50C-REDUCTASE INHIBITORS

The present invention belongs to the fields of pharmaceutical chemistry and pharmacology, and provides benzo [f] qumolinones which are pharmaceuticals for the inhibition of 5α-reductase.

It is now widely known that a number of undesirable physiological conditions are androgen-mediated and are dependent on 5α-dihydrotestosterone (DHT) . Such conditions include benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostate cancer. It has been demonstrated that inhibitors of 5α-reductase (5AR) bloc the formation of DHT, because 5AR mediates the conversion of testosterone to the more potent androgen DHT in various target organs. Fmasteride, a 5AR inhibitor, is now in the pharmaceutical marketplace and is approved for the treatment of benign prostatic hyperplasia. Mocellim e_£. al. , The Prostate. 22. 291-99 (1993) .

Recently it has been found that there are at least two 5AP isozymes in the human, Andersson ≤£. &1 . , Proc. Natl. Acad. sci. USA. £7, 3640-44 (1990); Andersson ≤^ ≤J. , Nature. 354 , 159-61 (1991) . The two isozymes, usually called Type I and Type II, exhibit differences in their biochemical properties, genetics and pharmacology. Both isozymes are now the subject of considerable research and it has been found that Type I is more prevalent in the scalp and is more involved in conditions such as androgenic alopecia, and that Type II is more prevalent in the prostate. In prostate, Type I is exclusive to the epithelial compartment in normal, benign hyperplastic and cancerous cells, and the Type II isoform predominates in the fibromuscular stroma.

The present invention provides a series of new compounds which are effective inhibitors of 5AR; many of the compounds are effective inhibitors of both of the 5AR isozymes.

- ") -

The present invention provides benzo [f] quinolmones of the formula

wherein

R and pi both represent hydrogen or combine to form a bond;

R ² represents hydrogen or C1-C3 alkyl; R3 represents methyl or ethyl;

R^ and -X-R ⁵ each occupies one of the 7-, 8- and 9- positions;

FA represents hydrogen, halo, methyl or ethyl;

X represents C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, a bond, -SO-, -SO2-, -CO-Y- (CH2)n~ • -Y-CO- (CH ₂ ) _n . -CC- , -Z-(CH2)n ^_ - or -SO3-; wherein X groups which are not symmetrical may be in either orientation;

Y represents -S-, -0- , or -NH-;

Z represents -O- or -S-; n represents 0-3;

R^ represents phenyl, naphthalenyl, pyridmyl, pyrazinyl, pyridazinyl, pyrimidmyl, anthracenyl, acenaphthalenyl, thiazolyl, benzimidazolyl, mdazolyl, thiophenyl, phenanthrenyl, qumolmyl, fluorenyl, isoquinolinyl, indanyl, benzopyranyl, indolyl, benzisoqumolinyl, benzmdolyl, benzothiazolyl, benzothiophenyl, quinoxalmyl, benzoxazolyl, tetrazolyl, naphthothiazolyl , qumazolmyl, thiazolopyπdinyl,

pyridazmoquinazol yl, benzisothiazolyl, benzodioxolyl, benzodiox yl, diphenylmethyl or tπphenylmethyl; the above F^ groups are unsubstituted or substituted with 1-3 groups chosen from the group consisting of halo, trifluoromethyl, trifluoroethoxy, C1-C alkyl, trifluoromethoxy, hydroxy, C1-C3 alkoxy, nitro, C1-C3 alkylthio, C -C6 alkanoyl, phenyl, oxo, phenoxy, phenylthio, C1-C3 alkylsulfmyl, C1-C3 alkylsulfonyl, cyano, ammo, C1 _. -C3 alkylam o, diphenylmethylammo, triphenylmethylammo, benzyloxy, benzylthio, (mono-halo, nitro or CF3 )benzyl (oxy or thio) , dι(Cχ-C3 alkyl, C3-C6 cycloalkyl, or C4-C8 cycloalkylalkyl )ammo, (mono-Cι-C3 alkyl, C1-C3 alkoxy or haio -(phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl ) , C2-Cβ alkanoylam o, benzoylam o, diphenylmethylammo (C1-C3 alkyl) , ammocarbonyl, C1-C3 alkylam ocarbonyl, dι(Cι~C3 alkyl) ammocarbonyl, halo-Ci-Cg alkanoyl, ammosulfonyl, C1-C3 alkylaminosulfonyl, dι(Cχ-C3 alkyl)ammosulfonyl, phenyl (oxy or thιo) (Cι~C3 alkyl), (halo, C1-C3 alkyl or C1-C3 alkoxy)phenyl (oxy or thιo) (Cι-C3 alkyl; , benzoyl, or (amino, C1 _. -C3 alkylammo or di (C1-C3 alkyl) ammo) (C1-C3 alkyl); or an above R^ group is substituted with a morphol o(C1-C3 alkyl) group, a phenyl (C1-C3 alkyl)pιperιdιnyl group, a phenyl (C1-C3 alkyl )- pipeπdinylaminocarbonyl group, a C2-C6 alkanoyl- ammothiophenyl group, or a (ammo, C1-C3 alkylammo or di (C1-C3 alkyl) ammo)naphthalenylsulfonylammo group; or R^ IS a perhalophenyl group; or a pharmaceutically acceptable salt thereof. The invention also provides pharmaceutical compositions comprising a compound of the above formula m combination with a pharmaceutically acceptable carrier, diluent or excipient.

Further, the invention provides a method for inhibiting 5α-reductase, more preferably, a method for inhibiting both Type I and Type II 5α-reductase. Further,

methods are provided for the treatment of benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostate cancer, which methods comprise administering an effective amount of a compound of formula I to a patient m need of such treatment. Still further, the invention provides a method for the treatment or prevention of such conditions comprising administering to a patient exhibiting excessive 5AR levels or excessive 5AR activity an effective 5AR-mhιbιtmg amount of a compound of formula I.

Still further, the invention provides the use of the compounds of Formula I for inhibiting 5α-reductase, particularly for inhibiting both Type I and Type II 5AP . The use of the compounds for treating benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostate cancer is also provided, as is the use of the compounds for the treatment or prevention of such conditions in a patient exhibiting excessive 5AR levels or excessive 5AP activity. The invention further provides a process for preparing a compound of Formula I

(aj wherein an intermediate of the formula

is reacted with a compound of the formula

X-R ⁵ in activated form; or

a compound of Formula II in activated form is reacted with a compound of the formula

L-X-R ⁵ ;

(b) wherein a compound of Formula I wherein X is -Z-(CH2)n ^_ is prepared by reacting a compound of Formula II with a compound of the formula

-X-R ⁵ ; or a compound of Formula II wherein - has been replaced by -Z is reacted with a compound of the formula L-X-R ⁵ ;

(c) wherein a compound of Formula I wherein X is -CO-Y- (CH2)n ^_ or -Y-CO- (CH2)n- is prepared by reacting a compound of Formula II wherein -L has been replaced with one of -YH, -CO-L, -(CH2) _n ^-YH ' ^or - (CH2)n-CO-L, with a compound of one of the formula

HY-R ⁵

L-CO-R ⁵

HY- (CH2)n-R ⁵ or

L-CO- ⁽ CH2 ⁾ n-R ⁵ - provided that one reactant has a -YH group and the other an L group, and no more than one reactant has a -(CH2)n~ group;

(d) wherein a compound of Formula I wherein X is alkyl is prepared by reacting a compound of Formula II in activated form with an aldehyde or ketone which provides the residue of -X-R ⁵ ;

(e) wherein a compound of Formula I wherein R ² is C1-C3 alkyl is prepared by reacting a compound of Formula I wherein R- is hydrogen with an alkyl iodide of the formula

R ² -I; (f) or oxidizing the product to prepare a compound of Formula I wherein R and R-*- combine to form a bond; (g) or oxidizing or reducing an X group; (h) or removing protecting groups; (i) or preparing a salt; (j) or isolating an optical isomer.

Throughout the present document, all temperatures will be described degrees Celsius and all expressions of concentration, percentage and proportion will be expressed weight units, except for mixtures of solvents, which will be described m volume units, unless otherwise stated.

Peferences to compounds of formula I in this document include the pharmaceutically acceptable salts of such compounds, unless otherwise stated.

The various positions on the benzo [ f] qumolme ring are indicated below.

The spatial configuration of the group R ³ at 10b and the hydrogen atom at 4a are required, and the synthetic methods for obtaining that configuration will be shown. The reader will understand that most of the compounds can exist in two stereochemical forms, or even more depending on the nature of the R ⁵ group, and that all stereochemical forms are included m the present invention. In some of the compounds prepared or described below, single enantiomers are prepared in pure form and are identified by (+) or (-) nomenclature. In other cases, the mixture of diastereomers is prepared. The groups R ⁴ and X-P ⁵ may occupy either the 7, 8, or 9-posιtιon.

The term "halo" includes chloro, bromo and fluoro. The various alkyl groups, such as Cι~C ₃ alkyl, C ₁ -C ₄ alkyl and the like include groups such as methyl, ethyl, propyl, isopropyl, t-butyl, butyl and isobutyl. When such

groups link other portions of a molecule, they are bivalent and the location of the linkages will be indicated in the chemical name.

Alkenyl and alkynyl groups constitute linking groups which are bivalent and are bonded to two other groups. For example, C ₂ -C ₄ alkenyl includes 2-propenyl, 3-butenyl and 2-butenyl; and C ₂ -C ₄ alkynyl includes, for example, ethynyl , 2-propynyl, 2-butynyl and ιso-2-butynyl .

The groups Cχ-C ₆ alkanoyl and C ₂ -C ₆ alkanoyl include such groups as formyl, acetyl, propionyl, isobutyryl, 2- ethylpropionyl and hexanoyl . The group C ₃ -Cg cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyi, and the group C ₄ -C ₈ cycloalkylalkyl includes, for example, cyclopropylmethyl, cyclohexylethyl, cyclobutylbutyl and cyclohexylmethyl.

Terms such as C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylsulfonyl, benzylthio, phenoxy, and C ₁ -C ₃ alkylammo refer to the indicated alkyl, benzyl or the like group linked to an oxygen atom, sulfur atom, sulfonyl group or ammo group as indicated.

Terms such as halo-C -ds alkanoyl, halophenyl or C ₁ -C ₃ alkylphenyl refer to the indicated basic group having substituted on it 1, 2, or 3 halo or C ₁ -C ₃ alkyl groups as ma be described in the individual case. The term perhalophenyl refers to a phenyl group which is fully substituted at all available positions with halogen atoms.

The compounds of formula I all have the benzo[f]- qumolme nucleus, on the phenyl ring of which is substituted a cyclic group, frequently an arylcyclic group, which is linked to the benzoqu olme through the X linker, which m many cases is simply a bond. The R ⁵ groups may be substituted with additional organic groups, and may bear as many as three of the indicated substituent groups. Multiple substituents may all be the same, as, for example, 2,3,5- trifluorophenyl, or may be different, such as, for example, 3 , 5-bιs (t-butyl) -4-hydroxyphenyl The specifically named

compounds which appear below m this document will further illustrate the contemplated X, R ⁵ and substituent groups.

The X groups which are not symmetrical may be either orientation on the molecule; for example, the atom Z of the group -Z-(CH ₂ ) _n ^~ ™ay be adjacent either to R ⁵ or to the phenyl ring of the nucleus of formula I.

The cyclic R ⁵ groups may take any permissible orientation. For example, the following specific R ⁵ groups are contemplated. phenyl

2-qumolmyl

4-qumolmyl

--quinolinyl

1-ιsoqumolιnyl 3-ιsoqumolmyl

8-ιsoqumol yl

2-qumoxalmyl

5-qumoxalιnyl

7-quιnoxalmyl 2-benzothιazolyl

4-benzothιazolyl

6-benzothιazolyl

7 -IH- mdazolyl

3-lH-mdazolyl 5-2H-ιndazolyl

2-2H-mdazolyl

7 -2H- mdazolyl

4-3H-ιndazolyl

3 - 3 H- mdazolyl 1- indolyl

3-mdolyl

3-2H-mdolyl

2 -3H- indolyl

6-2H-mdolyl 4-3H-mdolyl

2-benzoxazolyl

5-benzoxazolyl

3-1,2-benzisothiazolyl 5-1, 2-benzisothiazolyl 7-2, 1-benzisothiazolyl 4-2, 1-benzιsothιazolyl 2-pyridinyl

4-pyridinyl 3-pyridazinyl 5-pyridazinyl 2-pyrazinyl 5-pyrazinyl

2-naphtho [2,3-d] thiazolyl 8-naphtho [2, 3-d] thiazolyl 6-naphtho [2, 3-d]thiazolyl 1-naphtho [2, 1-d] thiazolyl 5-naphtho[2 , 1-d] thiazolyl

2-naphtho [1,2-d]thiazolyl 6-naphtho [1, 2-d] thiazolyl 1-naphthalenyl 2-naphthalenyl 2-thienyl

3-thienyl 1-anthracenyl 10-anthracenyl 6-anthracenyl 1-phenanthrenyl

4-phenanthreny1 9-phenanthreny1 1-3H-fluorenyl 3-3H-fluorenyl 9-3H-fluorenyl

1-fluorenyl 5-fluorenyl 1-acenaphthalenyl 5-acenaphthalenyl diphenylmethyl triphenylmethyl 2-thiazolyl

4-thιazolyl 2 -benz imidazolyl 6 -benz imidazolyl 1-mdanyl 4-mdanyl

3-2H-l-benzopyranyl 7-2H-l-benzopyranyl 2-chromanyl 5-chromanyl 4-4H-l-benzopyranyl

8-4H-l-benzopyranyl 3 -5H-l-benzopyranyl 5-5H-l-benzopyranyl 1-benz [g] lsoqu olmyl 5-benz [g] lsoqumolmyl

8-benz [g] lsoqumolmyl 4-benz [h] lsoqumolmyl 10-benz [h] lsoqumolmyl 2-benz [ f ] isoquinolinyl 6-benz [ f] isoquinolinyl

3-lH-benz [de] isoquinolinyl 9-lH-benz [de] isoquinolinyl 4-4H-benz [de] isoquinolinyl 6-4H-benz [de] lsoqumolmyl l-lH-benz[f] indolyl

4-lH-benz [f ] indolyl 2-3H-benz [f ] indolyl 7-3H-benz [f ] indolyl 2 -py lmidiny 1 5-pyrιmιdιnyl l-3H-carbazolyl 5-3H-carbazolyl 3-4aH-carbazolyl 4a-4aH-carbazolyl 2-8aH-carbazolyl

7-8aH-carbazolyl 8-carbazolyl

4-carbazolyl

2-lH-benz [g]indolyl

6-lH-benz [g] indolyl

3-3H-benz [g] indolyl 9-3H-benz [g] indolyl

1-lH-benz [e] indolyl

5-lH-benz [e] indolyl

3-3H-benz [e] indolyl

7-3H-benz [e]indolyl 2-benz [cd] indolyl

5-benz [cd] indolyl

2-1-benzothiophenyl

5-1-benzothiophenyl

1-2-benzothiophenyl 7-2-benzothiophenyl

5-IH- etrazolyl

1-1H- etrazolyl

5-2H-tetrazolyl

2-quinazolinyl 6-quinazolinyl

2-thiazolo[4, 5-b]pyridinyl

6-thiazolo[4, 5-b]pyridinyl

7-thiazolo[5, 4-b]pyridinyl

4-thiazolo[4, 5-c]pyridinyl 6-thiazolo[4, 5-c]pyridinyl

3-5H-thiazolo[3 ,2-a]pyridinyl

8-5H-thiazolo[3 , 2-a] yridinyl

2-7H-thiazolo[3 ,2-a]pyridinyl

7-7H-thiazolo[3 ,2-a]pyridinyl 3-3H-thiazolo[3 , 4-a]pyridinyl

5-3H-thiazolo[3 , -a]pyridinyl

10-lOH-pyridazino[3,2-b] uinazolinyl

4-10H-pyridazino [3 , 2-b]quinazolinyl

8-10H-pyridazino[3 ,2-b]quinazolinyl 3-3H-1, 2-benzodioxolyl

5-3H-1, 2-benzodioxolyl

2-1,3-benzodioxolyl

7-1 , 2-benzodιoxolyl 2-1, 4-benzodιoxιnyl 6-1, 4-benzodιoxmyl

Linking X groups, besides the alkyl, alkenyl and alkynyl groups, include the following, for example. The groups are named as they appear the generic formula, but it will be understood that the groups may, m fact, be oriented either direction. acetylthio sulfmyl sulfonyl oxycarbonyl propoxycarbonyl methylthiocarbonyl butyrylammo propionyloxy ethylammocarbonyl carbonyl oxy methoxy propylthio a bond oxysulfonyl

The cyclic R ⁵ groups may be substituted with a variety of substituent groups, as set out in general formula I. To assure that the reader fully understands the nature of those substituent groups, a representative group of them will be named as follows: chloro bromo fluoro trifluoromethyl methyl isopropyl

s -butyl trifluoromethoxy hydroxy methoxy isopropoxy nitro methylthio ethylthio formyl acetyl propionyl pentanoyl

2 , 2-dimethylbutyryl phenyl oxo phenoxy phenylthio methylsulfinyl propylsulfinyl ethylsulfonyl isopropylsulfonyl cyano amino me hylamino propylamino diphenylmethylammo triphenylmethylamino benzyloxy benzylthio 3-chlorobenzyloxy

4-fluorobenzylthio

2-nitrobenzyloxy

3-trifluoromethylbenzylthio dimethylamino diethylamino di (isopropyl) amino bis (cyclopropyl)amino

bis (cyclohexy1) ammo methyl (cyclohexy1) ammo bis (cyclohexyImethyl) ammo propyl (cyclopentylethyl) am o cyclopentyl (cyclopropylpropyl) ammo

3-methylpheny1

2-propylphenoxy

4-ethylphenylthιo

3-isopropylphenylsulfonyl 4-methoxyphenyl

2-ethoxyphenoxysulfonyl

3-ethoxyphenylthio

4-chlorophenyl

4-bromophenylthio 3-fluorophenoxysulfonyl acetylammo propionylammo pentanoylamino

2-ethylpropιonylammo benzoylamino diphenylmethylaminomethyl

3 - (diphenylmethylammo)propyl ammocarbonyl methylaminocarbonyl isopropylaminocarbonyl dime thy lammocarbonyl ethyl ( isopropyl ) ammocarbonyl chloroacetyl 3 -bromopropionyl 4 , 4 , 4 -trι f luorobutyryl

3 -chloro- 2 -methylbutyryl 3 , 4 -dιchlorohexanoyl ammosulf onyl me hylaminosul f onyl lsopropylammosul f onyl diethylaminosulfonyl methyl (propyl) ammosulfonyl

phenoxyme hyl

2-phenylthioethyl

2-phenoxypropy1

3-chlorophenylthiomethyl 2- (3 , 4-difluorophenoxy) ethyl

2- (2-methoxy-4-propylphenoxy) ethyl

3- (3, 5-diethoxyphenoxy)propyl

3- (4-chloro-3-ethoxyphenylthio)propyl

2 , 6-dichloro-4-propylphenylthiomethyl benzoyl aminomethyl

2-aminoisopropyl methylaminomethyl

2-ethylaminoethyl 3- (ethylamino)propyl dimethylaminomethy1 ethyl (isopropyl) aminomethyl

3- (ethyl (propyl) amino)propyl morpholinylmethyl 2-morpholinylpropyl

3-phenylmethyl-l-piperidinyl 4- (2-phenylpropyl) -1-piperidinyl 2-phenylmethyl-l-piperidinylaminocarbonyl 4- (3-phenylpropyl) -1-piperidinylaminocarbonyl 3-acetylamino-5-thiophenyl

2-hexanoylamino-4-thiophenyl

3-butyrylamino-4-thiophenyl

8-amino-2-naphthalenylsulfonylamino

2-methylamino-1-napththalenylsulfonylamino 5-isopropylamino-2-naphthalenylsulfonylamino

4-dimethylamino-2-naphthalenylsulfonylamino

3-methyl (propyl) amino-1-naphthalenylsulfonylamino perfluorophenyl perbromophenyl

While all of the compounds described by formula I are important in the concept of the present invention,

certain groups of those compounds constitute preferred aspects of the invention. The following table sets out a number of such preferred groups, each of which constitutes a preferred aspect of the invention, and the formulations, methods of use and the like associated with each such group are also preferred aspects. It will be understood that the reader can combine groups of preferred aspects listed the following table to produce additional more limited or more comprehensive preferred aspects.

a R and P ¹ both represent hydrogen; b P ³ represents methyl; c P ² represents C1-C ₃ alkyl; d P ² represents C1-C2 alkyl; e R ² represents methyl; f P ² represents methyl or hydrogen; g P ⁴ represents hydrogen; h P ⁴ represents hydrogen, halo or methyl; ι X represents alkyl, alkenyl or alkynyl;

D X represents a bond; k X represents a bond or a sulfur atom; 1 X represents -SO-, -SO2-, or -SO ₃ -; m X represents -CO- or -CO-Y- (CH2) _n ^_ n X represents -Z-(CH2>n-, alkyl or -CO-; o X represents a bond, -Z-(CH2) _n -, alkyl or -CO-;

P X represents a sulfur atom; q Y represents -0- or -S-; r Y represents -NH-; s n represents 0 or 1; t n represents 2 or 3; u n represents 0;

V Z represents -S-; w R ⁵ represents phenyl or naphthalenyl;

X R ⁵ represents pyridinyl, pyrazinyl, pyπdazmyl or pyrimidmyl; y ⁾ R ⁵ represents anthracenyl, phenanthrenyl, fluorenyl or acenaphthalenyl;

z) R ⁵ represents thiazolyl, thiophenyl or tetrazolyl; aa) R ⁵ represents benzimidazolyl, indanyl, indolyl or indazolyl; ab) R ⁵ represents quinolinyl, isoquinolinyl, quinoxalinyl or quinazolinyl; ac) R ⁵ represents benzopyranyl, benzothiazolyl, benzothiophenyl or benzisothiazolyl; ad) R ⁵ represents benzothiazolyl; ae) R ⁵ represents benzoxazolyl, benzodioxolyl, or benzodioxinyl; af) R ⁵ represents benzisoquinolyl, benzindolyl, naphthothiazolyl, thiazolopyridinyl or pyridazinoquinazolinyl; ag) R ⁵ represents diphenylmethyl or triphenylmethyl.

Further preferred classes of compounds are also important in the practice of the present invention. A particularly preferred class of compounds includes those wherein R ² represents methyl or hydrogen, particularly methyl; X represents a bond, a sulfur atom or an ethenyl group, particularly a bond or a sulfur atom; R ⁵ represents phenyl, naphthalenyl, isoquinolinyl, indolyl, benzothiazolyl, pyridinyl, indazolyl, thiazolonaphthalenyl, quinolinyl or diphenylmethyl; and the R ⁵ group is unsubstituted or substituted with 1-3, particularly 1, groups chosen from the group consisting of halo, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, C ₁ -C ₃ alkyl, methoxy, nitro, phenyl, toluenesulfonyl, and pivaloylamino.

A further preferred class of compounds of the present invention includes those described in the paragraph immediately above, and, in addition, those wherein X represents propyl, aminocarbonylmethyl, methoxycarbonyl and oxycarbonyl; R ⁵ represents thiophenyl, fluorenyl, indanyl, quinoxalinyl, pyridazinyl, thiazolopyridinyl, and benzisoquinolinyl; and the R ⁵ group is unsubstituted or substituted with 1-3, particularly 1, groups chosen from the

group consisting of hydroxy, C ₁ -C ₄ alkyl, oxo, benzyloxy, phenoxymethyl and benzylpiperid yl.

As described m formula I, the invention includes pharmaceutically acceptable salts of the compounds defined by the above formula. Although generally neutral, a particular compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of nontoxic inorganic bases, and nontoxic inorganic and organic acids, to form a pharmaceutically acceptable salt. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as β-toluenesulfon c, methanesulfonic acid, oxalic acid, p_-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, bucyne-1, 4-dιoate, hexyne-1, 6-dιoate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xyleneεulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid. Base addition salts include those derived from nontoxic inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates,

and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate. The potassium and sodium salt forms are particularly preferred. Thus, the groups R ⁴ and X-R ⁵ include a number of substitutions each of which may be placed at the 7, 8 or 9- position of the nucleus of formula I. All such substituents are easily understandable by the chemist, but a number of the contemplated substituent arrangements will be mentioned for the convenience of the reader.

