoisomers), 2.64-2.72 (m, 2H, fatty CH), 2.92-2.98 (m, 1H, fatty CH), 3.10-3.29 (m, 1H, fatty CH ), 5.94-6.00 (m, 1H, OCH(CH ₃ ) Ar), 6.92 & 6.93 (s, 1H, ArH, diastereomers), 7.16-7.22 (m, 2H, ArH), 745- 7.51 (m, 2H, ArH), 11.40 (s, 1H, NH); ¹⁹ F NMR (DMSO-d ₆ )-115.13 & -114.94 (s, diastereoisomers), MS (APCI ⁺ ) m/ z477.3(MH ⁺ ).Anal _{. Calcd} . for _{C29H33F1N2O3 :} 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2,4-dimethyl-, 1-(4-fluorophenyl) ethyl ester

Step A: Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid with benzoic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,4-dimethyl-, anhydride

According to the method of Example 45, Step A, pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8 , 9,10,12,13,14,14a,15-Decahydro-2,4-dimethyl-,phenylmethyl ester (1.10mmol, 0.491g) was transformed into a mixed anhydride intermediate (cream solid, 0.512 g, 100%): MS (APCI ⁺ ) m/z 459.3 (MH ⁺ ).

Step B: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2,4-dimethyl-, 1-(4-fluorophenyl) ethyl ester according to the method of Example 45, step B by pyrrolo [3 ', 2 ' with benzoic acid : 5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro- 2,4-Dimethyl-, anhydride (1.12 mmol, 0.512 g) was prepared. This product was purified by flash column chromatography on silica gel (10-20% acetone/hexanes) to give a fluffy off-white solid (0.227 g, 43%): mp 105-108 °C;

IR (KBr) 3325, 2931, 1674, 1512, 1433, 1222, 1109, 1059 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.12-1.26 (m, 3H, fatty CH), 1.39-1.72 (m, 7H, fatty CH), 1.57 (d, J=6.51Hz, 3H, OCH( _CH3 )Ar), 1.82-1.91 (m, 1H, fatty CH), 2.31-2.36 (m, 1H, fatty CH ), 2.33 & 2.34 (s, 3H, ArCH ₃ , diastereoisomers), 2.43-2.47 (m, 1H, aliphatic CH), 2.54 & 2.56 (s, 3H, ArCH ₃ , diastereoisomers conformation), 2.58-2.70 (m, 2H, fatty CH), 2.86-2.91 (m, 1H, fatty CH), 3.06-3.25 (m, 1H, fatty CH), 5.94-6.01 (m, 1H, OCH ( CH ₃ )Ar), 6.43&6.45(s, 1H, ArH, diastereomers), 7.16-7.22(m, 2H, ArH), 7.45-7.51(m, 2H, ArH), 11.31&11. 32 (s, 1H, NH, diastereomer); ¹⁹ F NMR (DMSO-d ₆ )-(115.13-115.08) &-(114.92-114.91) (m, diastereomer); MS (APCI ⁺ )m/z 477.3(MH ⁺ ).C ₂₉ H ₃₃ F ₁ N ₂ O ₃ ·0.12H ₂ O Calcd. Analysis: C, 72.75; H, 7.00; N, 5.85; F, 3.97; H ₂ O, 0.45. Found: C, 72.38; H, 7.13; N, 5.73; F, 3.61; H ₂ O, 0.31.

Example 47

步骤A：3-(1-羟基乙基)苯甲酸甲酯 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[3-(methoxycarbonyl)phenyl]ethyl ester

Step A: Methyl 3-(1-Hydroxyethyl)benzoate

The 500mL stainless steel reactor was filled with nitrogen and then filled with 1-(3-bromophenyl)ethanol (0.126mol, 25.4g), DMSO (150mL), methanol (3.70mol, 150mL), triethylamine (0.143mol, 20.0 mL), Pd(OAc) ₂ (2.78mmol, 0.625g) and 1,3-bis(diphenylphosphino)propane (2.62mmol, 1.08g). The reactor was sealed, filled with nitrogen, then CO, pressurized to 663 psi with CO, shaken and heated to 80°C for 12 hours. The reactor was repressurized to 724 psi with CO, shaken and heated to 100°C for 70 hours. The reaction was cooled to room temperature, filtered through celite, concentrated, and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane (3 x 100 mL), and the extract was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated to an oil. This product was purified by flash column chromatography on silica gel (10-25% ethyl acetate/hexanes) to give methyl 3-(1-hydroxyethyl)benzoate (15.1 g, 66%):

¹ H NMR (400MHz, CDCl ₃ ) δ 1.50 (d, J=6.59Hz, 3H, CH(CH ₃ )OH), 1.86 (d, J=3.66Hz, 1H, CH(CH ₃ )OH), 3.90 (s, 3H, CO ₂ CH ₃ ), 4.92-4.97 (m, 1H, CH(CH ₃ )OH), 7.39-7.43 (m, 1H, ArH), 7.57 (d, J=7.57Hz, 1H, ArH ), 7.92(d, J=7.57Hz, 1H, ArH), 8.02(s, 1H, ArH).

Step B: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-[3-(methoxycarbonyl)phenyl]ethyl ester

Add 3-(1-hydroxyethyl)methyl benzoate (18.0mmol, 3.24g) in the 100ml reaction flask, then add pyrrolo[3′,2′:5,6][1]benzene with benzoic acid Pyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride (implementation Example 86, 4.50 mmol, 2.00 g) and heated with stirring at 150°C until a homogeneous solution was obtained (4.5 minutes). The solution was cooled to room temperature, dissolved in ethyl acetate and stirred with saturated aqueous sodium bicarbonate. A white solid precipitated and was filtered off. The filtrate was separated, the aqueous layer was extracted with ethyl acetate (3 x 25ml), and the combined extracts were dried and concentrated to a viscous oil. The product was purified by flash column chromatography on silica gel (20% acetone/hexane) to give a white solid (0.776 g, 34%): mp 100-103, 155-156°C (diastereomers);

IR (KBr) 3375, 2931, 2855, 1725, 1704, 1432, 1200, 1078, 1065 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.20-1.29 (m, 1H, fatty CH), 1.32-1.34 (m, 2H, fatty CH), 1.38-1.47 (m, 1H, fatty CH), 1.53-1.58 (m, 2H, fatty CH), 1.62-1.82 (m, 4H, fatty CH), 1.68 (d, J =6.59Hz, 3H, OCH( _CH3 )Ar), 2.01-2.12(m, 1H, fatty CH), 2.41-2.45(m, 1H, fatty CH), 2.50-2.53(m, 1H, fatty CH), 2.60 & 2.62 (s, 3H, ArCH ₃ , diastereomers), 2.69-2.85 (m, 2H, fatty CH), 2.98-3.04 (m, 1H, fatty CH), 3.29-3.43 (m, 1H, fatty CH), 3.89 (s, 3H, CO ₂ CH ₃ ), 6.09-6.17 (m, 1H, OCH(CH ₃ ) Ar), 6.73 & 6.74 (d, J=8.55Hz, 1H, ArH, diastereomers), 7.01 & 7.02 (d, J = 8.79 & 8.55Hz, 1H, ArH, diastereomers), 7.41 & 7.42 (t, J = 7.81 & 7.57Hz, 1H, ArH, diastereomers), 7.61 & 7.63 (d, J=7.57Hz, 1H, ArH, diastereomers), 7.93-7.95 & 7.95-7.97 (m, 1H, ArH, non Enantiomer), 8.06 (bs, 1H, NH), 8.10 & 8.13 (s, 1H, ArH, diastereoisomer; MS (APCI ⁺ ) m/z 503.1 (MH ⁺ ).C Anal. Calcd. _{for 30} H ₃₄ N ₂ O ₅ : C, 71.69; H, 6.82; N, 5.57. Found: C, 71.58; H, 6.95; N, 5.42.

Example 48

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(3-carboxyphenyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2-methyl-,1-[3-(methoxycarbonyl)phenyl]ethyl ester (1.43mmol, 0.717g) in methanol (18mL) and 1N NaOH (5.71mmol, 5.71 mL) solution was heated at 55-60°C for 1 hour. The solution was cooled to room temperature, methanol was removed by rotary evaporation, and the aqueous phase was neutralized with 1N HCl. A precipitate formed and was filtered off, purified by flash column chromatography on silica gel (10-15% MeOH/ _CHCl3 ) to give a cream colored powder (0.522 g, 75%): mp 244-250°C (dec);

IR(KBr) 3413-3229(b), 2931, 1685, 1432, 1195, 1150, 1078, 1063cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.03-1.22(m, 3H, fatty CH ), 1.38-1.72(m, 7H, fatty CH), 1.57(d, J=6.35Hz, 3H, OCH(CH ₃ )Ar), 1.78-1.88(m, 1H, fatty CH), 2.28-2.38(m , 1H, fatty CH), 240-2.47 (m, 1H, fatty CH), 2.51 & 2.55 (s, 3H, ArCH ₃ , diastereomers), 2.56-2.69 (m, 2H, fatty CH) , 2.81-2.92 (m, 1H, fatty CH), 3.06-3.23 (m, 1H, fatty CH), 5.96-6.04 (m, 1H, OCH(CH ₃ ) Ar), 6.57 & 6.58 (d, J= 8.55 & 8.30Hz, 1H, ArH, diastereomers), 7.01 & 7.02 (d, J = 8.30Hz, 1H, ArH, diastereomers), 7.45-7.50 (m, 1H, ArH , diastereoisomers, 7.64 & 7.67 (d, J = 10.25 & 8.55Hz, 1H, ArH, diastereomers), 7.83 & 7.85 (d, J = 6.10 & 7.32Hz, 1H, ArH, diastereomers), 7.96 & 7.98 (s, 1H, ArH, diastereomers), 11.54 (s, 1H, NH), 13.00 (s, 1H, _CO2H ); MS (APCI ⁺ )m/z 489.1(MH ⁺ ).C ₂₉ H ₃₂ N ₂ O ₅ 0.50H ₂ O 0.20SiO ₂ Calcd. Analysis: C, 68.35; H, 6.53; N, 5.50; H ₂ O , 1.77. Found: C, 67.96; H, 6.81; N, 5.22; H ₂ O, 1.81. HPLC (ALLTECH/ALLTIMA C-18, 60:40-20:80 H ₂ O/CH ₃ CN+0.05% TFA): retention time = 4.843 & 4.970min (diastereoisomers), 95.53% purity.

Example 49

1-propylammonium, N, N, N-trimethyl-, with 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15-decahydro-2-methylpyrrolo[3', 2': Salt of 1-(3-carboxyphenyl)ethyl 5,6][1]-benzopyrano[3,2-i]quinazine-1-carboxylate (1:1)

An aqueous solution of choline bicarbonate (0.935 mmol, 0.165 mL, 5.66 M) was added to pyrrolo[3′,2′:5,6][1]benzopyrano[3,2i]quinazine-1 -Formic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,1-(3-carboxyphenyl)ethyl ester (0.935mmol, 0.457g) (23 mL), and the mixture was heated at 75-80° C. for 30 minutes, cooled to room temperature, and filtered. The filtrate was concentrated. The residue was stirred vigorously with ether and filtered to give a pale yellow solid. This solid was dissolved in hot _CHCl3 , filtered, concentrated, and dried under vacuum at 60°C to give a yellow powder (0.233g, 42%): mp 210-216°C;

IR(KBr) 3428-3211(b), 2930, 1684, 1566, 1432, 1878, 1870, 1079, 1063cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.03-1.26(m, 3H, Fatty CH), 1.36-1.72(m, 6H, Fatty CH), 1.55(d, J=6.35Hz, 3H, OCH( _CH3 )Ar), 1.80-1.88(m, 1H, Fatty CH), 2.30-2.42 (m, 2H, fatty CH), 2.51 & 2.52 (s, 3H, ArCH ₃ , diastereomers), 2.61-2.70 (m, 2H, fatty CH), 2.81-2.92 (m, 1H, fatty CH), 3.07(s, 9H, N(CH ₃ ) ₃ ), 3.11-3.23(m, 1H, fatty CH), 3.26-3.35(m, 2H, CH ₂ OH & fatty CH), 3.36(t, J= 4.88Hz, 2H, OCH ₂ CH ₂ N(CH ₃ ) ₃ ), 3.77-3.83(m, 2H, OCH ₂ CH ₂ N(CH ₃ ) ₃ ), 5.91-5.99(m, 1H, OCH(CH ₃ ) Ar), 6.54-6.58 (m, 1H, ArH), 7.01-7.04 (m, 1H, ArH), 7.21-7.28 (m, 1H, ArH), 7.32-7.38 (m, 1H, ArH), 7.71-7.79 (m, 1H, ArH), 7.91 & 7.93 (s, 1H, ArH, diastereoisomers), 11.70 (s, 1H, NH); MS (APCI-) m/z 487.1 (parent M- 1).C ₂₉ H ₃₁ N ₂ O ₅ · 0.88C ₅ H ₁₄ NO · 0.50H ₂ O · 0.50CHCl ₃ Calculated and analyzed: C, 62.84; H, 6.97; N, 6.23; H ₂ O, 1.39. Measured Values: C, 62.92; H, 6.17; N, 6.93; _H2O , 1.72.

Example 50

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (3-nitrophenyl) methyl ester

According to the method of Example 47, Step B, 3-nitrobenzyl alcohol (18.0mmol, 2.81g) and pyrrolo[3′,2′:5,6][1]benzopyrano[ 3,2-i] quinozine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride (Example 86, 4.50mmol , 2.00 g) into pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10 , 12, 13, 14, 14a, 15-Decahydro-2-methyl-, (3-nitrophenyl)methyl ester. This product was purified by silica gel flash column chromatography (25-50% ethyl acetate/hexane) and recrystallized from ethyl acetate to give a light yellow powder (1.10 g, 51%): mp 203-205°C;

IR (KBr) 3383, 3181, 2929, 2855, 1709, 1532, 1430, 1351, 1236, 1075, 886cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.02-1.16 (m, 2H, fat CH), 1.19-1.24(m, 1H, fat CH), 1.32-1.62(m, 7H, fat CH), 1.82(d, J=13.18Hz, 1H, fat CH), 2.33(d, J=9.76Hz , 1H, fatty CH), 2.41(d, J=11.23Hz, 1H, fatty CH), 2.48(s, 3H, ArCH ₃ ), 2.60-2.67(m, 2H, fatty CH), 2.84-2.89(m, 1H, fatty CH), 3.15-3.21 (m, 1H, fatty CH), 5.32-5.40 (m, 2H, OCH ₂ Ar), 6.59 (d, J=8.79Hz, 1H, ArH), 7.03 (d, J =8.55Hz, 1H, ArH), 7.65-7.69(m, 1H, ArH), 7.89(d, J=7.57Hz, 1H, ArH), 8.18(d, J=8.06Hz, 1H, ArH), 8.29( s, 1H, ArH), 11.58 (s, 1H, NH); MS (APCI ⁺ ) m/z 476.1 (MH ⁺ ). Anal. Calcd. for C ₂₇ H ₂₉ N ₃ O ₅ : C, 68.20; H, 6.15 ; N, 8.84. Found: C, 67.89; H, 6.20; N, 8.74.

Example 51

步骤A：3-(1-羟基乙基)苄腈 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(3-cyanophenyl) ethyl ester

Step A: 3-(1-Hydroxyethyl)benzonitrile

To a solution of 3-acetylbenzonitrile (68.9 mmol, 10.0 g) in MeOH (230 mL) was added _NaBH4 (68.9 mmol, 2.61 g) in portions at 0 °C under nitrogen atmosphere. After 2 hours of gradual warming to room temperature, 1 N HCl was added and the solvent was removed under reduced pressure. Dichloromethane (50 mL) was added, the layers were separated, and extracted with three portions of dichloromethane (50 mL). The combined extracts were washed with sodium bicarbonate (1 x 50 mL), saturated sodium chloride (1 x 50 mL), dried over magnesium sulfate, and concentrated in vacuo to give pure product as a yellow oil (10.0 g, 98%): ¹ H NMR (400MHz, CDCl ₃ ) δ 1.47 (d, J = 6.35Hz, 3H, ArCH(CH ₃ )OH), 1.99 (bs, 1H, OH), 4.92 (q, J = 6.35Hz, 1H, ArCH (CH ₃ )OH), 7.43 (t, J=7.81Hz, 1H, ArH), 7.53 (d, J=7.57Hz, 1H, ArH), 7.59 (d, J=7.81Hz, 1H, ArH), 7.66 (s, 1H, ArH).

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

Following the method of Example 47, step B, 3-(1-hydroxyethyl)-benzonitrile (13.5 mmol, 1.98 g) and pyrrolo[3′,2′:5,6][1] with benzoic acid Benzopyrano[3,2-i]quinolazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride ( Example 86, 3.37 mmol, 1.50 g) into pyrrolo[3′,2′:5,6][1]-benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15-Decahydro-2-methyl-, 1-(3-cyanophenyl)ethyl ester. This product was purified by flash column chromatography on silica gel (20-30% acetone/hexanes) to give a cream colored powder (0.614 g, 39%): mp 131-134 and 171-173°C (diastereomers);

IR (KBr) 3377, 2931, 2856, 2230, 1702, 1432, 1148, 1077, 1066 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ1.02-1.25 (m, 3H, fatty CH), 1.31 -1.72(m, 7H, fatty CH), 1.57(d, J=6.35Hz, 3H, OCH( _CH3 )Ar), 1.79-1.88(m, 1H, fatty CH), 2.32-2.44(m, 2H, Fat CH), 2.46 (s, 3H, ArCH ₃ ), 2.56-2.69 (m, 2H, Fat CH), 2.80-2.91 (m, 1H, Fat CH), 3.02-3.28 (m, 1H, Fat CH), 5.93-6.01 (m, 1H, OCH(CH ₃ ) Ar), 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 (m, 2H, ArH), 7.86 & 7.90 (s, 1H, ArH, diastereoisomers), 11.56 (s, 1H, NH); MS (APCI ⁺ ) m/z 470.1 (MH ⁺ ).C ₂₉ H ₃₁ N ₃ O ₃ 0.25H ₂ O Calcd. Analytical value: C, 73.47; H, 6.70; N, 8.86; H ₂ O, 0.95. Found: C, 73.18; H, 6.73; N , 8.56, H ₂ O, 0.58

Example 52

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[3-[(dimethylamino)carbonyl]phenyl]ethyl ester Step A: 3-(1-Hydroxyethyl)benzoic acid

A mixture of 3-(1-hydroxyethyl)benzonitrile (Example 51, Step A, 6.79 mmol, 1.00 g) in 10% aqueous sodium hydroxide (68 mL) was heated to reflux for 4.5 hours, cooled to room temperature, and distilled with ether Extract (2 x 50 mL). Discard the extract. The aqueous phase was acidified with concentrated hydrochloric acid, extracted with diethyl ether (3 x 50 mL), and the combined extracts were washed with brine, dried over magnesium sulfate, and concentrated to give a white solid (0.98 g, 87%): mp 107-110 °C;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.29 (d, J=6.35 Hz, 3H, ArCH(CH ₃ )OH), 4.71-4.78 (m, 1H, ArCH(CH ₃ )OH), 5.25 ( d, J=4.40Hz, 1H, OH), 7.39(t, J=7.57Hz, 1H, ArH), 7.53(d, J=7.57Hz, 1H, ArH), 7.76(d, J=7.57Hz, 1H , ArH), 7.91 (s, 1H, ArH), 12.87 (s, 1H, COOH); MS (APCI-) m/z 165.1 (M-1).

Step B: 3-(1-Hydroxyethyl)-N,N-dimethylbenzamide

To a solution of 3-(1-hydroxyethyl)benzoic acid (54.8 mmol, 9.10 g), dimethylamine (54.8 mmol, 27.4 mL of a 2.0 M solution in THF) and iPr ₂ NEt (109 mmol, 19.1 mL) in 55 mL of DMF, HBTU (54.8 mmol, 20.8 g) was added in two portions at 0 °C under nitrogen atmosphere. After 45 minutes, 1N HCl (50 mL) and diethyl ether (50 mL) were added, and the layers were separated. The aqueous phase was further acidified with 1N HCl and extracted with ether (4 x 50 mL). The extracts were combined and concentrated. The aqueous phase was also concentrated. The concentrates were combined, dissolved in _CH2Cl2 , washed with 10% HCl (1 x 20 mL), saturated sodium bicarbonate (1 x ₂₀ mL), brine (1 x 20 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (50-100% ethyl acetate/hexanes) to give 3-(1-hydroxyethyl)-N,N-dimethylbenzamide, _iPr2NEt and N, A mixture of N,N',N'-tetramethylureas. Yield based on ¹ H NMR was 6.56 g (62%). Rechromatographic purification of a small batch afforded the pure product as a clear, anhydrous oil: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 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 (m, 1H, ArCH(CH ₃ )OH), 5.20 (d, J=4.15Hz, 1H, OH) , 7.18-7.20 (m, 1H, ArH), 7.31-7.37 (m, 3H, ArH); MS (APCI ⁺ ) m/z 194.0 (MH ⁺ ).

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

According to the method of Example 47, Step B, 3-(1-hydroxyethyl)-N,N-dimethylbenzamide (14.9mmol, 2.88g) and pyrrolo[3′,2′ with benzoic acid : 5,6][1]-benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro -2-Methyl-, anhydride (Example 86, 3.73 mmol, 1.66 g) was mixed with xylene (10 mL) and heated at 150 °C for 5 minutes to form pyrrolo[3',2':5,6][1] Benzopyrano[3,2-i]quinolazine-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 flash column chromatography on silica gel (0-5% Et ₃ N/ethyl acetate), dissolved in ether/ethyl acetate and washed with water (15×20 mL) to remove unreacted 3-(1-hydroxyethyl )-N,N-dimethylbenzamide. The organic phase was concentrated and the residue was recrystallized from acetonitrile to give a white powder (1.65g, 86%): mp 199-202°C;

IR (KBr) 3416(br), 3219(br), 2930, 2855, 1684, 1622, 1432, 1188, 1146, 1091, 1062cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.02-1.28 (m, 3H, fatty CH), 1.32-1.70 (m, 7H, fatty CH), 1.57 (d, J=6.84Hz, 3H, OCH( _CH3 )Ar), 1.76-1.88 (m, 1H, fatty CH ), 2.32-2.43 (m, 2H, fatty CH), 2.50 & 2.51 (s, 3H, ArCH ₃ , diastereomers), 2.52-2.689 (m, 2H, fatty CH), 2.84 (s, 3H, NCH ₃ ), 2.84-2.89 (m, 1H, fatty CH), 2.92 (s, 3H, NCH ₃ ), 3.06-3.30 (m, 1H, fatty CH), 5.94-6.01 (m, 1H, OCH ( CH ₃ )Ar), 6.57 & 6.58 (d, J=8.55Hz, 1H, ArH, diastereoisomers), 7.01 & 7.02 (d, J=8.55Hz, 1H, ArH, diastereomers conformation), 7.29 (t, J=7.33Hz, 1H, ArH), 7.37-7.50 (m, 3H, ArH), 11.53 (s, 1H, NH); MS (APCI ⁺ ) m/z 516.3 (MH ⁺ ). Calcd for C ₃₁ H ₃₇ N ₃ O ₄ : C, 72.21; H, 7.23; N, 8.15. Found: C, 71.96; H, 7.25; N, 8.22.

