Indian Patents
Title of Invention

4-PHENYL-5-OXO-1,4,5,6,7,8-HEXAHYDROQUINOLINE DERIVATIVES AS MEDICAMENTS FOR THE TREATMENT OF INFERTILITY
Abstract 4-PHENYL-5-OXO-l,4,5,6,7,8-HEXAHYDROQUINOLINE DERIVATIVES AS MEDICAMENTS FOR THE TREATMENT OF INFERTILITY The invention relates to a 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative according to Formula (I), wherein the substituents are defined as in the description, or a pharmaceutically saU thereof. The compounds of this invention are potent FSH receptor activators and may be used for treating fertility disorders in e.g., controlled ovarian hyperstimulation and IVF procedures.
Full Text 4-PHENTL-5-OXO-l,4,5,6,7,8-HEXAHyDROQUINOLINE DERIVATIVES AS MEDICAIVIENTS FOR THE TREATMENT OF INFERTILITY
The present invention relates to 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroqi±iolme derivatives, to pharmaceutical compositions comprising the same and to the use of said derivatives for the manufacture of medicaments for the treatment of fertility disorders.
GonadotropiBS serve iir5)ortant functions in a variety of bodily fimctions including metabolism, temperature regulation and the reproductive process. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The pituitary gonadotropin FSH (follicle stimulating hormone) for example plays a pivotal role in the stimulation of follicle development and maturation whereas LH (luteinizing hormone) induces ovulation (Sharp, R.M. Clin Endocrinol. 33:787-807, 1990; Doirington and Armstrong, Recent Prog. Horm, Res. 35:301-342,1979). Currently, FSH is applied clinically, for ovarian stimulation i.e. ovarian hyperstimulation for in vitro fertilisation (IVF) and induction of ovulation in infertile anovulatory women (Insler, V,, Int. J. Fertility 33:85-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Embxyo Transfer 5:3-13, 1988), as well as for male hypogonadism and male infertility.
The gonadotropin FSH is released from the anterior pituitary under the influence of gonadotropin-releasing hormone and estrogens, and from tiie placenta during pregnancy. In the female, FSH acts on the ovaries promoting development of follicles and is the major hormone regulating secretion of estrogens. In the male, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis. Purified FSH is used clinically to treat infertility in femdes and for some types of feilure of spermatogenesis in males. Gonadotropins destined for therapeutic purposes can be isolated from human urine sources and are of low purity (Morse et al, Amer. J. Reproduct. finmimol. and Microbiology 17:143, 1988), Alternatively, they may be prepared as recombinant gonadotropins. Recombinant human FSH is available commercially and is being used in assisted reproduction (Olijve et al. Mol. Hum. Reprod. 2:371,1996; Devroey et al. Lancet 339:1170,1992).

The actions of the FSH honnone are mediated by a specific plasma membrane receptor that is a member of the large family of G-protein coupled receptors. These receptors consist of a single polypeptide with seven transmembrane domains and are able to interact with the Gs protein, leading to the activation of adenylate cyclase.
The FSH receptor is a highly specific target in the ovarian follicle growth process and is exclusively expressed in the ovary. Blocking of the receptor or inhibiting the signalling which is normally induced after FSH-mediated receptor activation will disturb folhcle development and thus ovulation and fertility. Low molecular weight FSH antagonists could form the basis for new contraceptives, while low molecular weight FSH agonists may be used for the same clinical purposes as native FSH, ie. for the treatment of infertility and for ovarian hyperstimulation on behalf of in vitro fertilisation.
Low molecular weight FSH mimetics with agonistic properties were disclosed in the Intemational AppUcation WO 2000/08015 (Applied Research Systems ARS Holding N.V.) and in WO 2002/09706 (Affymax Research Institute), Certain tetrahydroquinoline derivatives have recently been disclosed in the Intemational Application WO 2003/004028 (AKZO NOBEL N.V.) as FSH modulating substances, either having agonistic or antagonistic properties. There remains a need for low molecular weight hormone mimetics that selectively activate the FSH receptor.
To that aim the present invention provides 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives of general formula I


R^ is (1.6C)alkyl, (2-6C)aIkenyl or (2-6C)alkynyl;
R^ is halogen, (MQalkoxy, fluorinated (l-4C)alkoxy5 (l-4C)a]kyl, or fluorinated (l-4C)alkyl; or R^ may be H when R' is R^,R^*^-aminosulfonyl;
R^ is OH, NO2, CN, fluorinated (l-4C)alkoxy, (l-4C)aIkoxy(2-4C)a]koxy,
hydroxy(2-4C)alkoxy, (1 -4C)aIkoxycarbonyl, (3-4C)a]kenyloxycafbonyl,
(l-4C)alkoxycaibonyloxy, (3-4C)alkenyloxycarbonyloxy, R^,R^-amino, -ammo,
R^,R^^-amiaocarbonyl, R^jR^^'-aminosulfonyl or phenyl(l-4C)alkoxy, wherein the phenyl ring is optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (l-4C)aIlqrl, (2-4C)a]kenyl, (2-4C)alkynyl, (l-4C)alkoxy, (di)(l-4C)aIkylamino;
R'* is R^^-phenyl or R"-(2-5C)heteroaryl, wherein tiie phenyl or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluromethyl, cyano, (l-4C)a]kyl, (l-4C)aIkylthio, (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl;
R'isH,(l-4C)alkyl;
R^ is (1 -4C)alkylsulfonyl, (1 -4C)allcylcarbonyl, (2-4C)alkenylcarbonyl,
(3-6C)cycloalkylcarbonyl, (l-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl,
(l-4C)a]koxy(l-4C)alkylcarbonyl, (3-4C)alkenyloxy(l-4C)alkylcaTbonyl
phenylcarbonyl, (2-5C)heteroarylcarbonyl, phenyl(l-4C)a]kylcarbonyl,
(2-5C)heteroaryl(l-4C)alkylcarbonyl, wherein the phenyl ring or the heteroaromatic ring is optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (l-4C)alkyl, (2-4C)aIk:enyl, (2-4C)alkynyl, (l-4C)alkoxy, (di)(l-4C)alkylamino;
R^ and R^** are independentiy selected from H, (l-6C)alkyl, (3-6C)cycloalkyl, ; (3-6C)cycloalkyl(l"4C)alkyl and (l-4C)alkoxy(2-4C)a]kyl;
or R^ and R^** may be joined in a (4-6C)heterocycloalkenyl ring or a (2-6C)heterocycloalkyl ring, optionally substituted with one or more (l-4C)alkyl substituents;