8- ( 6-phenoxysulfonyl-4-qumolmyloxy) ⁷ -chloro-8- (3-chloromethyl-7-qumolmylthio 7- [2- (3-phenoxy-6-ιsoqumolmylamιnocarbonyl) ethyl]

9-fluoro-7- (l-methoxycarbonyl-4-ιsoqumo- lmylmethyl)

8- [3- (5-bromo-t-butyl-3-quinoxalinyl)propyl]

8-fluoro-7- [3- (8-butylthιo-2-quinoxalinyl) -3- propynyl] 7- (3-phenyl-1, 2-benzisothiazol-5-yloxycarbonyl)

8-bromo-9- (5-hexyloxysulfonylbenzoxazol-2-ylthιo>

9-methyl-7- (6-trifluoromethy1-2, l-benzιsothιazol-3- yi ⁾

7- (3 -ιsopropoxycarbonylammopyrιdmyl-2-ylmethyl ) 9-chloro-8- (7-hydroxy-4-benzothιazolylthιo)

7- (4-ιsopentoxycarbonyl-lH-mdazol-4-yloxy )

7-ethyl-9- [3- (6- [2-ethyl-5-methylphenoxysulfonyl] - lH-mdazol-3-yl ) -2-propynyl ] 9- [2- (6-ethoxycarbonyl-2H-ιndazol-2-yloxy ) ethyl]

8- [2- (3-f luoro-2H-ιndazol-6-yl) ethoxy]

9-chloro-7- (3-trifluoromethoxy-3H-mdazol-4-yl- thiocarbonylmethyl)

7- [2- (5-propoxy-4- [4-fluorophenoxy] -3H-mdazol-7- ylthio) ethyl]

8-ethyl-7- [4- (4- [3-chlorophenoxysulfonyl] -2- mdolyl)butyl]

8- [3- (7-methoxy-4- [2, 3-dichloropropoxycarbonyl- am o] 2-mdolyloxy]propyl

"- [ 2 - (5- [4-fluoro-3-methylphenoxysulfonyl] -2H- mdol-4-yl) ethylcarbonylthio]

8-methyl-7- [3- (6-chloro-2- [3-chloro-5- ethylphenoxyethyl] -2H-mdol-3-yl) -2-butynyl]

Synthesis of the compounds of formula I may proceed m various ways, depending m large part on the identity of the group -X-R ⁵ . It is very often advantageous to form the benzo[f] qumolme nucleus without the -X-R ⁵ group, and to add that group m a separate step, thus providing a convergent synthesis. In such a case, the -X-R ⁵ group of the compound of formula I is replaced by a leaving group, preferably a chlorine or bromine atom, when the benzo [ f] qumolme nucleus is prepared. Since the R ⁴ group of the nucleus is small, it may be m place throughout the synthesis. Thus, an important intermediate is the following compound of formula II.

wherein L represents a leaving group, preferably chloro or bromo.

A series of synthetic methods for the preparation of intermediates of formula II was taught by Audia ≤ ϋ-1. in U.S. Patent 5,239,075, issued August 24, 1993. That patent is incorporated by reference herein, and the reader readily will understand the synthetic methods taught by it.

A preferred method for preparing the intermediates of formula II is the heteroannulation carried out by reacting an enamine of the formula

with an acryloyl halide, particularly acryloyl chloride, acrylic anhydride, or acryloyl toluenesulfonate or methanesulfonate. The group R ⁶ in the above intermediate is a chiral directing group, in order to obtain the correct enantiomer of the intermediate of formula II. The most

preferred R ⁶ group is (R) - (+) -1-phenylethyl. This process is taught in general by EPO Publication 0564193.

The product of the heteroannulation ust described is of the formula

and the double bond at the 4a, 5- position must be reduced in a second step. The reduction is readily carried out under mild conditions with chemical reducing agents such as borohydrides. Cyanoborohydride is preferred; the reduction may be carried out, for example, in formic acid under ambient conditions. More conveniently, the reduction step may be combined with the removal of the R ⁶ group, by reaction with trifluoroacetic acid a reaction medium containing or consisting of triethylsilane at reduced temperature the range of from about -40° to 0°.

The above heteroannulation is carried out under mild process conditions. In most instances it will be found that excellent yields are obtained m short periods of time at temperatures in the range of ambient. For example, temperatures from about 0° to about 150° are used, and reaction times the range from a few minutes to a few hours are sufficient. Preferable reaction temperatures are m the range from about -20° to about ambient temperature, and most preferably the reactants are combined at very low temperatures m the range of -20° to -80°, and the reaction mixture is allowed to warm slowly to ambient temperature while the reaction occurs. The reaction mixture may be a biphasic mixture of a convenient organic solvent and an

aqueous solution of a mild base. For example, solvents may include haloalkanes, ethers, including tetrahydrofuran, and nitriles including acetonitrile. Preferred mild bases are alkali metal carbonates and bicarbonates; more highly basic reagents, such as alkali and alkaline earth metal hydroxides and the like may be used, but the bicarbonates are usually preferred.

A particularly preferred method of synthesis of a key intermediate of formula II proceeds according to the following scheme.

An intermediate of the formula

wherein L is chloro or bromo, and is located at the 7-, 8- or 9-position is prepared by reacting a compound of the formula

with methyl iodide in an ether solvent to prepare a compound of the formula

combining acrylic anhydride or acryloyl chloride with the reaction mixture comprising the compound of formula VII to prepare a compound of the formula

quenching the reaction with sodium bicarbonate, evaporating the organic solution comprising the compound of formula VIII; and combining the residue comprising the compound of formula VIII with a trialkylsilane and trifluoroacetic acid in the absence of a solvent to prepare the compound of formula V. The starting material of formula VI is prepared most conveniently by a modification of a process shown in European Patent Publication 0564193. A substituted 2- tetralone, having the desired L substituent on the unsaturated ring, is reacted with (R) -(+) -phenethylamine to prepare the intermediate of the formula

The reaction is conveniently carried out at elevated temperature, particularly the reflux temperature, in toluene the presence of a strong acid such as β-toluenesulfonic acid. Water must be removed as it is formed in this reaction, and the absence of water being formed is an indication of completion of the reaction. A slight excess of phenethylamine, such as about 1.05-1.10 equivalents, should be used. Alternatively, tetrahydrofuran (THF) may be used as the solvent, and it is particularly convenient in that case to use molecular sieves to dehydrate the reaction mixture, using at least twice the weight of molecular sieves compared to the amount of water which will be released by the process.

Tne above phenethylamino compound is lithiated to prepare the starting material of formula VI. The reaction may be carried out with, for example, n-butyllithium or with lithium dusopropylamide (LDA) . When the reaction is carried out, as is preferred, with LDA, the best results are obtained if the LDA is freshly generated from dnsopropylamme and n- butyllithium immediately before use in the process. A substantial excess, about 15-25%, of LDA should be used for best results.

The LDA reaction is best carried out in THF at a low temperature in the range of about -100° to about 0°, preferably about -78° to about -10°. The phene hylamino compound need not be purified or isolated, but the first reaction mixture should be evaporated under vacuum and the residue taken up in THF. It is preferred to add the phenethylammo material, in solution, to a solution of LDA in cold tetrahydrofuran; the opposite manner of addition is operable but provides lower yields. The reaction may be carried out in quite short periods of time, less than one hour in general.

The lithio compound of formula VI is difficult to isolate and purify, and so it should be introduced into the process as a solution in the lithiation reaction mixture.

In the first step of the present process, the lithio compound of formula VI is reacted with methyl iodide

to provide the compound of formula VII. It is advisable to use about 15-25% of excess methyl iodide, and to carry out the process in an ether solvent, such as diethyl ether, methyl butyl ether or, preferably, THF. The reaction is very rapid at low temperatures the range of about -100° to about -50°, most preferably, about -80° to about -60°. Reaction times in the range of from about a few minutes to about one hour are adequate, and a 20-mmute reaction time is often preferred. If the compound of formula VI is in the form of the reaction mixture from lithiation with LDA, and the reaction mixture therefore contains the residual diisopropylamme, that amme must be neutralized before further reaction of the compound of formula VII. Most conveniently, the methyl iodide mixture is allowed to warm to a temperature close to 0°, and a sufficient amount of methanesulfonic acid is added to neutralize the diisopropylamme. Other strong acids may be used, but methanesulfonic acid is particularly convenient because the resulting methanesulfonate salt of dusopropyl- amme is only slightly soluble and therefore may be easily removed by simple filtration or centrifugation.

The reaction mixture comprising the compound of formula VII is combined with acrylic anhydride or acryloyl chloride to initiate the aza-annulation reaction which forms the compound of formula VIII. It is best to generate the acrylic anhydride, the preferred reagent, immediately before use by the reaction of acryloyl chloride and acrylic acid, using triethylamine and a stabilizer, such as hydroqumone and butylated hydroxytoluene, m THF. The aza-annulation is best carried out by adding the acrylic anhydride or acryloyl chloride at a very low temperature, such as from about -100° to about -70°, and allowing the mixture to warm very slowly with stirring to a temperature in the range of about -20° to about 0°, or even up to about 10°-20°. A period of 12-15 hours is not too much for that period of time. When the reaction has gone as far toward completion as is desired, the reaction is quenched by

addition of sodium bicarbonate. It is preferred to use from about 1.5 to about 4 equivalents of base, most preferably about 2 equivalents. The base may be added as a solution, for example, in water or in an aqueous solvent such as water/dimethylammopyridme, but it is preferred to add the base in solid form. The reaction mixture is stirred with the quenching base for a brief period, and then the mixture is filtered, the volatiles are removed, and the solvent may be replaced with an ether solvent, preferably diethyl ether, and the organic solution may then be worked up by washing with aqueous base and aqueous acid, and perhaps with additional purification steps such as a wash with a saturated salt solution If such work up steps are used, the solution is then dehydrated and evaporated under vacuum to obtain the non-volatile portions of the reaction mixture, containing the final intermediate of formula VIII. On the other hand, the residue from the quenched reaction mixture may be carried on without work up if desired.

The residue from the aza-annulation step is cooled, and a chilled mixture of a trialkylsilane and trifluoroacetic acid is added. The addition should take place at a low temperature m the range of from about -40° to about 0°, and no other solvent is used. A large quantity of trifluoroacetic acid, in the range of about 10-50 equivalents, most preferably about 20-30 equivalents is used The preferred trialkylsilane is triethylsilane, although trimethylsilane, tπpropylsilane and the like may also be used. A substantial excess of trialkylsilane, in the range of about 5-20 equivalents, most preferably about 7-15 equivalents is used. The mixture is stirred for about 10-20 hours while it is allowed to warm slowly to about 30°, and then the mixture is slowly heated to an elevated temperature, preferably the reflux temperature, and is stirred at that temperature for a few hours, such as about 2-6 hours to complete the formation of the compound of formula V.

The residue containing the intermediate of formula V is dissolved, preferably in a haloalkane such as

dichloromethane, washed with base, such as aqueous sodium bicarbonate, and concentrated under vacuum. The residue is thoroughly washed with, for example, an ether solvent which may often preferably be diethyl ether to obtain the purified desired compound of formula V.

Further details of the process will be shown below as Preparations .

It will be understood that the principles of the above process may be applied to compounds of the present invention other than the specific intermediates shown. So long as the R^ and X-R ⁵ substituents of the compound to be prepared are stable under the reaction conditions, particularly the exposure to LDA, those substituents may be placed on the starting tetralone and carried through the steps of the process to prepare the complete compound of formula I in a single linked process, although the one-pot aspect of the above process may not be possible with such starting materials.

It is necessary in the synthesis to alkylate the nucleus to add the R ² substituent, if one is desired. U.S. Patent 5,239,075 shows such alkylation by reaction with an alkyl iodide the presence of a very strong base such as sodium hydride, a conventional process step. Similar alkylations are shown below in the presence of, preferably, potassium t- butoxide in t-butanol as solvent.

The present invention also provides a superior and preferred process for alkylating certain benzoquinolinone compounds which include many of the compounds of the present invention, and also many of the compounds previously disclosed in U.S. Patent 5,239,075. The process allows particularly economical and ready alkylation of the N-4 position of the molecule without the necessity to use unusually strong bases such as potassium t-butoxide and the like. The compounds which are prepared by the present alkylation process are of the formula

wherein R ² ' is methyl, ethyl or n-propyl ; R3 ' is hydrogen or methyl' R^ is hydrogen, halo, methyl or ethyl; R ⁵ ' is halo, nitro, cyano, C1-C6 alkyl, trifluoromethyl or Ci-Cβ alkoxy; or R ⁵ ' is a group -A-R^ wherein A is Cι~C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and R^ is halo, trifluoromethyl, or Ci-Cβ alkoxy; or R ⁵ ' is a group -X'-R ⁷ wherein X ¹ is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or a bond; and R ⁷ is phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, anthracenyl, acenaphthalenyl, thiazolyl, benzimidazolyl, indazolyl, thiophenyl, phenanthrenyl, quinolinyl, fluorenyl, isoquinolinyl, indanyl, benzopyranyl, indolyl, benzisoquinolinyl', benzindolyl, benzothiazolyl, benzothiophenyl, quinoxalinyl, benzoxazolyl, tetrazolyl, naphthothiazolyl, quinazolinyl, thiazolopyridinyl, pyridazinoquinazolinyl, benzisothiazolyl, benzodioxolyl, benzodioxinyl, diphenylmethyl or triphenylmethyl; the above R ⁷ groups are unsubstituted or substituted with 1-3 groups chosen from the group consisting of halo, trifluoromethyl, trifluoroethoxy, C1-C4 alkyl, trifluoromethoxy, hydroxy, C1-C3 alkoxy, nitro, C1-C3 alkylthio, C]_-C6 alkanoyl, phenyl, oxy, phenoxy, phenylthio, C3 _. -C3 alkylsulfonyl, cyano, benzyloxy, benzylthio, (mono- halo, nitro or trifluoromethyl) enzyl (oxy or thio), (mono-Ci- C3 alkyl, C1-C3 alkoxy or halo) - (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl) , halo-Ci-Cg alkanoyl,

phenyl(oxy or thio) (C1-C3 alkyl), (halo, C1-C3 alkyl or C1-C3 alkoxy)phenyl (oxy or thio) (Ci~C3 alkyl) , or benzoyl; or an above R ⁷ group is substituted with a morpholino (C1-C3 alkyl) group, or a phenyl (C1-C3 alkylJpiperidinyl group; or R ⁷ is a perhalophenyl group; the process comprises reacting a compound of the formula

with methyl, ethyl or n-propyl iodide in a reaction mixture comprising an organic solvent chosen from the group consisting of tetrahydrofuran, dimethoxyethane, diethoxyethane and methyl t-butyl ether, and aqueous sodium or potassium hydroxide.

The compounds prepared by the alkylation process are among those which have been described in full above, or have been described in full in the above-mentioned patent. No additional description of the products is necessary. Similarly, the starting materials of Formula B have also been thoroughly described, and they are prepared by the general methods of preparation described in this document or in U.S. 5,239,075.

The present process itself is readily carried out, and is distinguished by both particularly effective alkylation, under mild and easily controlled conditions, and by particularly easy isolation of the products. Frequently, prior art alkylations of similar types required the use of phase transfer catalysts to isolate the products in satisfactory yield and purity, but it has been found that the

products of the present alkylations are isolated by simple crystallization.

Certain aspects of the alkylation process are preferred and will be mentioned below specifically. It will be understood that the following aspects are each important individually, and also that preferred aspects may be combined to create further, more limited or more expansive, preferred aspects. a) R ² ' is methyl and the compound of formula B is reacted with methyl iodide; b) R ² ' is methyl or ethyl and the compound of formula B is reacted with methyl or ethyl iodide; c) pX is hydrogen; d) RX IS methyl; e) R^ IS hydrogen; f) R ⁵ ' is halo; g) the organic solvent is tetrahydrofuran; h) the hydroxide is sodium hydroxide;

I) the concentration of the aqueous sodium or potassium hydroxide is near saturation.

The alkylation process is carried out in conventional chemical plant equipment, preferably at ambient pressure and at moderate temperatures. It is preferably begun by slurrymg the starting material of formula B in the organic solvent at a temperature near ambient, such as from about 0° to about 50°, more preferably from about 15° to about 25°. The most preferred organic solvent is tetrahydrofuran (THF) , and it is preferred to use about 5-15 liters of solvent per kilogram of starting material; more preferable solvent volume is about 10 liters per kilogram. The alkyl iodide is then added as neat liquid. A substantial excess of alkyl iodide is preferably used, such as about 1.2-1.8 equivalents based on the starting material, most preferably about 1.5 equivalents. The aqueous sodium or potassium hydroxide is then added, still at about ambient temperature, m an amount of about 1-4 liters per kilogram of starting material. The quantity of aqueous base is

somewhat dependent on the concentration of the base and the choice of sodium or potassium hydroxide; when the most preferred base, 50% sodium hydroxide, is used, the most preferred amount of it is about 2 liters per kilogram of starting material. Then the reaction mixture, consisting of solid material slurried m two liquid phases is warmed to about 25-65° with vigorous agitation and the reaction is allowed to proceed at about constant temperature with constant agitation. The preferred reaction temperature is about 35-40°. As the reaction proceeds toward completion, the solid starting materia and alkyl iodide will dissolve and react, so the disappearance of solids is a crude indication of completion. The reaction may be followed by high pressure liquid chromatography (HPLC) on C-18 silica gel column, eluting with 1:1 acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220 nanometers. When the reaction has gone as far as is desired toward completion, the mixture is cooled to about ambient and the aqueous layer is separated and discarded.

The preferred purification and isolation procedure proceeds by diluting the organic layer with water, and neutralizing it with aqueous mineral acid. Then the solution is distilled until the vapor temperature rises to about 69- 80°, removing most of the THF. Slow cooling to about 5° over a period of about 1-14 hours crystallizes the product, which needs only washing with water and drying to be ready for use as an intermediate or as a pharmaceutical.

The alkylation process provides product in the same stereochemical form as the starting material, in satisfactory purity for the pharmaceutical industry, and in yields of or above 90% when operated according to the preferred manners. The following Examples further explain the process and provide details which will be of use to the skilled reader.

Example 1 (4aR)- (lObR) -8-chloro-4-methyl-l,2,3,4,4a,5, 6,10b- octahydrobenzo [f]quιnolm-3-one

To a 1-liter flask equipped with a condenser and a stirrer were added 470 mL of THF, 18.7 g of methyl iodide and

47 g of (4aR)-(10bR)-8-chloro-l,2,3,4,4a, 5,6,10b- octahydrobenzo[f]quinolin-3-one, and stirring was begun at ambient temperature. To the mixture was added 100 ml of 50% aqueous sodium hydroxide in one portion, and gentle heating was begun. The temperature was raised as high as 41° and was then gradually lowered to 29° at the end of 16 hours of stirring. HPLC liquid chromatography, eluting with 1:1 acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220 nanometers, then showed that all the starting material had been consumed and the aqueous layer was removed. The organic layer was concentrated to an oil under vacuum, and the residue was dissolved in ethyl acetate. The solution was washed with brine, and the organic layer was washed with 200 mL of water twice, and was dried over magnesium sulfate and evaporated under vacuum while heptane was added portionwise as the ethyl acetate was removed. A total of 500 mL of heptane was added, and the product began to crystallize when about half of it had been added. The slurry was concentrated to about 300 ml, and filtered, and the solids were washed with heptane and dried in vacuum at 40-50° to obtain 47.03 g of product, m.p. 97-99°, of 98.7% purity.

The following example shows an advantageous manner of isolating the product of the present alkylation.

Example J.A (4aR) - (lObR) -8-chloro-4-methyl-l, 2, 3 , 4, 4a, 5, 6, 10b- octahydrobenzo[f]quinolin-3-one

Two hundred L of THF was added to a reactor, and 24.6 kg of (4aR)- (10bR)-8-chloro-l,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinolin-3-one was added. Then 35 kg of methyl iodide was added, rinsed in with 10 L of THF. A 79.6 kg portion of 50% aqueous sodium hydroxide was added in 13 minutes at 15-25°, rinsed in with 40 L of THF. The mixture was stirred at 36-39° for 13 hours, and was then cooled to 15-25°. The layers were allowed to separate, and the water/THF phase was neutralized to pH 7 with hydrochloric

acid and heated to reflux. Distillate was removed until the temperature reached 77°. A total of 154 kg of water was added from time to time. The solution was cooled over 3 hours to 3-10°, and was then stirred vigorously at that temperature until solids began to form. Then the slurry was stirred gently at constant temperature for 3 hours. The slurry was filtered, and the vessel and filter cake were washed with cold water. The cake was air dried at 25-35° for 75 hours to obtain 27.3 kg of the desired product, potency 85.1% by liquid chromatographic analysis.

Example 2 (4aR) - (lObR) -8-chloro-4-ethyl-1,2, 3, 4, 4a, 5,6,10b- octahydrobenzo [ f] quinolin-3 -one A 9.4 g portion of (4aR) - (lObR) -8-chloro-

1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one was combined in a flask with 94 ml of THF, 20 mL of 50% aqueous sodium hydroxide and 9.36 g of ethyl iodide, and was stirred at reflux, about 66°, for about 16 hours. The mixture was cooled to ambient temperature, and the layers were separated. The organic layer was evaporated to an oil, which was dissolved in ethyl acetate and extracted three times with 100 mL portions of water. It was then dried and evaporated to half its volume while heptane was added in portions. The resulting white crystalline product was filtered, washed with heptane and dried under vacuum at 25° to obtain 3.15 g of the desired product, m.p. 108-110°. Analysis calculated for C15H18CI O:

C, 68.54; H, 6.83; N, 5.54 Found: C, 68.50; H, 6.88; N, 5.31

Mass spec, (f.d. ) : M+ 263

Example 3 (4aR)- (lObR) -8-chloro-4-ethy1-1,2, 3 ,4, 4a, 5, 6,10b- octahydrobenzo [ f] quinolin-3-one

A 9.4 g portion of (4aR) - (lObR) -8-chloro- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one was

combined with 150 mL of THF, 20 mL of 50% aqueous sodium hydroxide and 12.5 g of ethyl iodide m a flask, and was warmed with stirring to about 37°. Stirring at approximately constant temperature was continued for about 72 hours and the reaction was worked up as described above in Example 2 to obtain 3.88 g of the desired product, m.p. 108-110°. The product was found to be 98.6% pure by HPLC, eluting with 1:1 acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220 nanometers.

Example 4 (4aP) - flObR) -8-chloro-4-propyl-1,2, 3, 4, 4a, 5, 6,10b- octahydrooenzo[f]qumolm-3-one

A 2.35 g portion of (4aR) - (lObR) -8-chloro- 1, 2 , 3 , 4 , 4a, 5, 6, lOb-octahydrobenzo[f]qumolm-3-one was slurried 40 mL of THF and 5 mL of 50% aqueous sodium hydroxide, and 3.4 g of propyl iodide was added. The mixture was heated to about 60°, and the mixture was stirred at that temperature for about 22 hours. Workup was carried out by separating the organic layer and evaporating it to dryness, and adding water and ethyl acetate. The organic layer was separated, washed twice with water, dried, filtered and evaporated under vacuum to obtain 710 mg of white crystalline product, found to be of about 90% purity. It was then purified by silica gel flash chromatography, eluting with ethyl acetate, to obtain 510 mg of purified product, m.p. 110-11°, of 98.98% purity, by HPLC, eluting with 1:1 acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220 nanometers. Analysis calculated for Ci6H20 ^NC lO:

C, 69,18; H, 7.26; N, 5.04 Found: C, 68.92; H, 7.09; N, 5.15

If a product of formula I having an isopropyl R ² group is desired, alkylation of the intermediate of formula VIII may be accomplished with isopropyl iodide, using sodium hydride as an activating agent and operating the reaction in

a solvent of the group mentioned just above at an elevated temperature such as the reflux temperature.

Frequently a final stage intermediate such as that of formula VIII is produced in a racemic form as a mixture of the two trans-4a-10b isomers. Such an lsomeric mixture may be converted to substantially pure desired enantiomers by a process clearly explained in U.S. Patent 5,239,075, which proceeds by opening the piperidmone ring with a strong acid such as methanesulfonic acid, preparing a chiral salt with (- ) - (R,R) -di-p-toluyltartaric acid, and separating the desired enantiomeric form of the salt as typically is done in such resolutions The salt is then sprung w th aqueous base and the piperidmone ring is reclosed by simple heating.

Another operation which may be carried out on the nucleus of the compounds of the present invention is oxidation to provide the compounds wherein R and R ¹ represent a bond. Such oxidations are conveniently carried out by reaction with an oxidizing agent such as 2, 3-dιchloro-5, 6- dιcyano-1, 4-benzoqumone (DDQ) in the presence of bis (tπmethylsilyl) trifluoromethyl acetamide, preferably in dioxane as solvent. The oxidations are carried out at elevated temperature, such as the reflux temperature or frorr about 50° to about 150°, and preferably the reaction mixtures are stirred at about ambient temperature for a period of time before heating is begun. Further, information about such oxidations can be found below m the Examples.

In the course of preparing compounds having various X-P ⁵ groups, it is necessary or convenient to provide nucleus compounds having corresponding leaving groups or reactive groups. For example, compounds having carboxy, thio, hydroxy, ammo, formyl and B(OH) ₂ groups are needed for various syntheses and are readily prepared, as is demonstrated below, for example, in the Preparations. Such compounds are preferably prepared from compounds having a halogen atom, particularly a bromine atom but also iodine and chlorine atoms on the nucleus.

Various processes are conveniently used for placing the X-R ⁵ groups on the benzoquinolinone nucleus; the choice of processes is primarily dependent on the nature of the X group. Where the X group is merely a bond, a preferred process is dependent on palladium mediated boron chemistry.