Example 53

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[3-[(dimethylamino)methyl]phenyl]ethyl ester Step A: 1-(3-Dimethylaminomethylphenyl)ethanol

To a suspension of LiAIH ₄ (23.3 mmol, 0.931 g/95%) in THF (40 mL) was added 3-(1-hydroxyethyl)-N,N dimethylbenzamide at 0 °C under nitrogen atmosphere (Example 52, Step B, 15.5 mmol, 3.00 g) in 10 mL THF. After _H2 evolution ceased, the reaction was allowed to warm to room temperature. After standing at room temperature for 4 hours, the mixture was cooled to 0°C and ethyl acetate (0.74 mL) and 10% aqueous sodium hydroxide solution were added sequentially. The mixture was warmed to room temperature for 30 min, MgSO ₄ and Celite were added with stirring, and the mixture was filtered through Celite, washing with 20 mL THF. Concentration of this filtrate gave 2.73 g (99%) of pure 1-(3-dimethylaminomethylphenyl)ethanol:

¹ H NMR (400MHz, DMSO-d ₆ ) δ1.26 (d, J=6.59Hz, 3H, ArCH(CH ₃ )OH), 2.09(s, 6H, N(CH ₃ ) ₂ ), 3.31(s, 2H, ArCH ₂ N), 4.64-4.67 (m, 1H, ArCH(CH ₃ )OH), 5.08 (d, J=4.15Hz, 1H, OH), 7.07 (d, J=7.08Hz, 1H, ArH) , 7.15-7.25 (m, 3H, ArH); MS (APCI ⁺ ) m/z 180.0 (MH ⁺ ).

Step B: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-[3-[(dimethylamino)methyl]phenyl]ethyl ester

According to the method of Example 47, Step B, 1-(3-dimethylaminomethylphenyl)ethanol (15.2mmol, 2.73g) and pyrrolo[3′,2′:5,6] with benzoic acid [1] Benzopyrano[3,2-i]quinolazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl- , the anhydride (Example 86, 3.81 mmol, 1.69 g) was mixed with xylene (10 mL) and heated at 150° C. for 5 minutes to form pyrrolo[3′,2′:5,6][1]benzopyrano [3,2i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-[3-[(dimethyl ylamino)methyl]phenyl]ethyl ester. The usual extractive workup (ethyl acetate) followed. The aqueous phase was diluted with 100 mL of acetone, and the inorganic salts were filtered off. The filtrate was concentrated. The organic and aqueous residues were combined, mixed with 15 mL at room temperature under nitrogen and treated sequentially with pyridine (68.5 mmol, 5.54 mL) and acetic anhydride (34.3 mmol, 3.23 mL). After 48 hours, the white precipitate was filtered off, and the filtrate was washed with water (3 x 20 mL). The aqueous washings were concentrated and the product was purified by flash column chromatography on silica gel (0-5% _Et3N /ethyl acetate) to give a yellow solid (0.160 g, 8.4%): mp 95-100 °C;

IR (KBr) 2931, 2857, 1678, 1430, 1237, 1195, 1147, 1062cm ^-1 . ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.09-1.27 (m, 3H, fatty CH), 1.32-1.68 (m, 7H, fatty CH), 1.54 (d, J=6.35Hz, 3H, OCH(CH ₃ ) Ar), 1.79-1.84 (m, 1H, fatty CH), 2.07 & 2.08 (s, 6H, N (CH ₃ ) ₂ , diastereomers), 2.29-2.43 (m, 2H, fatty CH), 2.49 & 2.50 (s, 3H, ArCH ₃ , diastereomers), 2.59-2.69 ( m, 2H, fatty CH), 2.81-2.92 (m, 1H, fatty CH), 3.02-3.17 (m, 1H, fatty CH), 3.33 & 3.34 (s, 2H, _ArCH2N , diastereomers body), 5.90-5.98 (m, 1H, OCH(CH ₃ ) Ar), 6.56-6.59 (m, 1H, ArH), 7.00-7.03 (m, 1H, ArH), 7.12-7.21 (m, 1H, ArH ), 7.26-7.33 (m, 3H, ArH), 11.50 & 11.51 (s, 1H, NH, diastereomers); MS (APCI ⁺ ) m/z 502.2 (MH ⁺ ).C ₃₁ H ₃₉ N ₃ O ₃ 0.27C ₄ H ₈ O ₂

Calcd: C, 73.33; H, 7.90; N, 8.00. Found: C, 72.94; H, 7.90; N, 8.10.

Total method J

Diethyl azodicarboxylate (Aldrich, 1eq.) was added dropwise to 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (1eq.), triphenylphosphine (1eq. .) and the selected alcohol (1.5 eq.) in a THF mixture. After stirring at room temperature for 24 hours, the mixture was concentrated. This product was purified by recrystallization or flash column chromatography on silica gel (45% ethyl acetate: hexanes) to give the corresponding ester.

Total Method K

DBU (Aldrich, 1 eq.) was added to a solution of 5-acetoxy-2-methyl-1H-indole-3-carboxylic acid (1 eq.) in DMF by injection technique under nitrogen atmosphere. To this reaction mixture, a DMF solution of the selected alkyl halide (Aldrich, 1.1 eq.) was added. After stirring at room temperature for 24 hours, the reaction mixture was diluted with dichloromethane, causing precipitation of the desired product. The solid product was filtered off and washed with water.

total method L

Dimethylamine (2.2eq.) and formaldehyde (1.2eq.) were added to a solution of the selected ester (1.0eq.) in 10 mL of denatured ethanol. The mixture was stirred at reflux for 24 hours under nitrogen atmosphere. After the reaction was complete as judged by MS and TLC, the mixture was concentrated. This product _was purified by flash column chromatography on silica gel (30% MeOH: _CH2Cl2 ).

total method M

1,2,3,4,6,7,8,9-Octahydroquinazinium perchlorate (1.7 eq.) was dissolved in 2N NaOH (excess). This solution was extracted with ether. The combined organic layers were concentrated to a clear oil. This oil was dissolved in dioxane and added to a solution of the desired Mannich base (1 eq.) in dioxane. After heating at 110°C for 24 hours, the reaction was cooled to room temperature and the dioxane was removed to give a brown oil. This product was purified by flash column chromatography on silica gel (40% hexane:ethyl acetate).

total method N

A mixture of mixed anhydride (4 eq.) and alcohol of choice (4 eq.) was heated at 150° C. for 5 minutes or until the reaction was homogeneous. After cooling to room temperature, the oil was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was separated and concentrated to a brown oil. The product was purified by flash column chromatography on silica gel.

Total method O.

To a solution of the ester (1 eq.) in methanol was added 2N NaOH (4 eq.). The reaction became clear after heating at 55°C for 1 hour. The reaction mixture was cooled to 0°C and neutralized with concentrated hydrochloric acid. This product precipitated from solution as a white solid and was filtered off. Extraction of this mother liquor with ethyl acetate and removal of solvent afforded additional product.

total method P

To a suspension of the selected Mannich base (1 eq.) in anhydrous THF, solid _LiBH4 (5 eq.) was added slowly. MeOH (5 eq.) was immediately added dropwise via syringe. The resulting mixture was heated to reflux for 1 hour. After cooling to 0°C, 1N HCl was added to neutralize the reaction. This product precipitated from solution as a white solid. _The mother liquor was extracted with _CH2Cl2 . The combined organic layers were dried over magnesium sulfate, and the solvent was removed to give more product.

Example 54

步骤A：5-羟基-2-甲基-1H-吲哚-3-甲酸苯基乙酯 pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,1,13,14 , 14a, 15-Decahydro-2-methyl-, 2-phenylethyl ester

Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylated phenylethyl ester

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid phenylethyl ester was synthesized from 2-phenyl-ethanol (6.39 g, 52.3 mmol) according to Method J and recrystallized from hexane/ethyl acetate to give 2.40 g (31.1%) fine powder: mp186-188°C;

IR(KBr) 3231, 2978, 1644, 1463, 1173, 1101cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.49(s, 3H, CCH ₃ ), 3.03(t, J=6.99Hz, 2H, OCH ₂ CH ₂ ), 4.40 (t, J=6.75Hz, 2H, OCH ₂ CH ₂ ), 6.57 (dd, J=8.60, 2.29Hz, 1H, ArH), 7.09 (d, J=8.68Hz, 1H, ArH), 7.20(d, J=6.99Hz, 1H, ArH), 7.26-7.33(m, 5H, ArH), 8.81(s, 1H, OH), 11.49(s, 1H, NH); MS( APCI+): m/z 326.1 (MH ⁺ ). Analytical values calculated for C ₁₈ H ₁₇ N ₁ O ₃ : C, 73.20; H, 5.80; N, 4.74. Found: C, 73.23; H, 5.74; N, 4.67.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylated phenylethyl ester

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid phenethyl ester was prepared from 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid according to Method L Phenylethyl ester (2.89g, 9.78mmol) was synthesized and recrystallized from ethyl acetate to give 0.250g (15.0%) of a white solid: mp 200-201°C;

IR(KBr) 3138, 2971, 1673, 1585, 1437, 1279, 1099cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.34(s, 3H, CCH ₃ ) 2.68(s, 6H, N( _CH3 ) ₂ ), 3.00(t, J=6.59Hz, 2H _{, OCH2CH2} ), 4.43(t, J=6.59Hz, 2H, _OCH2CH2 ), 4.67(s, _2H , _NCH2Ar ) , 6.81(d, J=8.79Hz, 1H, ArH), 7.17-7.20(m, 1H, ArH), 7.23-7.28(m, 5H, ArH), 11.93(s, 1H, NH); MS(APCI+) : m/z 353.2 (MH ⁺ ). Anal. Calcd. for C ₂₁ H ₂₄ N ₂ O 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]quinazine-1-carboxylic acid, 3,7,8,9,10,1, 13,14,14a,15-Decahydro-2-methyl-,2-phenylethyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,1,13,14 , 14a, 15-Decahydro-2-methyl-, 2-phenylethyl ester from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid according to Method M Phenylethyl ester (0.250g, 0.709mmol) was synthesized and recrystallized from ethyl acetate/hexane to give 0.170g (54.0%) of a white solid: mp 185-186°C;

IR (KBr) 3297, 2931, 2856, 1673, 1432, 1199, 1080cm ^-1 ; ¹ HNMR (400MHz, CDCl ₃ ) δ1.20-1.81 (m, 10H, fatty CH), 2.07(d, J=13.92Hz , 1H, fatty CH), 2.41 (s, 3H, CCH ₃ ), 2.44-2.53 (m, 2H, fatty CH), 2.73-2.84 (m, 2H, fatty CH), 2.98-3.04 (m, 1H, fatty CH), 3.05-3.08 (m, 2H, OCH ₂ CH ₂ ), 3.38 (dd, J=17.95, 6.71 Hz, 1H, fatty CH), 4.50-4.53 (m, 2H, OCH ₂ CH ₂ ), 6.72 ( d, J=8.79Hz, 1H, ArH), 6.99(d, J=8.79Hz, 1H, ArH), 7.17-7.29(m, 5H, ArH), 7.99(s, 1H, NH); MS(APCI+) : m/z 445.3 (MH ⁺ ). Anal. Calcd. for C ₂₈ H ₃₂ N ₂ O ₃ : C, 75.56; H, 7.26; N, 6.30. Found: C, 75.36; H, 7.28; N, 6.13.

Example 55

步骤A：5-羟基-2-甲基-1H-吲哚-3-甲酸4-甲氧基羰基苄酯

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [4-(methoxycarbonyl)phenyl]methyl ester

Step A: 4-methoxycarbonylbenzyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester was synthesized according to Method K from methyl 4-bromomethylbenzoate (6.64 g, 29.0 mmol) and obtained from Precipitate from ether to obtain 4.88g (55.0%) of lavender powder: mp232-234°C;

IR (KBr) 3322, 2950, 1696, 1654, 1465, 1288, 1093 cm ^-1 ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ2.57 (s, 3H, CCH ₃ ), 3.80 (s, 3H, OCH ₃ ), 5.34(s, 2H, OCH ₂ Ar), 6.55(dd, J=8.67, 2.32Hz, 1H, ArH), 7.09(d, J=8.55Hz, 1H, ArH), 7.24(d, J= 2.20Hz, 1H, ArH), 7.54(d, J=8.06Hz, 2H, ArH), 7.94(d, J=8.30Hz, 2H, ArH), 8.83(s, 1H, OH), 11.59(s, 1H , NH); MS (APCI+): m/z 340.1 (MH ⁺ ). Analysis calculated for C ₁₉ H ₁₇ N ₁ O 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

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester was prepared from 5-hydroxy-2-methyl-1H- Indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (17.2 g, 50.7 mmol) was synthesized and triturated with ethyl acetate to give 8.50 g (43.0%) of a white solid: mp 125-126°C;

IR(KBr) 3142, 2959, 1672, 1585, 1434, 1285, 1095cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.12(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=8.44Hz, 1H, ArH), 7.09(d, J=8.44Hz, 1H, ArH), 7.60(d, J=8.20Hz, 2H, ArH), 7.98(d, J=8.20Hz, 2H, ArH), 11.56(s, 1H , NH); MS (APCI+): m/z 397.2 (MH ⁺ ). Analytical value calculated for C ₂₂ H ₂₄ N ₂ O 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]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [4-(methoxycarbonyl)phenyl]methyl ester was prepared from 4-dimethylaminomethyl-5-hydroxy-2-methyl- 1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (0.200g, 0.505mmol) was synthesized and recrystallized with tert-butyl methyl ether to obtain 0.090g (23.0%) of a granular off-white solid: mp179-180°C;

IR (KBr) 3173, 2930, 2856, 1725, 1615, 1433, 1275, 1079 ^{cm -1} ; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.21-1.81 (m, 10H, fatty CH), 2.06 (d, J = 8.79Hz, 1H, fat CH), 2.43 (d, J = 12.70Hz, 1H, fat CH), 2.50-2.53 (m, 1H, fat CH), 2.55 (s, 3H, _CCH3 ), 2.73-2.84 (m, 2H, fatty CH), 2.96-3.05 (m, 1H, fatty CH), 3.38 (dd, J=17.70, 7.20Hz, 1H, fatty CH), 3.89 (s, 3H, OCH ₃ ), 5.34 ( dd, J=16.36, 12.70Hz, 2H, OCH ₂ Ar), 6.73(d, J=8.79Hz, 1H, ArH), 7.01(d, J=8.79Hz, 1H, ArH), 7.47(d, J= 8.06Hz, 2H, ArH), 8.01(d, J=8.30Hz, 2H, ArH), 8.06(s, 1H, NH); MS(APCI+): m/z 489.3(MH ⁺ ). C ₂₉ H ₃₂ N ₂ O ₅ Calcd: C, 71.29; H, 6.60; N, 5.73. Found: C, 70.94; H, 6.26; N, 5.57.

Example 56

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 ,14a,15-Decahydro-2,-methyl-,(4-carboxyphenyl)methyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 ,14a,15-Decahydro-2-methyl-,(4-carboxyphenyl)methyl ester was synthesized according to method O and triturated with methanol to give 0.030 g (11.0%) of a fine off-white powder: mp 243-244°C;

IR (KBr) 2932, 2863, 1698, 1592, 1432, 1077cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.05-1.26 (m, 3H, fatty CH) 1.39-1.66 (m, 6H, Fat CH), 1.85(d, J=13.67Hz, 1H, Fat CH), 2.44(d, J=11.23Hz, 1H, Fat CH), 2.47-2.48(m, 1H, Fat CH), 2.48(s, 3H, CCH ₃ ), 2.63-2.69 (m, 2H, fatty CH), 2.85-2.91 (m, 1H, fatty CH), 3.19 (dd, J=18.07, 6.84Hz, 1H, fatty CH), 3.41-3.43 (m, 1H, fatty CH), 5.31 (dd, J=20.02, 12.94Hz, 2H, OCH ₂ Ar), 6.60 (d, J=8.55Hz, 1H, ArH), 7.04 (d, J=8.55Hz, 1H, ArH), 7.54(d, J=8.30Hz, 2H, ArH), 7.94(d, J=8.30Hz, 2H, ArH), 11.57(s, 1H, NH), 12.98(s, 1H, _CO2 H); MS (APCI+): m/z 475.3 (MH ⁺ ). Analysis calculated for C ₂₈ H ₃₀ N ₂ O ₅ : C, 70.1 7; H, 6.42; N, 5.85. Found: C, 69.78; H, 6.50; N, 5.62.

Example 57

1-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-1H-indol-4-ylmethyl]-1,2,3,4,6,7,8 , 9-octahydro-quinazinium; chloride

To pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1 carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [4-(methoxycarbonyl) phenyl] methyl ester (Example 56, step C, 1.00 g, 2.05 mmol) in 25.6 mL of methanol solution, was added 2N NaOH (4.09 mL, 8.19 mmol). After heating at 55°C for 1 hour, the mixture turned into a clear solution. The reaction mixture was cooled to 0°C and concentrated hydrochloric acid was slowly added until pH3. The aqueous layer was extracted with ethyl acetate (5 x 50 mL), and the combined organic layers were dried over magnesium sulfate, and the solvent was removed. This 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, 1083cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.20-1.30 (m, 1H, fatty CH) 1.43-1.51 ( m, 4H, fatty CH), 1.69-2.30 (m, 5H, fatty CH), 2.48 & 2.49 (s, 3H, CCH ₃ , open and closed ring forms), 2.48-2.55 (m, 2H, fatty CH) , 2.85-3.30 (m, 2H, fatty CH), 3.40-3.80 (m, 3H, fatty CH), 5.33-5.36 (m, 2H, OCH ₂ Ar), 6.79&6.82 (d, J=8.55&8. 06Hz, 1H, ArH, open and closed form), 7.11&7.20 (d, J=8.55&8.55Hz, 1H, ArH, open and closed form), 7.54-7.56 (m, 2H, ArH), 7.94 -7.96 (m, 2H, ArH), 9.19 (s, 1H, OH, open ring), 11.79 & 11.85 (s, 1H, NH, open and closed ring forms), 13.00 (s, 1H, CO ₂ H) ; MS (APCI+): m/z 475.3 (MH ⁺ ). Anal. Calcd. for C ₂₈ H ₃₁ N ₂ O ₅ Cl 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl ester

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

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester From 4-dimethylaminomethyl-5-hydroxy -2-Methyl-1H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (Example 56, Step B, 2.32 g, 5.84 mmol) was synthesized and triturated with acetone to give 0.993 g (47.0%) of white Solid: mp140-143°C; IR(KBr) 3140, 2777, 1686, 1583, 1435, 1092cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.51(s, 3H, CH ₃ ), 2.71( s, 6H, N(CH ₃ ) ₂ ), 4.47 (d, J=5.13Hz, 2H, ArCH ₂ OH), 4.73 (s, 2H, NCH ₂ Ar), 5.18 (t, J=5.62Hz, 1H, ArCH ₂ OH), 5.25 (s, 2H, OCH ₂ Ar), 6.84 (d, J=8.55Hz, 1H, ArH), 7.28 (d, J=8.55Hz, 1H, ArH), 7.31 (d, J= 7.81Hz, 2H, ArH), 7.40(d, J=7.81Hz, 2H, ArH), 8.60(s, 1H, OH), 11.97(s, 1H, NH); MS(APCI+): m/z369.2 (MH ⁺ ).HPLC (ALLTCH/ALLTIMAC-18 1:1-2:98 H ₂ O/CH ₃ CN+0.05% TFA): retention time = 4.57 min, 95.23% purity.

Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,[4-(hydroxymethyl)phenyl]methyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl ester was prepared from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H according to Method M - 4-hydroxymethyl-benzyl indole-3-carboxylate (0.969g, 2.63mmol) was synthesized and triturated with acetone to give 0.890g (49.0%) of a white solid: mp 198-200°C;

IR(KBr) 3405, 3237, 2931, 1660, 1424, 1237, 1081cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.11-1.27(m, 3H, fatty CH), 1.39-1.70(m , 7H, fat CH), 1.85 (d, J=13.50Hz, 1H, fat CH), 2.36 (d, J=10.37Hz, 1H, fat CH), 2.41-2.43 (m, 1H, fat CH), 2.47 (s, 3H, CCH ₃ ), 2.65-2.69 (m, 2H, fatty CH), 2.86-2.92 (m, 1H, fatty CH), 3.23 (dd, J=16.64, 9.64Hz, 1H, fatty CH), 4.48 (d, J=5.78Hz _, 2H, _ArCH2OH ), 5.17 (t, J=5.55Hz, 1H, ArCH2OH), 5.21 (dd, J=22.42, 12.06, Hz, 2H, _OCH2Ar ) , 6.59(d, J=8.44Hz, 1H, ArH), 7.03(d, J=8.68Hz, 1H, ArH), 7.31(d, J=7.72Hz, 2H, ArH), 7.39(d, J=7.96 Hz, 2H, ArH), 11.52 (s, 1H, NH); MS (APCI+): m/z 461.2 (MH ⁺ ). Analytical values calculated for C ₂₈ H ₃₂ N ₂ O 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]quinazine-2-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-naphthylmethyl ester Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalene-2-ylmethyl ester was synthesized according to Method K from 2-bromomethyl-naphthalene (7.63 g, 34.5 mmol) and precipitated from dichloromethane Get 5.01g (48.1%) of lavender powder: mp243-245°C;

IR(KBr) 3408, 3306, 3058, 1665, 1596, 1465, 1172, 1093cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.59(s, 3H, CCH ₃ ), 5.46(s, 2H , OCH ₂ Ar), 6.59 (dd, J=8.44, 2.41Hz, 1H, ArH), 7.12 (d, J=8.44Hz, 1H, ArH), 7.30 (d, J=2.41Hz, 1H, ArH), 7.51(dd, J=6.03, 3.38Hz, 1H, ArH), 7.59(d, J=1.69Hz, 1H, ArH), 7.61(d, J=1.69Hz, 1H, ArH), 7.90-7.96(m, 4H, ArH), 8.83 (s, 1H, OH), 11.58 (s, 1H, NH); MS (APCI+): m/z 332.2 (MH ⁺ ).HPLC (ALLTCH/ALLTIMA C-18 35:65- 2:98 H ₂ O/CH ₃ CN+0.05% TFA): retention time = 3.70 min, 95.81% purity.