In one preferred process, a benzoquinolinone nucleus compound having a bromine atom as the L substituent is reacted with an intermediate which constitutes the R ⁵ substituent group with a boronic acid (B(OH) ₂ ) at the point of attachment to the benzoquinolinone nucleus. The reaction is conveniently carried out in the presence of a catalytic amount of tetrakis (triphenylphosphine) palladium, in a basic reaction mixture including, for example, aqueous sodium carbonate or triethylamine. The preferred solvent is an ether such as THF or dimethoxyethane (DME) , and the reactions go cleanly at elevated temperatures such as the reflux temperature or from about 50° to about 100°. A useful variation on the above process is carried out using an ester of boronic acid as the intermediate, such as a diethylborane. The examples show illustrations of such syntheses.

Similarly, compounds having a bond as the X group may be synthesized by the palladium mediated reaction of a bromine-substituted compound providing the R ⁵ group with a boronic acid-substituted benzoquinolinone nucleus. Still another method for preparing compounds having no X group is to react a halo-substituted nucleus compound of formula IV with a compound comprising the desired R ⁵ group, substituted with a tri-n-butylstannyl group at the point of attachment. Such reactions are carried out in the presence of a small amount of bis (triphenylphosphine)palladium halide at high temperatures such as from about 60 to about 120°. A solvent such as acetonitrile may be used, and the reaction should be carried out in inert gas atmosphere.

Another particularly important group of compounds of formula I are those wherein X is a sulfur atom. Such groups are conveniently prepared by at least two main processes. In one process, a halo-substituted

benzoquinolinone nucleus compound is reacted with a disulfide of the formula R ⁵ -S-S-R ⁵ . For example, if a benzylthio substituent is to be provided, the disulfide would be dibenzyldisulfide. The reactions go readily at ambient temperature after combining the reactants at a very low temperature, such as from about -50° to about -100°, m an ether solvent in the presence of a very strong base, particularly a combination of methyllithium and t-k>utyl- lithium. The reactions are rapid and may be carried out in 1 hour or, at most, a few hours. Another method of synthesis of thiosubstituted compounds, which avoids the use of very low temperatures, is one where either the nucleus or the compound providing the P ⁵ group is substituted with an SH group and the other is substituted with a bromine, chlorine or iodine atom. Such reactions are carried out at ambient or moderately elevated temperatures, such as from about 50° to about 100°, in a high-boiling solvent such as dimethyl- formamide and in a basic reaction medium. Such bases as potassium carbonate, sodium bicarbonate, triethylamine and other moderately strong bases are adequate. Numerous examples of such syntheses are shown below.

Similarly, when the group X is an oxygen atom, the compounds are conveniently prepared by reactions where one cf the nucleus and the P ⁵ group - providing compound carries a halogen atom, and the other carries a hydroxy group. As usual with such reactions, basic conditions and moderately elevated temperatures, such as were just described, are adequate to provide reasonably prompt and clean production of the desired compound of formula I . Compounds wherein X is an oxyalkyl or thioalkyl group are prepared from a nucleus compound having formyl cr formylalkyl L substituent, which material is prepaid, as shown below, by reaction of a halo-substituted nucleus compound with dimethylformamide in the presence of a very strong base, to prepare the formyl substituted compound. It is reduced to form a hydroxymethyl group, which is converted

to a haloalkyl group, and finally reacted with an SH or OH- substituted compound providing the R ⁵ group.

The group of compounds of formula I where X is alkyl, alkenyl or alkynyl are made, in general, by processes where a halo-substituted nucleus compound is reacted with a compound providing the X-R ⁵ group, in the presence of a 9- borabicyclo [3.3. l]nonane alkyl compound (generated in situ by treatment of the appropriate alkene with 9- borabicyclo[3.3.1]nonane (9-BBN) ) or of a bιs(trι- substituted-phosphme)palladium compound, at a high temperature m an inert atmosphere. Solvents such as dimethylformamide may be used, and a basic environment provided by triethylamine or the like is appropriate. Temperatures the range of from about 80° to about 140° may be used for long periods of time up to as much as 24 hours. The resulting compounds may be hydrogenated in conventional manners to reduce them from alkynes to alkenes or from alkenes to alkyls.

Another method of synthesis of alkyl-lmked compounds may be carried out by reacting the halo-substituted benzoqumoline nucleus compound with a very strong base, preferably a combination of methyllithium and t-butyllιthιm, and then adding an aldehyde or ketone providing the desired X-R ⁵ substituent. For example, an example below shows the preparation of a compound wherein X is a bond and R ⁵ is diphenylmethyl by such a reaction of benzophenone. Such reactions should be carried out at low temperature, warming to ambient or slightly elevated temperature, preferably in an ether solvent. Compounds of formula I wherein X is a carbonyl group, an ester group or a carboxamide are prepared in manners following the general processes for synthesis of such compounds. For example, a compound where X is a carboxamide may conveniently be prepared by reacting a halo-substituted benzoquinolinone nucleus compound with an isocyanate carrying the desired R ⁵ group. Such reactions are carried out in

ether solvents, frequently preferably THF, in the presence of methyllithium/t-butyllithium at low temperatures.

Another method for synthesis of carbonyl- substituted compounds is to react an aldehyde with a halo- substituted nucleus compound, to provide a hydroxymethyl- εubstituted intermediate. Such a reaction is carried out the presence of methyllithium/t-butyllithium at low temperatures, again in an ethereal solvent by preference. The hydroxymethyl intermediate is oxidized, as with Jones reagent under the usual conditions for such reactions, to prepare the desired compound where X is a carbonyl group.

The benzoquinolinone intermediate having a carboxy substituent on the phenyl ring, the preparation of which is shown below as a Preparation, is conveniently used to prepare compounds where X incorporates an ester or amide linkage, by conventional esterification reactions with alcohols, or amide preparations with amines. All of the conventional reaction conditions are applicable, such as the use of carbonyldi- lmidazole as an initiator, or oxalyl chloπde/dimethyl- formamide. When an X group incorporates an alkylene chain together with an ester or amide linkage, appropriate starting materials including the alkylene chain are used as a chemist would anticipate.

On the other hand, when the X group comprises an amide linkage where the nitrogen is linked to the benzoquinolinone, the ammo-substituted intermediate prepared below is conveniently reacted with, for example, a carbonyl halide carrying the desired P ⁵ group under the conventional reaction conditions. Again, small alkylene groups may be incorporated as desired to make up any of the possible X groups the contemplation of the present invention.

For example, an unsaturated alkyl-substituted nucleus compound, prepared as discussed above, may be oxidatively cleaved to form the corresponding carboxyalkyl compound. Oxidizing agents such as periodates are commonly used for such transformation and may be used in these instances. The carboxy compound is then esterified or

amidated in the usual manner to prepare the desired alkyl- ester or alkyl-amide X group.

It will be understood that the above discussions of esters include thioesters where the group Y represents a sulfur atom, as well as the more commonly used esters.

Finally, numerous transformations are or may be carried out on R ⁵ groups, to transform one compound of the present invention to another compound. For example, a compound where the R ⁵ group is substituted with a functional group such as alkanoyl, especially formyl, may be reacted with an amme to prepare the corresponding ammoalkyl- substituted compound. Compounds having, for example, nitro groups may be reduced to form the corresponding ammo- substituted compounds, and amino-substituted compounds may be reacted with ketones or aldehydes the presence of reducing agents, or by subsequent reduction, to prepare the corresponding compounds wherein the R ⁵ group is substituted with alkyl ammo.

Further information about the preparation of compounds of the present invention is to be found in the following Preparations and Examples, which, while certainly not intended to limit the present invention, are illustrative of the processes by which all of the compounds are prepared. The first group of Preparations below illustrate the preferred synthesis of the benzoquinolinone nucleus compounds which process was described in detail above.

Preoaration 1 (R) -6-bromo-2- (1-phenylethylammo) -3 , 4- dihydronaphthalene, lithium salt

6-Bromo-2-tetralone, (45.0 g, 200 mmol uncorrected, potency of 90%, 0.90 equiv, correctedt was refluxed witn (P. - ( +) -phenethylamine (26.6 g, 220 mmol, 1.10 equiv, jo-toluene- sulfonic acid (160 mg, 0.84 mmol, 0.004 equiv) , and toluene (600 mL) m a 2000-mL round bottom flask fitted with a water separator. Reflux was continued until a water-free distillate was observed and then approximately 250 mL of toluene was collected over about 2 to 3 hours. The mixture was cooled to approximately 30-35° and concentrated under house vacuum.

The residue above, containing the enamme intermediate, was dissolved in tetrahydrofuran (THF, 480 g, 540 mL) and cooled below -50°. This solution of the enamme was added via cannula to a solution of lithium dusopropylamide (LDA, 1.15 equiv) at -50 to -60° over 5 minutes. The solution was warmed to -5° over 20 minutes and then recooled to -75° affording a 0.125 M solution of the lithium salt starting material. Proceed immediately to next step - unstable intermediate.

Preparation 2 (4aR) -lObR) -8-bromo-10b-methyl-l, 2, 3 , 4, 4a, 5, 6,10b- octahydrobenzo [f]quinolin-3-one

Step A - Methyl Iodide

Methyl iodide (14.4 mL, 230 mmol, 1.15 equiv.) was added via syringe to the reaction mixture from Preparation 1 at -75 to -70° over 3 minutes. This solution was warmed to -5° in 20 minutes and then treated with methanesulfonic acid (24.8 g, 16.8 mL, 1.3 equiv.) affording a solution of the desired enamine admixed with diisopropylamine methanesulfonate as a slightly soluble, off-white precipitate, which was then removed by filtration.

Step B - Aza-Annulation

The reaction mixture solution from the above step was treated with acryloyl chloride (1.7 equiv.) at -75° in one portion over about 5 minutes. The mixture was then allowed to warm to -8° over 15 hours. The reaction was

quenched by pouring into sodium bicarbonate (60 g m 240 mL of water at 5 to 7°, 15 minutes addition time, 20 minutes stir, pH should be basic) . Dimethylammopyridme (0.01 equiv, 2 mmol, 244 mg) was added and the mixture stirred another hour. The mixture was concentrated under vacuum (10- 25°, initial volume 2000 mL; final volume 400 mL) and methylene chloride (400 mLj was added and the organic phase was washed with aqueous sulfuric acid il.O N, two 100 mL portions, pH 1-3; and sodium bicarbonate (1.0 N, 50 mL, pH 9 ) . The organic extracts were dried and clarified by filtration over approximately 20 g of 4A molecular sieves. The mixture was concentrated under vacuum to a total weight of 129.6 σ.

Step C - Reduct ion-Cleavaαe

To about 103 g of the above residue were added 37 mL of triethylsilane and 46 mL of trifluoroacetic acid at 25°. After 1.5 hours reduction was approximately 50% complete. After an additional 12 hours the reduction was complete by TLC. The mixture was then refluxed for 2.5 hours. The mixture was allowed to cool and was concentrated m. vacuo to approximately 25 g. The residue above was dissolved 400 mL of methylene chloride, washed with aqueous sodium hydroxide (enough for pH 11) , and concentrated under vacuum. This concentrate was then treated with diethyl ether (approximately 5 volumes at 22° then 0° for several hours) . The mixture was filtered and rinsed with several small portions of ether affording the desired product after

drying as a crystalline, white solid (yield = approximately 60% based on purity of bromotetralone) .

Analysis by reverse phase high performance liquid chromatography on a Waters NOVA-PAK instrument, C-18 3.9 X 150 mm column, eluting with 2 ml/mm. of 25% aqueous acetonitrile containing 1% ammonium acetate, operating the detector at 220 nm.

Potency: 91.2% Related substances: 6.8% Anal Calcd for Cι H ₁₆ NOBr:

C, 57.16; H, 5.48; N, 4.76; Br, 27.16 Found: C, 55.08; H, 5.43; N, 4:30; Br, 27.78 ^1J C NMR (CDCI ₃ ) : 21.60, 24.62, 28.24, 29.48, 33.15, 36.90, 57.28, 121.03, 127.42, 130.09, 132.86, 137.51, 143.26, 173.62

IH NMR (CDCI3) : 1.18(ε, 3H) CC589 nm - 90° CC365 nm - 302° ee% > 98%, determined by chromatography on a Chiracel-OD instrument and 1 mL/mm, 40°, eluting with 10% isopropanol in hexane and operating the detector at 220 nm.

Preparation 3 acrylic anhydride Two hundred fifty ml of tetrahydrofuran was added to a 1 liter jacketed flask with stir bar and nitrogen purge, and 250 mg of butylated hydroxytoluene, 250 mg of hydroqumone and 25.3 g of triethylamine were added. The solution was cooled to 0°, and to it was added 18.0 g of acrylic acid over a 2 minute period. The solution was cooled again to 0°, and 22.6 g of acryloyl chloride was added over a 10 minute period. It is important to maintain the addition rate constant durmg the acryloyl chloride addition. Maintaining the jacket temperature at 0° and continuing the nitrogen purge, the εolution was εtirred for 1 hour, and then it was filtered in a vacuum filter and the cake was washed with 50 ml of additional tetrahydrofuran.

Preoaration 4 (R) -6-chloro-2- (1-phenylethylamino) -3,4- dihydronaphthalene, lithium salt

6-Chloro-2-tetralone (4.51 g, 25 mmol) was reacted with 3.32 g of (R) -(+) -phenethylamine and 20 mg of rj-toluene- sulfonic acid. The reaction was carried out as shown m Preparation 1 above in 100 mL of toluene, and when the reaction was complete the mixture was concentrated under vacuum and the residue was dissolved in 70 mL of tetrahydrofuran. The solution waε cooled to -50 to -60°, and was added quickly to a εolution of 1.15 equivalents of lithium diisopropylamide in 122 mL of tetrahydrofuran at -70 to -65 ^c . The solution was allowed to warm to -20° for 20 minutes, and waε then quickly recooled to -75°.

( 4a£) - ( 10bE) -8 -chloro- 10b-methyl - 1 , 2 , 3 , 4 , 4a , 5 , 6 , lOb-octahydrobenzo [ f ] qumolm-3 -one

To the cold εolution from Preparation 4, was added 1.15 equivalentε of methyl iodide, and the mixture was allowed to warm to -5° over a 15 minute period with continued good stirring. Then 1.3 equiv. of methanesulfonic acid waε added to the mixture over a 5 minute period.

That mixture waε vigorouεly εtirred for 10 minutes at -5°, and waε then cooled again to -75°. To it waε added in one portion, 2.4 equiv. of acrylic anhydride, with continued stirring, and the mixture was allowed to warm from -75° to 15° over a period of 13 hourε.

The resulting reaction mixture was poured into a well stirred solution of aqueous sodium bicarbonate ' 2 g/200 mL at 20°) and 100 mg of dimethylammopyridme. After two hours of stirring at ambient temperature, most of the volatiles were removed under vacuum, and 130 mL of methylene

chloride was added. The mixture was washed with 50 mL of 1 N hydrochloric acid, and then with aqueous sodium bicarbonate, and tne organic phase was dried and concentrated to a white foam (10.37 g) . The foam waε placed m a flaεk m a ice bath and was treated w th 40 mL triethylsilane and 60 mL of trifluoroacetic acid for 15 hours at 0° and was then held fcr four days at 25°. The volatiles were removed under vacuum, and the colorleεs oil was decanted from the solid product. The residue waε disεolved in 200 mL of methylene chloride and waεhed with saturated aqueouε sodium bicarbonate. The extracts were dried with 4A molecular sieves and evaporated. The residue was washed with 76 mL of diethyl ether to obtair 3.87 g of the desired product as a white solid admixed with a εmali amount of isomeric material.

MS = 249, 251 (M+, M+2) IR (CHC1 ₃ ) = 3396, 1662 cm ^"1 . Anal Calcd for Ci ₄ H ₁₆ NOCl :

C, 67.33; H, 6.46; N, 5.61; Cl, 14.20 Found: C, 66.57; H, 6.43; N, 5.40; Cl, 13.91

^X H NMR (CDCI ₃ 500 MHz) : 1.16 's, 3H) , 3.54 (dxd, IH) , UV (MeOH) : γ205 (21000) , 271(600) , 280(600)

The following group of exampleε illustrates the preparation of compounds where X is a εulfur atom by reactionε with disulfides.

Example 5 ( + ) - ( 4aR ) - ( lObR ) - 8 - ( 4 - chlorophenylthιo ) - l Ob-methyl - 1 , 2 , 3 , 4 , 4a , 5 , 6 , l Ob-octahydrobenzo [ f ] qumolm- 3 -one

To a 3-necked 125 ml flaεk waε added 50 ml of THF and 500 mg of (4aR) - (lObR) -8-bromo-10b-methyl- 1, 2, 3 , 4 , 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one at ambient temperature. The εolution waε cooled to -75°, and to it waε added dropwiεe 1.7 ml of methyllithium m diethyl ether. The mixture waε stirred for 15 minutes, and then 2.4 ml of t- butyllithium (1.7 M in pentane) was added and the temperature rose to -70°. The mixture was stirred for 5 minutes and then 1.95 g of bis (4-chlorophenyl) disulfide disεolved in 10 ml of THF was added m portions. The reaction mixture was stirred for 20 minutes at -75° and then was allowed to warm to ambient temperature. It was acidified with IN hydrochloric acid, and was diluted with 300 ml of ethyl acetate. The organic solution was waεhed successively with IN hydrochloric acid, 10% sodium carbonate solution, water and brine, and was then dried and concentrated under vacuum to obtain 2 g of a yellow oil. The oil was purified by chromatography over silica gel, elutmg with a solvent beginning with 2% methanol in dichloromethane and going to 3% methanol/dichloromethane . The product-containing fractionε were evaporated to obtain

540 mg of foam, which waε cryεtallized from ethyl acetate to obtain 453 mg of purified product. mp 169°-172° FDMS : m/e=357. α[D] ₅₈₉ =+83.91, α[D] ₃₆₅ =+293.47 (methanol) .

The following exampleε were carried out according to the proceεs of Example 5.

Example 6

(+) - (4aR) - (lObR) -8- (4-methylphenylthio) -lOb-methyl- 1,2,3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 481 mg of the desired product. mp 209°-212° FDMS: m/e=337. a[D] ₅₈₉ = +85.00, a[D] ₃₆₅ = +309.00 (chloroform) .

(+)- (4aR) - (lObR) -8- (2-chorophenyl ) -lOb-methyl-

1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 790 mg of the desired product. mp 189°-191° FDMS: m/e=357. α[D] ₅₈₉ = +80.66, α[D] ₃₆₅ = +281.3 (chloroform)

Example 8 (+) - (4aR) - (lObR) -8- (3-chlorophenylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 810 mg of the deεired product. mp 186°-187° FDMS m/e=357. α[D] ₅₈ Q = +80.5, α[D] ₃₆₅ = +292.6 (chloroform) .

Example 9 (+) - (4aR) - (lObR) -8- (2-methylphenylthio) -lOb-methyl-

1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 490 mg of the deεired product. mp 192°, 196°-199 ^c FDMS: m/e=337. α[D] ₅₈₉ = +87.8, α[D] ₃₆ 5 = +310.3

(chloroform) .

Example 10 (+) - (4aR) - (lObR) -8- (3-methylphenylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 480 mg of the deεired product. mp 189°-191° FDMS m/e=337. α[D] ₅₈₉ = +87.8, α[D] ₃₆₅ = +316.5 (chloroform) .

\ + ) - (4aR) - (lObR) -8- (1-naphthylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] qumolin-3-one

Yield: 555 mg of the deεired product. mp 199°-201° FDMS m/e=373. α[D] ₅₈₉ = +76.7, α[D] ₃₆ 5 = +238.6 (chloroform) .

Example 12 (+) - (4aR) - (lObR) -8- (2-methoxyphenylthio) -10b-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolin-3-one

Yield: 580 mg of the desired product. mp 176°-179° FDMS: m/e=353. α[D] ₅₈₉ = +80.4, α[D] ₃₆₅ = +287.9 (chloroform) .

Example 13 (+! - (4aR) - (lObR) -8- (4-methoxyphenylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 630 mg of the deεired product. mp 194°-196° FDMS: m/e=353. α[D] ₅₈₉ = +86.2, α[D] ₃₆₅ = +309.4 (chloroform) .

Example 14 (+) - (4aR) - (lObR) -8- (4-fluorophenylthio) -lOb-methyl-

1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 600 mg of the desired product. mp 179°-181° FDMS: m/e=341. α[D] ₅₈₉ = +88.9, α[D] ₃₆₅ = +313.2 (chloroform) .

(4aR) - (lObR) -8- (3-methoxyphenylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 650 mg of the deεired product. mp 154.5°-155.5° FDMS m/e=353.

Example 16 (+) - (4aR) - (lObR) -8- (3-fluorophenylthιo) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3 -one

Yield: 600 mg of the desired product. mp 154°-156° FDMS: α[D] ₅₈₉ = +84.8, α[D] ₃₆₅ = +300.6 (chloroform) .

(+ ⁾ - (4aR) - (lObR) -8- (2-f luorophenylthio ) -lOb-methyl-

1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumol -3-one

Yield: 640 mg of the desired product. mp 196°-198° FDMS m/e=341. α[D] ₅₈₉ = +84.2, α[D] ₃₆₅ = +300.8 (chloroform) .

(4aR) - (lObR) -8- (3-qumolmylthιo) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3-one

Yield: 340 mg of the desired product. mp 168°-170° FDMS: m/e=374.

Example 19 (4aR) - (lObR) -8- (2-quinolinylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] uinolin-3-one

Yield: 560 mg of the desired product. mp 220°-222° FDMS m/e=374.

Example 20 (+) - (4aR) - (lObR) -8- (8-quinolinylthio) -lOb-methyl-

1,2, 3, , 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 375 mg of the desired product. mp >260° FDMS: m/e=374. α[D] ₅₈₉ = +71.6, α[D] ₃₆₅ = absorbance (chloroform)

(4aR) - (lObR) -8- (2-pyridinylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6,lOb-octahydrobenzo[f] quinolin-3-one

Yield: 530 mg of the desired product. mp 223°-225° FDMS m/e=324.

Example 22 (4aR) - (10bR)-8-phenylthιo-10b-methyl-l,2, 3 , 4, 4a, 5, 6 , lOo- octahydrobenzo [f]quιnolm-3-one

Yield: 351 mg of the desired product. mp 183°-185° FDMS:

(4aP> - (lObR) -8-benzylthio-lOb-methy1-1, 2, 3 , 4 , 4a, 5, 6, 10b- octahydrobenzo [ f]qumolm-3-one

Yield: 329 mg of the desired product. mp 172°-174° FDMS: m, e=337. α[D] ₅₈₉ = 80.84 (c=0.57 chloroform) .

The following group of examples demonstrates syntheεes m which a bromine-substituted benzoquinolinone nucleus compound is reacted with a compound having a boronic acid leaving group and providing the R ⁵ group, where X is a bond.

Example 24 (+) - (4aR) - (lObR) -4-methyl-8- (4-chloro-3-trifluoromethyl ^■ phenyl) -lOb-methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - quinolin-3-one

A 15 mL round bottom flask was charged with (+)- (4aR) - (lObR) -4-methyl-8-bromo-10b-methyl-l,2,3,4,4a,5, 6,10b- octahydrobenzo[f] quinolin-3-one (200 mg, 0.65 mmol) , tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) , 4-chloro-3-trifluoromethylphenylboronic acid (175 mg, 0.78 mmol) , 0.65 mL of 2 M aq. sodium carbonate solution and 2 mL of THF, fitted with a reflux condenεer, and the εtirred mixture waε heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2 x 25 mL) . The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) , to give 188 mg (71%) of the title compound as a white solid. mp 134- 137°. FDMS: m/e = 407. α[D] ₅₈₉ = +59.74 (c = 1.02, chloroform) .

The following examples were carried out according to the process of Example 24.

Example 25 (+) - (4aR) - (lObR) -4-methyl-8- (3-chloro-4-hydroxyphenyl ) - lOb-methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 139 mg (61%) of the title compound as a white solid, mp 245°. FDMS: m/e = 355. α[D] ₅₈₉ = +17.62 (c = 1.02, chloroform) .

analysis: calculated found

C 70.88 70.74

H 6.23 6.27

N 3.94 4.10

Example 26 (+) - (4aR) - (lObR) -4-methyl-8- (2, 3-difluorophenyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[ f] quinolin-3-one

Yield: 111 mg (50%) of the title compound as a white solid, mp 147-148°. FDMS: m/e = 341 α[D] ₅₈₉ = +70.44 (c=1.08, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3 , 4-difluorophenyl) -10b- methy1-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 130 mg (58%) of the title compound as a white solid, mp 143-148°. FDMS: m/e = 341 α[D] ₅₈₉ = +65.12 (c=0.97, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-fluoro-4-hydroxyphenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 111 mg (50%) of the title compound as a white solid, mp >240°C. FDMS: m/e = 339. a[D] ₅₈₉ = +11.21 (c = 1.07, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3 , 4-ethylenedioxyphenyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 189 mg (80%) of the title compound aε an amorphouε solid. mp 183-189°. FDMS: m/e = 363. α[D] ₅₈₉ = +80.77 (c

1.04, chloroform) .