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid naphthalen-2-ylmethyl ester From 5-hydroxy-2-methyl-1H-indole - 3-Naphthalene-2-ylmethyl carboxylate (Example 57, step A, 3.38 g, 10.2 mmol) was synthesized and recrystallized from dichloromethane to obtain 0.750 g (19.0%) of a white solid: mp 170-171 ° C;

IR(KBr) 3120, 2964, 2853, 1675, 1592, 1431, 1257, 1088cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.11(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=8.68Hz, 1H, ArH), 7.08 (d, J =8.44Hz, 1H, ArH), 7.51-7.53(m, 2H, ArH), 7.60(d, J=8.44Hz, 1H, ArH), 7.91-7.99(m, 4H, ArH), 11.55(s, 1H , NH); MS (APCI+): m/z 389.2 (MH ⁺ ).HPLC (ALLTCH/ALLTIMAC-18 55:45-15:85 H ₂ O/CH ₃ CN+0.05%TFA): retention time=4.80 min, 94.36% purity.

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-2-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,2-naphthylmethyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-2-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-naphthylmethyl ester from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid according to Method M Naphthalene-2-ylmethyl ester (0.620g, 1.62mmol) was synthesized and recrystallized from ethyl acetate/hexane to give 0.690g (59.0%) of a granular white solid: mp 141-143°C;

IR (KBr) 3177, 3056, 2929, 1702, 1430, 1146, 1079cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ1.19-1.45 (m, 4H, fatty CH) 1.55-1.78 (m, 6H, Fat CH), 2.07(d, J=13.99Hz, 1H, Fat CH), 2.43-2.46(m, 1H, Fat CH), 2.52-2.55(m, 1H, Fat CH), 2.58(s, 3H, CCH ₃ ), 2.77-2.86 (m, 2H, fatty CH), 3.01-3.07 (m, 1H, fatty CH), 3.41 (dd, J=18.08, 6.75Hz, 1H, fatty CH), 5.48 (dd, J= 19.53, 10.61Hz, 2H, OCH ₂ Ar), 6.75(d, J=8.68Hz, 1H, ArH), 7.03(d, J=8.68Hz, 1H, ArH), 7.48-7.50(m, 2H, ArH) , 7.55-7.57 (m, 1H, ArH), 7.82-7.86 (m, 3H, ArH), 8.11 (s, 1H, NH); MS (APCI+): m/z481.3 (MH ⁺ ).C ₃₁ H Anal. Calcd. for ₃₂ N ₂ O ₃ : C, 77.47; H, 6.71; N, 5.83. Found: C, 77.13; H, 6.84; N, 5.51.

Example 60

步骤A：5-羟基-2-甲基-1H-吲哚-3-甲酸3-甲氧基羰基-苄酯

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester

Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonylbenzyl ester was synthesized according to Procedure K from methyl 3-bromomethylbenzoate (5.49 g, 24.0 mmol) and dissolved in ethyl acetate Ester was ground to give 2.01 g (27.0%) of a light gray powder: mp 160-162°C;

IR(KBr) 3383, 3310, 1721, 1666, 1465, 1289, 1095cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.56(s, 3H, CCH ₃ ), 3.81(s, 3H, OCH ₃ ), 5.35(s, 2H, OCH ₂ Ar), 6.57(dd, J=8.55, 2.20Hz, 1H, ArH), 7.10(d, J=8.55Hz, 1H, ArH), 7.25(d, J= 2.20Hz, 1H, ArH), 7.53(t, J=7.81Hz, 1H, ArH), 7.70(d, J=7.81Hz, 1H, ArH), 7.89(d, J=7.57Hz, 1H, ArH), 8.01(s, 1H, ArH), 8.82(s, 1H, OH), 11.58(s, 1H, NH); MS(APCI+): m/z 340.1(MH ⁺ ).C ₁₉ H ₁₇ N ₁ O ₅ Calcd: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.22; H, 4.75; N, 4.05.

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

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester was prepared from 5-hydroxy-2-methyl-1H- Indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (7.26g, 21.4mmol) was synthesized and triturated with ethyl acetate to give 4.80g (56.6%) fine white powder: mp 164-167°C;

IR(KBr) 3031, 2951, 1725, 1683, 1432, 1285, 1077cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.10(s, 6H, N(CH ₃ ) ₂ ), 2.49(s , 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=8.55Hz, 1H, ArH), 7.06(d, J=8.55Hz, 1H, ArH), 7.52(t, J=7.81Hz, 1H, ArH), 7.72(d, J=7.57Hz, 1H, ArH), 7.90(d, J =7.81Hz, 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 _H2O / _CH3CN +0.05% TFA): retention time = 4.91 min, 92.97% purity.

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester was prepared from 4-dimethylaminomethyl-5-hydroxy-2-methyl- 1H-Indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (2.09g, 5.27mmol) was synthesized and recrystallized from tert-butyl methyl ether to give 1.21g (47.1%) fine white powder: mp 169-170°C; IR (KBr) 3380, 2931, 2855, 1721, 1433, 1289, 1076cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.03-1.21(m, 3H, fatty CH) 1.36-1.63(m, 7H , Fat CH), 1.81(d, J=13.43Hz, 1H, Fat CH), 2.33(d, J=10.50Hz, 1H, Fat CH), 2.40-2.42(m, 1H, Fat CH), 2.46(s , 3H, CCH ₃ ), 2.56-2.67 (m, 2H, fatty CH), 2.82-2.88 (m, 1H, fatty CH), 3.14 (dd, J=18.07, 6.84Hz, 1H, fatty CH), 3.81 ( s, 3H, OCH ₃ ), 5.29 (dd, J=25.15, 12.45Hz, 2H, OCH ₂ Ar), 6.57 (d, J=8.79Hz, 1H, ArH), 7.02 (d, J=8.79Hz, 1H , ArH), 7.52(t, J=7.57Hz, 1H, ArH), 7.71(d, J=7.57Hz, 1H, ArH), 7.90(d, J=7.81Hz, 1H, ArH), 8.02(s, 1H, ArH), 11.55 (s, 1H, NH); MS (APCI+): m/z 489.2 (MH ⁺ ). Anal. Calcd. for C ₂₉ H ₃₂ N ₂ O ₅ : C, 71.29; H, 6.60; N , 5.73. Measured value: C, 71.22; H, 6.91; N, 5.43.

Example 61

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]methyl ester

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

4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester From 4-dimethylaminomethyl-5-hydroxy - 2-Methyl-1H-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (Example 60, Step B, 2.21 g, 5.58 mmol) was synthesized and triturated with dichloromethane to give 1.11 g (54.0% ) white powder: mp199-201℃; IR (KBr) 3065, 2884, 1681, 1586, 1432, 1090cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.25 (s, 3H, CCH ₃ ) 2.72(s, 6H, N( _CH3 ) ₂ ), 4.48(d, J=5.37Hz, 2H, _ArCH2OH ), 4.75(s, 2H, _NCH2Ar ), 5.22(t, J=5.62Hz, 1H, ArCH ₂ OH), 5.28 (s, 2H, OCH ₂ Ar), 6.87 (d, J=8.55Hz, 1H, ArH), 7.25-7.34 (m, 4H, ArH), 7.40 (s, 1H, ArH ), 8.59 (s, 1H, ArOH), 12.06 (s, 1H, NH); MS (APCI+): m/z 369.2 (MH ⁺ ).HPLC (ALLTCH/ALLTIMA C-18 98:2-75:25 H ₂ O/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]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]methyl ester was prepared from 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H according to Method M -Indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester (0.980g, 2.66mmol) was synthesized and triturated with tert-butyl methyl ether to obtain 0.420g (44.2%) of light yellow-green crystals: mp183-185°C;

IR (KBr) 3381, 3197, 2931, 1682, 1430, 1249, 1076cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.06-1.37 (m, 3H, fatty CH) 1.40-1.65 (m, 6H, fat CH), 1.82 (d, J = 13.43Hz, 1H, fat CH), 2.33 (d, J = 10.01Hz, 1H, fat CH), 2.40-2.43 (m, 1H, fat CH), 2.46 ( s, 3H, CCH ₃ ), 2.61-2.68 (m, 2H, fatty CH), 2.83-2.89 (m, 1H, fatty CH), 3.12-3.16 (m, 1H, fatty CH), 3.18 (dd, J= 18.31, 6.84Hz, 1H, fatty CH ₎ , 4.46 (d, J=5.62Hz, 2H, ArCH2OH), 5.18 (t, J=6.10Hz, 1H, ArCH2OH), 5.21 (dd, J= _20.27 , 12.21Hz, 2H, OCH ₂ Ar), 6.58(d, J=8.79Hz, 1H, ArH), 7.01(d, J=8.55Hz, 1H, ArH), 7.23-7.32(m, 3H, ArH), 7.36 (s, 1H, ArH), 11.51 (s, 1H, NH); MS (APCI+): m/z 461.1 (MH ⁺ ). Calcd for C ₂₈ H ₃₂ N ₂ O ₄ : C, 73.02; H , 7.00; N, 6.08. Found: C, 72.84; H, 7.07; N, 5.91.

Example 62

吡咯并[3’，2’：5，6][1]苯并吡喃并[3，2-i]喹嗪-1-甲酸，3，7，8，9，10，12，13，14，14a，15-十氢-2-甲基-，(3-羧基苯基)甲酯按照方法O由吡咯并[3’，2’：5，6][1]-苯并吡喃并[3，2-i]喹嗪-1-甲酸，3，7，8，9，10，12，13，14，14a，15-十氢-2-甲基-，[3-(甲氧基羰基)苯基]甲酯(实施例60，步骤C，0.923g，1.89mmol)合成，并用乙酸乙酯研磨得到0.456g(50.7％)的白色粉末：mp205-208℃；pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, (3-carboxyphenyl) methyl ester)

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (3-carboxyphenyl)methyl ester was synthesized from pyrrolo[3',2':5,6][1]-benzopyrano[ 3,2-i]quinolazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(methoxycarbonyl ) phenyl]methyl ester (Example 60, Step C, 0.923g, 1.89mmol) was synthesized and ground with ethyl acetate to give 0.456g (50.7%) of white powder: mp205-208°C;

IR (KBr) 2932, 2859, 1693, 1563, 1432, 1076cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.08-1.36 (m, 3H, fatty CH) 1.39-1.63 (m, 7H, Fat CH), 1.81(d, J=13.18Hz, 1H, Fat CH), 2.33(d, J=11.23Hz, 1H, Fat CH), 2.40-2.43(m, 1H, Fat CH), 2.47(s, 3H, CCH ₃ ), 2.56-2.67 (m, 2H, fatty CH), 2.84-2.88 (m, 1H, fatty CH), 3.15 (dd, J=17.82, 6.35Hz, 1H, fatty CH), 5.28 (dd , J=24.17, 12.45Hz, 2H, OCH ₂ Ar), 6.57(d, J=8.79Hz, 1H, ArH), 7.02(d, J=8.55Hz, 1H, ArH), 7.48(t, J=7.57 Hz, 1H, ArH), 7.65(d, J=7.57Hz, 1H, ArH), 7.87(d, J=7.81Hz, 1H, ArH), 8.00(s, 1H, ArH), 11.55(s, 1H, NH); MS (APCI+): m/z 475.1 (MH ⁺ ). Anal. Calcd. for C ₂₈ H ₃₀ N ₂ O ₅ : C, 69.18; H, 6.50; N, 5.75. Found: C, 68.83; H , 6.40; N, 5.63.

Example 63

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, with 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3 ',2': Salt of 5,6][1]-benzopyrano[3,2-i]quinazine-1-carboxylic acid (3-carboxyphenyl)methyl ester (1:1)

To pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1 carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, (3-carboxyphenyl) methyl ester (Example 62, 0.100g, 0.211mmol) in 5mL EtOH suspension, was added choline carbonate (0.037mL , 0.211 mmol, 5.66M). The reaction mixture was heated to reflux for 1 hour to obtain a clear solution. After cooling to room temperature, the mixture was concentrated to give a yellow oil. Trituration of the oil with ether gave 0.097 g (88.0%) of a beige solid: mp 165-170°C;

IR (KBr) 2930, 2855, 1685, 1566, 1436, 1077cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.09-1.28 (m, 3H, fatty CH) 1.39-1.70 (m, 7H, Fat CH), 1.86(d, J=13.50Hz, 1H, Fat CH), 2.35(d, J=10.37Hz, 1H, Fat CH), 2.42-2.45(m, 1H, Fat CH), 2.47(s, 3H, CCH ₃ ), 2.65-2.72 (m, 2H, fatty CH), 2.87-2.91 (m, 1H, fatty CH), 3.09 (s, 9H, N(CH ₃ ) ₃ ), 3.23 (dd, J= 15.19, 8.44Hz, _1H , fatty CH ₎ , 3.35-3.40 (m, 2H, NCH2CH2OH), 3.81-3.85 (m, _{2H ,} NCH2CH2OH), 5.20 (dd, J=23.63, 12.30 Hz, 2H, OCH ₂ Ar), 6.55(d, J=8.44Hz, 1H, ArH), 7.03(d, J=8.44Hz, 1H, ArH), 7.22(t, J=7.47Hz, 1H, ArH) , 7.29(d, J=7.23Hz, 1H, ArH), 7.75(d, J=7.48Hz, 1H, ArH), 7.89(s, 1H, ArH), 11.55(s, 1H, NH); MS(APCI+ ): m/z 475.1 (MH ⁺ ). C ₃₃ H ₄₃ N ₃ O ₆ : Calculated: C, 65.23; H, 7.68; N, 6.92. Found: C, 64.95; H, 7.68; N, 6.92.

Example 64

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [3-[(dimethylamino)methyl]phenyl]methyl ester

To stirred Ph ₃ P (0.161g, 0.616mmol) and pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3 , 7,8,9,10,12,13,14,14a,15-Decahydro-2-methyl-,[3-(hydroxymethyl)phenyl]-methyl ester (Example 61, Step B, To a solution of 0.284 g, 0.616 mmol) in 2.93 mL of anhydrous THF was added dropwise a solution of N-bromosuccinimide (0.110 g, 0.616 mmol) in 2 mL of THF at -18°C. After 10 minutes, the cooling bath was removed and dimethylamine was added in one portion. The reaction was heated at 80°C for 1 hour in a stainless steel vessel. THF was removed and the product was purified by flash column chromatography on silica gel (20% MeOH: _CH2Cl2 ) and _{recrystallized} from dichloromethane to give 1.21 g (40.3%) of crude off-white powder: mp 87-90°C;

IR (KBr) 2930, 2854, 1700, 1589, 1432, 1077cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.06-1.36 (m, 3H, fatty CH) 1.39-1.63 (m, 7H, Fat CH), 1.82 (d, J=13.18Hz, 1H, Fat CH), 2.11 (s, 6H, N(CH ₃ ) ₂ ) 2.34 (d, J=10.74Hz, 1H, Fat CH), 2.40-2.46 (m, 1H, fatty CH), 2.45 (s, 3H, CCH ₃ ), 2.59-2.67 (m, 2H, fatty CH), 2.83-2.89 (m, 1H, fatty CH), 3.15 (dd, J=18.31 , 6.84Hz, 1H, fat CH), 3.37(s, 2H, ArCH2N( _CH3 ) ₂ ), 5.20(dd, J=23.93, 12.21Hz _, 2H, _OCH2Ar ), 6.57(d, J= 8.79Hz, 1H, ArH), 7.02(d, J=8.79Hz, 1H, ArH), 7.22-7.31(m, 3H, ArH), 7.34(s, 1H, ArH), 11.53(s, 1H, NH) ; MS (APCI+): m/z 488.1 (MH ⁺ ). Anal. Calcd. for C ₃₀ H ₃₇ N ₃ O 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]phenyl]methyl ester Step A: 3-Hydroxymethyl-N,N-dimethyl-benzamide

To 3-(hydroxymethyl)benzoic acid (9.87g, 64.9mmol), dimethylamine (2M in THF, 32.4mL, 64.9mmol), N,N-diisopropylethylamine (22.6mL, 130mmol ) in 20 mL of DMF, a solution of HBTU (24.6 g, 64.9 mmol) in 55 mL of DMF was added at 0°C. After 5 minutes, the yellow solution turned orange. After stirring at 0°C for 1 hour, the reaction mixture was diluted with ether, washed with 10% HCl, saturated sodium bicarbonate, brine, dried over magnesium sulfate, and concentrated to give a brown oil. This product was purified by flash column chromatography on silica gel (3% MeOH: dichloromethane) to give 7.5 g (64.5%) of a yellow oil: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.88 (s, 3H , NCH ₃ ), 2.96(s, 3H, NCH ₃ ), 4.51(d, J=5.55Hz, 2H, OCH ₂ Ar), 5.25(t, J=5.79Hz, 1H, OH), 7.21-7.25(m , 1H, ArH), 7.31-7.47 (m, 3H, ArH); MS (APCI+): m/z 180.1 (MH ⁺ ).

Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,[3-[(dimethylamino)carbonyl]phenyl]methyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a,15-Decahydro-2-methyl-,[3-[(dimethylamino)carbonyl]-phenyl]methyl ester was prepared from 3-hydroxymethyl-N,N-dimethyl- Benzamide (1.04 g, 5.81 mmol) was synthesized and triturated with acetone to give 0.250 g (25.7%) of a fluffy white powder: mp 112-116 °C; IR (KBr) 2929, 2854, 1698, 1624, 1432, ^{1077 cm -1} ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.09-1.62(m, 10H, fatty CH), 1.82(d, J=14.16Hz, 1H, fatty CH), 2.33(d, J=10.25Hz, 1H, fatty CH), 2.40-2.43 (m, 1H, fatty CH), 2.45 (s, 3H, CCH ₃ ), 2.46 (s, 6H, N(CH ₃ ) ₂ ), 2.59-2.67 (m, 2H, Fat CH), 2.86-2.93 (m, 1H, Fat CH), 3.16 (dd, J=18.80, 7.81Hz, 1H, Fat CH), 5.24 (dd, J=20.75, 12.45Hz, 2H, OCH ₂ Ar) , 6.57(d, J=8.55Hz, 1H, ArH), 7.02(d, J=8.55Hz, 1H, ArH), 7.33(d, J=7.57Hz, 1H, ArH), 7.40-7.44(m, 2H , ArH), 7.49 (d, J=7.57Hz, 1H, ArH), 11.54 (s, 1H, NH); MS (APCI+): m/z 502.2 (MH ⁺ ) calculated for C ₃₀ H ₃₅ N ₃ O ₄ Analytical value: C, 71.83; H, 7.03; N, 8.38. Found: C, 71.44; H, 7.05; N, 8.21.

Example 66

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [2-(4-morpholinyl) ethyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,[2-(4-morpholinyl)ethyl ester was synthesized from 2-morpholin-4-yl-ethanol (0.300 mL, 2.64 mmol) according to Procedure N and treated with Trituration with dichloromethane gave 0.122 g (41.0%) of a white solid: mp 188-190°C;

IR(KBr) 2931, 2854, 1696, 1588, 1432, 1148cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.14-1.75 (m, 10H, fatty CH), 1.90 (d, J=13.18 Hz, 1H, fatty CH), 2.34-2.46(m, 2H, fatty CH), 2.46(s, 4H, N( _{CH2CH2 ) 2O} ), 2.49(s, 3H, _CCH3 ), 2.59(t , J=5.62Hz, 2H, CO ₂ CH ₂ CH ₂ ), 2.64-2.73 (m, 2H, fatty CH), 2.86-2.91 (m, 1H, fatty CH), 3.29 (dd, J=19.29, 10.25Hz , 1H, fatty CH), 3.52 (s, 4H, N(CH ₂ CH ₂ ) ₂ O), 4.18-4.30 (m, 2H, CO ₂ CH ₂ CH ₂ ), 6.58 (d, J=8.55Hz, 1H , ArH), 7.02 (d, J=8.55Hz, 1H, ArH), 11.48 (s, 1H, NH); MS (APCI+): m/z 454.1 (MH ⁺ ).C ₂₆ H ₃₅ N ₃ O ₄ Calcd: 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]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[1,1'-biphenyl]-4-ylethyl ester was prepared from 1-biphenyl-4-yl-ethanol (2.68 g , 13.5mmol) and ground with ether to give 0.619g (35.4%) of white powder: mp132-135°C;

IR(KBr) 2929, 2855, 1677, 1432, 1078cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.11-1.67(m, 10H, fatty CH), 1.59(d, J=6.59Hz, 2H, OCHCH ₃ ), 1.79-1.89 (m, 2H, fatty CH), 2.33-2.47 (m, 1H, fatty CH), 2.53 & 2.54 (s, 3H, CCH ₃ , diastereoisomers), 2.60-2.67 (m, 2H, fatty CH), 2.79-2.95 (m, 1H, fatty CH), 3.14 (dd, J=28.08, 10.12Hz, 1H, fatty CH), 5.96-6.03 (m, 1H, OCHCH ₃ ), 6.55-6.59 (m, 1H, ArH), 7.00-7.03 (m, 1H, ArH), 7.31-7.34 (m, 1H, ArH), 7.40-7.51 (m, 4H, ArH), 7.60-7.64 (m, 4H, ArH), 11.53 (s, 1H, NH); MS (APCI+): m/z 521.1 (MH ⁺ ). Calcd. for C ₃₄ H ₃₆ N ₂ O ₃ : C, 78.25; H, 7.36; N, 5.14. Found: C, 78.20; H, 7.76; N, 4.85.

Example 68

吡咯并[3’，2’：5，6][1]苯并吡喃并[3，2-i]喹嗪-1-甲酸，3，7，8，9，10，12，13，14，14a，15-十氢-2-甲基-，(2，6-二氟苯基)甲酯按照方法N由(2，6-二氟-苯基)-甲醇(1.50mL，13.5mmol)合成，并用乙醚研磨得到1.07g(68.0％)的蓬松的白色粉末：mp219-220℃；pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (2,6-difluorophenyl)methyl ester from (2,6-difluoro-phenyl)-methanol (1.50 mL, 13.5 mmol) according to Procedure N Synthesized and ground with ether to give 1.07g (68.0%) of fluffy white powder: mp219-220°C;

IR (KBr) 3330, 2928, 1664, 1473, 1059cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.03-1.35 (m, 3H, aliphatic CH), 1.38-1.56 (m, 7H, ring CH), 1.78 (d, J=13.18Hz, 2H, fat CH), 2.32-2.34 (m, 2H, fat CH), 2.41 (s, 3H, CCH ₃ ), 2.55-2.66 (m, 2H, fat CH CH), 2.83-2.88 (m, 1H, fatty CH), 3.08 (dd, J=18.31, 7.08Hz, 1H, fatty CH), 5.20 (d, J=11.96Hz, 1H, OCH ₂ Ar), 6.57 ( d, J=8.55Hz, 1H, ArH), 7.01(d, J=8.55Hz, 1H, ArH), 7.16(t, J=7.81Hz, 2H, ArH), 7.48-7.53(m, 1H, ArH) , 11.57 (s, 1H, NH); MS (APCI+): m/z 467.1 (MH ⁺ ). Anal. Calcd. for C ₂₇ H ₂₈ N ₂ O ₃ F ₂ : C, 69.32; H, 6.19; N, 5.80 .Measured values: C, 69.51; H, 6.05; N, 6.00.