Exarmole 30 (+) - (4aR) - (lObR) -4-methyl-8- (3 , 5-di [t-butyl] -4-hydroxy- phenyl) -lOb-methyl-l, 2 , 3 , 4, 4a, 5, 6, lOb-octahydrobenzo [ f] - quinolin-3-one

Yield: 170 mg (58%) of the title compound as a white solid, mp >265°. FDMS: m/e = 433 α[D] ₅₈₉ = +46.45 (c = 1.00, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-trifluoromethyl-4-fluoro¬ phenyl) -lOb-methyl-1,2,3, 4, 4a, 5, 6, lOb-octahydrobenzo[ f] - quinolin-3-one

Yield: 96 mg (38%) of the title compound as an amorphous foam, mp 70°. FDMS: m/e = 391. α[D] ₅₈₉ = +55.81 (c=0.60, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (1- [4-t-butylcarbonylamino] - naphthyl) -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - quinolin-3-one

Yield: 239 mg (81%) of the title compound aε an amorphous εolid. mp >260°. FDMS: m/e = 454. α[D] ₅₈₉ = +46.85 (c

0.51, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-chloro-5-trifluoromethyl- phenyl) -lOb-methyl-l, 2 , 3 , 4, 4a, 5, 6, lOb-octahydrobenzo[f] - quinolin-3-one

Yield: 170 mg (64%) of the title compound as an oil. FDMS: m/e =407. α[D] ₅₈₉ = +49.42 (c = 0.58, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-t-butylcarboxamidophenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 213 mg (81%) of the title compound as a waxy solid. FDMS: m/e = 404. α[D] ₅₈₉ = +54.34 (c = 0.45, chloroform) .

Example 3 5

(+) - (4aR) - (lObR) -4-methyl-8- (2- [l-diethylcarboxamido] - naphthyl) -lOb-methyl-l , 2,3,4, 4a, 5,6, lOb-octahydrobenzo [f] - quinolin-3-one

Yield: 240 mg (81%) of the title compound aε a white εolid. mp 208-211°. FDMS: m/e = 454. α[D] ₅₈₉ = +49.37 (c = 0.51, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-hydroxy-3-methoxyphenyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 91 mg (40%) of the title compound aε a white εolid. mp 247-250°. FDMS: m/e = 351. 0C[D] ₅₈₉ = +79.51 (c = 0.75, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-t-butylcarbonylaminophenyl) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobe: ^~ [f] quinolin-3-one

Yield: 104 mg (40%) of the title compound aε a brown εolid. mp >265°C. FDMS: m/e =404. α[D] ₅₈₉ = +49.42 (c = 0.56, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-fluorophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 172 mg (82%) of the title compound as a foam. mp 142- 150°. FDMS: m/e = 323. α[D] ₅₈₉ = +77.89 (c=0.69, chloroform) .

(+) - (4aR) - (lObR) - -methyl-8- (2-methoxyphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 160 mg (73%) of the title compound as a white solid. mp 152-156°. FDMS: m/e = 335. α[D] ₅₈₉ = +77.45 (c = 0.64 chloroform) .

Example 40 (+) - (4aR) - (lObR) -4-methyl-8- (2-methylphenyl ι -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qu olm-3-one

Yield: 146 mg (70%) of the title compound as an amorphouε εolid. mp 82-87°. FDMS: m/e =319. α[D] ₅₈₉ = +63.96 (c =

0.35, chloroform) .

Example 41

(+) - (4aR) - (lObR) -4-methyl-8- (2-chlorophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quιnolιn-3-one

Yield: 186 mg (84 %) of the title compound as an amorphous foam. mp 111-120°. FDMS: m/e =339. α[D] ₅₈₉ = +56.86 (c

0.64, chloroform) .

Example 42 (+) - (4aR) - (lObR) -4-methyl-8- (3 , 4-dιmethoxyphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quιnolm-3-one

Yield: 171 mg (72 %) of the title compound as an amorphous foam. mp 108-112°. FDMS: m/e =365. α[D] ₅₈₉ = +73.75 (c = 0.56, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-trifluoromethylphenyl) -10b- methyl-1, 2, 3, , 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 201 mg (83 %) of the title compound aε an oil. FDMS m/e =373. α[D] ₅₈₉ = +60.00 (c = 0.36, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-fluorophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 177 mg (84 %) of the title compound aε an amorphouε foam. mp 116-120°. FDMS: m/e =323. α[D] ₅₈₉ = +81.84 (c

0.47, chloroform) .

Example 45 (+) - (4aR) - (lObR) -8- (3-quinolinyl) -lOb-methyl-l, 2,3,4, 4a, - 5,6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 141 mg (63%) of the title compound aε a white εolid. mp 265-266°. FDMS: m/e = 342. α[D] ₅₈₉ = +88.70 (c =

0.84, chloroform) .

Example 46 (+) - (4aR) - (lObR) -4-methyl-8- (4-fluoro-3-trifluoromethyl¬ phenyl) -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[ f] - quinolin-3-one

Yield: 110 mg (43%) of the title compound aε an amorphouε foam. FDMS: m/e =323. α[D] ₅₈₉ = +51.47 (c = 0.52, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-methoxyphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 173 mg (79%) of the title compound aε a white solid, mp 150°. FDMS: m/e = 335. α[D] ₅₈₉ = +73.82 (c=1.01, methanol) .

Example 48 (+) - (4aR) - (lObR) -4-methyl-8- (3-methoxyphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 144 mg (66%) of the title compound as a white solid, mp 140°. FDMS: m/e = 335. α[D] ₅₈₉ = +77.45 (c=1.02, chloroform) .

Ex-ample 49

(+) - (4aR) - (lObR) -4-methyl-8-phenyl-10b-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] uinolin-3-one

Yield: 139 mg (70%) of the title compound as a white solid. mp 155°. FDMS: m/e = 305.

analysis: calculated found

C 82.59 82.79

H 7.59 7.59

N 4.59 4.39

Example 50 (+) - (4aR) - (lObR) -4-methyl-8- (4-chlorophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 166 mg (75%) of the title compound as a white solid, mp 192°. FDMS: m/e = 339. α[D] ₅₈₉ = +76.14 (c = 1.00, chloroform) .

Example 51 (+ i - (4aPj - (lObR) -4-methyl-8- (4-methylphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[ f] qumolm-3-one

Yield: 150 mg (72%) of the title compound aε a white εolid. mp 178°. FDMS: m/e = 319. α[D] ₅₈₉ = +77.14 (c=1.00, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3 , 5-dιchlorophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumol -3-one

Yield: 145 mg (60%) of the title compound aε a white εolid. mp 172°. FDMS: m/e = 374 α[D] ₅₈₉ = +70.91 (c=0.55, chloroform) .

analysiε: calculated found

C 67.39 67.43

H 5.65 5.67

N 3.74 3.65

Example 53

(+) - (4aR) - (lObR) -4-methyl-8- (1-naphthyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumolm-3-one

Yield: 116 mg (50%) of the title compound as a white solid. mp 159°. FDMS: m/e = 355. α[D] ₅₈₉ = +60.00 (c=0.50, chloroform) .

Example 54 (+) - (4aR) - (lObR) -4-methyl-8- (3-pyridyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 112 mg (56%) of the title compound aε a white εolid. mp 135°. FDMS: m/e = 306.

(+) - (4aR) - (lObR) -4-methyl-8- (3-biphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 176 mg (71%) of the title compound as a white solid. mp 131°. FDMS: m/e = 381. α[D] ₅₈₉ = +71.15 (c = 0.52, CHC1 ₃ ) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-phenoxyphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 206 mg (80%) of the title compound as a white solid. mp 148-150°. FDMS: m/e = 397. α[D] ₅₈₉ = +64.51 (c = 0.62 chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-formylphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 141 mg (65%) of the title compound aε a white solid, mp 163°. FDMS: m/e = 333.

Example 58 (+) - (4aR) - (lObR) -4-methyl-8- (3-formy1-4-hydroxyphenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f]quinolin-3-one

Yield: 85 mg (37%) of the title compound as a white solid. mp 184-187°. FDMS: m/e = 349.

Example 59 (+) - (4aR) - (lObR) -4-methyl-8- (4-dimethylaminophenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 119 mg (53%) of the title compound aε an amorphouε foam. mp 197-202°. FDMS: m/e = 348. α[D] ₅₈₉ = +76.84

(c=0.95, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2- [6-hydroxy]naphthyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 47 mg (20%) of the title compound as a white solid. mp >260° (decomp.) FDMS: m/e = 371.

analysis: calculated found

C 80.83 79.84

H 6.78 6.73

N 3.77 3.25

Example 61 (+) - (4aR) - (lObR) -4-methyl-8- (9-anthracenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 112 mg (43%) of the title compound as an amorphouε εolid. mp 95-110°. FDMS: m/e = 405. α[D] ₅₈₉ = +45.73 (c=0.66, chloroform) .

analyεis: calculated found

C 85.89 84.93

H 6.71 6.55

N 3.45 3.01

Example 62 (+) - (4aR) - (lObR) -4-methyl-8- (2- [6-benzyloxy]naphthyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f]quinolin-3-one

Yield: 73 mg (24%) of the title compound as a white εolid. mp 173-176° FDMS: m/e = 361. α[D] ₅₈₉ = +66.07 (c = 0.56, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-chlorophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 164 mg (74%) of the title compound as an amorphous foam. mp 158-65°. FDMS: m/e = 339. α[D] ₅₈₉ = +74.90 (c

1.00, methanol) .

(+) - (4aR) - (lObR) -4-methyl-8- (1- [4-fluoro] naphthyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f]quinolin-3-one

Yield: 188 mg (77%) of the title compound aε an amorphouε foam. mp 115-125°. FDMS: m/e = 373. α[D] ₅₈₉ = +60.78 (c=1.02, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (1- [4-methyl]naphthyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 36 mg (15%) of the title compound as a white solid. mp 175-178°. FDMS: m/e = 369. α[D] ₅₈₉ = +63.81 (c=1.05, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (5-acenaphthenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 170 mg (69%) of the title compound as a white solid, mp > 200° (decomp.) FDMS: m/e = 381 α[D] ₅₈₉ =

+61.47 (c=0.84, chloroform) .

analysis: calculated found

C 85.00 85.24

H 7.13 7.17

N 3.67 3.51

Example 67 (+) - (4aR) - (lObR) -4-methyl-8- (9-phenanthrenyl) -1Ob-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]qumolm-3-one

Yield: 80 mg (30%) of the title compound aε a white solid, mp 218-220°. FDMS: m/e = 405. α[D] ₅₈₉ = +63.01 (c=0.98, chloroform) .

Example 68

(+) - (4aR) - (lObR) - -methyl-8- (4- [N-propyl,N-cyclopropyl- methylammo] -1-naphthyl) -lOb-methyl-l, 2, 3 , 4, 4a, 5, 6, 10b- octahydrobenzo[f] quinolin-3-one

Yield: 193 mg (64%) of the title compound as an oil. FDMS: m/e = 466. α[D] ₅₈₉ = +50.52 (c=0.95, chloroform) .

Exam le 69

(+) - (4aP) - (lObR) -4-methyl-8- (2, 3-dimethylphenyl) -lOb-methyl- 1, 2, 3 , 4, 4a, 5, 6, lOb-octahydrobenzo[f]qumolm-3-one

Yield: 55 mg (25 %) of the title compound as an amorphous solid. mp 133-140°. FDMS: m/e = 333. α[D] ₅₈₉ = +61.90 (c

1.05, methanol) .

Examole 70 (+) - (4aR) - (lObR) -4-methyl-8- (3, 4-methylenedioxyphenyl) -1Ob- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 130 mg (57%) of the title compound as an amorphous solid. mp 146-152°. FDMS: m/e = 349. α[D] ₅₈₉ = +67.92 (c

1.06, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-naphthyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 126 mg (55%) of the title compound as a white solid, mp 221-223°. FDMS: m/e = 355. α[D] ₅₈₉ = +73.58 (c = 1.06, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (1- [2-methyl] naphthyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 104 mg (44%) of the title compound aε a white solid, mp 196-200°. FDMS: m/e = 369. α[D] ₅₈₉ = +54.72 (c = 1.06, chloroform) .

Example 73 (+) - (4aP) - (lObR) -4-methyl-8- (2 , 3-dichlorophenyl ) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]qumolm-3-one

Yield: 193 mg (79%) of the title compound as an off-white solid. mp 131-134°. FDMS: m/e = 373 α[D] ₅₈₉ = +81.02 (c

1.05, chloroform) .

Example 74 ι+) - (4aR) - (lObR) -4-methyl-8- (2- [N,N-dιethylcarboxamιdo] - phenyl) -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - qumolm-3-one

Yield: 180 mg (68%) of the title compound as a white solid, mp 147-149°. FDMS: m/e = 404 α[D] ₅₈₉ = +56.86 (c = 1.02, chloroform) .

Example 75 (+) - (4aR) - (lObR) -4-methyl-8- (4-t-butylphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 163 mg (69%) of the title compound as an amorphous solid. mp 141-147°. FDMS: m/e = 361 α[D] ₅₈₉ = +67.88 (c =

1.05, chloroform) .

analysis: calculated found

C 83.06 83.34

H 8.64 8.72

N 3.87 3.76

Example 76

(+) - (4aR) - (lObR) -4-methyl-8- (4-n-butylphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 180 mg (77%) of the title compound as a white solid. mp 102-108°. FDMS: m/e = 361. α[D] ₅₈₉ = +68.70 (c = 1.05, chloroform) .

analysis: calculated found

C 83.06 82.98

H 8.64 8.73

N 3.87 3.64

Example 77 (+) - (4aR)- (lObR) -4-methyl-8- (3 , 4-dichlorophenyl ) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 156mg (64%) of the title compound as a foam, mp 129- 135°. FDMS: m/e = 374. α[D] ₅₈₉ = +68.66 (c=1.03, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-trifluoromethoxyphenyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f]quinolin-3-one

Yield: 137 g (56%) of the title compound aε a waxy εolid. FDMS: m/e = 389. α[D] ₅₈₉ = +48.95 (c = 0.96, chloroform)

Example 79

(+) - (4aR) - (lObR) -4-methyl-8- (4-trifluoromethylphenyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 137 mg (56%) of the title compound aε a white εolid. mp 86-89°. FDMS: m/e = 373 α[D] ₅₈₉ = +28.90 (c = 1.04, chloroform) .

Example 80 (+) - (4aR) - (lObR) -4-methyl-8- (3-trifluoromethylphenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 180 mg (77%) of the title compound as an amorphous foam. mp 64-87°. FDMS: m/e = 373. α[D] ₅₈₉ = +64.42 (c=1.04, chloroform) .

(+; - (4aR) - (lObR) -4-methyl-8- (2- [6-methoxy]naphthyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 233 mg (93%) of the title compound aε a white εolid mp 216-221°. FDMS: m/e = 385. α[D] ₅₈₉ = +59.64 (c=0.97

(+) - (4aR) - (lObR) -4-methyl-8- (2-benzothienyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 190 mg (81%) of the title compound as a white solid. mp 247-250°. FDMS: m/e = 361. α[D] ₅₈₉ = +93.33 (c=0.36, chloroform) .

Examole 83 (+ ) - (4aR) - (lObR) -4-methyl-8- (3 , 5-dimethylphenyl ) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 186 mg (86 %) of the title compound as a white solid mp 129-130°. FDMS: m/e =333. α[D] ₅₈₉ = +73.31 (c = 1.00, chloroform) .

Example 84

(+) - (4aR) - (lObR) -4-methyl-8- (4-biphenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 178 mg (72 %) of the title compound as a white εolid. mp 206-207°. FDMS: m/e =381. α[D] ₅₈₉ = +63.93 (c = 1.01, chloroform) .

Example 85 (+) - (4aR) - (lObR) -4-methyl-8- (4-fluorophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 140 mg (67 %) of the title compound as a white solid, mp 121-122°. FDMS: m/e =323. α[D] ₅₈₉ = +79.46 (c = 0.99, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-nitrophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one Yield: 159 mg (70 %) of the title compound as a tan εolid . mp 181-183°. FDMS: m/e =350. α[D] ₅₈₉ = +80.70 (c = 1.04. chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3 , 5-bis [trifluoromethyl]phenyl) - 1Ob-methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 194 mg (68 %) of the title compound as a white solid. mp 110-112°. FDMS: m/e =441 α[D] ₅₈₉ = +80.70 (c = 1. methanol) .

Example 88 (+) - (4aR) - (lObR) -4-methyl-8- (3-chloro-4-fluorophenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 170 mg (73%) of the title compound aε a white εolid. mp 114-116°. FDMS: m/e =357. α[D] ₅₈₉ = +86.00 (c = 1.00 methanol) .

(+) - (4aR) - (lObR) -4-methyl-8- (4- [4-ethoxy]biphenyl) -10b- methyl-1, 2, 3, 4, 4a, , 6, lOb-octahydrobenzo [ f]quinolin-3-one

Yield: 166 mg (60%) of the title compound as a white solid.

(c 1.03,

(+) - (4aR) - (lObR) -4-methyl-8- (3-aminophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 170 mg (82%) of the title compound as a tan εolid. mp 230-231° (decomp. ) FDMS: m/e = 320. α[D] ₅₈₉ = +80.00

(c = 1.05, methanol) .

Example 91 (+) - (4aR) - (lObR) -4-methyl-8- [3- ( [5-dιmethylammo-l- naphthyl] sulfonylamino)phenyl] -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, 10b- octahydrobenzo[f]qumolm-3-one

Yield: 94 mg (63%) of the title compound as a yellow solid, mp 130-140° (decomp. ) FDMS: m/e = 553. α[D] ₅₈₉ = +3.01 (c

= 1.03 methanol) .

Example 92

(+) - (4aR) - (lObR) -8- (1-naphthyl) -lOb-methyl-l, 2 , 3 , 4 , 4a, - 5,6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 405 mg (70%) of the title compound as a white solid. mp 247-248°. FDMS: m/e = 341. α[D] ₅₈₉ = +1.93 (c = 1.04, methanol) .

Example 93 (+) - (4aR) - (lObR) -8- (3-nιtrophenyl) -lOb-methyl-l, 2, 3 , ,4a, - 5,6, lOb-octahydrobenzo[f]quιnolin-3-one

Yield: 456 mg (80%) of the title compound as a white solid, mp 223-225°. FDMS: m/e = 336. α[D] ₅₈ o = +45.63 (c = 1.03, methanol) .

Example 94 (+) - (4aR) - (lObR) -4-methyl-8- (2, 4-dιchlorophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 157 mg (65%) of the title compound as an amorphouε foam. mp 45-48°. FDMS: m/e = 374.

The following group of examples illustrate alkylations, other than the preferred alkylations of Examples 1-4 above, which provide modifications of the benzoquinolinone nucleus.

Example 95 (+) - (4aR) - (lObR) -4, 10b-dιmethyl-8- (4-chlorophenylthιo) - 1,2, 3, 4, -4a, 5, 6, lOb-octahydrobenzo [ f]qumolm-3-one

A 350 mg portion of (4aR) - (lObR) -10b-methyl-8- (4- chlorophenylthio) -1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - qumolm-3-one was slurried 14 ml of t-butanol in a nitrogen-blanketed flask, and 0.2 ml of a 25 mg/ml aqueous solution of methyl iodide was added, followed by 330 mg of potassium t-butoxide. The mixture was stirred at ambient temperature for 5 hours, and then the reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed witn water and with brine, dried over sodium sulfate and concentrated under vacuum to obtain an oil, which was purified by silica gel chromatography on a Chromatotron (Harrison Research Co.), using dichloromethane containing from 1% to 3% of methanol as the eluent. The product- containing fractions were combined and concentrated under vacuum to obtain 330 mg of solid, which was crystallized from heptane/ethyl acetate to obtain 254 mg of the desired product. mp 122°-124° FDMS: m/e=371. α[D] ₅₈ Q = +60.2, α[D] ₃₆₅ = +262.55 (chloroform) .

The following examples were carried out according to the proceεε of Example 95.

Example 96 (+) - (4aR) - (lObR) -4, 10b-dimethyl-8- (4-methylphenylthio) - 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 280 mg of the deεired product. mp 154°-156° FDMS: m/e=351. α[D] ₅₈₉ = +76.6, α[D] ₃₆₅ = +282.53 (chloroform) .

(+) - (4aR) - (lObR) -4, 10b-dimethyl-8- (phenylsulfonyl) -1, 2, 3 , 4 , 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 144 mg of the desired product. mp 165°-167° FDMS: m/e=369. α[D] ₅₈₉ = +76.2, α[D] ₃₆₅ = +269.7 (chloroform) .

Example 98 (+) - (4aR) - (lObR) -4,10b-dimethyl-8- (2-naphthylthio) -1,2,3,4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 137 mg of the desired product. mp 138°-139.5° FDMS: m/e=387. α[D]s ₈₉ = +69.6, α[D] ₃₆₅ = +261.4 (chloroform) .

(+) - (4aR) - (lObR) -4, 10b-dimethyl-8- (2-chlorophenylthio) - 1,2, 3, 4, -4a, 5, 6, lOb-octahydrobenzo[ f]quinolin-3-one

Yield: 420 mg of the desired product. mp 123°-125° FDMS m/e=371. α[D] ₅₈₉ = +76.0, α[D] ₃₆₅ = +255.3 (chloroform) .

(+) - (4aR) - (lObR) -4, 10b-dimethyl-8- (3-chlorophenylthio) - 1,2,3,4, -4a, 5,6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 525 mg. FDMS: m/e=371. α[D] ₅₈₉ = +72.9, α[D] ₃₆₅ +265.2 (chloroform) .

17 -

Example 101 (+) - (4aR) - (lObR) -4, 10b-dimethyl-8- (2-methylphenylthio) - 1,2, 3, 4, -4a, 5, 6, lOb-octahydrobenzo [ f]quinolin-3-one

Yield: 330 mg of the desired product. mp 105°-106° FDMS m/e=351. α[D] ₅₈₉ = +77.0, α[D] ₃₆₅ = +282.8 (chloroform) .

(+) - (4aR) - (lObR) -4, 10b-dimethyl-8- (3-methylphenylthio) - 1,2, 3, 4, -4a, 5, 6, lOb-octahydrobenzo [ f]quinolin-3-one

Yield: 290 mg of the desired product. mp 103°-104° FDMS: m/e=351. α[D] ₅₈₉ = +80.3, α[D] ₃₆₅ = +292.2 (chloroform) .

(+) - (4aR) - (lObR) -4, 10b-dimethyl-8- (1-naphthylthio) -1,2,3,4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 300 mg of the desired product. mp 161°-162° FDMS: m/e=387. α[D]s ₈₉ = +65.2, α[D] ₃₆₅ = +248.4 (chloroform) .

Example 104 (+) - (4aR) - (lObR) -4, 10b-dιmethyl-8- (2-methoxyphenylthιo) - 1,2,3,4, -4a, 5,6, lOb-octahydrobenzo [ f ] qumolm-3 -one

Yield: 300 mg of the desired product. mp 166°-167.5° FDMS m/e=367. α[D] ₅₈ q = +72.7, α[D] ₃₆₅ = +265.1 (chloroform) .

(+/ - (4aR) - (lObR) -4, 10b-dιmethyl-8- ( 4-methoxyphenylthιo) -

1,2, 3, 4, -4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3 -one

Yield: 400 mg of the desired product. mp 150°-151° FDMS m/e=367. α[D] ₅₈₉ = +74.1, α[D] ₃₆₅ = +276.8 (chloroform) .

(4aR) - (lObR) -4, 10b-dιmethyl-8- (3-quιnolmylthιo) -1 , 2 , 3,4,- 4a , 5 , 6 , lOb-octahydrobenzo [ f ] qumolm-3 -one

Yield: 255 mg of the deεired product, aε an amorphous solid, FDMS: m/e=388.

Example 107 (+) - (4aR) - (lObR) -4 , 10b-dimethyl-8- (2-quinolmylthio) - 1,2,3,4, -4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 300 mg of the desired product. mp 175°-177° FDMS: m/e=388. α[D]s ₈₉ = +65.9, α[D] ₃ g ₅ = absorbance (chloroform)

(+) - (4aR) - (lObR) -4, 10b-dimethyl-8- (2-fluorophenylthio) - 1,2,3,4, -4a, 5,6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 490 mg of the desired product, which was not crystalline. mp 100°-103° FDMS: m/e=354. α[D] ₅₈₉ = +76.5 α[D] ₃₆₅ = +273.6 (chloroform) .

(+) - (4aR) - (lObR) -4 , 10b-dimethyl-8- (3-fluorophenylthio) - 1,2, 3, 4, -4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 430 mg of the desired product in the form of an oil FDMS: m/e=355. α[D] ₅₈₉ = +76.5, α[D] ₃₆₅ = +275.2

(chloroform) .

Examole 110 (4aR) - (lObR) -4,10b-dimethyl-8- (8-quinolinylthιo) -1,2,3,4, - 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 114 mg of the deεired product. mp 241°-242° FDMS: m/e=388.

(+) - (4aR) - (lObR) -4,10b-dimethyl-8- (2-pyridinylthio) -1,2,3,4 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 330 mg of the desired product. mp 174°-176° FDMS: m/e=338. α[D] ₅₈₉ = +79.8, α[D] ₃₆₅ = +288.7 (chloroform) .

(4aR) - (lObR) -4,10b-dimethyl-8- (2-benzothiazolylthio) - 1, 2, 3 , 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 84 mg of the desired product. mp 188°-189° FDMS m/e=394.

Example 113 (4aR) - (lObR) -4,1Ob-dimethyl-8- (1-isoquinolinylthio) -1,2,3,4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 90 mg of the desired product. mp 196°-199° FDMS: m/e=388.