Example 69

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-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 prepared from 2,2,2-trifluoro-1-phenylethanol ( 1.58g, 9.00mmol) and ground with tert-butyl methyl ether to give 0.356g (31.8%) of fluffy white powder: mp115-117°C;

IR (KBr) 3382, 2931, 1718, 1432, 1067cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.07-1.68 (m, 10H, fatty CH), 1.87-1.90 (m, 2H, fatty CH), 2.35-2.46 (m, 2H, fatty CH), 2.58-2.62 (m, 1H, fatty CH), 2.61 & 2.62 (s, 3H, _CCH3 , diastereoisomers), 2.62-2.90 (m, 1H, fatty CH), 3.18 (dd, J=17.82, 6.84Hz, 1H, fatty CH), 6.52-6.57 (m, 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+): m/z499. 1(MH ⁺ ). Anal. Calcd. for C ₂₈ H ₂₉ N ₂ O ₃ F ₃ : C, 67.46; H, 5.86; N, 5.62. Found: C, 67.40; H, 6.03; N, 5.44.

Example 70

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[3-(trifluoromethyl)phenyl]ethyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[3-(trifluoromethyl)phenyl]ethyl ester was prepared from 1-(3-trifluoromethyl-phenyl)-ethanol ( 2.06mL, 13.5mmol) and triturated with ether to give 0.793g (45.8%) of white solid: mp102-105°C;

IR(KBr) 3380, 2931, 1680, 1432, 1075cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.05-1.59(m, 10H, fatty CH), 1.59(d, J=6.59Hz, 3H, OCHCH ₃ ), 1.77-1.88 (m, 1H, fatty CH), 2.33 (d, J=9.03Hz, 1H, fatty CH), 2.41 (d, J=8.55Hz, 1H, fatty CH), 2.51&2 .52 (s, 3H, CCH ₃ , diastereomers), 2.51-2.67 (m, 2H, fatty CH), 2.83-2.86 (m, 1H, fatty CH), 3.06 (dd, J=18.07, 6.84Hz, 1H, fatty CH), 6.01-6.05(m, 1H, OCHCH ₃ ), 6.58-6.60(m, 1H, ArH), 7.01-7.04(m, 1H, ArH), 7.57-7.67(m, 2H , ArH), 7.71-7.75 (m, 2H, ArH), 11.56 (s, 1H, NH); MS (APCI+): m/z 513.1 (MH ⁺ ). Calcd for C ₂₉ H ₃₁ N ₂ O ₃ F ₃ Analytical value: C, 67.69; H, 6.08; N, 5.44. Found: C, 67.34; H, 6.35; N, 5.24.

Example 71

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-(dimethylamino)ethyl ester was synthesized according to Procedure N from 2-dimethylamino-ethanol (1.36 mL, 13.5 mmol) and triturated with diethyl ether to give 0.489 g (34.9%) of granular off-white solid: mp190-191°C;

IR(KBr) 3274, 2950, 1653, 1518, 1248cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.13-1.59(m, 10H, fatty CH), 1.71-1.76(m, 1H, fatty CH), 1.90(d, J=13.43Hz, 1H, fatty CH), 2.05(s, 6H, N(CH ₃ ) ₂ ), 2.35(d, J=10.25Hz, 1H, fatty CH), 2.48(s , 3H, CCH ₃ ), 2.52 (t, J=5.86Hz, 2H, OCH ₂ CH ₂ ), 2.64-2.74 (m, 2H, fatty CH), 2.85-2.89 (m, 1H, fatty CH), 3.31 ( dd, J=18.56, 7.08Hz, 1H, fatty CH), 4.14-4.27 (m, 2H, OCH ₂ CH ₂ ), 6.58 (d, J=8.55Hz, 1H, ArH), 7.02 (d, J=8.79 Hz, 1H, ArH), 11.56 (s, 1H, _NH ); MS (APCI+): m/z 412.2 (MH ⁺ ). Calcd. for C ₂₄ H 33 N ₃ O 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-(1-pyrrolidinyl) ethyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-(1-pyrrolidinyl)ethyl ester was synthesized from 2-pyrrolidin-1-yl-ethanol (1.02 g, 8.85 mmol) according to Procedure N and treated with tert Butyl methyl ether was ground to give 0.253 g (26.0%) of a white solid: mp 195-196°C;

IR (KBr) 3377, 2930, 1700, 1432, 1081cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.12-1.78 (m, 10H, fatty CH), 1.61-1.69 (m, 8H, ring CH ₂ ), 1.92(d, J=13.26Hz, 1H, fat CH), 2.37(d, J=10.61Hz, 1H, fat CH), 2.47-2.49(m, 1H, fat CH), 2.50(s , 3H, CH ₃ ), 2.66-2.76 (m, 2H, fatty CH), 2.72 (t, J = 6.51 Hz, 2H, OCH ₂ CH ₂ ), 2.87-2.93 (m, 1H, fatty CH), 3.32 ( dd, J=19.05, 13.02Hz, 1H, fatty CH), 4.19-4.30 (m, 2H, OCH ₂ CH ₂ ), 6.60 (d, J=8.68Hz, 1H, ArH), 7.04 (d, J=8.68 Hz, 1H, ArH), 11.49 (s, 1H, NH); MS (APCI+): m/z 438.2 (MH ⁺ ). Anal. Calcd. for C ₂₆ H ₃₅ N ₃ O ₃ : C, 71.37; H, 8.06 ; N, 9.60. Found: C, 70.99; H, 8.13; N, 9.49.

Example 73

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

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(1-naphthyl)ethyl ester was synthesized from 1-naphthalen-1-yl-ethanol (2.32 g, 13.5 mmol) according to Procedure N and triturated with diethyl ether 0.707g (40.9%) fine white powder: mp140-145°C;

IR(KBr) 3387, 2929, 1682, 1432, 1078cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ0.94-1.72(m, 10H, fatty CH), 1.72(d, J=2.69Hz, 3H, OCHCH ₃ ), 1.83 (d, J=12.94Hz, 1H, fatty CH), 2.30-2.63 (m, 3H, fatty CH), 2.50 & 2.52 (s, 3H, CCH ₃ , diastereomers body), 2.83-2.88 (m, 2H, fatty CH), 3.21 (dd, J=32.72, 26.12Hz, 1H, fatty CH), 6.52-6.58 (m, 1H, ArH), 6.74-6.75 (m, 1H , OCHCH ₃ ), 6.98-7.03 (m, 1H, ArH), 7.46-7.65 (m, 4H, ArH), 7.84-7.89 (m, 1H, ArH), 7.93-7.96 (m, 1H, ArH), 8.12 -8.14 (m, 1H, ArH), 11.54 (s, 1H, NH); MS (APCI+): m/z 513.1 (MH ⁺ ). Anal. value calculated for C ₃₂ H ₃₄ N ₂ O ₃ : C, 76.66; H, 6.92; N, 5.58. Found: C, 76.29; H, 6.96; N, 5.40.

Example 74

步骤A：1-苯基-环丁醇

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-phenylcyclobutyl ester

Step A: 1-Phenyl-cyclobutanol

To a solution of phenylmagnesium bromide (1 M in THF, 148 mL, 148 mmol) in 87 mL of anhydrous ether was added cyclobutanone (10.0 g, 143 mmol) in 15 mL of ether at 0°C. The reaction mixture was stirred in an ice bath for 1 hour. Add saturated ammonium chloride and stir for 10 minutes. The reaction mixture was washed with _H2O (2 x 250 mL), dried over magnesium sulfate, and concentrated to give a yellow oil. This product was purified by flash column chromatography on silica gel (10% acetone:hexanes) to give 10.1 g (47.7%) of a yellow oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ 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, 1H, ArH), 7.31-7.38(m, 2H, ArH), 7.38-7.50(m, 2H, ArH); MS(APCI+): m/z171.5(MH ⁺ ) .

Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-phenylcyclobutyl ester was synthesized from 1-phenyl-cyclobutanol (1.33 g, 9.00 mmol) according to Procedure N and triturated with diethyl ether to give 0.201 g (19.0 %) white powder: mp218-220°C;

IR (KBr) 3328, 2930, 1674, 1434, 1080cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.09-1.84 (m, 10H, fatty CH), 1.94-2.00 (m, 1H, fatty CH), 2.33 (d, J=9.03Hz, 1H, fatty CH), 2.40-2.46 (m, 1H, fatty CH), 2.46 (s, 3H, CCH ₃ ), 2.56 (s, 6H, C of the ring ( CH ₂ ) ₃ Ar), 2.52-2.64 (m, 2H, fatty CH), 2.83-2.88 (m, 1H, fatty CH), 3.15 (dd, J=18.80, 7.08Hz, 1H, fatty CH), 6.56 ( d, J=8.55Hz, 1H, ArH), 7.00(d, J=8.55Hz, 1H, ArH), 7.22(t, J=7.08Hz, 1H, ArH), 7.33(t, J=7.57Hz, 2H , ArH), 7.47 (d, J=7.32Hz, 2H, ArH), 11.48 (s, 1H, NH); MS (APCI+): m/z 671.1 (MH ⁺ ).C ₃₀ H ₃₅ N ₂ O ₃ Calcd: C, 74.72; H, 7.56; N, 5.81. Found: C, 74.43; H, 7.26; N, 5.41.

Example 75

步骤A：1-苯基-环丙醇 pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-phenylcyclopropyl ester

Step A: 1-Phenyl-cyclopropanol

1-Phenyl-cyclopropanol was synthesized as described in Kulinkovich, O.G.; Sviridov, S.V.; Vasilevskii, D.A.; Savchenko, A.I.;

Step B: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i)quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-phenylcyclopropyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-phenylcyclopropyl ester was synthesized from 1-phenyl-cyclopropanol (1.22 g, 9.00 mmol) according to Procedure N and triturated with diethyl ether to give 0.078 g (7.57 %) shiny yellow powder: mp130-135°C;

IR(KBr) 3384, 2929, 1690, 1431, 1069cm ^-1 ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ1.06-1.69(m, 10H, fatty CH), 1.86(d, J=13.43Hz, 1H , fatty CH), 2.34 (d, J=10.01Hz, 1H, fatty CH), 2.41-2.44 (m, 1H, fatty CH), 2.46 (s, 3H, CCH ₃ ), 2.52 (s, 4H, cyclic C(CH ₂ ) ₂ Ar), 2.63-2.70 (m, 2H, fatty CH), 2.81-2.89 (m, 1H, fatty CH), 3.20 (dd, J=18.56, 7.33Hz, 1H, fatty CH), 6.59(d, J=8.55Hz, 1H, ArH), 7.03(d, J=8.55Hz, 1H, ArH), 7.15-7.19(m, 3H, ArH), 7.26-7.30(m, 2H, ArH), 11.57 (s, 1H, NH); MS (APCI+): m/z 457.1 (MH ⁺ ). C ₂₉ H ₃₂ N ₂ O ₃ : Calculated and analyzed: C, 76.29; H, 7.06; N, 6.14. Measured Values: C, 76.12; H, 7.39; N, 5.83.

Example 76

步骤A：1-吡嗪-2-基-乙醇

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-pyrazinyl ethyl ester

Step A: 1-pyrazin-2-yl-ethanol

To a solution of 1-pyrazin-2-yl-ethanone (5.00 g, 40.9 mmol) in 100 mL of MeOH, NaBH ₄ (0.774 g, 20.5 mmol) was added portionwise at 0°C. After stirring at room temperature for 24 hours, the reaction mixture was quenched with 1N HCl and extracted with dichloromethane (3 x 100 mL). The organic layer was dried over sodium sulfate and concentrated to give 2.60 g (51.2%) of a yellow oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.54 (d, J=6.59 Hz, 3H, CHCH ₃ ), 3.54 (s, 1H , OR), 4.97 (q, J=6.59Hz, 1H, CH ₃ CH), 8.49 (s, 2H, NCHCHN), 8.65 (s, 1H, CCHN); MS (APCI+): m/z 125.1 (MH ⁺ ).

Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-pyrazinyl ethyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-pyrazinyl ethyl ester was synthesized from 1-pyrazin-2-yl-ethanol (1.12 g, 9.00 mmol) according to Procedure N and triturated with cold acetone to give 0.303 g (30.3%) of crude white powder: mp224-225°C;

IR(KBr) 3172, 2930, 1704, 1431, 1073cm ^-1 ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ1.06-1.63(m, 10H, fatty CH), 1.61(d, J=3.17Hz, 3H , OCHCH ₃ ), 1.77-1.98(m, 1H, fatty CH), 2.34(d, J=10.25Hz, 1H, fatty CH), 2.40-2.43(m, 1H, fatty CH), 2.52&2.53(s , 3H, CCH ₃ , diastereoisomers), 2.62-2.68 (m, 1H, fatty CH), 2.84-2.87 (m, 1H, fatty CH), 3.12 (dd, J=19.04, 6.84Hz, 1H , fatty CH), 5.99 (q, J=7.08Hz, 1H, OCHCH ₃ ), 6.56-6.60 (m, 1H, ArH), 7.01-7.04 (m, 1H, ArH), 8.57 (s, 1H, ArH) , 8.62 (s, 1H, ArH), 8.71 & 8.73 (s, 1H, ArH, diastereomers), 11.56 (s, 1H, NH); MS (APCI+): m/z 447.1 (MH ⁺ ). Calcd for C ₂₆ H ₃₀ N ₄ O ₃ : C, 69.90; H, 6.79; N, 12.50. Found: C, 69.51; H, 6.78; N, 12.35.

Example 77

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(4-quinolyl) ethyl ester Step A: 1-Quinolin-4-yl-ethanol

To a solution of quinoline-4-carbaldehyde (5.00 g, 31.8 mmol) in 127 mL of anhydrous THF was added methylmagnesium bromide (13.8 mL, 41.4 mmol) at -40°C. After stirring for 5 hours, the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (5 x 100 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a purple solid. Trituration of this solid with acetone afforded 4.52 g (82.2%) of a lavender solid:

¹ H NMR (400MHz, CDCl ₃ ) δ1.60 (d, J=6.35Hz, 3H, CHCH ₃ ), 3.70 (s, 1H, OH), 5.62 (q, J=6.35Hz, 1H, CHCH ₃ ), 7.50(t, J=7.57Hz, 1H, CCCHCH), 7.56(d, J=4.40Hz, 1H, NCHCH), 7.63(t, J=7.32Hz, 1H, NCCHCH), 7.97(d, J=8.55Hz , 1H, CCCHCH), 8.05 (d, J=8.30Hz, 1H, NCCHCH), 8.73 (d, J=4.39Hz, 1H, NCHCH), MS (APCI+): m/z 174.1 (MH ⁺ ).

Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-(4-quinolyl)ethyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(4-quinolinyl)ethyl ester was synthesized from 1-quinolin-4-yl-ethanol (1.56 g, 9.00 mmol) according to Procedure N and treated with acetone Grind to obtain 0.192g (17.1%) of light yellow powder: mp165-168°C;

IR(KBr) 2930, 2853, 1690, 1429, 1074cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.00-1.46(m, 10H, fatty CH), 1.70(d, J=6.35Hz, 3H, OCHCH ₃ ), 1.85 (d, J=13.18Hz, 1H, fatty CH), 2.32-2.63 (m, 3H, fatty CH), 2.57 & 2.58 (s, 3H, CCH ₃ , diastereomers body), 2.83-2.86 (m, 2H, fatty CH), 3.20 (dd, J=18.31, 6.84Hz, 1H, fatty 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, 1H, ArH), 7.75-7.79 (m, 1H, ArH ), 8.04-8.06(m, 1H, ArH), 8.21-8.23(m, 1H, ArH), 8.84-8.88(m, 1H, ArH), 11.61(s, 1H, NH); MS(APCI+): m /z496.2 (MH ⁺ ). Anal. Calcd. for C ₃₁ H ₃₃ N ₃ O ₃ : C, 74.12; H, 7.00; N, 7.83. Found: C, 73.73; H, 7.09; N, 7.44.

Example 78

步骤A：1-嘧啶-2-基-乙酮 pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(2-pyrimidinyl) ethyl ester

Step A: 1-Pyrimidin-2-yl-ethanone

1-Pyrimidin-2-yl-ethanone was synthesized as described in Naumenko, I.I.; Mikhaleva, M.A.; Mamaev, V.P. Chem. Het. Cmpds. 1981; 17:710-714.

Step B: 1-pyrimidin-2-yl-ethanol

To a solution of 1-pyrimidin-2-yl-ethanone (2.34 g, 19.2 mmol) in 65 mL of MeOH was added _NaBH4 (0.726 g, 19.2 mmol) in portions at 0 °C. After stirring at room temperature for 4 hours, the reaction mixture was quenched with 1N HCl and extracted with dichloromethane (3 x 100 mL). The organic layer was dried over sodium sulfate and concentrated to give 0.984 g (41.3%) of a yellow oil: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.36 (d, J = 6.59 Hz, 3H, CHCH ₃ ), 4.73 (q , J=6.59Hz, 1H, CH ₃ CH), 5.21 (s, 1H, OH), 7.33-7.36 (m, 1H, NCHCH), 8.73-8.77 (m, 2H, NCHCH); MS (APCI+): m /z125.1(MH ⁺ ).

Step C: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(2-pyrimidinyl)ethyl ester was synthesized from 1-pyrimidin-2-yl-ethanol (1.01 g, 8.10 mmol) according to Procedure N and triturated with acetone 0.360g (29.9%) fine off-white powder: mp220-222°C;

IR(KBr) 3176, 2932, 1686, 1426, 1078cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.06-1.54(m, 10H, fatty CH), 1.59(d, J=6.59Hz, 3H, OCHCH ₃ ), 1.84 (d, J=13.92Hz, 1H, fatty CH), 2.34-2.55 (m, 2H, fatty CH), 2.58 (s, 3H, CCH ₃ ), 2.64-2.69 (m, 2H , fatty CH), 2.81-2.86 (m, 1H, fatty CH), 3.17 (dd, J=18.31, 6.59Hz, 1H, fatty CH), 5.84 (q, J=6.84Hz, 1H, OCHCH ₃ ), 6.57 (d, J=8.79Hz, 1H, ArH), 7.02 (d, J=9.03Hz, 1H, ArH), 7.37-7.38(m, 1H, ArH), 8.76-8.77(m, 2H, ArH), 11.53 (s, 1H, NH); MS (APCI+): m/z 447.1 (MH ⁺ ). Calcd. for C ₂₆ H ₃₀ N ₄ O ₃ : C, 69.86; H, 7.04; N, 12.07. Found: C, 69.50; H, 6.94; N, 11.71.

Example 79

步骤A：6-氯-5-羟基-2-甲基-1H-吲哚-3-甲酸苄酯

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

Step A: Benzyl 6-chloro-5-hydroxy-2-methyl-1H-indole-3-carboxylate

To a solution of benzyl 3-amino-but-2-enoate (10.1 g, 52.9 mmol) in 211 mL of EtOH was added 2-chloro-1,4-benzoquinone (9.04 g, 63.4 mmol). After heating at 50°C for 24 hours, the mixture was cooled to room temperature and concentrated to give a brown oil. This 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 a pale yellow powder: mp 221-224°C; IR (KBr) 3409 , 3226, 1642, 1461, 1181cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ2.55(s, 3H, CCH ₃ ), 5.29(s, 2H, OCH ₂ Ar), 7.27(s, 1H , ArH), 7.30(d, J=6.84Hz, 1H, ArH), 7.36(t, J=8.30Hz, 2H, ArH), 7.42(d, J=7.57Hz, 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 O/CH ₃ CN+0.05% TFA): retention time = 5.47 min, 95.86% purity

Step B: Benzyl 6-chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Benzyl 6-chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate was prepared from 6-chloro-5-hydroxy-2-methyl-1H according to Method L - Benzyl indole-3-carboxylate (7.77g, 24.6mmol) was synthesized and triturated with cold ethanol to give 6.77g (73.8%) of white solid: mp178-180°C;

IR(KBr) 3298, 2951, 1687, 1425, 1437, 1264, 1078cm ^-1 ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ2.14(s, 6H, N(CH ₃ ) ₂ ) 4.06(s, 2H , NCH ₂ Ar), 5.23 (s, 2H, OCH ₂ Ar), 7.22 (s, 1H, ArH), 7.31-7.39 (m, 3H, ArH), 7.44 (d, J=6.84Hz, 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 O/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]quinazine-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]quinazine-1-carboxylic acid, 5-chloro-3,7,8,9,10,12 , 13, 14, 14a, 15-Decahydro-2-methyl-, phenylmethyl ester was prepared from 6-chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole according to Method M Benzyl indole-3-carboxylate (6.77g, 18.2mmol) was synthesized and triturated with acetone to give 6.05g (71.7%) of a shiny powder: mp90-93°C;

IR(KBr) 3291, 2933, 2858, 1673, 1427, 1076cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.01-1.71(m, 10H, fatty CH), 1.75(d, J=13.43 Hz, 1H, fat CH), 2.37(d, J=10.50Hz, 1H, fat CH), 2.45-2.46(m, 1H, fat CH), 2.46(s, 3H, _CCH3 ), 2.64-2.74(m , 2H, fatty CH), 2.94-2.99 (m, 1H, fatty CH), 3.38 (dd, J=18.56, 7.08Hz, 1H, fatty CH), 5.21 (dd, J=26.12, 12.21Hz, 2H, OCH ₂ Ar), 7.18 (s, 1H, ArH), 7.29-7.43 (m, 5H, ArH), 11.62 (s, 1H, NH); MS (APCI+): m/z 465.2 (MH ⁺ ).C ₂₇ H ₂₉ N ₂ O ₃ Cl ₁

Calcd: C, 69.74; H, 6.29; N, 6.02. Found: C, 69.45; H, 6.68; N, 5.82.

Example 80

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 5-chloro 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl,1-(4-fluorophenyl)ethyl ester

Step A: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid with benzoic acid, 5-chloro-3,7, 8, 9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl, acid anhydride

In a 250mL three-neck round bottom flask, add pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 5-chloro 3 , 7, 8, 9, 10, 12, 13, 14, 14a, 15-decahydro-2methyl-, phenylmethyl ester (Example 79, Step C, 5.44g, 11.7mmol), THF (58.6mL , 0.2 M), Et ₃ N (1.63 mL, 11.7 mmol), and 10% Pd(OH) ₂ /C (1.26 g). This mixture was stirred under a hydrogen atmosphere (balloon) for 1 hour. The reaction mixture was filtered through a celite pad, and the yellow filtrate was subjected to the next reaction. To this yellow filtrate was added benzoyl chloride (1.36 mL, 11.7 mmol) dropwise. The mixture was stirred at room temperature for 48 hours and the solvent was removed to give a brown oil. Grinding with acetone gave 3.50 g (62.4%) of a yellow powder: mp 160-165°C;

¹ H NMR (400MHz, DMSO-d ₆ ) δ1.10-1.58 (m, 10H, fatty CH), 1.83 (d, J=12.94Hz, 1H, fatty CH), 2.41-2.46 (m, 2H, fatty CH ), 2.51 (s, 3H, CCH ₃ ), 2.66-2.71 (m, 1H, fat CH), 2.98-3.01 (m, 2H, fat CH), 3.38 (dd, J=17.82, 6.59Hz, 1H, fat CH), 7.29(s, 1H, ArH), 7.58(t, J=7.57Hz, 2H, ArH), 7.74(t, J=7.57Hz, 1H, ArH), 8.07(d, J=7.08Hz, 2H , ArH), 12.14 (s, 1H, NH); MS (APCI+): m/z 479.1 (MH ⁺ ).