(4aRi - (lObR) -4, 10b-dimethyl-8- (4-isoquinolinylthio) -1,2,3,4, 4a, 5, 6, 10b-octahydrobenzo[f]quinolin-3-one

Yield: 140 mg of the desired product. mp 161°-163° FDMS: m/e=388.

(+)- (4aR) - (lObR) -4,10b-dimethyl-8- (4-pyridinylthio) -1,2,3,4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 228 mg of the desired product. mp 157°-158° FDMS: m/e=338. α[D] ₅₈₉ = +77.5, α[D] ₃₆₅ = absorbance (chloroform) .

Example 116 (4aR) - (lObP) -4, lOb-dimethyl-8-phenylthio-1, 2 , 3, 4, -4a, 5, 6, 10b- octahydrobenzo[f]qumolm-3-one

Yield: 0.90 g of white crystals: mp 109-112°; FD MS 337 M+; Calcd for C ₂ ιH ₂₃ N ₁ 0ιSι.

(+) - (4aR) - (lObR) -4-methyl-8- (1-naρhthyl) -lOb-methyl- 3 , , 4a, 5, 6 , lOb-hexahydrobenzo[f] quιnolιn-3-one

Yield: 16 mg (70%) of the title compound as a yellow solid, upon trituration from diethyl ether/hexaneε . mp 172-173°. FDMS: m/e = 353.

(+) - (4aR) - (lObR) -4-methyl-8- (3-nιtrophenyl) -lOb-methyl- 3 , 4, 4a, 5, 6 , lOb-hexahydrobenzo[f] qumolm-3-one

Yield: 9 mg (75%) of the title compound as a white solid, upon trituration from diethyl ether/hexanes . mp 175-177°. FDMS: m/e = 348.

Example 119 (+) - (4aR) - (lObR) -4-methyl-8- (4-nitrophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 10 mg (70%) of the title compound as a white solid, mp 59-60°. FDMS: m/e = 350.

Example 120 (+) - (4aR) - (lObR) -4-methyl-8- (4-methylthiophenyl) -lOb-methyl- 1, 2, 3 , 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 15 mg (72%) of the title compound as a white solid, mp 115-117°. FDMS: m/e = 351.

Example 121

(+) - (4aR) - (lObR) -4-methyl-8- (4-cyanophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 20 mg (80%) of the title compound as a white solid. mp 148-150°. FDMS: m/e = 330.

(+) - (4aR) - (lObR) -4-methyl-8- (4- [isopropylcarbonyl]phenyl) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 20 mg (54 %) of the title compound as a white solid. mp 101-103°. FDMS: m/e = 375.

Example 123 (+) - (4aR) - (lObR) -4-methyl-8- (4-methylεulfonamidophenyi ^' -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 20 mg (56%) of the title compound as an oil. FDMS: m/e = 398.

Example 124 (+) - (4aR) - (lObR) -4-methyl-8- (2-nitrophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 50 g (80 %) of the title compound as a white εolid. mp 130-131°. FDMS: m/e = 350.

Ex m l 125

(+) - (4aR) - (lObR) -4-methyl-8- (2-cyanophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 50 mg (87 %) of the title compound aε a white εolid. mp 54-55°. FDMS: m/e = 330. α[D] ₅₈₉ = +74.33 (c = 0.36, chloroform) .

Example 126 (+) - (4aR) - (lObR) -4-methyl-8- (2- [5- (phenoxymethyl) thienyl] ) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 65 mg (90 %) of the title compound aε a white solid, mp 149-151°. FDMS: m/e = 417 α[D] ₅₈₉ = +68.50 (c = 0.89, chloroform) .

Example 127 (+) - (4aR) - (lObR) -4-methyl-8- (2-methylthiopheny1) -1Ob-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 15 mg (26 %) of the title compound as an oil. FDMS: m/e = 351.

Examole 128 (+> - (4aR) - (lObR) -4-methyl-8- (2,4, 5-trιfluorophenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumolm-3-one

Yield: 40 mg (89%) of the title compound as a foam. FDMS: m/e = 359.

Example 129 (+) - (4aR) - (lObR) -4-methyl-8- (2- [5- (4-fluorophenoxy-methyl) - thienyl] ) -lOb-methyl-l, 2 , 3 , 4 , 4a, 5, 6, lOb-octahydrobenzo[f] - qumolm-3-one

Yield: 35 mg (71 %) of the title compound as a white solid, mp 136-138°. FDMS: m/e = 435 α[D] ₅₈₉ = +63.40 (c = 0.74, chloroform) .

Example 130 (+) - (4aR) - (lObR) -4-methyl-8- (2,3, 5-trifluorophenyl) -10b- methyl-1, 2,3,4, 4a, 5,6, lOb-octahydrobenzo[ f] quinolin-3-one

Yield: 30 mg (83%) of the title compound aε a foam. FDMS: m/e = 359.

Example 131 ( + ) - (4aP) - (lObR) -4-methyl-8- (2-fluorenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]qumolm-3-one

Yield: 26 mg (82%) of the title compound as an off-white solid. mp 175° (decomp) . FDMS: m/e = 393.

Example 132 (+) - (4aR) - (lObR) -4-methyl-8- (3- [2, 5-dιchlororo] thienyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[ f]qumolin-3-one

Yield: 35 mg (69%) of the title compound aε an oil. FDMS: m/e = 379.

Examplg 133 (+) - (4aR) - (lObR) -4-methyl-8- (4-nιtro-2-trιfluoromethyl¬ phenyl) -lOb-methyl-l,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - qumolιn-3-one

Yield: 35 mg (70%) of the title compound as a white solid, mp 128-130°. FDMS: m/e = 418.

Example 134 (+) - (4aR) - (lObR) -4-methyl-8- (2-nιtro-4-tπfluoromethyl¬ phenyl) -lOb-methyl-l,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - qu olιn-3-one

Yield: 38 mg (76%) of the title compound as an off- white solid. mp 55-57°. FDMS: m/e = 418. α[D] ₅₈₉ = +60.50 (

= 0.16, methanol) .

Example 135 ( + ■ - (4aR) - (lObR) -4-methyl-8- (4-chloro-2, 3 ,5, 6-tetrafluoro- phenyl) -lOb-methyl-l, 2 ,3 , 4,4a, 5, 6, lOb-octahydrobenzo[f] - quιnolm-3-one

Yield: 30 mg (66%) of the title compound as an off-white solid. mp 150-151°. FDMS: m/e = 412 α[D] ₅₈₉ = +68.57 (c = 0.12, chloroform) .

Example 136 (4aR) - (lObR) -8-benzylthio-4,10b-dimethyl-l,2,3, 4, 4a, 5, , 10b- octahydrobenzoff]quinolin-3-one

Yield: 150 mg of the deεired white solid (52% yield,' . mp 137-138°. FDMS: m/e = 351. α[D] ₅₈₉ = 59.44 (c=0.36 in methanol) .

(4aR) - (lObR) -8-phenylthiomethyl-4,10b-dimethyl-l,2,3, 4, - 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 134 mg of the deεired white εolid (82% yield) . mp 144-146°. FDMS: m/e = 351. α[D] ₅₈₉ = 78.54 (c=0.5 in methanol) .

(4aR)- (lObR) -8- (2-benzothiazole) thiomethyl-4, lOb-dimethyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 158 mg of the desired white solid (76% yield) . mp 182-184°. FDMS: m/e = 408. α[D] ₅₈₉ = 67.31 (c=0.5 in methanol) .

(4aR) - (lObR) -8-diphenylmethyl-4, lOb-dimethyl-1, 2,3,4, 4a, 5, 6 , lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 33 mg of the deεired product. mp 145-146°; FDMS m/ e = 396; α[D] ₅₈₉ = 58.93 (c=0.5 in chloroform) .

The following group of examples demonεtrate oxidationε which provide hexahydroquinolinoneε in which the groups P. and R ¹ represent a bond.

Example 140 (+) - (4aR) - (lObR) -8- (1-naphthyl) -10b-methyl-3 , 4, 4a, 5, 6 , 10b- hexahydrobenzo[ f] quinolin-3-one

To a suspension of (+) - (4aR) - (lObR) -8- (1-naphthyl) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] -quinolin-3- one (295 mg, 0.865 mmol) , in 3.5 mL of 1,4-dioxane was added DDQ (216 mg, 1.1 equiv.) followed by biεtrimethylεilyl- trifluoromethyl acetamide (998 mg, 4.5 equiv.) , and the solution was stirred at room temperature for 2 h, then heated at 100° for 20h. The mixture was cooled to room temperature,

diluted with ethyl acetate, and washed with 2 M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 60 mg (20%) of the title compound aε a white εolid. mp 199-201° (decomp.) FDMS m/e = 339. α[D] ₅₈₉ = +35.98 (c = 0.67, chloroform) .

The following examples were carried out according to the process of Example 140.

Example 141 (+) - (4aR) - (lObR) -8- (3-nitrophenyl) -10b-methyl-3 , 4, 4a, 5,6,10b- hexahydrobenzo[f]quinolin-3-one

Yield: 55 mg (21%) of the title compound as an orange solid, mp 205-206°. FDMS m/e = 334. α[D] ₅₈₉ = +57.23 (c = 0.66, chloroform) .

(+) - (4aR) - (lObR) -8- (3-isoquinolinyl) -lOb-methyl- 3 , 4 , 4a, 5, 6 , lOb-hexahydrobenzo [f]quιnolin-3-one

Yield: 18mg (24%) of the title compound aε a white εolid. mp 248° (decomp.) FDMS m/e = 340.

Preparation 6 l4aR) - (lObP) -8-formyl-10b-methyl-l,2,3,4, 4a, 5, 6, 10b- octahydrobenzo [ f ] qumolm-3 -one

Methyllithium (1.5 mL, 2.1 mmol of a 1.4 M solution m diethyl ether) was added to (4aR) - (lObR) -8-bromo-10b- methy1-1, 2, 3, 4, -4a, 5, 6, lOb-octahydrobenzo [f] qumolm-3-one (0.500 g, 1.7 mmol) m 25 mL of anhydrous THF which had been cooled in a dry ice/isopropanol bath under nitrogen, and was stirred for 15 mm before addition of t-butyllithium (2.0 mL, 3.4 mmol of a 1.7 M solution in pentane.) After 30 mm, dimethylformamide (0.4 mL) was added, and the mixture waε allowed to warm to 0°, and additional dimethylformamide (0.2 mL) waε added. The ice bath waε removed and the reaction was quenched with 1 N hydrochloric acid to make pH = 2, and then the mixture was extracted with 10% isopropanol/chloroform. The combined organic extracts were washed well with water, dried over εodium εulfate, and evaporated. The resulting product was slurried in diethyl ether before recrystallizing from 50% ethyl acetate/hexane to give off-white crystals: mp 185-189°. FD MS 243 M+; Calcd for C ₁₅ H ₁₇ N ₁ 0 ₂ : C, 74.05; H,

7.04; N, 5.76; Found: C, 73.85; H, 7.11; N, 5.91.

Preoarat ion 7 ( 4aR ) - ( lObR ) - 8 - carboxy -10b-methyl - l , 2 , 3 , 4 , 4a , 5 , 6 , 10b- octahydrobenzo [ f ] qumolιn-3 -one

In a flame-dried 3-neck round bottom flask equipped with magnetic stirrer and nitrogen mlet waε dissolved (4aR - (lObR) -8-bromo-10b-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydro- benzo [f]qumolme-3-one (500 mg, 1.7 mmol) . The solution waε cooled to -78° and treated with ethereal methyllithium (1.7 mL, 1.4M, 2.4 mmol) added dropwise over 2 mm. After further stirring for 15 mm., a solution of t-butyllithium (2.9 mL, 1.7 M in pentane, 5.0 mmol) waε added dropwise. Following complete addition, the suspension was treated with excess carbon dioxide, (generated from dry ice, dried by pasεage through calcium εulfate) added subεurface for 2 mm. The mixture waε allowed to warm to ambient temperature and waε acidified with IN aqueouε hydrochloric acid. The mixture was extracted with 10% ιsopropanol/-chloroform and the organic phase dried over anhydrous magnesium εulfate. Removal of εolvent under reduced preεsure afforded the crude product (520 mg) contaminated with pivalic acid. Trituration with ethyl acetate afforded product (322 mg) as a white powder (mp >320°) m/e 259.

Example 143 (+) - (4aR) - (lObR) -4-methyl-8- (phenylcarboxamido) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

A 50 mL round bottom flask was charged with (+)- (4aR) - (lObR) -4-methyl-8-carboxy-lOb-methy1-1, 2, 3, 4,4a, - 5, 6, lOb-octahydrobenzo[f]qumolm-3-one (100 mg, 0.37) and 2 mL of benzene. Oxalyl chloride (1.1 mmol) was added dropwise via syringe to the stirred mixture, followed by a catalytic amount of dimethylformamide (one drop) . Allowed to stir at room temperature for 25 min, then removed volatiles in vacuo. Added 1 mL of THF, followed by a solution of aniline and pyridme (4 eq) in 1 mL of THF to the acid chloride solution at 0°. Allowed to warm to room temperature. Diluted with 50 mL of chloroform, and washed with 1 N hydrochloric acid (2 x 25 mL) , 10% aq. sodium bicarbonate (2 x 25 mL), water, (2 x 25 mL) , and brine (2 x 25 mL) . The combined organic extracts were dried over sodium sulfate, concentrated and chromatographed on εilica (ethyl acetate eluent), to give 24 mg (19%) of the title compound aε an amorphouε yellow foam. FDMS: m/e = 348.

The following exampleε were carried out according to the proceεε of Example 143.

Example 144 (+) - (4aR) - (lObR) -4-methyl-8-benzyloxycarbonyl-10b-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 11 mg (8 %) of the title compound aε an amorphouε yellow foam. FDMS: m/e = 349.

Example 145 (+) - (4aR) - (lObR) -4-methyl-8-phenoxycarbonyl-10b-methyl- 1, 2, 3 , 4 , 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 43 mg (11%) of the title compound as a yellow solid, mp 194-196°. FDMS: m/e = 349. α[D] ₅₈₉ = +78.53 (c=1.00, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (benzylcarboxamido) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 40 mg (30%) of the title compound as an amorphouε brov/n foam. FDMS: m/e = 362.

Example 147 (4aR) - (lObR) - , 10b-dimethyl-8-diphenylmethoxycarbonyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 91 mg (57%) of the deεired product. An analytical sample was recrystallized from ethyl acetate/water. mp 130- 131°. FDMS: m/e = 439.

(4aR) - (lObR) -4, 10b-dιmethyl-8-diphenylmethylcarboxamido- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 94 mg (40%) of the deεired product. mp 210-211°. FDMS : m X = 438.

The following preparation and example illustrateε εyntheεeε of compounds making use of an SH-εubstituted benzoquinolinone nucleus compound.

Preparation 8

(+) - (4aR) - (lObR) -4-methyl-8-mercapto-10b-methyl-l, 2, 3 , 4, 4a, - 5,6, lOb-octahydrobenzo[f]quinolin-3-one

To a solution of (+) - (4aR) - (lObR) -8-bromo-10b- methyl-1, 2, 3, 4, a, 5, 6, lOb-octahydrobenzo [ fj quinolin-3-one (5.88 g, 20 mmol) in 300 mL of anhydrous THF was added

methyllithium (158 mL, 1.4 M solution in diethyl ether) at -78°. The mixture was allowed to stir at -78° for 20 min, then t-butyllithium (26 mL, 1.7 M in pentane) was added. The mixture was stirred for an additional 90 min, and N,N- diisopropylthiuram disulfide (14.1 g, 40 mmol) in 80 mL of anhydrous THF was added at -78°. The mixture waε stirred for 15 min, the cold bath was removed, and the mixture was allowed to warm to room temperature. To the mixture was added 100 mL of IN hydrochloric acid, the organic phase was separated and washed with 1 N hydrochloric acid (200 mL) , 10% sodium bicarabonate (2 X 200 mL) , and brine (2 X 200 mL) . The organic layer was dried over sodium sulfate, concentrated, and purified by silica gel chromatography (100% ethyl acetate - 5% methanol/ethyl acetate eluent gradient) to give 6.14 g (79% ) of material which was dissolved in 61 L of t-butanol, and potassium t-butoxide (7.42 g, 62.8 mmol) was added. The mixture waε allowed to εtir at room temp for 30 min (became homogeneous), cooled to 0°, and methyl iodide (62.8 mmol in 10 mL of t-butanol) was added dropwiεe via addition funnel. The cold bath waε removed and the mixture waε allowed to εtir at room temperature for 16 h. The mixture waε then diluted with 300 mL of ethyl acetate, the organic phaεe waε separated, washed with brine, dried over sodium sulfate and concentrated to give 6.08 g (96%) of (+)- (4aR) -lObR) -4-methyl-8- ( [N,N-diisopropyl] thiuramyl) -

1, 2 , 3 , 4, 4a, 5, 6, lb-octahydrobenzo[f] -quinolin-3-one aε a white solid. mp 181-182°. FDMS m/e = 404. α[D]589 = +72.11 (c =

0.21, chloroform) .

The above thiuram (6.08 g, 15.0 mmol) was dissolved in 250 mL of trifluoroacetic acid and heated at 72° for 16 h. The solution was cooled, the volatiles were removed via

rotary evaporator, the resulting oil was dissolved chloroform, and the organic layer was washed with 10% sodium bicarabonate solution (2 X 200 mL) followed by brme (2 X 200 mL) . The organic extract was dried over sodium sulfate, and concentrated to give 3.80 g ^f 96%) of the title 8-mercapto compound as oil, used directly without further purification. FDMS m/e = 261.

Example 149 (+) - (4aR) - QObR -4-methyl-8- (2-thιazoylthιo) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

A 15 mL round bottom flask was charged with (+)-

(4aR) - (lObR) -4-methyl-8-mercapto-10b-methyl-l, 2 , 3, 4, 4a, - 5, 6, lOb-octahydrobenzo [f]quιnol -3-one (100 mg, 0.38 mmol) , potasεium carbonate (158 mg, 1.14 mmol) , 2-bromothιazole (75 mg, 0.46 mmol) and 1 mL of anhydrouε dimethylformamide, fitted with a reflux condenεer, and the εtirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture waε cooled, diluted with ethyl acetate (75 mL) and waεhed with brme (2 x 25 mL) . The combined organic extractε were drieα over εodium εulfate, concentrated, and purified by εilica gel chromatography (ethyl acetate eluent) to give 30 mg (23%^ of the title compound as an amorphouε εolid. mp 140-142°. FDMS: m/e = 344.

The following examples were carried out according to the procesε of Example 149.

Example 150 (+) - (4aR) - (lObR) -4-methyl-8- (2-benzoxazolylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 65 mg (45%) of the title compound aε an amorphous foam. FDMS: m/e = 378.

(+) - (4aR) - (lObR) -4-methyl-8- (2-pyrimidinylthio) -lOb-methyl- 1,2, 3, , 4a, 5, 6, lOb-octahydrobenzo [f]qumolin-3-one

Yield: 30 mg (23%) of the title compound as an oil. FDMS: m/e = 339

Example 152 (+) - (4aR) - (lObR) -4-methyl-8- (2-pyrazmylthιo) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]qumolm-3-one

Yield: 63 mg (49%) of the title compound as an off white solid. mp 94-95°. FDMS: m/e = 339. α[D] ₅₈₉ = +88.14 (c

0.92, chloroform) .

(+) - (4aRl - (lObR) -4-methyl-8- (2-qumoxalmylthιo) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]qumolm-3-one

Yield: 82 mg (55%) of the title compound aε an amorphouε foam. FDMS: m/e = 389. α[D] ₅₈₉ = +68.96 (c = 0.81, chloroform) .

Example 154 (+) - (4aR) - (lObR) -4-methyl-8- (2- [3-phenyl] tetrazoylthio ι -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f]quιnolιn-3-one

Yield: 81 mg (53%) of the title compound as a white solid. mp 128-130°. FDMS: m/e = 405. α[D]589 = +69.47 (c = 0.5' chloroform) .

E?cam le 155 (+) - (4aR) - (lObR) -4-methyl-8- (2- [5-trifluoromethyl]pyridyl- thio) -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - quinolin-3-one

Yield: 90 mg (58%) of the title compound as an amorphous solid . mp 134-140°. FDMS: m/e = 406. α[D] ₅₈₉ = +76.80 (c=0.42, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-indazolylthio) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 60 mg (16%) of the title compound as an oil. FDMS: m/e = 377.

Example 157 ( + - (4aR) - (lObR) -4-methyl-8- (2- [4-isopropyl]benzothiazolyl- thio) -10b-methyl-l,2,3 , 4,4a, 5, 6, lOb-octahydrobenzo[f] - qumolin-3-one

Yield: 57mg (34%) of the title compound as an amorphous solid, mp 166-170°. FDMS: m/e = 436.

Example 158 (+) - (4aR) - (lObR) -4-methyl-8- (6-chloro-2-benzothiazolylthio) - 1Ob-methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 86 mg (53%) of the title compound as an amorphouε solid . mp 156-162°. FDMS: m/e = 429. α[D] ₅₈₉ = +63.53 (c=0.66, chloroform) .

( + < ^■ - (4aR) - (lObR) - -methyl-8- (4-methyl-2-benzothιazolylthιo) - lOb-methyl-l,2,3, 4,4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 66 mg (43%) of the title compound as an amorphous solid . mp 134-142°. FDMS: m/e = 408. α[D] ₅₈₉ = +62.80

(c=0.74, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (5-nιtro-2-benzothιazolylthιo) - lOb-methyl-l,2, 3, 4,4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 97 mg (58%) of the title compound aε an amorphouε solid . mp 96-100°. FDMS: m/e = 439. α[D] ₅₈₉ = +61.35 (c=0.64, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (6-methoxy-2-benzothiazolylthio > - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 76 mg (47%) of the title compound as an amorphouε solid . mp 102-107°. FDMS: m/e = 424. α[D] ₅₈₉ = +64.29

(c=0.71, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-fluoro-2-benzothiazolylthio) - lOb-methyl-l,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 91 mg (58%) of the title compound as an amorphous solid . mp 140-145°. FDMS: m/e = 412. α[D] ₅₈₉ = +70.06 (c=0.52, chloroform) .

Example 163 (+) - (4aR) - (lObR) -4-methyl-8- (2-naphtho<l, 2-d>-thiazolylthιo 1Ob-methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] -quinolin-3- one

Yield: 94 mg (56%) of the title compound as an amorphouε solid. mp 179-184°. FDMS: m/e = 444. α[D] ₅₈₉ = +60.59

(c=0.67, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-chloro-2-benzothiazolylthio) - 10b-methy1-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 80mg (49%) of the title compound aε an amorphouε εolid. mp 207-209°. FDMS: m/e = 429 α[D] ₅₈₉ = +63.86 tc=0.57, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (5, 6-dichloro-2-benzothiazolyl- thio) -1Ob-methyl-1,2, 3 , 4, 4a, 5, 6, lOb-octahydrobenzo [f] - quinolin-3-one

Yield: 54 mg (31%) of the title compound as an amorphous foam. FDMS: m/e = 463.

Example 166 (+) - (4aR) - (lObR) -4-methyl-8- (5-nitro-2-pyridinylthio) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 106 mg (73%) of the title compound as an amorphous foam. mp 188-191°. FDMS: m/e = 383. tt[D] ₅₈₉ = +57.07

(c=0.68, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-nitro-2-pyridinylthio) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 95 mg (65%) of the title compound aε an amorphouε foam . mp 80-84°. FDMS: m/e = 383. α[D] ₅₈₉ = +73.78 (c=0.49, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (6-nitro-2-quinolinylthio) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[ f] uinolin-3-one

Yield: 88 mg (53%) of the title compound aε a tan solid . mp 195-196°. FDMS: m/e = 433. α[D] ₅₈₉ = +64.56 (c=0.78, chloroform) .

( + ) - (4aP ' - (lObR) -4-methyl-8- (5-nιtro-2-qumolmylthιo ) -10b- me thy 1-1 ,2, 3, , 4a, 5, 6, lOb-octahydrobenzo [ f ] qumol -3 -one

Yield: 29 mg (56%) of the title compound aε an amorphouε foam. mp 149-154°. FDMS: m/e = 433. α[D] ₅₈₉ = +60.00

(c=0.10, chloroform) .

Example 170 ( + ) - (4aR) - (lObR) -4-methyl-8- (8-nιtro-2-quιnolmylthιo ) -10b- methyl-1 , 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3 -one

Yield: 90 mg (55%) of the title compound as a solid, mp 199-

200°. FDMS: m/e = 433. CC[D] ₅₈₉ = +76.80 (c=0.42, chloroform) .

( + ) - (4aR) - (lObR) -4-methyl-8- (6-phenyl-3-pyndazmylthιo) -10b- methyl-1 ,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3 -one

Yield: 77 mg (49%) of the title compound as an amorphous solid, mp 199-200°. FDMS: m/e = 415. α[D] ₅₈₉ = +67.26

(c=0.63, chloroform) .

(+ι - (4aR) - (lObR) -4-methyl-8- (2-phenyl-4-quinazolinylthio) - lOb-methyl-l ,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one Yield: 112 mg (63%) of the title compound as an off white solid. mp 185-193°. FDMS: m/e = 465. 0C[D] ₅₈₉ = +49.59 (c =

0.57, chloroform) .

⁽ +) - (4aR) - (lObR) -4-methyl-8- (6-fluoro-2-quinolinylthio) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] quinolin-3-one

Yield: 96 mg (62%) of the title compound as a solid, mp 152- 155°. FDMS: m/e = 406. α[D] ₅₈₉ = +63.16 (c=0.61, chloroform) .

Example 174 (- - (4aR) - (lObR) -4-methyl-8- (8-fluoro-2-quinolinylthio) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[ f] quinolin-3-one

Yield: 78 mg (50%) of the title compound as an amorphous foam. FDMS: m/e = 406. α[D] ₅₈₉ = +63.29 (c = 0.56,

(+) - (4aR) - (lObR) -4-methyl-8- (4-thieno[3 , 2-c]pyridylthio) -10b- methy1-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 37 mg (25%) of the title compound as a white solid. mp 196-197°. FDMS: m/e = 394. α[D] ₅₈₉ = +75.17 (c = 0.57, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (10-oxo-10H-2-pyridazino[6, 1-b] quinazolinylthio) -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydro- benzo [f] quinolin-3-one

Yield: 103 mg (62%) of the title compound aε an amorphouε foam. mp 110-114°. FDMS: m/e = 456. α[D] ₅₈₉ = +54.77 (c

0.49, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-phenyl-l-isoquinolinylthio) - lOb-methyl-l,2, 3, 4, a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 64 mg (42%) of the title compound as an off white solid. p 183-189°. FDMS: m/e = 464. α[D] ₅₈₉ = +54.61 (c

0.53, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-methyl-2-quinolinylthio) -10b- methyl-1,2,3,4, 4a, 5,6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 9 mg (16%) of the title compound as an amorphous foam, mp 185-193°. FDMS: m/e = 402.

Examole 179 (+) - (4aR) - (lObRj -4-methyl-8- [3-phenyl-4- i 4-methoxyphenyl) -2 - qumolmylthio] -lOb-methyl-l,2, 3, 4, 4a, 5, 6, lOb-octahydro- benzo[f]qumolm-3-one

Yield: 56 mg (43%) of the title compound as an off white solid. mp 239-242°. FDMS: m/e = 570. α[D] ₅₈₉ = +45.00 (c

1.40, chloroform) .

(+) - (4aRi - ilObR) -4-methyl-8- (3- [1, 2-benzisothiazolyl] hio) - 10b-methy1-1,2, , 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumol -3-one

Yield: 54 mg (36%) of the title compound as an amorphous foam. FDMS: m/e = 394.

Example 181 (+) - (4aR) - (lObR) -4-methyl-8- (2- [4, 6-diphenyl]pyridylthio) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolm-3-one

Yield: 40 mg (27%) of the title compound as an amorphouε solid. FDMS: m/e = 490. α[D] ₅₈₉ = +37.97 (c = 0.39, chloroform) .

Example 182 (+) - (4aR) - (lObR) -4-methyl-8- (4-methoxy-2-benzothiazolylthio) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 107 mg (66%) of the title compound aε an off white solid. mp 200-205°. FDMS: m/e = 424. α[D] ₅₈₉ = +60.56 (c =

0.96, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-bromo-2-benzothiazolylthio) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 142 mg (79%) of the title compound as an off white solid. mp 206-210°. FDMS: m/e = 474. α[D] ₅₈₉ = +56.25 (c

= 0.59, chloroform) .

(+) - (4aR) - (lObR) - -methyl-8- (4-phenyl-2-benzothiazolylthio) - lOb-methyl-l,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yie, d: 110 mg (61%) of the title compound aε an amorphouε foam. FDMS: m/e = 470. α[D] ₅₈₉ = +53.51 ic = 0.66, chloroform) .

(+ ι - (4aR) - ilObP) -4-methyl-8- (4, 7-dιmeth^ 1-2-benzothιazolyl- thio) -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] - qumolm-3-one

Yield: 111 mg (69%) of the title compound as an amorphous foam. FDMS: m/e = 422. α[D] ₅₈₉ = +63.27 (c=0.95, chloroform] .

Example 186 (+) - (4aR) - (lObR) -4-methyl-8- (4-propyl-2-benzothιazolylthιo) - lOb-methyl-l, 2,3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumol -3-one

Yield: 116 mg (70%) of the title compound as an amorphous solid. mp 109-111°. FDMS: m/e = 436. α[D] ₅₈₉ = +45.00

\c=0.80, chloroform) .

Examole 187 (+) - (4aR) - (lObR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

A 200 mL round bottom flask waε charged with (+) (4aR) - (lObR) -4-methyl-8-mercapto-10b-methyl-l, 2 , 3, 4, 4a, - 5, 6, lOb-octahydrobenzo [f] quinolin-3-one (1.36g, 5.20 mmol) , potaεεium carbonate (2.16 g, 15.6 mmol) , 2-chloro-4-ethyl- benzothiazole (1.23g, 6.20 mmol) and 14 mL of anhydrouε dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18h. The mixture was cooled, diluted with ethyl acetate (750 mL) and waεhed with brine (6 x 250 mL) . The combined organic extractε were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 1.51g (69%) of the title compound aε an amorphous foam. FDMS: m/e = 422. α[D]s ₈₉ +62.74 (c=0.67, chloroform) .

Examole 188 (+) - (4aR) - (lObR) -4-methyl-8- (4-trifluoromethoxy-2-benzo- thiazolylthio) -lOb-methyl-l, 2 , 3 , , 4a, 5, 6, lOb-octahydro- benzo[f] -qumolm-3-one

Yield: 141 mg (77%^ of the title compound aε a white solid, p 168-173°. FDMS: m/e = 478. α[D] ₅₈₉ = +57.89 (c =

0.59, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- [4,7-dι (t-butyl) -2-benzo- thiazolylthio] -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydro- benzo[f] -qumolm-3-one

Yield: 33 mg (17 %) of the title compound as an amorphous foam. FDMS: m/e = 506.

Example 190 (+) - (4aRi - (lObR) -4-methyl-8- (4-methyl-7-trιfluoromethyl-2- benzothiazolylthio) -lOb-methyl-l, 2, 3,4, 4a, 5,6, 10b- octahydrobenzo[f]qumolm-3-one

Yield: 94 mg (52%) of the title compound as an amorphous foam. mp 50-54°. FDMS: m'e = 476.

Examole 191 (+) - (4aR) - (lObR) -8- (3-ιsoqumolinylmethylthιo) -4,10b- dιmethyl-1, 2,3,4, 4a, 5,6, lOb-octahydrobenzo [f] qumolme-3-one

Yield: crystalline solid (91 mg), mp = 129-130°. m/e 402. OF (c=1.0, methanol) @ 589 nM, +64.2°, @ 365 nM, +226.7°.

(+ ) - (4aP) - (lObR) -8- (2-benzothιazolylmethylthιo) -4, 10b- dιmethyl-1 ,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumolιne-3-one

Yield: a crystalline solid (55 mg) , mp = 78-80°. m/e 408. OR (c=0.3, methanol) @589 nM, +66.3°.

(4aR) - (lObR) -4, 10b-dimethyl-8- (7-chloro-2-benzothιazolyl- thio) -1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]qumoline-3-one

Yield: 195 mg of the desired product. mp 90-91°. FDMS: m/e = +428.

Example 194 (4aRι - (lObR) -4, 10b-dιmethyl-8- (5-chloro-2-benzothiazolyl- thio) -1,2, 3, 4, a, 5, 6, lOb-octahydrobenzo[f] qumol e-3-one

Yield: 56 mg of the desired product. mp 179-180°. FDMS: m/e = +428.

(4aP - (lObR; -8-dιphenylmethylthιo-4 , lOb-dimethyl-

1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] -qumolme-3-one

Yield: 146 mg of the desired product. mp 102-104°. FDMS m/e = +427. α[D] ₅₈₉ = 60.28.

The following preparation and examples illustrate the syntheεiε of compoundε of the preεent invention through an intermediate having a boronic acid εubεtituent on the benzoquinolinone nucleuε.

Preoaration 9 (+) - (4aR) - (lObR) -4-methyl-10b-methyl-l,2,3,4,4a,5, 6,10b- octahydrobenzo [f]quinolin-3-one-8-boronic acid

To a solution of (+) - (4aR) - (lObR) -4-methyl-8- bromo-10b-methyl-l,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] - quinolin-3-one (5.0 g, 16.2 mmol) in 500 mL of anhydrouε THF waε added t-butyllithium (37.5 mL, 1.3 M solution in cyclohexane) at -78°. The mixture was allowed to stir at -78 ^c for 75 min, and a solution of triisopropyl borate (2.0 equiv.) in 12.5 mL of anhydrous THF was added dropwise. The mixture was stirred for an additional 45 min, then the cold bath was removed, and the mixture was allowed to warm to room temperature. The mixture was quenched with 5 N hydrochloric acid (50 mL) , and volatiles were removed on rotary evaporator. The mixture was then treated with 35 mL of 5 N εodium hydroxide, and was extracted with THF (300 mL) . The organic extract was dried over sodium sulfate, filtered, and concentrated. The resulting solid was heated in boiling ethyl acetate for 15 min, followed by filtration (while still hot) , to yield 3.65 g (82%) of the title compound as a white εolid. mp 200° (decomp.) α[D] ₅₈₉ = +72.27 (c = 0.89, methanol) .

Example 196 (+) - (4aR) - (lObR) -8- {3 -quinolinyl) -lOb-methyl-l , 2 , 3 , 4 , 4a, 5,6, lOb-octahydrobenzo [ f ] qumolm-3-one

A 15 mL round bottom flask was charged with (+)- (4aR) - (lObR) -10b-methyl-l,2,3,4,4a, 5,6,10b- octahydrobenzo[f]qumolm-3-one-8-boronιc acid (168 mg, 0.65 mmol) , tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3-bromoqumolme (135 mg, 0.65 mmol) , 0.65 mL of aqueous 2 M sodium carbonate and 2mL of THF, fitted with a reflux condenser, and the stirred mixture waε heated at 80°, under nitrogen, for 24 h. The mixture waε cooled, diluted with chloroform (75 mL) and washed with br e (2 x 25 mL) .

The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol / ethyl acetate eluent) to give 141 mg (63%) of the title compound as a white solid. mp 265-266°. FDMS: m/e = 342. α[D] ₅₈₉ = +88.70 (c = 0.84, chloroform) .

The following examples were carried out according to the proceεs of Example 196.

Examole 197 (+) - (4aR) - (lObR) -8- (4- [2, 8-bistrifluoromethyl] quinolinyl) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] uinolin-3-one

Yield: 186 mg (60%) of the title compound as a white solid. mp 214-215°. FDMS: m/e = 478. α[D] ₅₈₉ = +62.00 (c = 1.10, chloroform) .

Example 196 (+)- (4aR)- (10bR)-8-(2-thiazolyl) -lOb-methyl-l, 2 , 3 , 4, 4a, - 5,6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 64 mg (35%) of the title compound as a white solid, mp 206-207°. FDMS: m/e = 298. OC[D] ₅₈₉ = +101.7 (c = 0.97, chloroform) .

Example 199 (+) - (4aR) - (lObR) -8- (5-nitro-2-pyridinyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 71 mg of the title compound as a white solid. mp 123-124°. FDMS: m/e = 337. α[D] ₅₈₉ = +85.60 (c = 0.61, chloroform) .

E ple 200

(+) - (4aR) - (lObR) -4-methyl-8- (4-isoquinolinyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 110 mg (47%) of the title compound as an amorphous foam. FDMS: m/e = 356. α[D] ₅₈₉ = +67.82 (c=0.40, methanol) .

Example 201 ( + ) - (4aR) - (lObR) -4-methyl-8- (3-qumolmyl ) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3-one

Yield: 130 mg (56%) of the title compound as an amorphous solid, mp: 180-185°. FDMS: m/e = 356. α[D] ₅₈ = +80.22

(c=0.37 , chloroform) .

( + ⁾ - ι4aR) - (lObR) -4-methyl-8- ( 5-nιtro-2-pyrιdmyl ) -10b-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3-one

Yield: 148 mg (65%) of the title compound as an amorphous foam. mp 70-80°. FDMS: m/e = 351. α[D] ₅₈₉ = +85.59 (c =

0.48, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- [2 , 8-bιs (trif luoromethyl ) -4- qu olmyl] - 10b- methyl -1 , 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f ] - quιnolιn-3-one

Yield: 153 mg (48%) of the title compound aε an amorphouε foam. mp 100-106°. FDMS: m/e = 492. α[D] ₅₈₉ = +51.86 (c

0.47, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-methylsulfonylphenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[ f]quinolin-3-one

Yield: 137 mg (55%) of the title compound as a white solid, mp 229°. FDMS: m/e = 383.. α[D] ₅₈₉ = +28.24 (c = 0.23, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2,3,4,5, 6-pentafluorophenyl) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 97 mg (38%) of the title compound as an amorphous foam. mp 92-100°. FDMS: m/e = 395. α[D] ₅₈₉ = +64.15 (c =

0.42, chloroform) .

Example 206

(+) - (4aR) - (lObR) -4-methyl-8- (3 , 4, 5-trifluorophenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 117 mg (50%) of the title compound aε an amorphous wax. FDMS: m/e = 359 α[D] ₅₈₉ = +75.86 (c = 0.47, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (1-oxo-5-indanyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 91 mg (39%) of the title compound aε a white εolid. mp 175-178°. FDMS: m/e = 359. [D] ₅₈₉ = +74.81 (c = 0.5; chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-fluoro-3-trifluoromethyl¬ phenyl) -1Ob-methyl-1, 2,3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - quinolin-3-one

Yield: 130 mg (51%) of the title compound as an oil. FDMS m/e = 391. α[D] ₅₈₉ = +68.49 (c = 0.38, chloroform) .

Example 209

(+) - (4aR) - (lObR) -4-methyl-8- (3- [l-benzyl-4-piperidinyl- carboxamido]phenyl) -lOb-methyl-l,2, 3, 4, 4a, 5, 6, 10b- octahydrobenzo[f]quinolin-3-one

Yield: 148 mg (44%) of the title compound as an amorphouε foam. FDMS: m/e = 521. α[D] ₅₈₉ = +53.50 (c = 0.45 , chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-fluoro-4-trifluoromethyl- phenyl) -lOb-methyl-l, 2 ,3,4, 4a, 5,6, lOb-octahydrobenzo [f] - quinolin-3-one

Yield: 171 mg (67%) of the title compound as an amorphous εolid. mp 72-79°. FDMS: m/e = 391. α[D] ₅₈₉ = +62.50 (c=0.48, chloroform) .

(+) - (4aR) - (10bR) -4-methyl-8- (2-fluoro-5-trifluoromethyl- phenyl) -lOb-methyl-l,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] - quinolin-3-one

Yield: 113 mg (44%) of the title compound as an oil. FDMS m/e = 391. α[D] ₅₈₉ = +55.84 (c = 0.34 , chloroform) .

Example 212 (+^ - (4aP) - (lObR) -4-methyl-8- (3-methylthιophenyl ) -lOo-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumolm-3-one

Yield: 110 mg (48%) of the title compound as an oily solid. FDMS: m/e = 351. α[D] ₅₈₉ = +90.00 (c=0.17, chloroform) .

{ + t - (4aP) - (lObP) -4-methyl-8- (4-carboxamιdophenyl) -lOb- ethyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quιnolm-3-one

Yield: 21 mg (9%) of the title compound as amorphous foam, mp 177-189° (decomp.) FDMS: m/e = 348.

Example 214 (+) - (4aR) - (lObR) -4-methyl-8- [2-oxo-3- (N,N-diethyl- carboxamido) -l-2H-benzopyran-6-yl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 138 mg (45%) of the title compound as an amorphous foam. mp 120-125°. FDMS: m/e = 472. α[D] ₅₈₉ = +54.69 (c

0.49, chloroform) .

Examole 215 (+) - (4aR) - (lObR) -4-methyl-8- [2- (t-butylcarbonylamino) -5- pyridinyl] -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] - quinolin-3-one

Yield: 84 mg (32%) of the title compound as a brown εolid. mp 248-250°. FDMS: m/e = 405. α[D] ₅₈₉ = +70.74 (c = 0.45, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (3-fluoro-5-trifluoromethyl¬ phenyl) -lOb-methyl-l, 2,3,4, 4a, 5,6, lOb-octahydrobenzo[f] - quinolin-3-one

Yield: 145 mg (57%) of the title compound as an oil. FDMS m/e = 391. α[D] ₅₈₉ = +67.32 (c = 0.55, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (5-nitro-2-thienyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 118 mg (51%) of the title compound as a white solid. mp 147-149°. FDMS: m/e = 356. α[D] ₅₈₉ = +83.48 (c = 0.54, chloroform) .

(+ i - (4aR> - (lObP) -4-methyl-8- ( 5 -chloro- 2- thienyl ) - 1 Ob-methyl ^■ 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3-one

Yield: 125 mg (56%) of the title compound aε an oil. FDMS: m/e = 345. α[DX ₈₉ = +74.03 (c = 0.51 , chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-chloro-3-fluorophenyl ι -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ ]quinolin-3-one

Yield: 125 mg (56%) of the title compound as an amorphouε foam. FDMS: m/e = 357. α[D] ₅₈₉ = +74.28 (c = 0.35, chloroform) .

Example 220 (+) - (4aR - (lObR) -4-methyl-8- (4-εulfonamidophenyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 34 mg (14%) of the title compound as a white solid, mp 200° (decomp. ) FDMS: m/e = 384. α[D] ₅₈₉ = +201.8 (c =

0.43, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- [4- (4-chlorobutyryl)phenyl] -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f]quinolin-3-one

Yield: 113 mg (42%) of the title compound an oil. FDMS: m/e = 409. α[D] ₅₈₉ = +60.00 (c = 0.18, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4- [ (2-t-butylcarbonylamino] -5- thienyl]phenyl) -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydro- benzo [f] quinolin-3-one

Yield: 88 mg (28%) of the title compound a brown solid. mp 240° (decomp.) FDMS: : e = 487. α[D] ₅₈₉ = +61.73 (c = 0.47, chloroform) .

(+) - (4aR^ - (lObP) -4-methyl-8- (2, 3-dιoxo-5-ιndolιnyl) -10b- methy1-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]qumolm-3-one

Yield: 36 mg (15%) of the title compound as a white solid. mp --250° FDMS: m/e = 374. α[D] ₅₈₉ = +75.33 (c = 0.53, chloroformι .

( + ^ - (4aR) - (lObR) -4-methyl-8- (2- ( 2 -dimethy lam oethy 1 ) -1H- benzo<de>ιsoqumolιn-6-yl-l , 3- (2H) dione) - 1 Ob-methyl - 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f ] qumolm-3 -one

Yield: 141 mg (44%) of the title compound as a white solid, mp 190-192°. FDMS: m/e = 495. α[D] ₅₈₉ = +74.71 (c=0.53, chloroform) .

Examole 225 (+) - (4aR)- (lObR) -4-methyl-8- (2aR, S-l-benzoyl-4-di- propylamino-2, 2a,3 , 4-tetrahydrobenz [cd] -lH-indol-7-yl ) -10b- methyl-1,2,3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] uinolin-3-one

Yield: 64 mg (17%) of the title compound as an amorphouε foam. mp 110-115°. FDMS: m/e = 589. α[D] ₅₈₉ = +80.14 (c

= 0.46, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2aR, 4S-l-benzoyl-4-amino- 2,2a, 3, 4-tetrahydrober.- [cd] -lH-indol-7-yl) -lOb-methyl- 1,2, 3, , 4a, 5, 6, lOb-octahydrobenzo[f] uinolin-3-one

Yield: 187 mg (57%) of the title compound as an amorphous foam. mp 134-136°. FDMS: m/e = 505.

Example 227 (+)- (4aR) - (lObR) -4-methyl-8- ( , 5-difluorophenyl ) -lOb-methyl 1,2, 3, 4, a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 137 mg (62%) of the title compound as an oil. FDMS: m/e = 341. α[D] ₅₈₉ = +79.29 (c = 0.28, chloroform) .

Example 228 (+) - (4aR) - (lObR) -4-methyl-8- (2, 6-difluorophenyl -1Ob-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]qumolm-3-one

Yield: 98 mg (44%) of the title compound as an amorphous solid. mp 125-130°. FDMS: m/e = 341 α[D] ₅₈ o = +71.79 ic

= 0.58, chloroform) .

\ + i - (4aR) - (lObR) -4-methyl-8- (2, 5-difluorophenyl ) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quιnolm-3-one

Yield: 105 mg (47%) of the title compound as an oil. FDMS: m/e = 341. α[D] ₅₈₉ = +70.96 (c = 0.38, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2,4, 6-trifluorophenyl ^■ < -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] qumolm-3-one

Yield: 116 mg (50%) of the title compound as an oil. FDMS: m/e = 359. α[D]s ₈₉ = +68.65 (c = 0.35, chloroform) .

Example 2-.- (+) - (4aRX (lObR) -4-methyl-8- (2, 4-difluorophenyl ) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 106 mg (48%) of the title compound aε white εolid. mp 108-112°. FDMS: m/e = 341. α[D] ₅₈₉ = +82.90 (c = 0.52, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2, 3 , 4-trifluorophenyl) -10b- methy1-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 100 mg (43%) of the title compound as a white solid. mp 100-102°. FDMS: m/e = 359. α[D] ₅₈₉ = +7837 (c = 0.33, chloroform) .

(+) - (4aR)- (lObR) -4-methyl-8- (4- [4-nitrobenzyl] thiophenyl) - lOb-methyl-l, 2, 3, 4, 4a, , 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 166 mg (54%) of the title compound as an oily solid. FDMS: m/e = 472. α[D] ₅₈₉ = +65.63 (c=0.41, chloroform) .

Example 234 (+) - (4aR) - (lObR) -4-methyl-8- (2- (2- [l-morpholino] ethyl) -1H- benzo<de>iεoquinolin-6-yl-l, 3- (2H)dione) -1Ob-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 176 mg (50%) of the title compound as an amorphouε εolid. mp 100-105°. FDMS: m/e = 537. α[D] ₅₈₉ = +45.10

(c=0.53, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (4-pyridinyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 85 mg (43%) of the title compound aε an oil. FDMS: m/e = 306. analvεiε: calculated found C 78.40 78.56

H 7.24 7.00

N 9.14 8.68

Example 236 (+) - (4aR) - (lObR) -4-methyl-8- (1-p-tolueneεulfonylindol-5-yl) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 49 mg (15%) of the title compound aε an amorphouε foam. FDMS: m/e = 498.

Example 237 (+) - (4aR) - (lObR) -4-methyl-8- (l-acetyl-7-nιtromdolm-5-yl) - 1Ob-methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 63 mg (22%) of the title compound a yellow solid. mp 235-240°. FDMS: m/e = 433. α[D] ₅₈₉ = +65.72 (c = 0.99, chloroform) .

( + ) - (4aR) - (lObR) -4-methyl-8- (l-acetylindolm-5-yl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]qumolm-3-one

Yield: 67 mg (26%) of the title compound as a yellow solid. mp 197-200°. FDMS: m/e = 388. CC[D] ₅₈₉ = +77.92 (c = 0.36, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (8-quinolιnyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 88 mg (38%) of the title compound a tan solid. mp 205-207°. FDMS: m/e = 356 α[D] ₅₈₉ = +7o.28 (c = 0.47, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (5-quinolinyl ) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 128 mg (55%) of the title compound as an amorphouε foam. mp 100-104°. FDMS: m/e = 356. α[D] ₅₈₉ = +61.77

= 0.35, chloroform) .

( + - (4aR) - (lObR) -4-methyl-8- (5-isoquinolinyl) -1Ob-me hyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [fJquinolin-3-one

Yield: 98 mg (42%) of the title compound aε an amorphous εolid. mp 182-184°. FDMS: m/e = 356. α[D] ₅₈₉ = +57.25 (

= 0.49, chloroform) .

Example 242 (+) - (4aR) - (lObR) -4-methyl-8- (2-pyridinyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 98 mg (49%) of the title compound as an oil. FDMS: m/e = 306. α[D] ₅₈₉ = +83.48 (c = 0.38, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2, 5-difluoro-4-nitrophenyl) -10b- methyl-1, 2,3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 128 mg (51%) of the title compound as an amorphous solid, mp: 130-140°. FDMS: m/e = 386. α[D] ₅₈₉ = +73.44 (c=0.53, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (6-quinolinyl) -lOb-methyl- 1, 2, 3 , 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 107 mg (46%) of the title compound as an amorphous solid. mp 185-190°. FDMS: m/e = 356. α[D] ₅₈₉ = +78.73 (c

= 0.56, chloroform) .

Example 245 (+) - (4aR) - (lObR) -4-methyl-8- (1-hydroxy-5-indanyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]qumolm-3-one

Yield: 79 mg (34%) of the title compound as an amorphouε solid, mp: 185-190°. FDMS: m/e = 361. α[D] ₅₈₉ = +77.38

(c=0.35, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- [2- (4- [N-benzyl]piperidmyl) -1H- benzo<de>ιεoqumolm-6-yl-l, 3- (2H) dione] -1Ob-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quιnolιn-3-one

Yield: 197 mg (51%) of the title compound aε an amorphous foam. FDMS: m/e = 597. α[D] ₅₈₉ = +51.09 (c=0.58, chloroform) .