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

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 5-chloro-3,7,8,9,10,12 , 13, 14, 14a, 15-Decahydro-2methyl-, 1-(4-fluorophenyl)ethyl ester was prepared from 1-(4-fluoro-phenyl)-ethanol (0.900g, 7.16mmol ) and pyrrolo[3′,2′:5,6][1]-benzopyrano[3,2-i]quinazine-1-carboxylic acid with benzoic acid, 5-chloro-3,7, 8, 9, 10, 12, 13, 14, 14a, 15-Decahydro-2-methyl, anhydride (0.857 g, 1.79 mmol) synthesis. This product was recrystallized with tert-butyl methyl ether to give 0.210 g (23.6%) of white powder: mp 102-107°C;

IR(KBr) 2934, 2859, 1674, 1428, 1055cm ^-1 ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ1.06-1.81(m, 11H, fatty CH), 1.55(d, J=6.59Hz, 3H, OCHCH ₃ ), 2.37(d, J=10.25Hz, 1H, fatty CH), 2.44-2.46(m, 1H, fatty CH), 2.46(s, 3H, CCH ₃ ), 2.63-2.75(m, 2H , fatty CH), 2.97-3.14 (m, 1H, fatty CH), 3.20 (dd, J=13.18, 6.59Hz, 1H, fatty CH), 5.95 (q, J=6.59Hz, 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 ⁺ ).C ₂₈ H ₃₀ N Anal. Calcd. for ₂ O ₃ F ₁ Cl ₁ : C, 66.82; H, 6.15; N, 5.57. Found: C, 66.96; H, 6.39; N, 5.46.

Example 81

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

To pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1 carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, To a solution of 15-decahydro-2-methyl-,(4-fluorophenyl)methyl ester (0.500 g, 1.11 mmol) in 125 mL of dichloromethane was added ethereal HCl in portions until the solution became cloudy. After removing the solvent, the yellow residue was triturated with acetone to give 0.307 g (61.0%) of a white powder: mp 179-185 °C;

IR(KBr) 3408, 3193, 2934, 1697, 1431, 1152cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ1.37-1.52(m, 1H, fatty CH), 1.52-1.77(m, 8H, fatty CH), 2.07-2.15 (m, 1H, fatty CH), 2.26 (d, J=14.65Hz, 1H, fatty CH), 2.40-2.54 (m, 2H, fatty CH), 2.58 (s, 3H, CCH ₃ ), 3.10-3.18 (m, 2H, fatty CH), 3.34-3.48 (m, 2H, fatty CH), 5.28 (dd, J=14.65, 12.45Hz, 2H, OCH ₂ Ar), 6.78 (d, J= 14.65Hz, 1H, ArH), 7.05(t, J=8.55Hz, 1H, ArH), 7.14(d, J=8.79Hz, 1H, ArH), 7.41(t, J=5.37Hz, 1H, ArH), 8.58 (s, 1H, OH), 12.52 (s, 1H, NH); MS (APCI+): m/z 449.3 (MH ⁺ ). Calcd. for C ₂₇ H _{30 N 2 O 3} F ₁ Cl ₁ Analysis: 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-1, 2-dimethyl-, (4-fluorophenyl) methyl ester

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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) was added to NaH (60% dispersion in mineral oil , 0.049g, 1.23mmol, washed with hexane), and stirred at room temperature for 1 hour. Iodomethane (0.076 mL, 1.23 mol) was added to the reaction mixture. The reaction was stirred for 2 hours, quenched with 15 mL _H2O , and extracted with ether (5 x 50 mL). The organic layer was concentrated to give a yellow solid, which was triturated with acetone to give 0.274 g (52.7%) of a white solid: mp 179-180 °C;

IR(KBr) 3466, 2932, 2854, 1673, 1482, 1155cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ) δ1.06-1.21(m, 3H, fatty CH), 1.36-1.58(m, 7H, fatty CH), 1.79 (d, J=14.20 Hz, 1H, fat CH), 2.34 (d, J=10.74 Hz, 1H, fat CH), 2.42-2.49 (m, 2H, fat CH), 2.49 (s, 3H , CCH ₃ ), 2.64 (t, J=10.74Hz, 1H, fat CH), 2.86 (t, J=11.48Hz, 1H, fat CH), 3.10 (dd, J=18.31, 6.84Hz, 1H, fat 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), 7.16-7.22 (m, 3H, ArH), 7.48 (t, J=7.81Hz, 1H, ArH); MS (APCI+): m/z 463.1 (MH ⁺ ).C ₂₈ H ₃₁ N ₂ O ₃ F _1Calc .: C, 72.71; H, 6.76; N, 6.06. Found: C, 72.89; H, 6.72; N, 5.92.

Example 83

步骤A：5-乙酰氧基-2-甲基-1H-吲哚-3-甲酸-1-苯基-丙酯 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-phenylpropyl ester

Step A: 5-Acetoxy-2-methyl-1H-indole-3-carboxylate-1-phenyl-propyl ester

This mixture was prepared according to Method 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

5-Acetoxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester (1.36 g, 3.86 mmol) was mixed with 10 mL of methanol, then _NaOCH3 (0.834 g, 15.4 mmol) was added . The resulting reaction mixture was stirred at reflux for 1 min, then cooled to room temperature. The reaction mixture was further mixed with 10 mL of water, and the resulting reaction mixture was treated with 5% HCl to pH = 1 to give a white precipitate. This mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic mixture was dried over sodium sulfate and concentrated in vacuo to give a black viscous oil which was further purified by chromatography using 10% MeOH in chloroform as eluent to give 1.13 g (98%) of the desired product , as a brown solid: ¹ H NMR (DMSO-d ₆ ) δ 0.917 (t, J = 7.33 Hz, 3H, CHCH ₂ CH ₃ ), 1.84-2.03 (m, 2H, CHCH ₂ CH ₃ ), 2.59 (s , 3H, ArCH ₃ ), 5.84 (t, J=5.68Hz, 2H, CHCH ₂ CH ₃ ), 6.59 (dd, J=8.61, 2.38Hz, 1H, ArH), 7.12 (d, J=8.61Hz, 1H , ArH), 7.23-7.41 (m, 6H, ArH), 8.87 (s, 1H, exchangeable proton), 11.6 (bs, 1H, exchangeable proton).

Step C: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid, 1-phenyl-propyl ester (1.07g, 3.60mmol) and aqueous dimethylamine (40%, 0.99mL, 7.92mmol) with 2.4mL EtOH was mixed and this mixture was heated with a heat gun until a clear solution was obtained. After cooling to room temperature, aqueous HCHO (37%, 0.35 g, 4.3 mmol) was added. The resulting reaction mixture was stirred at 50°C for 4 hours and then at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (30 mL), washed with water (2 x 30 mL), and dried over sodium sulfate. Concentration in vacuo followed by chromatography using 100% EtOAc, then 10% MeOH in chloroform as eluents afforded 0.50 g (38%) of the pure title compound as a yellow foam: mp 50-62°C (decomposition ); MS (APCI ⁺ ): m/z 367.2 (MH ⁺ ).

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

To a mixture of perchlorate (0.38 g, 1.6 mmol, Example 3, Step B) and 30 mL of diethyl ether was added 30 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 30 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 10 mL of dioxane, then indole mannich base (0.45 g, 1.2 mmol) was added and the resulting reaction mixture was refluxed under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to afford 0.40 g (71%) of the title compound as a white foam: mp 90-115°C; MS (APCI ⁺ ): m/z 459.3 (MH ⁺ ).

Example 84

Quinolinium, 1,2,3,4,6,7,8,9-octahydro-1-[[5-hydroxy-2-methyl-3-[(phenylmethoxy)carbonyl]-1H -indol-4-yl]methyl]-, chloride

To pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1 carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, To a solution of 15-decahydro-2-methyl-,phenylmethyl ester (0.209 g, 0.485 mmol) in dichloromethane was added ethereal HCl. After stirring at room temperature for 1 minute, the reaction mixture was concentrated in vacuo. This residue was triturated with 2-butanone. Filtration followed by vacuum drying afforded 0.18 g (79%) of the desired product as a white solid: MS (APCI+): m/z 431.3 (MH ⁺ ). Anal. _C27H30N2O3 · _1.0HCl · _0.3H2O : C _, 68.65; H, 6.74; _N , 5.93; Cl, 7.50; _H2O , 1.14. Found: C, 68.62; H, 6.80; N, 6.00; Cl, 7.54; _H2O , 0.93.

Example 85

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (4-nitrophenyl) methyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2-methyl-,phenylmethyl ester (0.149g, 0.341mmol) was dissolved in 15mL THF, and to this solution was added N,N-dimethylacetamide dimethyl acetal (0.5 mL) and Pd(OH) ₂ /C (20%, 0.125 g). The resulting reaction solution was stirred at room temperature under a hydrogen atmosphere until the benzyl ester was completely reacted. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo at room temperature and used directly in the next reaction without purification.

To a DMF solution of the crude product of the debenzylation reaction, p-nitrobenzyl bromide and DBU were added. The resulting reaction solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of EtOAc and washed sequentially with saturated aqueous sodium bicarbonate (3 x 50 mL) and water (3 x 50 mL). After drying over sodium sulfate, the solution was concentrated in vacuo and purified twice by chromatography eluting with 10% MeOH in chloroform and 50% EtOAc in hexanes to afford 28 mg (17%) of the desired product, As a yellow solid: mp 240-242°C; MS (APCI ⁺ ): m/z 476.3 (MH ⁺ ).

Example 86

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid with benzoic acid, 3,7,8,9,10,12 , 13, 14, 14a, 15-decahydro-2-methyl-, anhydride

Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2-methyl-,phenylmethyl ester (10.15 g, 23.58 mmol) was dissolved in 110 mL THF, and this solution was transferred to a three-way switch with a stir bar and attached to a balloon balloon in a round bottom flask. To this solution was added triethylamine (3.287 mL, 23.58 mmol), followed by Pd(OH) ₂ /C (20%, 2.7 g). The reaction vial was filled with hydrogen several times. The resulting reaction solution was stirred at room temperature under a hydrogen atmosphere until the benzyl ester was completely reacted (2 hours here). The catalyst was removed by filtration, and the filtrate was used in the next reaction.

To this filtrate was added benzoyl chloride (2.737 mL, 23.58 mmol). The resulting reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 hours. The white precipitate formed was removed by filtration. The filtrate was concentrated in vacuo to give a viscous oil; trituration with diethyl ether afforded 9.18 g (88% overall yield in two steps) of the desired product as a white solid: mp 159-160° C.; MS (APCI+): m/z 443.3 ( MH ⁺ ).

General Method Q: Synthesis of Esters from Mixed Anhydrides

The mixed anhydride (1 eq.) was mixed with the corresponding alcohol (>2 eq.) and the resulting slurry was heated at 120-150°C until a clear solution was obtained. After cooling to room temperature, the solution was diluted with ethyl acetate and mixed with aqueous sodium bicarbonate (sat.). Leave this mixture for 5 minutes. Separated into two layers, and the organic layer was washed with brine and water, then dried over magnesium sulfate. Purification by flash chromatography or recrystallization affords the desired product.

Example 87

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1R)-1-phenylethyl ester was synthesized according to Method Q from (R)-(+)-1-phenylethanol. The crude product was chromatographed on a preparative silica gel plate using 100% acetonitrile as eluent to give 25 mg of the desired product as a white solid: mp 100-112°C; MS (APCI ⁺ ): m/z 445.3 (MH ⁺ ).

Example 88

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-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-(p-fluorophenyl)ethanol. The crude product was chromatographed on a silica gel column (30% EtOAc in hexanes as eluent) and then on a preparative silica plate (100% acetonitrile as eluent) to give 54.5 mg (37%) of Desired product as a yellow foam: mp 98-110°C; MS (APCI ⁺ ): m/z 463.1 (MH ⁺ ).

General Method R: Parallel Synthesis of 6 Esters from Mixed Anhydrides

Mixed anhydride (1eq.) and corresponding alcohol (2eq.) were mixed in VWR60826-202 tube. The tube was capped loosely and immersed in an oil bath at 120°C for 7 minutes. After cooling to room temperature, 10 mL of diethyl ether and 10 mL of saturated aqueous sodium sulfate were added to the tube. The mixture was stirred for 1 minute, then the ether layer was transferred to a new tube filled with magnesium sulfate. After 10 minutes, the magnesium sulfate was removed by filtration. The filtrate was blown off with a stream of nitrogen and the residue was redissolved in 0.2 mL of ether and transferred to an SPE cartridge containing 1 g of silica gel. The cartridge was eluted with 20 mL of 10% EtOAc in hexanes. Fractions containing mainly the corresponding alcohol were collected and discarded. The column was then eluted with 5 mL of 10% EtOAc in hexanes. The collected fractions were concentrated (blown with a stream of nitrogen) to give the crude product.

Example 89

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,phenyl ester was synthesized according to Procedure R from phenol. The crude product was no longer purified: white solid; MS (APCI ⁺ ): m/z 417.1 (MH ⁺ ).

Example 90

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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 according to method R from 1,1,1,3, 3,3-Hexafluoro-2-phenyl-2-propanol synthesis. The crude product was no longer purified: white solid; MS (APCI-): m/z 565.1 (M-H).

Example 91

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, bicyclo[2.2.1]heptane-2-yl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,bicyclo[2.2.1]heptan-2-yl ester was synthesized by method R from exo-norbornyl. The crude product was no longer purified: white solid; MS (APCI-): m/z 433.2 (M-H).

Example 92

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(4-fluorophenyl)-1-methylethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(4-fluorophenyl)-1-methylethyl ester was synthesized according to Procedure Q from 2-(4-fluorophenyl)-2-propanol. The crude product was chromatographed on a silica gel column (50-70% diethyl ether in hexane as eluent) to give 0.15 g (9%) of the desired product as a white solid mp 110-112 °C; MS (APCI ⁺ ): m /z477.1(MH ⁺ ).

Example 93

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-phenylcyclopentyl ester was synthesized according to Method Q from 1-phenyl-1-cyclopentanol. The crude product was chromatographed on silica gel (50% diethyl ether in hexane as eluent) to give 0.15 g (6%) of the desired product as a white solid: mp 205-206 °C; MS (APCI ⁺ ): m/ z483.1 (MH ⁺ ).

Example 94

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-phenylcyclohexyl ester was synthesized according to Method Q from 1-phenylcyclohexanol. The crude product was chromatographed on silica gel (50-70% diethyl ether in hexane as eluent) 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,3-(hydroxymethyl)phenyl ester was synthesized according to Method Q from 3-hydroxybenzyl alcohol. The crude product was chromatographed on silica gel (50-100% EtOAc in hexanes as eluent) 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]quinazine-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][1j benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14, 14a, 15-Decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester Synthesized according to Method Q from 3-hydroxybenzyl alcohol. The crude product was chromatographed on silica gel (50-100% EtOAc in hexanes as eluent) 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1S)-1-(4-pyridyl) ethyl ester

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

Example 98

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridyl]methyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,[6-(methoxycarbonyl)-2-pyridyl]methyl ester was synthesized according to Procedure Q from ethyl 6-(hydroxymethyl)-picolinate. The crude product in EtOAc (40 mL) was mixed with 40 mL of 0.5N HCl solution in a separatory funnel and shaken well, then the aqueous phase was basified to pH = 1 with 2N NaOH solution and shaken well. Then divide into two layers. The organic layer was dried over sodium sulfate. Chromatography on silica gel column (50-100% EtOAc in hexane as eluent) gave 0.87 g (53%) of the desired product as a white foam: mp 90-100 °C; MS (APCI ⁺ ): m/z 490.1 (MH ⁺ ).

Example 99

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-pyridylmethyl ester Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-pyridylmethyl ester was synthesized according to Method Q from 2-pyridylmethanol. The crude EtOAc solution (40 mL) was mixed with 40 mL 0.5N HCl solution in a separatory funnel and shaken well, then the aqueous phase was basified to pH=1 with 2N NaOH solution and shaken well. Then divide into two layers. After this procedure was repeated 3 times, the organic layer was separated and dried over sodium sulfate. Chromatography on a silica gel column (60-100% EtOAc in hexanes as eluent) gave 1.39 g (72%) of the desired product as a white foam: mp 85-95°C; MS (APCI ⁺ ): m/z 432.2 (MH ⁺ ).

Example 100

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (6-carboxy-2-pyridyl) methyl ester

To pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2-methyl-,[6-(methoxycarbonyl)-2-pyridyl]methyl ester (797.4 mg, 1.629 mmol) in MeOH (20 mL) was added 1 N 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 chloroform as eluent) to give 0.62 g of a mixture of the free acid and the sodium salt. 0.5 g of this mixture was dissolved in MeOH/chloroform and mixed with 0.64 mL of 1N HCl. The mixture was concentrated in vacuo and the residue was purified by chromatography (10-30% MeOH in chloroform as eluent) followed by recrystallization from methanol to give 0.25 g of the desired product as a white solid: MS (APCI-): m /z474.1(M-H).

Example 101

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, with (6-carboxy-2-pyridyl)methyl 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15- Decahydro-2-methylpyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylate (1:1) salt formation

To pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2-methyl-,(6-carboxy 2-pyridyl)methyl ester (167.5mg, 0.3522mmol) in ethanol suspension, was added choline bicarbonate aqueous solution (5.66M, 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, then diluted with 70 mL of ether. After cooling in an ice bath, the precipitate was collected by filtration to give 0.15 g (74%) of the desired product as a yellow solid: mp 120-130°C; MS (APCI-): m/z 474.1 (MH). Analyze the theoretical value C. _{H28N3O5 · 1.0C5H14N1O1 · 0.2C5H15N1O2} · _{1.8H2O :} C, 62.38; _H , _{7.71 ; N} , 9.26 _. Found: C, 62.40; H, 7.58; N, 9.03.

Example 102

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridyl]methyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,[5-(methoxycarbonyl)-3-pyridyl]methyl ester was synthesized according to Procedure Q from 5-hydroxymethyl-nicotinic acid methyl ester. The crude EtOAc solution (40 mL) was mixed with 40 mL 0.5N HCl solution in a separatory funnel and shaken well, then the aqueous phase was basified to pH=1 with 2N NaOH solution and shaken well. Then divide into two layers. After repeating this procedure twice, the organic layer was separated and dried over magnesium sulfate. Chromatography on silica gel column (50-100% EtOAc in hexanes as eluent) followed by recrystallization from diethyl ether afforded 0.4254 g (25%) of the desired product as a yellow solid: mp 195-197°C; MS (APCI ⁺ ): m/z 490.1 (MH ⁺ ).

Example 103

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (5-carboxy-3-pyridyl) methyl ester

To pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, To a solution of 14,14a,15-decahydro-2-methyl-,[5-(methoxycarbonyl)-3-pyridyl]methyl ester (391.6 mg, 0.7999 mmol) in MeOH (30 mL) was added 1N NaOH (3.2 mL, 3.2 mmol). The resulting reaction mixture was stirred at 50°C for 60 minutes. After cooling to room temperature, 3.2 mL of 1N aqueous hydrochloric acid solution was added, followed by concentration in vacuo. This residue was purified by chromatography (10-30% MeOH in chloroform as eluent) followed by trituration with diethyl 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

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, with (5-carboxy 3-pyridyl)methyl 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15- Decahydro-2-methylpyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylate (1:1) salt formation

To pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2-methyl-,(5-carboxy-3-pyridyl)methyl ester (170.3mg, 0.3580mmol) in ethanol suspension, was added choline bicarbonate aqueous solution (5.66M , 0.0569mL, 0.322mmol). 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, then diluted with 70 mL of ether. After cooling in an ice bath, the precipitate was collected by filtration to give 0.163 g (79%) of the desired product as a beige solid: mp 147-152°C; MS (APCI-): m/z 474 (MH). Analytical value C ₂₇ H ₂₈ N ₃ O ₅ 1.0C ₅ H ₁₄ N ₁ O ₁ 0.28C ₄ H ₁₀ O 1.2Si ₁ O ₂ 1.4H ₂ O: C, 57.09; H, 6.89; N, 8.04. Found: C, 57.09; H, 6.70; N, 7.77.

Example 105

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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 prepared from 1-(4'-methyl Base-biphenyl-3-yl)-ethanol synthesis. The crude product was chromatographed on a silica gel column (40% EtOAc in hexanes as eluent) to give 0.67 g (36%) of the desired product as a white foam: mp 105-115 °C; MS (APCI ⁺ ): m /z535(MH ⁺ ).

Example 106

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(2,6-dimethylphenyl)ethyl ester was synthesized from 1-(2,6-dimethyl-phenyl)-ethanol according to Method Q . The crude product was chromatographed on a silica gel column (30-50% EtOAc in hexanes as eluent) to give 1.02 g of the desired product, containing impurities, as a yellow foam: mp 100-105 °C; MS (APCI ⁺ ): m/z 473.3 (MH ⁺ ).

Method S: method of array synthesis:

Mix the mixed anhydride (1 eq.) and the corresponding alcohol (2-4 eq.) in a VWR60826-202 tube. The tube was capped loosely and immersed in a 120°C oil bath until a clear solution was obtained (typically 5-7 minutes). After cooling to room temperature, 6 mL of EtOAc and 5 mL of saturated aqueous sodium sulfate were added to the tube. The mixture was shaken and stirred for an additional 1 min, then the organic layer was pipetted off and filtered through a pad of magnesium sulfate (packed in a syringe filter), followed by washing with 1 mL of EtOAc. The filtrate was collected in a 2-dram vial and the sample was blown dry with a stream of nitrogen. Chromatography of the residue on a silica gel column using an ISCO system affords the desired product.

Example 107 to Example 142 were prepared in parallel according to Method S:

Example 107

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

MS (APCI ⁺ ): m/z 502 (MH ⁺ ).

Example 108

MS(APCI⁺)：m/z502(MH⁺)。实施例109吡咯并[3′，2′：5，6][1]苯并吡喃并[3，2-i]喹嗪-1-甲酸，3，7，8，9，10，12，13，14，14a，15-十氢-2-甲基-，1-萘酯

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

MS (APCI ⁺ ): m/z 502 (MH ⁺ ). Example 109 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-naphthyl ester

MS (APCI ⁺ ): m/z 467 (MH ⁺ ).

Example 110

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, diphenylmethyl ester

MS (APCI ⁺ ): m/z 507 (MH ⁺ ).

Example 111

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1R)-2,3-dihydro-1H-inden-1-yl ester

MS (APCI ⁺ ): m/z 457 (MH ⁺ ).

Example 112

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1,2-dihydro-1-acenaphthyl ester

MS (APCI ⁺ ): m/z 493 (MH ⁺ ).

Example 113

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, cyclohexyl (phenyl) methyl ester

MS (APCI ⁺ ): m/z 513 (MH ⁺ ).