( + ) - (4aR) - (lObR) -4-methyl-8- (2-qumolmyl ) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f ] qumolm-3-one

Yield: 126 mg (54%) of the title compound aε an amorphous foam. mp 140-145°. FDMS: m/e = 356.. α[D] ₅₈₉ = +74.01 (c

0.46, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-oxo-l-benzopyran-6-yl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 108 mg (40%) of the title compound an amorphous solid, mp 180° (decomp.) FDMS: m/e = 373. α[D] ₅₈₉ = +40.48 (c

0.42, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (6-benzothiazolyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 106 mg (47%) of the title compound as an amorphous εolid. mp 183-187°. FDMS: m/e = 362. α[D]s ₈₉ = +87.80(c

= 0.55, chloroform) .

Example 250 ( + ) - (4aR) - (lObR) -4-methyl-8- ( 1- [t-butoxycarbonyl] -5-mdolyl ι - lOb-methyl-l ,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f ] qumolm-3-one

Yield: 113 mg (39%) of the title compound as an amorphous foam. FDMS: m/e = 445. α[D] ₅₈₉ = +68.17 (c = 0.47, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-benzoxazolyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumolm-3-one

Yield: 45 mg (20%) of the title compound as an amorphous foam. FDMS: m/e = 346.

Example 252 (+) - (4aP) - (10bR) -4-methyl-8- (2-benzothιazolyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qu olm-3-one

Yield: 107 mg (45%) of the title compound as an amorphous solid, mp: 207-212°. FDMS: m/e = 362. α[D] ₅₈₉ = +88.83

(c=0.60, chloroform) .

Examole 253 (+) - (4aR) - (lObR) -4-methyl-8- (2-pyrazinyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 132 mg (66%) of the title compound as an amorphous foam. FDMS: m/e = 308. α[D] ₅₈₉ = +89.71 (c=0.34, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-pyrimidinyl) -lOb-methyl- 1,2, 3, , 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

Yield: 102 mg (51%) of the title compound as an amorphous foam, mp 160-162°. FDMS: m/e = 307. α[D] ₅₈₉ = +95.71

(c=0.28, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-quinoxalinyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 156 mg (67%) of the title compound as a foam, mp 129- 135°. FDMS: m/e = 357. α[D] ₅₈₉ = +72.94 (c=0.63, chloroform) .

Examole 256 (+) - (4aR) - (lObR) -4-methyl-8- (2-benzιmιdazolyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 57 mg (25%) of the title compound as an amorphouε foam, mp 183-186°. FDMS: m/e = 345.

( + ) - (4aR) - (lObR) -4-methyl-8- (3-mdazolyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

Yield: 49 mg (11%) of the title compound as an amorphous foam. FDMS: m/e = 345.

Example 258 (+ - (4aR) - (lObR) -4-methyl-8- (2- [3-phenyl] tetrazolyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f]qumolm-3-one

Yield: 69 mg (28%) of the title compound aε an amorphous foam. mp 85-90°. FDMS: m/e = 373. α[D] ₅₈₉ = +84.79

(c=0.65, chloroform) .

Example 259 (+) - (4aR) - (lObR) -4-methyl-8- (2- [5-trifluoromethyl]pyridinyl) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] σuinolin-3-one

Yield: 141 mg (58%) of the title compound as an amorphous foam. mp 65-68°. FDMS: m/e = 374. α[D] ₅₈₉ = +81.90 (c =

0.84, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2-naphtho<l, 2-d>thiazolyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 192 mg (72%) of the title compound as an amorphous solid. mp 105-107°. FDMS: m/e = 412. α[D] ₅₈₉ = +86.44

(c=0.70, chloroform) .

(+) - (4aR) - (lObR) -4-methyl-8- (2- [4-fluoro]benzothiazolyl) -10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 181 mg (73%) of the title compound as an amorphous foam, mp 170-190°. FDMS: m/e = 380. α[D] ₅₈₉ = +92.40 (c=0.50, chloroform) .

(+) - (4aP) - (lObR) -4-methyl-8- (2- [4-chloro]benzothiazolyl; -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [ f] qumolm-3-one

Yield: 177 mg (69%) of the title compound aε an amorphouε solid. mp 206-209°. m/e = 396. α[D] ₅₈₉ = +91.10 (c=0.81, chloroform) .

(+ι - (4aR) - (lObR) -4-methyl-8- (2- [5, 6-dιchloro]benzothiazolyl * - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumol -3-one

Yield: 113 mg (40%) of the title compound as an amorphous foam. FDMS: m/e = 431. α[D] ₅₈₉ = +79.41 (c=0.79, chloroform) .

Examole 264

(+) - (4aR) - (lObR) -4-methyl-8- (2- [4-isopropyl]benzothiazolyl) - lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 94 mg (36%) of the title compound as an amorphous solid, mp: 170-180°. FDMS: m/e = 404.

Example 265 (+) - (4aR) - (lObR) -4-methyl-8- (2- [6-chloro]benzothiazolyl) -10b- methyl-1, 2,3,4, 4a, 5,6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 100 mg (39%) of the title compound as a white solid, mp: 123-125°. FDMS: m/e = 396. α[D] ₅₈₉ = +73.63 (c=1.26, methanol) .

The following preparation and example illustrate the synthesis of compounds of the present invention wherein the X group is an oxygen atom.

Preparation 10

(+)- (4aRX (lObR) -4-methyl-8-hydroxy-10b-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

To a suspension of (+) - (4aR) - (lObR) -4-methyl-10b- methyl-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] -qumolm-3-one-8- boronic acid (1.0 g, 3.7 mmol) in 30 mL of THF was added 3 N sodium hydroxide (6 mL) followed by 6.0 mL of 30% hydrogen peroxide at -30°. The cold bath was removed, and the mixture was stirred at room temperature for 2.5 h. Six mL of saturated aqueouε εodium sulfite solution waε added, followed by 5 N hydrochloric acid until solution was acidic. Volatiles were removed via rotary evaporation, and the crude solid was heated in ethyl acetate and filtered to give 441 mg (53%) of the title compound as an amorphous solid. FDMS m/e = 245.

Example 266 (+) - (4aR) - (lObR) -4-methyl-8- (2-qumolιnyloxy) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quιnolm-3-one

A 50 mL round bottom flask was charged with (+)-

(4aR) - (10bR)-4-methyl-8-hydroxy-10b-methyl-l,2,3,4,4a,- 5, 6, lOb-octahydrobenzo[f]qumolιn-3-one (300 mg, 1.22 mmol), tetrabutylammonium chloride (339 mg, 1.22 mmol) , 2-chloro- qumolme (200 mg, 1.22mmol) , 4 mL of 50% sodium hydroxide solution, and 4 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 100°, under nitrogen, for 24 h. The mixture was cooled, diluted with water (50 mL) and extracted with chloroform (3 x 100 mL) . The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (60% ethyl acetate/hexanes eluent; followed by an additional

chromatography on a short silica column, eluting with 10% ethyl acetate/dichloromethane) to give 52 mg (11%) of the title compound as a white solid. mp 172-174°. FDMS: m/e 372. α[D] ₅₈₉ = +67.74 (c=0.43, chloroform) .

The following preparation and examples illustrate syntheses of compounds of the invention wherein the group X incorporates an amino group, and the synthesis uses a starting material having an amino substituent on the benzoquinolinone nucleus.

Preparation 11 (4aR) - (lObR) -8-formamido-4,10b-dimethyl-l,2,3, 4, 4a, 5, 6, 10b- octahydrobenzo[f]quinoline-3-one

In a sealable, heavy-walled pyrex tube equipped with teflon εtirring bar was placed (4aR) - (lObR) -8-bromo-

4, lOb-dimethyl-1, 2, 3, 4, a, 5, 6, lOb-octahydrobenzo[f]quinoline- 3-one (500 mg, 1.6 mmol), copper(I) iodide (340 mg, 1.8 mmol) , powdered potassium carbonate (500 mg, 3.6 mmol) and formamide (40 mL) . The mixture was purged with nitrogen for 10 minutes and the tube sealed. The mixture was heated to 125° for 18 h. After cooling to ambient temperature, the tube was opened and the contents partitioned between water

(250 mL) and ethyl acetate (250 mL) . The aqueous phase waε extracted with ethyl acetate (2X 100 mL) and the combined organic phase was dried over anhydrous magnesium sulfate and concentrated to afford crude 8-formamιdo intermediate product (220 mg) which was utilized without further purification. m/e 272.

The crude intermediate product was dissolved in ethyl acetate (50 mL) , 5 N hydrochloric acid solution (10 mL) was added and the solution stirred at ambient temperature for 2.5 h. The mixture was made basic with aqueous ammonium hydroxide solution and extracted with ethyl acetate (2 X 50 mL) . The combined organic phase was dried over anhydrouε magneεium εulfate and concentrated to afford crude product (90 mg) which waε utilized without further purification, m/e 244.

Example 267 ( + ) - ( 4aR) - ( lObR) -4 , 10b-dιmethyl -8 -benzoylamιno- l , 2 , 3 , 4 , 4a , 5 , 6 , lOb-octahydrobenzo [ f ] quιnolm-3 -one

A 200 mg portion of (4aR) - (lObR) -4, 10b-dιmethyl-8- ammo-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] -qumolm-3-one waε diεsolved in 50 mL of THF and a slight excesε of benzoyl chloride was added. The mixture was stirred at ambient temperature for 3 h, and volatileε were then removed under vacuum. The resulting oil was triturated with diethyl ether, and the resulting solids were purified by chromatography on silica gel, elutmg with 50% methanol/ethyl acetate. A yield

of 104 mg of solid product was obtained from the column and found to be the desired product, m.p. 220-222°. FDMS: m/e = 348. α[D] ₅₈₉ = +75.53°

The following examples were carried out according to the process of Example 267.

Example 268 (+) - (4aR) - (lObR) -4,10b-dimethyl-8- (3-nitrobenzoylamino) - 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 595 mg of the desired product, m.p. 240-242°. FDMS: m/e = 393. α[D] ₅₈₉ = +75.79°

(4aR) - (lObR) -4, 10b-dimethyl-8- (4-nitrobenzoylamino) - 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] uinolin-3-one

Yield: 38.2 mg of the desired product, m.p. 269-270°. FDMS: m/e = 393.

Examole 270 (4aR) - (lObR) -4, 10b-dimethyl-8- (3-aminobenzoylamino) - 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

Yield: 80.5 mg of purified product, m.p. 154-156°. FDMS: m/e = 363.

(4aR) - (lObR) -4, 10b-dimethyl-8- (4-aminobenzoylamino) - 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 30.6 mg of the desired product. FDMS: m/e = 363

(+) - (4aR) - (lObR) -4-methyl-8- (3-diphenylmethylaminophenyl) - lOb-methyl-l, 2,3,4, 4a, 5,6, lOb-octahydrobenzo[f] quinolin-3-one

Yield: 28 mg (83%) of the title compound as a white solid. mp 109-111°. FDMS: m/e = 486. α[D] ₅₈₉ =+46.90 (c = 0.49, methanol) .

Examole 273

(+)- (4aR)- (lObR) -4-methyl-8- (3- [benzoylamino] henyl) -10b- methyl-1,2,3,4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 50 mg (76%) of the title compound as an amorphous foam, mp 257-262° (decomp.) FDMS m/e = 424. α[D] ₅₈₉ = +62.50 (c

= 0.61, chloroform) .

(+)- (4aRX (lObR) -4-methyl-8- (3- [pivaloylamino]phenyl) -10b- methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

Yield: 25 mg (64%) of the title compound as a yellow solid. mp 95-98°. FDMS m/e = 404. α[D]s ₈₉ = +62.50 (c = 0.16, chloroform) .

The following group of examples demonstrates typical synthesis of compounds having X groups which are alkyl, alkenyl, and alkynyl.

Examole 275 (+) - (4aR) - (lObR) -4-methyl-8- (3-phenylpropyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

To a solution of allylbenzene (106 mg, 0.89 mmol) in 0.5 mL of THF was added 9-BBN (0.89 mmol, 1 equiv) in THF, at 0°. Let stir for 1 h, warming to 5°. To the mixture was added (+) - (4aR)- (lObR) -8-bromo-10b-methyl-l, 2, 3 , 4, 4a, 5, 6, 10b- octahydrobenzo[f]quinolin-3-one (250 mg, 0.812 mmol) , triphenyl phosphine (42 mg, 0.16 equiv.) , tetrakis (triphenylphosphine) palladium(0) (19 mg, 0.02 equiv. ) , 1 mL of 3 N sodium hydroxide solution and an additional 1 mL of THF. The resulting mixture was heated at 80° for 18 h, cooled, and ethanolamine was added, followed by ethyl acetate. The resulting organic phase was washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel chromatography (50-100% ethyl acetate / hexanes eluent gradient) to give 160 mg (59%) of the title compound as an oil. FDMS m/e = 347.

E.xawple 27$ (+)- (4aRX (lObR) -4-methyl-8- (2- [2-naphthyl] ethyl) -lOb-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

To a solution of 2-vinylnaphthalene (138 mg, 0.89 mmol) in 0.5 mL of THF was added 9-BBN (0.89 mmol, 1 equiv) in THF, at 0°. Let stir for 1 h, warming to 5°. To the mixture was added (+) - (4aR) - (lObR) -4-H-8-bromo-10b-methyl- 1, 2, 3 , 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one (250 mg, 0.812 mmol), triphenyl phosphine, (42 mg, 0.16 equiv.), tetrakis (triphenylphosphine) palladium(0) (19 mg, 0.02 equiv. ) , 1 mL of 3 N sodium hydroxide solution and an additional 1 mL of THF. The resulting mixture was heated at 80° for 18 h, cooled, and ethanolamine was added, followed by ethyl acetate. The resulting organic phase was washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel chromatography (50-100% ethyl acetate / hexanes eluent gradient) to give 186 mg (60%) of the title compound as a tan solid. mp 109-110°. FDMS m/e = 383. α[D] ₅₈₉ =

+46.45 (c =0.66, chloroform) .

Preparation 12 (4aR)-(10bR)-4,10b-dimethyl-8-allyl-l,2,3,4,4a, 5,6,10b- octahydrobenzo[f]quinolin-3-one

A 9 g portion of (4aR) - (lObR) -4, 10b-dimethyl-8- bromo-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one was combined with 11.1 g of tri-n-butyl-2-propenylεtannane and 1.69 g of tetrakis (triphenylphosphene) palladium in 40 mL of acetonitrile in a sealable tube. Argon was bubbled through the mixture, the cap replaced, and the reaction heated at 90° for 18 h. Upon cooling, the mixture was filtered and the filtrate waε concentrated under vacuum. The residue was triturated with diethyl ether to obtain 4.23 g of crystalline product, and a second crop of 1.31 g of product was also obtained. mp 144 -146°; FDMS 255 M+; Calcd for C ₁₇ H ₂₁ N ₁ θ ₂ :

Preoara ion 13 (4aR) - (10bR)-4,10b-dimethyl-8-carboxymethyl-l,2,3,4,4a, 5,6,lOb-octahydrobenzo[f] uinolin-3-one

A 158 mg portion of the product of Preparation 12 was dissolved in 4 mL of acetonitrile, and a solution of 378 mg of sodium periodate in 4 mL of water was added, followed by 18 mg of ruthenium trichloride. The mixture was stirred at ambient temperature for 18 h, and diluted with dichloromethane. The organic layer was removed, and the aqueous layer extracted with dichloromethane. The organic layers were combined, washed with water, dried, filtered and evaporated to a brown foam. The residue was dissolved in dichloromethane and extracted with saturated aqueous sodium bicarbonate to which a few milliliters of 10% aqueous sodium carbonate had been added. The basic aqueous extract was made acid with hydrochloric acid, and extracted with dichloro- methane. The organic layer was then dried and evaporated under vacuum to obtain 51 mg of a solid, which was recrystallized from ethyl acetate/hexane to obtain the desired product in purified form, mp: 200-202°;

Examole 277 (4aR) - (lObR) -4, 10b-dimethyl-8-phenylaminocarbonylmethyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

A 200 mg portion of the product of Preparation 13 was dissolved in 5 mL of dimethylformamide, and 135 mg of 1, 1 ' -carbonyldiimidazole was added. The reaction mixture was blanketed with nitrogen, and was stirred at ambient temperature for 4 h, at which time 0.1 mL of aniline was added. The solution was then stirred briefly, and concentrated under vacuum. The residue was dissolved in dichloromethane and washed with IN hydrochloric acid, 10% sodium sulfate, water and brine. The solution was then dried, filtered and evaporated to obtain 220 mg of crude product. It was purified by chromatography on a silica gel column, eluting with 3% isopropanol in chloroform. The product-containing fractions were combined, evaporated and recrystallized from ethyl acetate to obtain the deεired product in pure form, mp 192-195°; FDMS 362 M+;

Example 278 (4aR)- (lObR) -4, 10b-dimethyl-8- (2-thioρhenyl) -1, 2, 3 , 4, 4a, 5,6, lOb-octahydrobenzo[f]quinolin-3-one

Five hundred mg of (4aR) - (lObR) -4, 10b-dimethyl-8- bromo-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one waε combined with 730 mg of 2- (tri-n-butylstannyl) thiophene and 100 mg of bis (triphenylphosphene) palladium chloride in 6 mL of acetonitrile in a screw capped sealable tube. The mixture was fluεhed with argon for 5 minutes, capped and heated at 90° for 20 h. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuum. The reεidue was purified by chromatography on a silica gel column, eluting with ethyl acetate, and the isolated product was recrystallized from ethyl acetate/hexane/chloroform to obtain 167 mg of the desired product. mp: 193-195°; FDMS 311.

Example 279 ( 4aR ) - ( lObR) -4 , 10b-dιmethyl - 8- ( 2 -phenylethenyl ) - 1 , 2 , 3 , 4 , 4a , 5 , 6 , l Ob-octahydrobenzo [ f ] qumol m- 3 - one

Five hundred mg of (4aR) - (lObR) -4, 10b-dιmethyl-8- bromo-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] qumolm-3-one, 4 mg of palladium acetate, 20 mg of tri-o-tolylphoεphme, 0.34 mL of triethylamine and 5 mL of dimethylformamide were placed a εcrew capped sealable tube with a stir bar. The mixture was warmed to 60° and then 200 mg of styrene was added and the vesεel waε fluεhed with argon. The veεεel waε then capped and heated at 120° for 24 h. The reaction mixture waε cooled, diluted with ethyl acetate and filtered and the filtrate waε concentrated under vacuum. The reεidue waε dissolved in chloroform and washed twice with water. The organic layer waε dried, filtered and evaporated under vacuum to obtain 400 mg of reεidue, which waε recrystallized from ethyl acetate to obtain the desired product, m.p. 173-175°. FDMS m/e = 331.

found

83.12

7.64 4.14

gxample 2 Q

(4aR) - (lObR) -4,10b-dimethyl-8- (2-phenylethyl) - 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

A 150 mg portion of the product of Example 279 was hydrogenated on a Parr apparatus at 40 p.s.i. in 50 mL of ethanol containing 5 mL of dimethylformamide and 20 mg of 10% palladium/carbon catalyst. When the starting material had been consumed, the mixture was filtered and the filtrate waε concentrated under vacuum. The residue was purified by chromatography on silica gel, eluting with 90% ethyl acetate/hexane to obtain a product which was recrystallized from ethyl acetate/hexane to produce the deεired product, m.p. 109-111°.

Example 281 (4aR) - (lObR) -4, 10b-dιmethyl-8- (2- [4-ιsoqumolmyl] ethenyl) 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]qumol -3-one

A 508 mg portion of (4aR) - (lObR) -4, 10b-dιmethyl-8- bromo-1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one, 4 mg of palladium acetate, 20 mg of tri-o-tolylphosphme, 0.34 mL of triethylamine and 5 mL of dimethylformamide were combined m a sealable tube with a stir bar, and the mixture was warmed to 50° under argon. An 0.26 g portion of 4- ethenylisoqumolme was added. Then the veεεel waε blanketed with argon and εealed and the mixture was heated with stirring at 120° for 20 hours. It waε then cooled, and concentrated under vacuum and the residue was purified by chromatography on silica gel, elut g with 5% isopropanol in chloroform. An 0.29 g portion of an oil was obtained, which was recrystallized from ethyl acetate/hexane to obtain the desired product m crystalline form. mp 183-185°; FDMS 382 M+.

Examole 282 (4aR) - (lObR) -4, 10b-dimethyl-8- (2- [3-quinolinyl] ethenyl: 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

A 290 mg portion of 3-ethenylquinoline was used in a process otherwise εimilar to that of Example 281 to obtain the title product. mp 181-183°; FDMS 382.

Example 283 (4aR) - (lObR) -4, 10b-dimethyl-8- (2- [2-quinolinyl] ethenyl) 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f] quinolin-3-one

The procesε of Example 281 waε substantially repeated, using 0.34 g of 2-ethenylquinoline as the starting material to obtain the title product. mp 233-236°; FDMS 382.

Examole 284 (4aR) - (lObR) -4,10b-dimethyl-8- (2-phenylethynyl) - 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one

A 1 g portion of (4aR) - (lObR) -4, 10b-dimethyl-8- bromo-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one was reacted with 0.4 mL of phenylacetylene in a process substantially similar to that of Example 281 to obtain the desired title product in pure form. mp 205-208°; FDMS 329.

Example 285 (4aR) - (lObR) -4, 10b-dιmethyl-8- (2-phenyiethenyl) - 1,2, 3, , 4a, 5, 6, lOb-octahydrobenzo[f] qumolm-3-one

A 300 mg portion of the product of Example 284 waε hydrogenated over palladium/barium sulfate catalyεt 25 mL of pyridme at 15 pεi hydrogen preεεure at ambient temperature for 1 h. The mixture waε tnen filtered and concentrated under vacuum, and the residue waε purified oy chromatography on silica gel, elutmg with 75 % ethyl acetate ''hexane. The product thereby obtained was further purified on a Chromatatron, elut g witn 5% isopropanol m chloroform to obtain the desired product in the form of a yellow oil. High resolution mass εpectroscopy showed the correct molecular ion of 332.201440.

Example 286 (4aR)- (10bR)-8-benzoyl-4,10b-dimethyl-l,2,3,4,4a,5, 6, 10b- octahydrobenzo[ ]quinolin-3-one

A. To a solution of (4aR) - (lObR) -10b-methyl-8- bromo-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo[f]quinolin-3-one in 25 mL of THF at -78° under an atmosphere of nitrogen was added 330 μL of a 1.4 M solution of methyllithium in diethyl ether (0.46 mmol) . The reaction mixture turned bright yellow, and after 10 min, 470 μl of a 1.7 M solution of t- butyllithium in pentane (0.80 mmol) was added. The reaction mixture was stirred for 10 min before the addition of benzaldehyde (80 μL, 0.79 mmol) as a single aliquot. The reaction waε warmed to room temperature and stirred for 30 min before partitioning between diethyl ether and IN hydrochloric acid. The ether layer was dried over sodium εulfate, filtered and evaporated under reduced preεsure to afford 0.1818 g crude product. The material was purified on a Chromatotron (2mm plate, dry loaded with chloroform, eluted with 5% methanol/chloroform) to give 106 mg of desired product. A portion of this material was triturated with diethyl ether to yield a white solid. mp 116-118; FDMS: m/e = 321. α[D] ₅₈₉ = 130.39

B. To a εolution of the alcohol prepared aε deεcπbed above (395 mg, 1.2 mmol) m 40 mL of acetone at 0° waε added dropwise 1 mL (2.54 mmol) of a 2.54 M solution of Jones Reagent. The reaction mixture was stirred at 0° for 15 mm. before the addition of 2 mL of lεopropanol to quench the excess reagent. The mixture was partitioned between ethyl acetate and brme. The aqueous layer waε extracted with chloroform. The combined organic layers were washed with water (100 mL) , dried (sodium sulfate) , filtered and evaporated under reduced pressure to afford crude product. This material was purified on a chromatotron (2mm plate, dry loaded with chloroform, eluted with 5% methanol/chloroform) to give 166 mg of desired product (42% yield) . This mterial was methylated using the εtandard potassium t-butoxide/methyl iodide m t-butanol method to afford 170 mg crude product. This material was purified on a chromatotron (2mm plate, eluted wih ethyl acetate) to give 113 mg of desired white solid (65% yield) ; mp 173-175°; FDMS: m/e=334; α[D] ₅₈₉ = 80.39 (c=0.5 in chloroform) .