Example 114

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 9H-fluoren-9-yl ester

MS (APCI ⁺ ): m/z 505 (MH ⁺ ).

Example 115

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1,2,3,4-tetrahydro-1-naphthyl ester

MS (APCI ⁺ ): m/z 471 (MH ⁺ ).

Example 116

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [(2R, 3R)-3-phenyloxiranyl] methyl ester

MS (APCI ⁺ ): m/z 473 (MH ⁺ ).

Example 117

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl, 2-oxo-1, 2-diphenylethyl ester

MS (APCI ⁺ ): m/z 535 (MH ⁺ ).

Example 118

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl ester

MS (APCI ⁺ ): m/z 533 (MH ⁺ ).

Example 119

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (2-methylphenyl) phenylmethyl ester

MS (APCI ⁺ ): m/z 521 (MH ⁺ ).

Example 120

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, cyclopropyl (4-fluorophenyl) methyl ester

MS (APCI ⁺ ): m/z 489 (MH ⁺ ).

Example 121

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3,4-dihydro-2H-benzothiopyran-4-yl ester

MS (APCI ⁺ ): m/z 489 (MH ⁺ ).

Example 122

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

MS (APCI ⁺ ): m/z 524 (MH ⁺ ).

Example 123

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2,2,2-trifluoroethyl ester

MS (APCI ⁺ ): m/z 423 (MH ⁺ ).

Example 124

MS(APCI⁺)：m/z475(MH⁺)。Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [(2S, 3S)-3-phenyloxiranyl] methyl ester

MS (APCI ⁺ ): m/z 475 (MH ⁺ ).

Example 125

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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

MS (APCI ⁺ ): m/z 505 (MH ⁺ ).

Example 126

MS(APCI⁺)：m/z585(MH⁺)。实施例127吡咯并[3′，2′：5，6][1]苯并吡喃并[3，2-i]喹嗪-1-甲酸，3，7，8，9，10，12，13，14，14a，15-十氢-2-甲基-，1-环戊基-1-苯基乙酯 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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

MS (APCI ⁺ ): m/z 585 (MH ⁺ ). Example 127 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-cyclopentyl-1-phenylethyl ester

MS (APCI ⁺ ): m/z 513 (MH ⁺ ).

Example 128

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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

MS (APCI ⁺ ): m/z 535 (MH ⁺ ).

Example 129

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

MS (APCI ⁺ ): m/z 469 (MH ⁺ ).

Example 130

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1, 1-diphenylethyl ester

MS (APCI ⁺ ): m/z 521 (MH ⁺ ).

Example 131

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-methyl-1, 2-diphenylethyl ester

MS (APCI ⁺ ): m/z 535 (MH ⁺ ).

Example 132

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

MS (APCI ⁺ ): m/z 517 (MH ⁺ ).

Example 133

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1,2-diphenylethyl ester

MS (APCI ⁺ ): m/z 521 (MH ⁺ ).

Example 134

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

MS (APCI ⁺ ): m/z 455 (MH ⁺ ).

Example 135

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 ,14a,15-Decahydro-2-methyl-,[1,1,-biphenyl]-4-ylmethyl ester

MS (APCI ⁺ ): m/z 507 (MH ⁺ ).

Example 136

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 4-pyridylmethyl ester

MS (APCI ⁺ ): m/z 432 (MH ⁺ ).

Example 137

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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-isoquinoline ester

MS (APCI ⁺ ): m/z 546 (MH ⁺ ).

Example 138

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[3-(dimethylamino)phenyl]ethyl ester

MS (APCI ⁺ ): m/z 488 (MH ⁺ ).

Example 139

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1,1-dimethyl-2-pyrazinyl ethyl ester

MS (APCI ⁺ ): m/z 475 (MH ⁺ ).

Example 140

MS(APCI⁺)：m/z520(MH⁺)。Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 4-(dipropylamino)-1,1-dimethyl-2-butynyl ester

MS (APCI ⁺ ): m/z 520 (MH ⁺ ).

Example 141

MS(APCI⁺)：m/z457(MH⁺)。Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1S)-2,3-dihydro-1H-inden-1-yl ester

MS (APCI ⁺ ): m/z 457 (MH ⁺ ).

Example 142

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1S, 2S)-2-(dimethylamino)-1-phenylpropyl ester

MS (APCI ⁺ ): m/z502 (MH ⁺ )

Example 143

步骤A：5-羟基-2-甲基-1H-吲哚-3-甲酸-4-三氟甲基苄酯 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]methyl ester

Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid-4-trifluoromethylbenzyl ester

To 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (4.5g, 23.54mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.58g , 23.54 mmol) in DMF (50 mL), 2'-bromo-2,2,2-trifluoro-p-xylene (6.2 g, 25.89 mmol) was added. The mixture was stirred at room temperature for 2 days, then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give a residue which was recrystallized from ethyl acetate to give 4.26 g (52%) of the desired product as a white solid: mp 224-225°C; MS (APCI ⁺ ): m/z 350.1 (MH ⁺ ); theoretical for C ₁₈ H ₁₄ F ₃ N ₁ O ₃ : C, 61.89; H, 4.04; N, 4.01. Found: C, 61.87; H, 4.00; N, 3.98.

Step B: 4-Trifluoro-methylbenzyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

4-trifluoromethylbenzyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (3.0 g, 8.59 mmol) and aqueous dimethylamine (40%, 2.37 mL, 18.9 mmol) were mixed with 6.7 mL ethanol mixed. This mixture was heated with a heat gun until a clear solution was obtained. After cooling to room temperature, aqueous HCHO (37%, 0.83 g, 10.31 mmol) was added. The resulting reaction mixture was stirred overnight at 50°C. The reaction mixture was concentrated in vacuo to -half volume to give a solid which was filtered. This solid was washed with ethanol-water and dried in vacuo to give 1.8 g (52%) of the pure title compound as an off-white foam: MS (APCI ⁺ ): m/z 407.2 (MH ⁺ ).

向高氯酸盐(1.37g，5.75mmol，实施例3，步骤B)和100mL乙醚的混合物中，加入150mL氢氧化钠水溶液(2N)。所得混合物在分液漏斗中摇动直到所有固体溶解。分为两层，水层用乙醚萃取(2×50mL)。合并的醚层用硫酸钠干燥并真空浓缩。残余的油状物溶解于25mL二噁烷，然后加入吲哚mannich碱(1.8g，4.42mmol)，所得反应混合物在氮气氛下回流6小时。将此反应混合物冷却至室温，并真空浓缩得到粘稠油状物。粗品进一步通过色谱纯化(10％-30％乙酸乙酯在己烷中)得到1.21g(55％)标题化合物，为白色泡沫：mp97-99℃；MS(APCI⁺)：m/z499.2(MH⁺)；Step C: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,[4-(trifluoromethyl)phenyl]methyl ester

To a mixture of perchlorate (1.37 g, 5.75 mmol, Example 3, Step B) and 100 mL of diethyl ether was added 150 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 50 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (1.8 g, 4.42 mmol) was added and the resulting reaction mixture was refluxed for 6 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo to a thick oil. The crude product was further purified by chromatography (10%-30% ethyl acetate in hexanes) to give 1.21 g (55%) of the title compound as a white foam: mp 97-99°C; MS (APCI ⁺ ): m/z 499.2 ( MH ⁺ );

_{Calcd for C28H29F3N2O3 :} C, 67.46; H, 5.86; N, 5.62; _F , _11.43 . Found: C, 67.13; H, 5.86; N, 5.45; F, 11.32.

Example 144

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (4-chlorophenyl) methyl ester Step A: 4-chlorobenzyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate

To 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (5.0g, 26.15mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.98g , 26.15 mmol) in DMF (50 mL), 4-chlorobenzyl bromide (5.9 g, 28.77 mmol) was added. The mixture was stirred at room temperature for 2 days, then partitioned between ethyl acetate and water. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give a residue which was recrystallized from ethyl acetate to give 5.0 g (61%) of the desired product as an off-white solid: mp 236-237°C; MS ( APCI-): m/z 314.1 (M-H).

Step B: 4-Chlorobenzyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

Mix 4-chlorobenzyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (4.0 g, 12.7 mmol) and aqueous dimethylamine (40%, 3.5 mL, 27.8 mmol) with 10.4 mL of ethanol . This mixture was heated with a heat gun until a clear solution was obtained. After cooling to room temperature, aqueous HCHO (37%, 1.24 g, 15.2 mmol) was added. The resulting reaction mixture was stirred overnight at 50°C. The reaction mixture was concentrated in vacuo to give a residue which was chromatographed using 100% ethyl acetate as eluent to afford 2.3 g (49%) of pure title 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,(4-chlorophenyl)methyl ester To a mixture of perchlorate (1.9 g, 8.02 mmol, Example 3, Step B) and 150 mL of diethyl ether was added 200 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. The layers were separated and the aqueous layer was extracted with ether (2 x 100 mL). The combined ether layers were dried over sodium sulfate 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, and the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to a thick oil. The crude product was further purified by chromatography (20%-25% ethyl acetate in hexanes) to give 1.7 g (59%) of the title compound as a white solid: mp 220-221 °C; MS (APCI ⁺ ): m/z 465.3 ( MH ⁺ ).

Example 145

步骤A：5-羟基-1H-吲哚-3-甲酸苄酯 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-, phenylmethyl ester

Step A: Benzyl 5-Hydroxy-1H-indole-3-carboxylate

To 5-hydroxy-1H-indole-3-carboxylic acid (4.5g, 25.4mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.87g, 25.4mmol) in To the mixture in DMF (50 mL), benzyl bromide (4.78 g, 27.94 mmol) was added. The mixture was stirred at room temperature for 2 days, then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give a residue, which was recrystallized from ethyl acetate-hexane to give 2.4 g (36%) of the desired product as an off-white solid: mp 184-186 °C; MS (APCI-): m/z 266.1 (M-H).

Step B: Benzyl 4-Dimethylaminomethyl-5-hydroxy-1H-indole-3-carboxylate

Benzyl 5-hydroxy-1H-indole-3-carboxylate (2.3 g, 8.6 mmol) and aqueous dimethylamine (40%, 2.37 mL, 18.9 mmol) were mixed with 6.67 mL of ethanol. This mixture was heated with a heat gun until a clear solution was obtained. After cooling to room temperature, aqueous HCHO (37%, 0.84 g, 10.32 mmol) was added. The resulting reaction mixture was stirred overnight at 50°C. The reaction mixture was concentrated in vacuo to give a residue which was chromatographed using 50%-100% ethyl acetate in hexanes as eluent to afford 2.16 g (77%) of pure title 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13, 14, 14a, 15-decahydro-, phenylmethyl ester

To a mixture of perchlorate (1.91 g, 8.02 mmol, Example 3, Step B) and 150 mL of diethyl ether was added 200 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separate into two layers and extract the aqueous layer with ether (2 x 100 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannich base (2.0 g, 6.17 mmol) was added, and the resulting reaction mixture was refluxed under nitrogen atmosphere for 6 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a viscous oil which was recrystallized from acetonitrile to give 1.2 g (47%) of the title compound as an off-white solid: mp 255-257 °C; MS (APCI ⁺ ): m/z 417 .3(MH ⁺ ).

Example 146

步骤A：5-羟基-1H-吲哚-3-甲酸乙酯

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

Step A: Ethyl 5-Hydroxy-1H-indole-3-carboxylate

To 5-hydroxy-1H-indole-3-carboxylic acid (4.5g, 25.4mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.87g, 25.4mmol) in To the mixture in DMF (50 mL), iodoethane (4.36 g, 27.94 mmol) was added. The mixture was stirred overnight at room temperature, then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give a residue which was recrystallized from ethyl acetate-hexane to give 2.2 g (42%) of the desired product as a light brown solid: MS (APCI ⁺ ) : m/z 206.2 (MH ⁺ ).

Step B: 4-Dimethylaminomethyl-5-hydroxy-1H-indole-3-carboxylic acid ethyl ester

Ethyl 5-hydroxy-1H-indole-3-carboxylate (2.1 g, 10.23 mmol) and aqueous dimethylamine (40%, 2.83 mL, 22.51 mmol) were mixed with 7.7 mL of ethanol. This mixture was heated with a heat gun until a clear solution was obtained. After cooling to room temperature, aqueous HCHO (37%, 0.99 g, 12.28 mmol) was added. The resulting reaction mixture was stirred overnight at 50°C. The reaction mixture was concentrated in vacuo to give a residue which was chromatographed using 50%-100% ethyl acetate in hexanes as eluent to afford 2.1 g (78%) of the pure title compound as a gum: MS (APCI ⁺ ):) m/z 263.1 (MH ⁺ ).

Step C: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13, 14, 14a, 15-decahydro-, ethyl ester

To a mixture of perchlorate (2.36 g, 9.9 mmol, Example 3, Step B) and 150 mL of diethyl ether was added 250 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 100 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannich base (2.0 g, 7.6 mmol) was added, and the resulting reaction mixture was refluxed under nitrogen atmosphere for 6 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a viscous oil which was recrystallized from acetonitrile to give 1.7 g (63%) of the title compound as an off-white solid: mp 242-244 °C;

MS (APCI ⁺ ): m/z 355.3 (MH ⁺ ).

Example 147

步骤A：5-羟基-2-甲基-1H-吲哚-3-甲酸羟基乙酯 Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-hydroxyethyl ester

Step A: 5-Hydroxy-2-methyl-1H-indole-3-carboxylated hydroxyethyl ester

To 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (5.0g, 26.15mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.91g , 26.15 mmol) in DMF (100 mL), 2-bromoethanol (3.6 g, 28.77 mmol) was added. The mixture was stirred at room temperature for 7 days, then partitioned between ethyl acetate and water. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give a residue which was chromatographed using 30%-100% ethyl acetate in hexanes as eluent to give 2.4 g (39%) of the compound The desired product is a gum: MS (APCI ⁺ ): m/z 236.1 (MH ⁺ ).

Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylated hydroxyethyl ester

Hydroxyethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (2.3 g, 9.8 mmol) and aqueous dimethylamine (40%, 2.7 mL, 21.5 mmol) were mixed with 7.4 mL of ethanol. This mixture was heated with a heat gun until a clear solution was obtained. After cooling to room temperature, aqueous HCHO (37%, 0.95 g, 11.7 mmol) was added. The resulting reaction mixture was stirred overnight at 50°C. The reaction mixture was concentrated in vacuo to give a residue which was chromatographed using 100% ethyl acetate followed by 20% methanol in dichloromethane as eluents to afford 2.0 g (70%) of the pure title compound as a gum: MS (APCI ⁺ ): m/z 293.2 (MH ⁺ ).

Step C: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,2-hydroxyethyl ester

To a mixture of perchlorate (2.1 g, 8.9 mmol, Example 3, Step B) and 150 mL of diethyl ether was added 250 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 100 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 6.84 mmol) was added and the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue as a viscous oil which was recrystallized from acetonitrile to give 1.6 g (61%) of the title compound as a light brown solid: mp 221-223°C; MS (APCI ⁺ ): m/z 385.2 (MH ⁺ ).

Example 148

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (3-methylphenyl) methyl ester Step A: 3-Methylbenzyl 5-Hydroxy-2-methyl-1H-indole-3-carboxylate

To 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (4.0g, 20.92mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.18g , 20.92 mmol) in DMF (100 mL), α-bromo-m-xylene (4.28 g, 23.1 mmol) was added. The mixture was stirred at room temperature for 7 days, then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give a residue which was chromatographed using 20%-50% ethyl acetate in hexanes as eluent to afford 3.0 g (48%) of the compound The desired product is a tan solid: mp 165-167°C; MS (APCI ⁺ ): m/z 296.2 (MH ⁺ ).

Step B: 3-methylbenzyl 4-dimethylaminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylate

5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid 3-methylbenzyl ester (2.7g, 9.14mmol) and aqueous dimethylamine (40%, 2.52mL, 20.1mmol) were mixed with 7.4mL ethanol mix. This mixture was heated with a heat gun until a clear solution was obtained. After cooling to room temperature, aqueous HCHO (37%, 0.89 g, 10.97 mmol) was added. The resulting reaction mixture was stirred overnight at 50°C. The reaction mixture was concentrated in vacuo to give a residue which was chromatographed using 50%-100% ethyl acetate in hexanes as eluent to afford 2.0 g (62%) of the pure title compound as a gum: MS ( APCI ⁺ ): m/z 353.3 (MH ⁺ ).

Step C: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,(3-methylphenyl)methyl ester

To a mixture of perchlorate (1.75 g, 7.38 mmol, Example 3, Step B) and 100 mL of diethyl ether was added 150 mL of aqueous sodium hydroxide (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Separated into two layers, the aqueous layer was extracted with ether (2 x 50 mL). The combined ether layers were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 5.67 mmol) was added, and the resulting reaction mixture was refluxed under nitrogen atmosphere for 6 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to a thick oil. The crude product was further purified by chromatography (10%-25% ethyl acetate in hexanes) to give 1.8 g (55%) of the title compound as a white solid: mp 80-82 °C; MS (APCI ⁺ ): m/z 445.4 ( MH ⁺ ).

Example 149

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1S)-1-phenylethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1S)-1-phenylethyl ester was synthesized according to Method Q from (S)-(-)-1-phenylethanol. The crude product was chromatographed using 30% ethyl acetate in hexanes as eluent to give 75 mg of the desired product as a white solid: mp 98-100°C; MS (APCI ⁺ ): m/z 445.2 (MH ⁺ ).

Example 150

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-phenylethyl ester was synthesized according to Method Q from 1-phenylethanol. The crude product was chromatographed using 40% diethyl ether in hexane followed by 50% ethyl acetate in hexane as eluent to give 480 mg of the desired product as a white solid: mp 89-90°C; MS (APCI ⁺ ): m/z 445.2 (MH ⁺ ).

Example 151

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-thioxoic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,S-(phenylmethyl)ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-thioxoic acid, 3,7,8,9,10,12, 13, 14, 14a, 15-Decahydro-2-methyl-, S-(phenylmethyl) esters were synthesized according to Method Q from benzyl mercaptan. The crude product was chromatographed using 50% diethyl ether in hexanes as eluent to give 150 mg of the desired product as a white solid: MS (APCI ⁺ ): m/z 447.1 (MH ⁺ ).

Example 152

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-pyridylmethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,3-pyridylmethyl ester was synthesized according to Method Q from 3-pyridylmethanol. The crude product was chromatographed using 50% ethyl acetate in hexane followed by 10% methanol in ethyl acetate as eluent 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[4-(trifluoromethyl)phenyl]ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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-α-methylbenzyl alcohol. The crude product was chromatographed using 40%-50% diethyl ether in hexanes as eluent to give 180 mg of the desired product as a white solid: mp 104-106°C; MS (APCI-): m/z 511.1 (M-H).

Example 154

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(pentafluorophenyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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-α-methylbenzyl alcohol. The crude product was chromatographed using 40% diethyl ether in hexane as eluent 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]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a,15-Decahydro-2-methyl-,1-(2,6-difluorophenyl)ethyl ester was synthesized according to Procedure Q from 2,6-difluoro-α-methylbenzyl alcohol. The crude product was chromatographed using 40% diethyl ether in hexane as eluent to give 180 mg of the desired product as a white solid: mp 85-87°C; MS (APCI ⁺ ): m/z 481.1 (MH ⁺ ).

Example 156

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1S)-1-(2-furyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1S)-1-(2-furyl)ethyl ester was synthesized according to Method Q from S(-)-1-(2-furyl)ethanol. The crude product was chromatographed using 40%-60% diethyl ether in hexane as eluent to give 300 mg of the desired product as a white solid: mp 84-86°C; MS (APCI ⁺ ): m/z 435.1 (MH ⁺ ).

Example 157

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-(4-morpholinyl)-1-phenylethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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 α-phenyl-4-morpholinoethanol. The crude product was chromatographed using 40%-60% diethyl ether in hexane as eluent to give 130 mg of the desired product as a white solid: mp 251-252°C; MS (APCI-): m/z 528.2 (M-H).

Example 158

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1R)-1-(2-furyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1R)-1-(2-furyl)ethyl ester was synthesized according to Procedure Q from R(+)-1-(2-furyl)ethanol. The crude product was chromatographed using 40%-60% diethyl ether in hexane as eluent 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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-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)-(+)-methylmandelate. The crude product was chromatographed using 40%-60% diethyl ether in hexane as eluent 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][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(3-pyridyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(3-pyridyl)ethyl ester was synthesized according to Procedure Q from 1-(3-pyridyl)ethanol. The crude product was chromatographed using 50% diethyl ether in hexane followed by 10% methanol in dichloromethane as eluent to give 300 mg of the desired product as a white solid: mp 78-80 °C; MS (APCI ⁺ ): m /z446.2(MH ⁺ ).

Example 161

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester

To pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, To a solution of 14,14a,15-decahydro-2-methyl-,2-methoxy-2-oxo-1-phenylethyl ester (650mg, 1.33mmol) in methanol (60mL) was added 1N 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 eluent) to give 0.58 g of a mixture of the free acid and the sodium salt. All of this mixture (0.58 g) was dissolved in methanol-chloroform, then mixed with 0.53 mL of 1 N HCl. The mixture was concentrated in vacuo and the residue was purified by chromatography (10-30% methanol in chloroform as eluent) followed by recrystallization from methanol to give 0.35 g of the desired product as a white solid: mp 250-251°C; MS ( APCI-): m/z 473.1 (MH), C ₂₈ H ₃₀ N ₂ O ₅ ·0.36 H ₂ O Calc.: C, 69.91; H, 6.44; N, 5.82. Found: C, 69.96; H, 6.33; N, 5.59.

Example 162

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, 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]quinazine-1-carboxylate (1:1) salt formation

To pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, To a suspension of 14,14a,15-decahydro-2-methyl-,(S)-carboxy(phenyl)methyl ester (181 mg, 0.38 mmol) in ethanol (5 mL), was added an aqueous solution of choline bicarbonate (5.66 M, 0.06 mL, 0.34 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and diluted with 70 mL of ether. After cooling in an ice bath, the precipitate was collected by filtration to give 0.17 g (77%) of the desired product as an off-white solid: mp 223-225°C; MS (APCI+): m/z 475.2 (MH ⁺ ). Anal _. Calc _{. for C28H29N2O5 -} C5H14NO _{- 1.2H2O} : C, _66.13 ; H, 7.64; _N , 7.01. Found: C, 65.96; H, 7.56; N, 6.78.

Example 163

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1R)-2-methoxy-2-oxo-1-phenylethyl ester was prepared from (R)-(-)-methylmandine according to method Q Ester synthesis. The crude product was chromatographed using 40%-60% diethyl ether in hexane as eluent to give 750 mg of the desired product as a white solid: mp 106-108°C; MS (APCI ⁺ ): m/z 489.2 (MH ⁺ ).

Example 164

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (R)-carboxy(phenyl)methyl ester

To pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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), IN NaOH (5.5 mL, 5.5 mmol) was added. The resulting reaction mixture was stirred at 50 °C for 1 h and 1 N HCl (5.5 mL) was added. This mixture was concentrated in vacuo to give a residue which was purified by chromatography (10-30% methanol in chloroform as eluent) 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).

Example 165

Ethyl ammonium, 2-hydroxy-N,N,N-trimethyl-, with (R)-carboxy(phenyl)methyl, 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15 -Decahydro-2-methylpyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylate (1:1) into Salt

To pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2-methyl-,(R)-carboxy(phenyl)methyl ester (210mg, 0.44mmol) in ethanol (5mL) suspension, was added choline bicarbonate aqueous solution (5.66 M, 0.07 mL, 0.40 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and 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 ⁺ ). C ₂₈ H ₂₉ N ₂ O ₅ ·C ₅ H ₁₄ NO · 1.8H ₂ O Anal. Calc.: C, 64.96; H, 7.7.70; N, 6.89. Found: C, 65.04; H, 7.59; N, 6.55.

Example 166

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 4-pyridylmethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 4-pyridylmethyl ester was synthesized according to Method Q from 4-pyridylmethanol. The crude product was chromatographed using 50% ethyl acetate in hexanes followed by 100% ethyl acetate as eluent to give 260 mg of the desired product as a white solid: mp 199-201 °C; MS (APCI ⁺ ): m/ z432.5 (MH ⁺ ).

Example 167

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(4-pyridyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(4-pyridyl)ethyl ester was synthesized according to Procedure Q from 1-(4-pyridyl)ethanol. The crude product was chromatographed using 50% ethyl acetate in hexanes followed by 100% ethyl acetate as eluent to give 210 mg of the desired product as a white solid: mp 219-221 °C; MS (APCI ⁺ ): m/ z446.2 (MH ⁺ ).

Example 168

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(2-pyridyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(2-pyridyl)ethyl ester was synthesized according to Method Q from 1-(2-pyridyl)ethanol. The crude product was chromatographed using 50%-75% ethyl acetate in hexanes as eluent to give 200 mg of the desired product as a white solid: mp 87-89°C; MS (APCI ⁺ ): m/z 446.2 (MH ⁺ ).

Example 169

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-thienylmethyl ester was synthesized according to Method Q from 3-thiophenemethanol. The crude product was chromatographed using 50% diethyl ether in hexane as eluent to give 330 mg of the desired product as a white solid: mp 115-116°C; MS (APCI ⁺ ): m/z 437.5 (MH ⁺ ).

Example 170

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,11,12,13 , 14, 14a, 15-Decahydro-2-methyl-, (1S)-1-(4-fluorophenyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,(1S)-1-(4-fluorophenyl)ethyl ester was synthesized according to Procedure Q from S(-)-1-(4-fluorophenyl)ethanol. The crude product was chromatographed using 30%-50% diethyl ether in hexane as eluent to give 300 mg of the desired product as a white solid: mp 108-110°C; MS (APCI ⁺ ): m/z 463.3 (MH ⁺ ) .

Example 171

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1R)-1-(4-fluorophenyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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-fluorophenyl)ethanol. The crude product was chromatographed using 30%-50% diethyl ether in hexanes as eluent 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-pyridylmethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,3-pyridylmethyl ester was synthesized according to Method Q from 3-pyridylmethanol. The crude was chromatographed (1:1 hexanes/EtOAc) to afford 1.43 g (49.4%) of the desired product as a solid: mp 73-80°C; MS (APCI ⁺ ): m/z 432.6 (MH ⁺ ).

Example 173

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-ethoxy-2-oxo-ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,2-ethoxy-2-oxo-ethyl ester was synthesized according to Method Q from ethyl glycolate. The crude was chromatographed (1:1 hexanes/EtOAc) to afford 0.5287 g (36.8%) of the desired product as a solid: mp 60-70°C; MS (APCI ⁺ ): m/z 427.2 (MH ⁺ ).

Example 174

Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3′,2′:5,6][ 1] Benzopyrano[3,2-i]quinazin-1-yl)carbonyl]oxy]methyl]-1-methyl-, methanesulfonate

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 3-pyridylmethyl ester (1eq) and methyl methanesulfonate (4eq) were mixed with 1,2-dichloroethane and refluxed at 88°C for 30 minute. After cooling to room temperature, the precipitate was isolated by suction filtration and washed with diethyl ether to give 86 mg (41.2%) of pure desired product as crystals: mp 228-232°C; MS (APCI ⁺ ): m/z 446.2 (M ⁺ ).

Some compounds of the ring-closed formula I can further form N-oxides and N-alkyl quaternary ammonium salts on the ring nitrogen atom at the N-11 position. In addition, some compounds of ring-closed formula I also form N-oxides and N-alkyl quaternary ammonium salts on any optionally present nitrogen atom 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]quinazinium, 3,7,8,9,10,12,13,14,14a, 15-Decahydro-2,11-dimethyl-1-[(S)-(1-phenylethoxy)carbonyl]-, methanesulfonate

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-Decahydro-2-methyl-, (1S)-1-phenylethyl ester (0.6g, 1.349mmol) and methyl methanesulfonate (1.089g, 10.7964mmol) in 1,2- Dichloroethane (8ml) was mixed together and refluxed at 88°C for 18 hours. The reaction mixture was concentrated in vacuo. The crude was chromatographed (2:10 MeOH/ _CH2Cl2 ) to give 0.41 g (61.5%) of the desired product as a solid: mp _160-170 °C; MS (APCI ⁺ ): m/z 459.3 (M ⁺ ) .

Some compounds of the ring-closed formula I can further form N-oxides and N-alkyl quaternary ammonium salts on the ring nitrogen atom at the N-11 position. In addition, some compounds of ring-closed formula I also form N-oxides and N-alkyl quaternary ammonium salts on any optionally present nitrogen atom in R ₁₀ . These structural forms are within the scope of the present invention.

Example 176

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-furyl methyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,3-furylmethyl ester was synthesized according to Method Q from furan-3-yl-methanol. The crude was chromatographed (1:1 hexanes/EtOAc) to afford 0.40 g (42.4%) of the desired product as a solid: mp 174-177°C; MS (APCI ⁺ ): m/z 421.4 (MH ⁺ ).

Example 177

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (2-nitrophenyl) methyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (2-nitrophenyl)methyl ester was synthesized according to Method Q from 2-nitrobenzyl alcohol. The crude product was chromatographed (1:1 hexanes/EtOAc) to give 0.39 g (35.9%) of the desired product: mp 200-203°C; MS (APCI ⁺ ): m/z 476.5 (MH ⁺ ).

Example 178

吡咯并[3′，2′：5，6][1]苯并吡喃并[3，2-i]喹嗪-1-甲酸，3，7，8，9，10，12，13，14，14a，15-十氢-2-甲基-，2-呋喃基甲酯按照方法Q由呋喃-2-基-甲醇合成。粗品进行色谱纯化(1∶1己烷/EtOAc)，得到0.24g(24.8％)所需产物，为固体：mp65-77℃；MS(APCI+)：m/z421.4(MH⁺)。Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-furyl methyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,2-furylmethyl ester was synthesized according to Method Q from furan-2-yl-methanol. The crude was chromatographed (1:1 hexanes/EtOAc) to afford 0.24 g (24.8%) of the desired product as a solid: mp 65-77°C; MS (APCI+): m/z 421.4 (MH ⁺ ).

Example 179

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 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 the desired product as a solid: mp 95-105°C; MS (APCI ⁺ ): m/z 479.2 (MH ⁺ ).

Example 180

吡咯并[3′，2′：5，6][1]苯并吡喃并[3，2-i]喹嗪-1-甲酸，3，7，8，9，10，12，13，14，14a，15-十氢-2-甲基-，2-乙氧基-2-氧代-乙酯(0.47g，0.96mmol)与存在于甲醇中的1N NaOH(5.73mmol，5.73mL)混合并保持在50℃油浴中加热3小时。然后将此反应混合物冷却至室温，接着加入1N HCl中和。将此反应混合物真空浓缩，粗品进行色谱纯化(开始1∶1己烷/乙醚，然后10％MeOH在氯仿中)，得到0.374g粗品固体。此粗品固体再溶解在氯仿中并过滤得到78mg(20.6％)所需产物，为固体：MS(APCI⁺)：mp260℃；m/z399.1(MH⁺)。Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, carboxymethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,2-ethoxy-2-oxo-ethyl ester (0.47 g, 0.96 mmol) was mixed with 1N NaOH in methanol (5.73 mmol, 5.73 mL) And keep heating in a 50°C oil bath for 3 hours. The reaction mixture was then cooled to room temperature, followed by addition of 1N HCl for neutralization. The reaction mixture was concentrated in vacuo and the crude product was chromatographed (starting with 1:1 hexane/ether, then 10% MeOH in chloroform) to afford 0.374 g of a crude solid. This crude solid was redissolved in chloroform and filtered to give 78 mg (20.6%) of the desired product as a solid: MS (APCI ⁺ ): mp 260°C; m/z 399.1 (MH ⁺ ).

Example 181

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(2,6-dichlorophenyl) ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(2,6-dichlorophenyl)ethyl ester was synthesized according to Procedure Q from 1-(2,2-dichlorophenyl)ethanol. The crude product was chromatographed (1:1 hexane/ether) to give 93 mg (5.30%) of the desired product as a solid: mp 130-135°C; MS (APCI ⁺ ): m/z 513.1 (M ⁺ ).

Example 182

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(2-methoxyphenyl)ethyl ester was synthesized according to Procedure Q from 1-(2-methoxyphenyl)ethanol. The crude product was chromatographed (1:1 hexane/ether) to give 0.90 g (42%) of the 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, (1S)-1-phenylethyl ester, 11-oxide

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a,15-Decahydro-2 _- methyl-,(1S)-1-phenylethyl ester (0.3 g) was mixed with 50% _H2O2 in methanol and this mixture was stirred at room temperature for 3 hours . Then, excess H ₂ O ₂ was destroyed with Pd/C. The reaction solution was filtered and concentrated in vacuo. The crude was chromatographed (10% MeOH in dichloromethane) to give 52mg (48.2%) pure desired product as a solid: mp 180-190°C; MS (APCI ⁺ ): m/z 461.2 (MH ⁺ ) .

Some compounds of the ring-closed formula I can further form N-oxides and N-alkyl quaternary ammonium salts on the ring nitrogen atom at the N-11 position. In addition, some compounds of ring-closed formula I also form N-oxides and N-alkyl quaternary ammonium salts on any optionally present nitrogen atom 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-(5-carboxy-3-pyridyl) ethyl ester

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 _2NH2SO4 and the mixture was refluxed for 24 hours. The reaction solution was neutralized with solid sodium bicarbonate and extracted with ether. The organic phase was dried and ether evaporated to give 6.06 g (89.5%) of pure desired product as crystals: MS (APCI ⁺ ): m/z 201 (MH ⁺ ).

Step B: 1-(5-Bromo-pyridin-3-yl)-ethanol

Compound 1-(5-bromo-pyridin-3-yl)-ethanone (5.85 g, 29.2 mmol) was dissolved in MeOH (100 mL) and NaBH ₄ (1.104 g, 29.19 mmol) was added slowly. The reaction was monitored by TLC. When the starting material reacted completely, the mixture was neutralized with sodium bicarbonate solution and extracted with ether to give the crude product. The crude product was mixed with 1:1 hexane/ethyl acetate and filtered. The filtrate was concentrated to give pure desired product. MS (APCI ⁺ ): m/z 203 (MH ⁺ ).

Step C: 5-(1-Hydroxy-ethyl)-nicotinic acid methyl ester

1-(5-Bromo-pyridin-3-yl)-ethanol (6.0 g), palladium acetate (0.14 g), DPPP (0.28 g), triethylamine (6 mL), DMSO (60 mL) and MeOH (60 mL) Mix together and heat the reaction mixture with stirring at 100-110°C for 18 hours. At the end of the reaction, the mixture was filtered to remove the solid, and the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate and filtered, and the filtrate and solid were collected. This solid was dissolved in sodium bicarbonate and extracted with ethyl acetate. The extracts and the filtrate were combined and dried over sodium sulfate. Concentration in vacuo gave a crude product which was chromatographed eluting with 1:1 hexanes/EtOAc to give 3.32 g (61.8%) of pure desired product: MS (APCI ⁺ ): m/z 182 (MH ⁺ ).

Step D: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-[5-(methoxycarbonyl)-3-pyridyl]ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-[5-(methoxycarbonyl)-3-pyridyl]ethyl ester was prepared from 5-(1-hydroxy-ethyl)-nicotinic acid according to Method Q Methyl ester synthesis. The crude was chromatographed (1:1 hexanes/EtOAc) to afford 0.81 g (37%) of the desired product as a solid: MS (APCI ⁺ ): m/z 504.3 (MH ⁺ ).

Step E: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-(5-carboxy-3-pyridyl)ethyl ester

Example 184, Step D, Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9, 10,12,13,14,14a,15-Decahydro-2-methyl-,1-[5-(methoxycarbonyl)-3-pyridyl]ethyl ester (0.2202g, 0.4378mmol) and 1N NaOH ( 1.75 mmol, 1.75 mL) was mixed in MeOH (10 mL). The reaction vial was kept heated in a 50°C oil bath for 1 hour. Then, the reaction mixture was cooled to room temperature, and then 1N HCl (2 mL) was added to neutralize the reaction mixture. The mixture was concentrated in vacuo to give a crude product, which was chromatographed (20:10, MeOH/dichloromethane) to give 0.2665 g (100%) of the desired product as a solid: MS (APCI ⁺ ): m/z 490.2 ( MH ⁺ ).

Example 185

1,3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2': 5,6][1]benzopyrano[3,2-i]quinazin-1-yl)carbonyl]oxy]methyl]-, diethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid with benzoic acid, 3,7,8,9,10,12 , 13,14,14a,15-decahydro-2-methyl-,anhydride (Example 86) (0.502g, 1.13mmol) and diethyl-5-(hydroxymethyl)isophthalate ( 0.859 g, 3.40 mmol) were mixed and placed in a 150 °C oil bath for 6 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate and saturated sodium bicarbonate and stirred until all residue was dissolved. The layers were separated and the organic layer was washed with water and brine, dried ( _MgSO4 ) and evaporated. The product was purified by column chromatography eluting with an ether/hexane gradient (30% yield).

¹ H NMR (CDCl3, 300MHz): δ8.64(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): _{575.2C33H38N2O7 0.67H2O} . Calculated: C, 67.50 ; H, 6.70; N, 4.77. Found: C, 67.19; H 6.54; N, 4.37.

Example 186

1,3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2': 5,6][1]benzopyrano[3,2-i]quinazin-1-yl)carbonyl]oxy]methyl]-

1,3-Benzene dicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo [3′,2′:5,6][1]benzopyrano[3,2-i]quinazin-1-yl)carbonyl]oxy]methyl]-, diethyl ester (0.4787g, 0.83mmol), 2mL MeOH and 0.83mL (1.66mmol) of 2M NaOH were mixed and heated to 50-60°C. Two 0.83 mL batches of 2M NaOH were added until the reaction was complete by MS. The reaction was cooled to room temperature and washed with ether. The aqueous layer was neutralized and concentrated. This residue was dissolved in hot MeOH and filtered to remove sodium chloride. The filtrate was concentrated and dissolved in MeOH at room temperature and filtered again. The filtrate was dried over magnesium sulfate, filtered and concentrated. This product was lyophilized to yield 362.2 mg (83%). LCMS: 88.17%

Example 187

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl ester

Step A: 2-Chloro-5-nitrobenzyl alcohol

An oven-dried 3-neck flask fitted with 2 compartments and a reflux condenser was 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). This solution was heated to reflux for 2 hours at which time borane methyl sulfide complex (2M/THF, 18 mL, 36 mmol) was added dropwise over 30 minutes. Reflux was continued for another 2 hours until the reaction was complete as determined by TLC. The reaction was cooled to room temperature and 4 mL of 1:1 THF/ _H2O was added slowly, followed by 20.5 mL of 5M NaOH. The reaction was heated at reflux for 16 hours and filtered hot through a coarse sintered glass funnel, the solids were washed with THF (2x). The filtrate was dried ( _MgSO4 ), filtered, concentrated and purified by column chromatography eluting with a gradient of ethyl acetate/hexanes. This product was triturated with hexane and filtered to give the product in 79% yield. ¹ H NMR (CDCl ₃ , 300 MHz): δ8.45 (d, 1H), 8.11 (dd, 1H), 7.52 (d, 1H), 8.86 (d, 2H), 2.18 (t, 1H). MS (APCI, AP ^- ) 186.9

Step B: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-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 (1.0879g, 5.80mmol) and pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i ]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride (Example 86) (0.512g, 1.15mmol) Mix and place in a 150°C oil bath for 6 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate, water and brine, dried ( _MgSO4 ), filtered, concentrated and purified by column chromatography eluting with a gradient of ethyl acetate/hexanes to give the product in 57% yield.

¹ H NMR (DMSO, 300MHz): δ11.65(s, 1H), 8.39(s, 1H), 8.24(dd, 1H), 7.85(d, 1H), 7.07(d, 1H), 6.63(d, 1H), 5.42(d, 2H), 3.23(m, 1H), 2.8-3.0(m, 1H), 2.60-2.70(m, 2H), 2.30-2.60(m, 3H), 2.37(s, 3H) , 1.82-1.87 (m, 1H), 1.0-1.75 (m, 11H) MS (APCI, Ap ⁺ ): 510.1 LCMS: 98.23% Retention time: 7.627 minutes

Example 188

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (5-amino-2-chlorophenyl) methyl ester

Step A: 5-Amino-2-chlorobenzoic acid

Raney-Nickel (3 gm) was added to a solution of 5-nitro-2-chlorobenzoic acid (10 gm, 150 mL) in methanol, then this mixture was connected to a hydrogen source, and after 4 hours, monitored by TLC The reaction was complete (30% _MeOH / _CH2Cl2 ). The catalyst was removed by filtration and the filtrate was evaporated to dryness. 8 g of product were collected and used in the next step without purification. MS (APCI, AP ⁺ ): 172.0

Step B: 5-Amino-2-chlorobenzyl alcohol

An oven-dried two-necked flask fitted with a septum and condenser was charged with 5-amino-2-chlorobenzoic acid (2.611 g, 15.22 mmol) and 7.5 mL of THF. _BF3 - _OEt2 was added dropwise and the reaction was heated to reflux for 2 hours. Borane methyl sulfide complex (2M/THF, 10 mL, 20 mmol) was added dropwise. The reaction was refluxed for 3 hours and an additional 3.8 mL of borane methylsulfide complex (7.2 mmol) was added. Reflux was continued for 1 hour, cooled to room temperature, and 3 mL of 1:1 THF/ _H2O was added slowly, followed by 11.2 mL of 5M NaOH. The reaction was heated to reflux for 16 hours and filtered through a coarse sintered glass funnel, washing the solids with THF (2x). The filtrate was concentrated and the residue was partitioned between dichloromethane/ _H2O . This product was extracted three times with dichloromethane. The tan solid in the organic layer was collected by filtration and dried in a vacuum oven at 40°C overnight to yield 0.6374 g of product. The organic filtrate was dried ( _MgSO4 ), filtered, concentrated and purified by column chromatography eluting with a MeOH/dichloromethane gradient to afford 0.56 g of product. ¹ H NMR (DMSO, 300 MHz): δ6.93 (d, 1H), 6.75 (d, 1H), 6.39 (dd, 1H), 5.16 (s, 2H), 4.38 (d, 2H). MS (APCI, AP ⁺ ): 158.0

Step C: pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,(5-amino-2-chlorophenyl)methyl ester

5-Amino-2-chlorobenzyl alcohol (1.055 g, 6.70 mmol) and pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i] with benzoic acid Quinazine-1-carboxylic acid, 3, 7, 8, 9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, anhydride (Example 86) (0.7023g, 1.58mmol) mixed And placed in a 150°C oil bath for 6 minutes. The reaction was cooled, diluted with ethyl acetate and saturated sodium bicarbonate and stirred until all residue was dissolved. The organic layer was washed with water and brine, dried ( _MgSO4 ), filtered and concentrated. This product was purified by column chromatography eluting with 5% MeOH/dichloromethane. The product was placed under high vacuum for two days to yield 0.260 g (34%) of a pale pink solid.

¹ H NMR (DMSO, 300MHz): δ11.16(s, 1H), 10.13(s, 1H), 8.02(d, 1H), 7.60(dd, 1H), 7.29(d, 1H), 7.05(d, 1H ), 6.60(d, 1H), 5.37(t, 1H), 4.51(d, 2H), 3.14-3.18(m, 1H), 2.90-3.00(m, 1H), 2.65-2.72(m, 1H), 2.30-3.20 (m, 3H), 2.39 (s, 3H), 1.10-1.75 (m, 11H). MS (APCI, Ap ⁺ ): 480.1 LCMS: 91.44% Retention time: 4.623 minutes

Example 189

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-acetic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-α-oxo-, ethyl ester

2-Methyl-pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine (0.296 gm, 1 mm) and ethyl oxalate (0.123 mL, 1.1 mm) in 20 mL THF and the mixture was stirred at room temperature for 48 hours. THF was evaporated and the residue was redissolved in EtOAc, the organic layer was washed with bicarbonate, brine and evaporated to dryness. The pure product (50 mg, 12.4%) was isolated by column chromatography eluting with hexane/EtOAc = 1:1. MS (APCI, Ap ⁺ ): 397.1. ¹ H NMR (CDCl ₃ , 300MHz): δ8.3 (s, NH), 7.05 (d, 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 ₂₈ N ₂ O ₄ 1/3H ₂ O. Calculated value: C, 68.69; H, 7.19; N, 6.96. Found: C, 68.85; H6.98; N, 6.51. MP: 200℃

Example 190

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2,4,5-trimethyl-,phenylmethyl ester

Step A: 2,3-Dimethylquinone

To a solution of NaOAc (16.4 gm, 60 mm) in 200 mL of water was added a solution of 2,3-dimethyl-4-hydroxyphenol (5.526 gm, 20 mm) and benzyltrimethylammonium tribromide (17.6 gm, 22 mm) . The mixture was stirred until the solution faded (3 hours). The organic layer was separated and washed with brine, dried and evaporated to a total weight of 5 gm. This material was used in the next step without purification.

Step B: Ethyl 5-Hydroxy-2,6,7-trimethyl-1H-indole-3-carboxylate

To a solution of 2,3-dimethylquinone (3.5 gm, 25.7 mm) in 60 mL of EtOH was added a solution of benzyl 3-amino-but-2-enoate (5.41 gm, 28.3 mm) under nitrogen. The white solid was filtered and the filtrate was concentrated, the product was purified by column chromatography and eluted with hexane/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-carboxylic acid ethyl ester

37.5% formaldehyde solution (0.157 mL, 1.94 mm) and 40% dimethylamine solution were added to a solution of ethyl 5-hydroxy-2,6,7-trimethyl-1H-indole-3-carboxylate in 11 mL EtOH. The reaction mixture was stirred at 55°C for 48 hours. The solvent was removed, and the pure product was separated by column chromatography, eluting with MeOH/EtOAc=1:4 (0.22 gm, 37.3%). MS (APCI, AP ⁺ ): 367.1.