Examole 287 (4aR) - (10bR)-8-benzyl-4,10b-dimethyl-l,2,3,4,4a,5, 6,10b- octahydrobenzo[f]quinolin-3-one

A solution of the hydroxymethyl compound prepared in part A of the example above, in 80 mL of ethanol with 23.5 mg of 10% Pd/C catalyst, was shaken under an atmosphere of 40 psi of hydrogen for 24 h. Reaction was not complete and an additional 29 mg of 10% Pd/C was added. After an additional 48 h, the mixture was filtered through celite and concentrated under reduced pressure to yield 141 mg of crude product which was methylated using the standard potassium t-butoxide/methyl iodide in t-butanol method to afford 120 mg of deεired product. This material was purified on a Chromatotron (2mm plate, eluted with 1% isopropanol in ethyl acetate) to give 87 mg of white solid. This material was further purified by recrystallizatio from a 10:1 mixture of hexane.-ethyl acetate to afford 30 mg of product. mp 99- 101°C; FDMS: m/e = 319 α[D] ₅₈₉ = 77.08

Exampl e 288

(4aR - (lObR) -8- (2-chlorobenzoyl) -4, 1Ob- imethy1-1, 2 , 3 , 4,4a, 5,6, lOb-octahydrobenzo [f]qumolm-3-one

To a solution of (4aR) - (lObR) -10b-methyl-8-bromo- 1, 2 , 3 , 4 , 4a, 5, 6, lOb-octahydrobenzo [f] qumolm-3-one m 50 mL of THF at -78° under an atmoεphere of nitrogen waε added 2.25 mL of a 1.4 M solution of methyllithium diethyl ether (3.15 mmol) . After 10 mm, 3.34 mL of a 1.7 M solution of t-butyllithium in pentane (5.68 mmol) was added. The reaction mixture waε εtirred for 10 mm before the addition of 2-chlorobenzaldehyde (870 mL, 7.72 mmol) aε a single aliquot. The reaction was warmed to room temperature and stirred for 2 h before partitioning between ethyl acetate and IN hydrochloric acid. The organic layer was dried, filtered and evaporated under reduced pressure to afford 1.7 g of crude product. The material waε purified on a Chromatotron 14 mm plate, dry loaded with chloroform, eluted with 5% methanol/chloroform) to give 435.5 mg of deεired product (47% yieldX mp 105-115°; FDMS: m/e = 355, 35'

To a solution of the alcohol prepared as described above (211.7 mg, 0.6 mmol) m 25 mL of acetone at 0° was added dropwise 0.5 mL (1.27 mmol) of a 2.54 M solution of Jones Reagent. The reaction mixture waε εtirred at 0° for 30

min before the addition of 2 mL of ι_ _. oropanol to quench the excess reagent. The mixture was partitioned between chloroform and brine. The organic layer was dried, filtered and evaporated under reduced pressure to afford crude product. This material was purified on a Chromatotron (2mm plate, dry loaded with chloroform, eluted with 5% methanol/chloroform to give 81.0 mg of desired product.

This material waε methylated uεing the εtandard potassium t-butoxide/methyl iodide in t-butanol method to afford 160 mg crude product. This material was purified on a Chromatotron (2mm plate, eluted with 2% methanol/ethyl acetate) followed by a εecond Chromatotron run (2mm plate, eluted with 5% methanol/chloroform) to give 61 mg of white foam after concentration from diethyl ether (65%) yield: mp 65-70°

Example 289

(4aR) - (lObR) -8-phenylthiomethyl-10b-methyl- 1,2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f]quinolin-3-one

A. To a solution of (4aR) - (lObR) -10b-methyl-8- bromo-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one in 60 mL of THF at -78° under an atmoεphere of nitrogen was added 2.9 mL of a 1.4 M solution of metryllithium in diethyl ether (4.1 mmol) . After 20 min, 4.8 mL of a 1.7 M solution of t-butyllithium in pentane (8.2 mmol) was added. The reaction mixture was stirred for 45 min before the addition of dimethylformamide (0.63 mL, 8.1 mmol) . The reaction was warmed to room temperature before partitioning between ethyl acetate and 1 N hydrochloric acid. The organic layer was

waεhed with additional 1 N hydrochloric acid, εaturateα sodium bicarbonate, brine and then dried (sodium sulfate , filtered and evaporated under reduced preεεure to afford 665 mg deεired product (80% crude yield) . Thiε material waε taken on without further purification.

B. To a εolution of the aldehyde prepared above (665 mg, 2.73 mmol) in 50 mL of abεolute ethanol waε added 2 equivalentε of εodium borohydride (207 mg, 5.4 mmol ⁾ . The reaction mixture waε εtirred at room temperature for 18 h before the addition of 50 mL of IN hydrochloric acid. After stirring for 1.5 h, ethyl acetate was added and the material concentrated to remove ethanol. The residual aqueouε layer waε extracted with ethyl acetate and the organic layer waε washed with brme, dried (sodium sulfate) , and concentrated under reduced pressure to afford 436 mg of crude product. This material was purified on a Chromatotron (eluted with 3% methanol/chloroform) to give 310 mg of desired white solid (46 % yield) : mp 176-177 °; FDMS: m/e = 245; α[D] 89 = 120.08 (c = 0.5 m methanol) .

C. To a solution of the alcohol prepared as described above (462.3 mg, 1.88 mmol) m 40 mL of anhydrouε acetonitrile was added 0.8 mL of neat trimethylsilyl iodide (5.6 mmol) . After 30 minutes, the reaction mixture was concentrated and the residue partitioned between ethyl acetate and saturated thiosulfate. The organic layer waε waεhed with brine, dried (εodium εulfate) and concentrated under reduced pressure to yield 664 mg of crude product. This material was purified on a Chromatotron (4 mm plate, eluted with 3% methanol/chloroform) to give 597 mg of desired solid (89 % yield) : mp 215-217 °; FDMS: m/e = 355, 228 (m -

1) ; α[D]589 = 99.12 (c = 0.5 in methanol . Material was taken on without further purification.

D. To a solution of the iodide prepared aε described above (249.4 mg, 0.70 mmol) in 25 mL of THF was added a εolution of 145 μL of phenylmercaptan (1.4 mmol) and 210 μL of DBU (???) (1.4 mmol) in 5 mL of THF. After εtirring at room temperature for 2 dayε, the reaction mixture waε partitioned between IN hydrochloric acid and ethyl acetate. The organic layer waε washed sequentially with IN hydrochloric acid, IN sodium hydroxide, and brine before being dried (sodium sulfate) and concentrated under reduced pressure to yield 293 mg of crude product. This material was purified on a Chromatotron (4 mm plate, eluted with 3% methanol/chloroform) followed by recrystallization from ethyl acetate to give 166 mg of desired white solid (70% yield) : mp 187-189°; FDMS: m/e = 337; α[D]589 = 82.27 (c = 0.5 in methanol) .

(4aR) - (lObR) -8- (2-benzothiazolyl) thiomethyl-lOb-methyl- 1,2, 3, 4, a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one

To a solution of the lodomethyl compound prepared in Step C of Example 289 in 25 mL of THF was added a solution of 252 mg of 2-mercaptobenzothιazole (1.5 mmol) and 226 mL of diazabicycloundecane (DBU) (1.5 mmol) m 5 mL of THF. After stirring at room temperature for 2 days, the reaction mixture was partitioned between IN hydrochloric acid and ethyl acetate. The organic layer waε washed sequentially with IN hydrochloric acid, IN εodium hydroxide, and br e before being dried (εodium sulfate) and concentrated under reduced pressure to yield 382 mg of crude product. Thiε material was purified on a Chromatotron (4 mm plate, eluted with 3% methanol/chloroform) followed by recryεtallization from ethyl acetate to give 193 mg of desired white solid. mp 201-202°. FDMS: m/e = 394. α[D] ₅₈₉ = 75.70

(+) - (4aR) - (lObR) -8-phenylcarboxamιdo-1Ob-methyl-1,2, 3 , 4,4a, 5,6, lOb-octahydrobenzo [f] quιnol e-3-one

In a flame-dried 3-neck round bottom flaεk equipped with magnetic stirrer and nitrogen mlet was dissolved (4aR)- (lObR) -8-bromo-1Ob-methyl-1,2, 3, 4, 4a, 5,6, lOb-octahydro- benzo[f]quιnolιne-3-one (500 mg, 1.7 mmol) , anhydrous THF

(50 mL) . The solution waε cooled to -78° and treated with ethereal methyllithium (1.3 mL, 1.4M, 1.8 mmol) added dropwise over 2 mm. After further stirring for 15 min., a solution of t-butyllithium (2.1 mL, 1.7 M pentane, 3.6 mmol) was added dropwise. Following complete addition, the suspension was treated with phenylisocyanate (418 μL, 3.6 mmol) a single portion. The mixture was warmed to ambient temperature and acidified with 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate and the organic phase washed with brme and dried over anhydrous magnesium sulfate. Removal of solvent and chromatography of the crude product on silica gel (0.5% aqueous ammonium hydroxide/ethyl acetate as eluent) and crystallization from ethyl acetate afforded product as tan solid, m/e 334, OR

(c=1.0, MeOH) @589 nM, +100.1°, @365 nM, +308.4°.

(+ - (4aR) - (lObR) -4-methyl-8- (3-dιphenylmethylammo- methylphenyl) -lOb-methyl-l, 2, 3, 4, 4a, 5, 6, lOb-octahydro- benzo [f]qumolm-3-one

To a suspenεion of (+) - (4aR) - (lObR) -4-methyl-8- (3- formylphenyl) -lOb-methyl-l, 2 , 3 , 4, 4a, 5, 6,10b- octahydrobenzo [f] qumolm-3-one (30 mg, 0.09 mmol) , m 0.75 mL of methanol waε added benzhydryl amme (0.09 mmol) , εodium cyanoborohydride (0.09 mmol) and 2 dropε of glacial acetic acid (mixture became homogeneouε; pH = 4) . The reaction was εtirred at room temperature for 60 h. The mixture waε diluted with ethyl acetate, εaturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted repeatedly with ethyl acetate. The combined organic extractε were dried over εodium εulfate, concentrated, and purified by silica gel cnromatography (ethyl acetate eluent) , followed by trituration of the resulting oil with ether / hexanes, to give 36 mg (80%) of the title compound as a white solid. mp 55-57°. FDMS: m/e = 500. α[D] ₅₈₉ =+48.40 (c = 0.64, methanol) .

Bioloσical Testing

Representative compounds of the present invention have been tested in standardized biological test methods in order to determine their activity aε inhibitors of both Type I and Type II 5AR. The following test methods are adapted to routine use and may be followed conveniently by the skilled reader.

Methodology of Human Type I and Type II Steroid 5α -Reductase Assays

Preparation of Type I 5α-Reductase from Human Scalp:

Scalp punch biopsies from graft recipient sites were obtained from human hair transplant procedures immediately after surgery and were frozen on dry ice and stored at -80°C. Approximately 60-75 punches from one surgical procedure were used to generate an enzyme preparation. The subcutaneous tissue was cut away and discarded. The skin was frozen with liquid nitrogen and pulverized to powder. The powder was homogenized in 30 mL of ice-cold buffer (20 mM Triε-HCl, pH 7.5) using a Brinkmann Polytron (Westbury, NY) with a PTA 10- S probe and a setting of 7. The homogenization procedure consiεted of four 15 second pulses. Connective tissue was cleared from the probe with forceps between pulses. The homogenate was then filtered through cheese cloth and the filtrate centrifuged at 100,000 x g for one hour in a Beckman L8-60M ultracentrifuge. The pellet was resuspended by homogenization with a Dounce homogenizer using the same buffer solution. An aliquot was taken for protein determination by the Lowry method, Lowry, e_£ ϋl- Protein Measurement with the Folin Phenol Reagent, J. Biol. Chem.. 193. 265-75 (1951) . Aliquots of the enzyme preparation were stored at -80° until use.

Preparation of Type II 5α -Reductase from Human Prostate: The same procedure as above was used for preparations using tisεue from proεtate εurgery with the following changeε: The buffer used was 20 mM sodium phoεphate, pH 6.5; and the pellet waε reεuεpended m the εodium phoεphate buffer containing 20% glycerol .

Human 5α-Reductase Assay: Thiε enzyme aεεay lε based on the conversion of [3H] -testosterone to [^H]-5α -dihydrotestoεterone (DHT) and other 5α -reduced metabolites. While about 90% of the 5α-reduced metabolites formed m these assays was DHT, androεtanedione waε formed at about 10%. Essentially no androεterone was detected. In a total volume of 1.0 mL, the Type I asεay contained 2.6 μCi [-^H]- teεtoεterone (50 nM) , 500 μM of reduced nicotine adenme dmucleotide phosphate, 100 mM Triε-HCl, pH 7.5 , (m Type II assayε, 40 mM sodium acetate at pH 5.5 is used instead of Tris-HCl) and teεt compoundε aε indicated. Teεt compounds were added in 20 μL of dimethylsulfoxide (20 μL of dimethylsulfoxide was added to blanks and controls) . The reaction was initiated by the addition of 0.5 mg of Type I or Type II 5α -reductase. The reaction mixture was incubated at

25° for 30 mm m Type II assays, or 180 mm m Type I assays, and terminated by the addition of 1 mL ice-cold stopping solution. The stopping solution contained 40 μM each of non-radioactive teεtoεterone, DHT, androstenedione, androεtanedione, androεterone, androεtan-3β, 17β- diol, and androstan-3α, 17β-dιol.

The samples were prepared for high performance liquid chromatography by solid phaεe extraction. Diεpoεable solid matrix extraction columnε (C-18 reversed phase, 6 mL, 500 mg; Bond Elut™ from Analytichem International; Harbor City, CAi were conditioned by washing with 5 mL of methanol followed b 5 mL of deionized water. The reaction mixtures were tnen applied to the columns. The columns were subεequently washed

with 5 mL of acetone:water (1:4) , followed by 0.3 mL of methanol. The εampleε were then eluted with 3 mL of methanol and collected in 20 mL εcintillation vialε. Three mL of water waε then added to each εcintillation vial. The εolutionε were then tranεferred to tubeε and centrifuged for 30 min at 1000 x g to remove any particulate material before chromatography.

The [^H] -teεtoεterone εubstrate and its metabolites were separated by chromatography using a C-18 reversed phase column (Beckman Ultrasphere 5μm spherical 80A pore, part no. 235329, 4.6 mm i.d. x 25 mm length) with an isocratic mobile phase (46 water: 46 methanol: 8 tetrahydrofuran by volume) . The column temperature was maintained at 35° and the flow rate waε 1.5 mL/min. A 400 μL aliquot waε injected onto the column and radioactivity waε determined uεing a Beckman 171 in-line flov; radioiεotope detector in conjunction with Rainin Dynamax™ εoftware and a Macintoεh computer. The flow rate of the Atomflow™ εcintillation fluid waε 4.5 mL / min.

While in moεt instances the compounds listed below have been tested at various concentrations, only the test reεults at 0.3 μ M concentration are shown here, in order to reduce the bulk of the following table. The data are reported as percent inhibition of Type I and Type II AR produced by each compound at that concentration, compared to control reaction mixtureε.

Table I

Type II

51 91 14 52 68 10 53 100, 66 41 54 22 55 68 11 56 92 3 57 20 58 65 24 59 31 60 42 61 53 36 62 45 42 63 19 64 81 22 65 79 42 66 67 33 67 22 54 68 31 37 69 84 6 70 36 71 80 47 72 16 26 73 87 16 74 16 26 75 63 40 76 83 46 77 88 46, 33 78 3 79 34 80 76 29 81 92 25 82 85 31 83 12 84 88 23 85 12 86 66 51 87 83 28 88 96 43 89 15 90 22 91 87 32 92 10 93 9 94 1 95 9- 35 96 52 97 98 76 61, 44 99 88 65, 29 100 96 51, 34 101 75 43 102 92 61 103 81 58 104 89 41 105 92 33

106 73 39

107 80 83

108 100 29

109 97 25

110 97 73

111 44 38

112 64 90, 92

113 70 51

114 55 47

115 31 20

116 - 24

117 46 49

118 25 43

119 84 59, 24

120 93 37

121 - 41

122 - 36

123 10 27

124 23 32

125 64 36

126 85 43

127 - 40

128 82 40

129 91 36

130 83 29

131 57 44

132 87 24

133 77 34

134 97 46

135 92 31

136 100 32

137 90 37

138 88 26

139 30 59

140 - 20

141 - 19

142 22 40

143 63 18

144 90 40

145 85 41

146 13 32

147 35 83, 83

148 2 12

149 58 33

150 67 69

151 31 28

152 47 10

153 49 71

154 56 25

155 58 60

156 71 70

157 88 79

158 78 63

159 87, 87 87, 83

160 61 38

161 71 51

162 79 87

163 80 86

164 85, 87 86, 85, 79

165 61 74

166 50 49

167 62 31

168 85 41

169 75 61 170

171 43 63

172 55 36

173 65 78, 77

174 82 80

175 58 40

176 25 15

177 58 15 178

179 61 28

180 59 30

181 63 31

182 63 100

183 89 88, 87

184 73 81

185 88 90

186 90 79

187 93 94

188 88 78

189 84 19

190 76 26

191 65 19, 28

192 80 33 193

194

195 90 71

196 11 45

197 - 37

198 - 7

199 - 30

200 59 72, 64

201 69 60, 57

202 41 48

203 8 34

204 34 39

205 100 37

206 97, 100 32

207 45 16

208 77 10

209 24 11

210 81 38

211 70 29

212 73 31

213 64 28

214 26 29

215 84 42

L oo t b

h^ Lπ ib b l ib ib i i J Lπ L L π L rvJ L i b L U^ ω iii ^μ fc o i ^μ io o ib m co M ^j oj M fc m fc M w σi fc W fc i'-. ω j j ω -j M o co - μ w μ

271 - 3 ₆

272 86 11

273 - 27

274 34 32

275 75 44

276 92 33

277 42 40

278 - 28

279 85 60

280 97, 100 33

281 75 44

282 75 37

283 87 37

284 86 63

285 93 36

286 53 38

287 82 37

288 19 12

289 23 24

290 25 8

291 - 19

292 86 11

The Table above clearly showε that the compoundε of the present invention are useful for inhibiting the conversion of testosterone to 5α -dihydrotestosterone 5AP , and, more particularly, that many of the compounds are quite effective m inhibiting that action of both Type I and Type II 5AR. Accordingly, an important embodiment of the present invention lε a method for inhibiting 5α -reductaεe which compriεes the administration of a compound of formula I to a patient m need of εuch treatment. Further, the invention provideε a method for treating or preventing conditions consequent upon an exceεs of 5α -reductase or an excess of 5α -reductase activity, comprising the administration of a compound of formula I to such patient.

Still further, the invention provides for the treatment or prevention of benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism or prostate cancer, which methods are carried out by the administration of a compound of formula I to a patient suffering from such condition, or to a patient who is predispoεed toward such condition by an exceεε of 5α -reductaεe or excessive 5α -reductase activity.

Aε haε been noted, Type I 5AR lε found particularly m the εcalp, and lε particularly involved the pathology of conditionε such as alopecia, seborrhea, prostate cancer, acne vulgaris, male pattern baldness and hirsutism. Type II 5AR, on the other hand, is particularly found the prostate and is a strongly contributing factor to prostatic hyperplaεia and perhapε prostate cancer. Accordingly, it is clear that, when a compound is being sought for the treatment of a condition in which Type I 5AR is particularly concerned, one would choose one of the compoundε which lε particularly active in the inhibition of Type I AP . hen the condition to be treated is one which particularly relates to the prostate, then the compound of choice would probably be one which is particularly active against Type II 5AP. It is clear from the above data, however, that the invention provideε numerouε compoundε which are particularly highly active againεt both

lsozymeε, and it is accordingly those doubly highly active compounds which are moεt preferred and are most preferred for use the present methods of therapy.

The administration of compounds of formula I in order to practice the present methods of therapy lε carried out by administering an effective amount of the chosen compound to the patient in need of such treatment or prophylaxis. The effective amount of an individual compound is determined, the final analysis, by the physician m charge of the case, but depends on factorε εuch as the exact diseaεe to be treated, the εeverity of the diseaεe and other diεeases or conditionε from which the patient εuffers, the chosen route of administration, other drugs and treatments which the patient may concomitantly require, and no doubt other factorε in the phyεician'ε judgment. It will be observed that the compounds are active at very low concentrations, and hence at low dosage levels, thereby allowing effective treatment or prophylaxis with slight probability of side effects or cross-reactions with other treatments or drugs. Accordingly, a typical daily dose of a compound of formula I is in the range of from about 0.01 mg/kg to about 1.0 mg/kg of body weight per day. More preferred rangeε of daily dosage are from about 0.05 mg kg tc about 0.5 mg/kg, and, more particularly, from about 0.0" mg/kg to about 0.3 mg/kg per day. The compounds may be administered in a single daily dose, or the daily dose may be administered in portions at intervals through the day, aε is preferred m the judgment of the phyεician.

The compounds can be administered by of routes IΓ luding oral, rectal, transdermal, su: eous, intravenous, intramuscular, mtranasal, and top^_ for male pattern baldness, acne vulgaris, and hirsutism. The compounds of the present invention are preferably formulated prior to administration. Therefore, another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of Formula I or

a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient therefor.

When a compound of Formula I is to be administered for treatment of baldness, acne, seborrhea, alopecia or hirsutiεm, it lε often preferred to formulate it m a topical formulation such aε a gel, ointment or the like, and apply it to the affected skm.

The active ingredient m εuch formulationε compπεeε from 1% to 99% by weight of the formulation. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the compoεition of the preεent invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper, or other container. When the carrier serveε aε a diluent, it may be a solid, semi-solid or liquid material which actε aε a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be m the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions solutions, syrupε, aerosols, (as a solid or in a liquid medium) , soft and hard gelatin capsuleε, εuppoεitories, sterile injectable solutions, sterile packaged powderε, and the like. Typical formulationε designed for topical administration are ointments, creams, gels, and lotions containing, for example, up to 10% by weight of the active compound.

Ointments generally are prepared using either (1) an oleaginous base, i.e., one consisting of fixed oils or hydrocarbons, such as white petrolatum or mineral oil, or (2 an absorbant base, i.e., one consiεting of an anhydrouε εubstance or substances which can absorb water, for example,

anhydrous lanolin. Customarily, following formation cf the base whether oleaginous or absorbent, the active ingredient is added in an amount affording the desired concentration.

Creams are oil/water emulsionε. They conεist of an oil phase (internal phase), comprising typically fixed oils, hydrocarbons, and the like, εuch aε waxes, petrolatum, mineral oil, and the like, and an aqueous phaεe (continuous phase), comprising water and any water-soluble subεtanceε, such as added saltε. The two phaεeε are εtabilized by use of an emulsifying agent, for example, a εurface active agent, εuch as sodium lauryl sulfate; hydrophilic colloids, such as acacia colloidal clays, veegum, and the like. Upon formation of the emulsion, the active ingredient customarily is added in an amount to achieve the desired concentration. Gels comprise a base selected from an oleaginous baεe, water, or an emulεion-εuspension base, such aε described above. To the base is added a gelling agent which forms a matrix in the base, increasing its viεcosity. Examples of gelling agents are hydroxypropyl cellulose, acrylic polymers, and the like. Customarily, the active ingredient is added to the formulation at the desired concentration at a point preceding addition of the gelling agent.

The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way. "Active ingredient," of course, means a compound according to Formula I or a pharmaceutically acceptable salt thereof.

Formulation 1 Hard gelatin capεuleε are prepared using the following ingredients.

Quantity

(mα/caosule) Example 186 250

Search, dried 200

Magnesium stearate 10 Total 460 mg

Formulation 2 A tablet is prepared using the ingredients below:

Quantity (mσ/capsule)

Example 158 250

Cellulose, microcrystallme 400

Silicon dioxide, fumed 10

Stearate acid 5_ Total 665 mg

The components are blended and compressed to form tablets eacn weighing 665 mg.

Formulation 3

An aerosol solution is prepared containing the following components:

Weight Example 157 0.25

Ethanol 25.75

Propellant 22

(Chlorodifluoromethane) 70.00

Total 100.00

The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to

-30°C and tranεferred to a filling device. The required amount iε then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.

Formulation 4

Example 110

Starch Microcrystalline celluloεe

Polyvinylpyrrolidone

(aε 10% solution in water)

Sodium carboxymethyl starch

Magnesium stearate Talc

Total 150 mg

The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.

The aqueous solution containing polyvinyl - pyrrolidone is mixed with the resultant powder, and the mixture then is paεεed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh

U.S. εieve. The εodium carboxymethyl εtarch, magneεium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compresεed on a tablet machine to yield tabletε each weighing 150 mg.

Formulation 5 Capεuleε, ch containing 80 mg of active ingredient, are made follows:

Example 107 80 mg

Starch 59 mg Microcrystalline cellulose 59 mg

Magnesium stearate 3 mα

Total 200 mg

The active ingredient, celluloεe, εtarch, and magneεium εtearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capεuleε in 200 mg quantities.

Formulation 6

Suppositorieε, each containing 225 mg of active ingredient per 5 ml doεe, are made aε follows: Example 188 225 mg

Saturated fatty acid glycerides 2.000 mα

Total 2,225 mg

The active ingredient lε passed through a No. 60 mesh U.S. εieve and suspended in the saturated fatty acid glycerideε previously melted using the minimum heat necessary. The mixture is then poured into a εuppoεitory mold of nominal 2 g capacity and allowed to cool.

Formulation 7 Suεpensions, each containing 50 mg of active ingredient per 5 ml doεe, are made as follows:

Example 164 50 mg

Sodium carboxymethyl cellulose 50 mg

Syrup 1.25 ml

Benzoic acid solution 0.10 ml

Flavor q.v. Color q.v. Purified water to total 5 ml

The active ingredient is pasεed through a No. 45 meεh U.S. εieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the

water and added, with stirring. Sufficient water iε then added to produce the required volume.

Formulation 8 An intravenous formulation may be prepared as follows :

Example 159 100 mg

Isotonic εaline 1,000 ml

The εolution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.