Step D: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2,4,5-trimethyl-,phenylmethyl ester

1,2,3,4,6,7,8,9-Octahydro-quinazinium perchlorate (0.204 gm, 0.855 mm) was dissolved in 10 mL 1 N NaOH and extracted with 3 x 35 mL diethyl ether. The ether was concentrated and the residue was redissolved in 4 mL of dioxane. This imine solution was added to ethyl 4-dimethylaminomethyl-5-hydroxy-2,6,7-trimethyl-1H-indole-3-carboxylate in 8 mL of dioxane. The reaction was heated at reflux at 110°C for 18 hours. The solvent was evaporated and the pure product was separated by column chromatography, eluting with MeOH/EtOAc=1:4 (0.117 gm, 44.5%). MS (APCI, AP ⁺ ₎ : 459.2. _{MP: 75-80°C C23H28N2O4 ·} 2/ _{3H2O .} Theoretical: C, 74.11; H, 7.52; N, 5.966.96. Found: C, 74.12; H 7.37; N, 5.77.

Example 191

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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: m/z 407.52 (MH ⁺ ).

Example 192

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2,2,2-trichloro-1,1-dimethylethyl ester from 1,1,1-trichloro-2-methyl- Propan-2-ol Synthesis. MS: m/z 500.86 (MH ⁺ ).

Example 193

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-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 from adamantan-1-ol according to Procedure Q. MS: m/z 474.63 (MH ⁺ ).

Example 194

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-methyl-1-phenylethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,1-methyl-1-phenylethyl ester was synthesized according to Procedure Q from 2-phenyl-propan-2-ol. MS: m/z 459.59 (MH ⁺ ).

Example 195

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-methylcyclohexyl ester

pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-methylcyclohexyl ester was synthesized according to Method Q. MS: m/z 437.59 (MH ⁺ ).

Example 196

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-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 Method Q. MS: m/z 425.58 (MH ⁺ ).

Example 197

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-methylcyclopentyl ester was synthesized according to Method Q. MS: m/z 423.56 (MH ⁺ ).

Example 198

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1-cyclohexyl-1-methylethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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 Method Q. MS: m/z 465.64 (MH ⁺ ).

Example 199

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1,4-dimethyl-4-piperidinate

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 1,4-dimethyl-4-piperidinate was synthesized according to Method Q. MS: m/z 452.60 (MH ⁺ ).

Example 200

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 4-fluorophenyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,4-fluorophenyl ester was synthesized according to Method Q. MS: m/z 435.50 (MH ⁺ ).

Example 201

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,3-methylphenyl ester was synthesized according to Method Q. MS: m/z 431.54 (MH ⁺ ).

Example 202

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,phenyl ester was synthesized according to Method Q. MS: m/z 417.51 (MH ⁺ ).

Example 203

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-(methoxycarbonyl)phenyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-(methoxycarbonyl)phenyl ester was synthesized according to Method Q. MS: m/z 475.55 (MH ⁺ ).

Example 204

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-pyridyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-pyridyl ester was synthesized according to Method Q. MS: m/z 417.50 (MH ⁺ ).

Example 205

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-(trifluoromethyl)-, ethyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-(trifluoromethyl)-, ethyl ester was synthesized according to Method Q. MS: m/z 423.44 (MH ⁺ ).

Example 206

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, [5-[(dimethylamino)methyl]-2-furyl]methyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,[5-[(dimethylamino)methyl]-2-furyl]methyl ester was synthesized according to Method Q. MS: m/z 478.60 (MH ⁺ ).

Example 207

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-carboxy-2-methylpropyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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 Method Q. MS: m/z 441.53 (MH ⁺ ).

Example 208

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 3-(dimethylamino)-2,2-dimethylpropyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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 Method Q. MS: m/z 454.62 (MH ⁺ ).

Example 209

With 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3′,2′:5,6][1]benzopyrano[ 3,2-i]Quinazine-1-carboxylic acid, malonic monoanhydride, 1,1-dimethylethyl ester

With 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3′,2′:5,6][1]benzopyrano[ 3,2-i] Malonic monoanhydride, 1,1-dimethylethyl ester of quinozine-1-carboxylic acid was synthesized according to Method Q. MS: m/z 483.57 (MH ⁺ ).

Example 210

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-(dimethylamino)-2-methylpropyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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 Method Q. MS: m/z 440.59 (MH ⁺ ).

Example 211

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-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]quinazine-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 Method Q. MS: m/z 435.53 (MH ⁺ ).

Example 212

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, 2-benzofuryl methyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-,2-benzofuranylmethyl ester was 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]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenylpropyl ester

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenylpropyl ester According to method Q from (1R, 2S) dimethylamino-benzene Synthesis of yl-propan-1-ol. MS (APCI ⁺ ): m/z 502.1 (MH ⁺ ).

Example 214

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

Pyrrolo[3′,2′:5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenylpropyl ester was prepared from (1S, 2R)-2-(dimethyl Synthesis of amino-phenyl-propan-1-ol. MS (APCI ⁺ ): m/z 502.1 (MH ⁺ ).

Example 215

步骤A：1-(4-氟苯基)环丙醇 pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) cyclopropyl ester

Step A: 1-(4-Fluorophenyl)cyclopropanol

Preparation of 1-phenylcyclopropanol as reported by Kulinkovich, OG; Sviridov, SV; Vasilevskii, DA; Savchenko, AI; The method of converting ethyl 4-fluorobenzoate (65.72mmol, 11.05g) into 1-(4-fluorophenyl)cyclopropanol (5.34g, 53%) was a yellow liquid; ¹ H NMR (400MHz, CDCl ₃ ) δ0.99-1.02 (m, 2H, cyclopropyl CH ₂ ), 1.23-1.26 (m, 2H, cyclopropyl CH ₂ ), 2.22 (bs, 1H, OH), 6.98-7.05 (m, 2H, ArH), 7.26-7.32 (m, 2H, ArH) · ¹⁹ F NMR (CDCl ₃ ) δ-117.09 (d, J=15.43 Hz); MS (APCI ⁺ ) m/z 152.9 (MH ⁺ ).

Step B: Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-Decahydro-2-methyl-,1-(4-fluorophenyl)cyclopropyl ester

According to the method of Example 47, Step B, 1-(4-fluorophenyl)-cyclopropanol (35.1 mmol, 5.34 g) and pyrrolo[3′,2′:5,6][1 ]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride (Example 86), (8.77mmol, 3.90g) converted to pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-Decahydro-2-methyl-,1-(4-fluorophenyl)cyclopropyl ester. This product was purified by flash column chromatography on silica gel (25-50% ethyl acetate/hexanes, then 30-50% diethyl ether/hexanes) and recrystallized from 2,2,4-trimethylpentane to give a pale yellow solid ( 0.364g, 9%): mp130-135℃;

IR (KBr) 3302, 29.31, 2857, 1689, 1515, 1429, 1221, 1194, 1147, 1068cm ^-1 ; ¹ HNMR (400MHz, DMSO-d ₆ ) δ1.13-1.60 (m, 13H, fatty CH), 1.71-1.74 (m, 1H, fat CH), 1.88 (d, J=13.18Hz, 1H, fat CH), 2.36 (d, J=10.74Hz, 1H, fat CH), 2.43-2.49 (m, 1H, Fat CH), 2.53 (s, 3H, ArCH ₃ ), 2.66-2.71 (m, 2H, Fat CH), 2.87-2.90 (m, 1H, Fat CH), 3.22 (dd, J=18.31, 6.84Hz, 1H , fatty CH), 6.61 (d, J=8.79Hz, 1H, ArH), 7.04 (d, J=8.55Hz, 1H, ArH), 7.11-7.15 (m, 2H, ArH), 7.28-7.32 (m, 2H, ArH), 11.57 (s, 1H, NH); ¹⁹ F NMR (DMSO-d ₆ ) δ-117.03; MS (APCI ⁺ ) m/z 475.2 (MH ⁺ ).C ₂₉ H ₃₁ F ₁ N ₂ Analytical values calculated for _O3 : C, 73.40; H, 6.58; F, 4.00; N, 5.90. Found: C, 73.58; H, 6.79; F, 3.93; N, 5.52.

Claims (17)

1. the compound or pharmaceutically acceptable salt thereof of formula I,

Wherein:

A is O, S, and when X be C-R ₉The time, A can also be NR ₁

When A is NR ₁The time, X is N, perhaps

X is C-R ₉, R wherein ₉Be halogen, hydrogen atom, alkyl ,-CF ₃, CH ₂F, CHF ₂,-(CH ₂) _m-OR ₁, aryl, aralkyl ,-(CH ₂) _m-NR ₇R ₈Or

Wherein m is 0 to 2 integer, and when occurring, m is 0 to 2 integer independently at every turn, and q is 0 to 1 integer, and r is 0 to 3 integer;

Y is hydrogen atom, alkyl, aralkyl, aryl, (CH ₂) _m-NR ₇R ₈,-N (R ₁)-(CH ₂) _v-C (R ₇R ₈)-aryl or OR ₁₀, R wherein ₁₀Be hydrogen atom, alkyl, cycloalkyl, with aromatic ring condensed cycloalkyl, aryl, (CH ₂) _sAryl ,-CH ₂CF ₃, (CH ₂) _tC (R ₇R ₈)-(CH ₂) _uAryl,

Wherein s is 1 to 3 integer, and t is 0 to 3 integer, and u is 0 to 3 integer, and v is 1 to 3 integer, and w is 0 to 2 integer;

Z is CR or N;

R ₁Be hydrogen atom or alkyl, and when occurring, R. at every turn ₁Be hydrogen atom or alkyl independently;

R and R ₂Be independently from each other:

Hydrogen atom,

Alkyl,

Halogen,

-CN，

-NO ₂，

-(CH ₂) _m-NR ₇R ₈，

-(CH ₂) _m-COOR ₇，

-(CH ₂) _m-CONR ₇R ₈，

-(CH ₂) _m-OR ₇，

-(CH ₂) _m-SO ₂NR ₇R ₈, and

-(CH ₂) _m-S (O) _pR ₇, when wherein occurring at every turn, R ₇And R ₈Be independently of one another hydrogen atom, alkyl, aryl, aralkyl ,-CF ₃, or R ₇And R ₈Can form the ring of 3 to 7 atoms together, in this ring O, S or NR can be arranged ₁, and p is 0 to 2 integer;

R ₃Be hydrogen atom or alkyl;

R ₄Be hydrogen atom, alkyl, aryl or aralkyl;

R ₅Be alkyl, aryl, aralkyl, acyl group; Or

R ₄And R ₅Form the ring of 5 to 7 atoms with the atom that connects with them;

R ₆Be hydrogen atom or alkyl;

When not with R ₄One time-out, R ₅Can with R ₆Form the ring of 5 to 7 atoms with the atom that connects with them;

N-R ₅It also is corresponding N-oxide compound;

R ₁₁Be hydrogen atom or alkyl;

N is 1 to 3 integer; J is 1 to 2 integer, and when Y was hydrogen atom, alkyl, aralkyl or aryl, j was an integer 0;

Condition be do not comprise pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester.

2. the compound of claim 1, wherein R ₁It is hydrogen atom.

3. the compound of claim 1, wherein R ₁Be hydrogen atom, and X is C-R ₉

4. the compound of claim 1, wherein R ₁Be hydrogen atom, and X is C-R ₉, R wherein ₉It is alkyl.

5. the compound of claim 1, wherein R ₁Be hydrogen atom, X is C-R ₉, R wherein ₉It is alkyl; R ₄And R ₅Form the ring of 5-7 atom with the atom that connects with them; And Y is OR ₁₀

6. the compound of claim 1, wherein R ₁Be hydrogen atom, X is C-R ₉, R wherein ₉It is alkyl; R ₄And R ₅Form 6 yuan of rings together; And Y is OR ₁₀, R wherein ₁₀Be alkyl, aryl or-(CH ₂) _sAryl ,-(CH ₂) _t-C (R ₇R ₈)-(CH ₂) _u-aryl.

7. the compound of claim 1, wherein R ₁Be hydrogen atom, X is C-R ₉, R wherein ₉Be Me; R ₄And R ₅Form 6 yuan of rings together; R ₆It is hydrogen atom; N is 2; And Y is OR ₁₀, R wherein ₁₀Be alkyl, aryl or R ₁₀Be-(CH ₂) _t-C (R ₇R ₈)-(CH ₂) _u-aryl, wherein t is O, R ₇And R ₈Can be independently of one another H, alkyl ,-(CH ₂) _vOH or (CH ₂) _uCOOR ₇And-(CH ₂) _vNR ₁R ₂, wherein u and v definition as above.

8. the compound of claim 1 is characterized in that being selected from following compound:

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-bromo-3,7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methyl propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2-dimethyl propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the cyclopropyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(piperidino) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(phenyl methyl)-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-ethyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 2-cyclopropyl-3,7,8,9,10,12,13,14, and 14a, the 15-decahydro-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-propyl group-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(2-methyl-propyl)-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl ethyl ester;

2,6a, 7-trimethylammonium-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diazacyclo penta [a] anthracene-1-ethyl formate;

7-ethyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;

6a-ethyl-2,7-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;

6a, 7-diethyl-2-methyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;

7-benzyl-2,6a-dimethyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;

2,7-dimethyl-6a-phenyl-7,8,9,10,10a, 11-six hydrogen-3H, 6aH-6-oxa--3,7-diaza-ring penta [a] anthracene-1-ethyl formate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-e] indoles-1-formic acid also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, ethyl ester;

3H, 7H-pyrroles's piperazine be [1 ', 8 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 8,9,11,12,12a, 13-six hydrogen-2-methyl-, ethyl ester;

2-methyl-8,9,10,10a, 11,12,12a, 13-octahydro-3H, 6aH, 7H-6-oxa--3,6b-diaza-benzo [a] ring penta [h] anthracene-1-ethyl formate;

3H-pyrido [1 ", 2 ": 1 ' 2 '] azepines is [3 ' 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, 7,8,9,10,12,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester or

The 7H-azepines is [1 ", 2 ": 1 ' 2 '] pyrido [3 ' 2 ': 5,6] pyrans [3,2-e] indoles-1-acetate also also, and 3,8,9,10,11,13,14,15,15a, 16-decahydro-2-methyl-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-N-(phenyl methyl)-;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-methane amide also, N-ethyl-8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formaldehyde also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-methane amide also, and 8,9,11,12,13,13a, 14,14a-octahydro-N, the 2-dimethyl-;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 8,9,11,12,13,13a, 14,14a-octahydro-2-methyl-, (4-fluorophenyl)-methyl esters;

Indazole is [4 ', 5 ': 5,6] pyrans [3,2-i] quinolizine-1-formic acid also also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,12, the 12-trimethylammonium-, the phenyl methyl esters,

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,10, the 10-trimethylammonium-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;

The 12H-furo [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 5-fluoro-7,8,9,10,13,14,14a, 15-octahydro-2-methyl-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two fluoro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 4,5-two chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-4,5-dimethoxy-2-methyl-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 5-dimethyl-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the 4-dimethyl-, the phenyl methyl esters;

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

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

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

1-third ammonium, N, N, the N-trimethylammonium-, with 1-(3-carboxyl phenyl) ethyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl) methyl esters;

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

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

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,1,13,14,14a, 15-decahydro-2-methyl-, the 2-phenyl chlorocarbonate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl) phenyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2 ,-methyl-, (4-carboxyl phenyl) methyl esters;

1-[3-(4-carboxyl-benzyloxycarbonyl)-5-hydroxy-2-methyl-1H-indoles-4-ylmethyl]-1,2,3,4,6,7,8,9-octahydro-quinolizine; Muriate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl) phenyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-2-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-naphthyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl) phenyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [3-(hydroxymethyl) phenyl]-methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-carboxyl phenyl) methyl esters);

The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (3-carboxyl phenyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1]-chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) methyl] phenyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 3-[(dimethylamino) carbonyl]-phenyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-4-base ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2, the 6-difluorophenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 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] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[3-(trifluoromethyl) phenyl]-ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1-pyrrolidyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(1-naphthyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring butyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-pyrazinyl ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-quinolyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyrimidyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14, and 14a, 15-decahydro-2-methyl-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, 5-chloro-3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl, 1-(4-fluorophenyl) ethyl ester;

Quinolizine, the 1-[[(4-fluorophenyl) methoxyl group] carbonyl]-5-hydroxy-2-methyl-1H-indoles-4-yl] methyl]-1,2,3,4,6,7,8, the 9-octahydro-, muriate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-1, the 2-dimethyl-, (4-fluorophenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl propyl ester;

Quinolizine, 1,2,3,4,6,7,8,9-octahydro-1-[[5-hydroxy-2-methyl-3-[(phenyl methoxyl group) carbonyl]-1H-indoles-4-yl] methyl]-, muriate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-nitrophenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-the 1-phenyl chlorocarbonate;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-phenyl-1-(trifluoromethyl) ethyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, two ring [2.2.1] heptane-2-base ester;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-benzyl ring pentyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenyl cyclohexyl;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxymethyl) phenyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(hydroxy phenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(4-pyridyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-pyridyl methyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (6-carboxyl-2-pyridyl) methyl esters;

The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (6-carboxyl-2-pyridyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-carboxyl-3-pyridyl) methyl esters;

The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (5-carboxyl-3-pyridyl) methyl 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4 '-methyl [1,1 '-xenyl]-3-yl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-3,5-dimethylphenyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-naphthalene ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the phenylbenzene methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2,3-dihydro-1H-indenes-1-base ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-dihydro-1-acenaphthene ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclohexyl (phenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 9H-fluorenes-9-base ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydrochysene-1-naphthalene ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2R, 3R)-3-phenyl epoxy ethyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxo-1,2-phenylbenzene ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 10,11-dihydro-5H-dibenzo [a, d] suberene-5-base ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-aminomethyl phenyl) phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, cyclopropyl (4-fluorophenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3,4-dihydro-2H-1-benzo thiapyran-4-base ester;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2, the 2-trifluoro ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [(2S, 3S)-3-phenyl epoxy ethyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-methyl isophthalic acids-(trifluoromethyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three fluoro-1-(4-fluorophenyl)-1-(trifluoromethyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclopentyl-1-phenyl chlorocarbonate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-[1,1 '-xenyl]-4-base-1-methyl ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl-2-propynyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-phenylbenzene ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid, 2-phenylbenzene ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) cyclohexyl;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2-phenylbenzene ethyl ester;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [1,1 '-xenyl]-4-base methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydrochysene-7,8-dimethoxy-2-methyl-4-isoquinoline 99.9 ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 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] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-pyrazinyl ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-(dipropyl amino)-1,1-dimethyl-2-butyne ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-2,3-dihydro-1H-indenes-1-base ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2S)-2-(dimethylamino)-1-phenyl propyl ester;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (4-chloro-phenyl-) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 2-hydroxy methacrylate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (3-aminomethyl phenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-the 1-phenyl chlorocarbonate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 1-phenyl chlorocarbonate;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(pentafluorophenyl group) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-difluorophenyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-1-(2-furyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)-1-phenyl chlorocarbonate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-1-(2-furyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-methoxyl group-2-oxo-1-phenyl chlorocarbonate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(3-pyridyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (S)-carboxyl (phenyl) methyl esters;

The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (S)-carboxyl (phenyl) methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R)-2-methoxyl group-2-oxo-1-phenyl chlorocarbonate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (R)-carboxyl (phenyl) methyl esters;

The second ammonium, the 2-hydroxy-n, N, the N-trimethylammonium-, with (R) carboxyl (phenyl) methyl, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-carboxylicesters (1: 1) salify also;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 4-pyridyl methyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-pyridyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-pyridyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-thienyl methyl esters;

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

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridyl methyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-oxyethyl group-2-oxo ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-furyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-nitrophenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-furyl methyl esters;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, carboxyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2, the 6-dichlorophenyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(2-p-methoxy-phenyl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(5-carboxyl-3-pyridyl) ethyl ester;

1, the 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-, diethyl ester;

1, the 3-phthalic acid, 5-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (5-amino-2-chloro-phenyl-) methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-acetate also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-. alpha-oxo--, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,4, the 5-trimethylammonium-, the phenyl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1-dimethyl-2-propynyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2,2,2-three chloro-1,1-dimethyl ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, three rings [3.3.1.13,7] last of the ten Heavenly stems-1-ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl isophthalic acid-phenyl chlorocarbonate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl cyclohexane ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,1,2-trimethylammonium propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1) chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-methyl ring pentyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-cyclohexyl-1-methyl ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1,4-dimethyl-4-piperidine ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-fluorobenzene ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-methyl phenyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, phenyl ester;

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

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, the 3-pyridine ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [the 5-[(dimethylamino) methyl]-the 2-furyl] methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-carboxyl-2-methyl propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 3-(dimethylamino)-2,2-dimethyl propyl ester;

With 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1]-chromene propanedioic acid of [3,2-i] quinolizine-1-formic acid also, an acid anhydrides, 1,1-dimethyl ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)-2-methyl propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(1H-imidazoles-1-yl) ethyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-benzofuryl methyl esters;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1R, 2S)-2-(dimethylamino)-1-phenyl propyl ester;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S, 2R)-2-(dimethylamino)-1-phenyl propyl ester; With

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene is [3,2-i] quinolizine-1-formic acid also, and 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-(4-fluorophenyl) encircles propyl ester.

9. compound, its name be called pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine also, 3,7,8,9,10,12,13,14,14a, the 15-decahydro-, or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-compound.

10. pharmaceutical composition, wherein contain with pharmaceutical excipient, the described compound of diluent or carrier blended claim 1 or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester.

11. regulate the method for mammalian chemokines receptor active, comprising the described compound of the claim 1 of using significant quantity or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or its pharmaceutical salts.

12. regulate the method for Mammals CCR-5 chemokine receptor activity, comprising the described compound of the claim 1 of using significant quantity or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or its pharmaceutical salts.

13. prevention HIV infects, treatment HIV infects, postpones the method for AIDS outbreak or treatment AIDS, comprising the described compound of claim 1 of giving the administration treatment significant quantity that needs described treatment or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or its pharmaceutical salts.

14. the method for treatment inflammatory diseases, comprise to the described compound of claim 1 of the administration of the described treatment of needs treatment significant quantity or pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, ethyl ester or its pharmaceutical salts.

15. formula I compound and one or more are used to prevent and/or treat the cooperative programs of AIDS preparation.

16. compound, it is selected from as follows:

Pyridine, 3-[[[(3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methylpyrrole also [3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-yl also) carbonyl] the oxygen base] methyl]-the 1-methyl-, mesylate;

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2, the carbonyl of 11-dimethyl-1-[(S)-(1-phenyl ethoxy)]-, mesylate; And

Pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (1S)-and the 1-phenyl chlorocarbonate, the 11-oxide compound.

17. compound, its name be called with benzoic pyrrolo-[3 ', 2 ': 5,6] [1] chromene [3,2-i] quinolizine-1-formic acid also, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, acid anhydrides.