R" is H, (l-6C)alkoxycarbonyl, R^^R^-amino, (l-6C)alkylcarbonyl, (l-6C)alkylsulfonyl, R^*-oxy, R^^R"-almllo, R^'^,R^'-ammocarbonyl, R*^R^^-ammosulfonyl;
R^^isH,(l-4C)a]kyl;
R" is (l-4C)aIkylsulfonyl, (l-4C)aIkylcaTbonyl, (3-6C)cycloalkylcarboiiyl,
(l-4C)a3koxycarbonyl, (3-4C)a]keiiyloxycarbonyl, (di)(l-4C)alkylainino-
(1 -4C)alkylcarbonyl, (2-6C)heterocycloalkyl( 1 -4C)aIkylcarbonyl, (4-6C)heterocyclo-a]kenyl(l-4C)aIkylcarbonyl or (l-4C)alk;oxy(l-4C)aIkylcarbonyl;
R^" and R" are independently selected from H, (l-6C)a]kyl, (3-4C)alkenyl,
(3-4C)alkynyl, (3-6C)cycloa]kyl, (3-6C)cycloalkyl(l-4C)alkyl, hydroxy(2-4C)alkyl,
amino(2-4C)a]kyl, (l-4C)a]koxy(2-4C)alkyl, (di)(l-4C)a]kylamino(2-4C)aIkyl,
(2-6C)heterocycloalkyl(2-4C)alkyl, (4-6C)lieterocycloalkenyl(2-4C)a]kyl,
phenyl(l-4C)aIkyl and (2-5C)heteroaryl(l-4C)alkyl;
X is O or R^*-N;
Y is CH2, C(0) or SO2;
Z is CN or NO2;
R^^ isH, (l-4C)alkyl, (l-4C)alkylcarbonyl;
or a phaimaceutically acceptable salt thereof.
The 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives according to the present invention are potent FSH receptor activators and may be used for the same clinical purposes as native FSH since they behave like agonists, with the advantage that they may be prepared synthetically, may display altered stability properties and may be administered differently.
Thus, the FSH-receptor agonists of the present invention may be used for treating fertility disorders in e.g. controlled ovarian hyperstimulation and IVF procedures.

The terms (MQalkyl and (l-6C)alkyl as used in the definition mean branched or unbranched alkyl groups having 1-4 and 1-6 carbon atoms, respectively, being methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and tert-butyl, etc.
The term (2-4C)aIkoxy(2-4C)alkyl means an alkoxy group, the alkyl group of which contains 2-4 carbon atoms, attached to an alkyl group having 2-4 carbon atoms.
The terms fluorinated (MQalkyl and fluorinated (l-4C)a]koxy mean branched or unbranched alkyl and alkoxy groups, having 1-4 carbon atoms respectively and which are substituted with at least one fluorine atom.
The terms (2-4C)alkenyl, (3-4C)a]kenyl and (2-6C)alkenyl mean branched or unbranched alkenyl groups having 2-4, 3-4 and 2-6 carbon atoms, respectively, such as ethenyl, 2-butenyl, and n-pentenyL
The terms (2-4C)aIkynyl mean branched or unbranched alkynyl groiq)S having 2-4 carbon atoms, such as ethynyl and propynyL
The term (3-6C)cycloalkyl means a cycloalkyl group having 3-6 carbon atoms, being cyclopropy], cyclobutyl, cyclopentyl and cyclohexyl.
The term (3-6C)cycloalkyl(l-4C)alkyl means a (l-4C)alkyl groiq), as previously defined, substituted with a (3-6C)cycloalkylalkyl group, as previously defined.
The term (2-6C)heterocycloalkyl means a heterocycloalkyl group having 2-6 carbon atoms, preferably 3-S carbon atoms, and at least including one heteroatom selected fi'om N, O and/or S, which may be attached via a heteroatom if feasible, or a carbon atora Preferred heteroatoms are N or O. Most preferred are piperidin-1-yl, morpholin-4-yl, pyrrohdin-1-yl andpiperazin-l-yL
The term (4-6C)heterocycloalkenyl means a heterocycloalkenyl group having 4-6 carbon atoms, preferably S-6 carbon atoms, and at least including one heteroatom i selected firom N, O and/or S, which may be attached via a heteroatom if feasible, or a carbon atom. Preferred heteroatoms are N or O.
The term (2-5C)heteroaryl means a heteroaromatic group having 2-5 carbon atoms and at least one heteroatom selected fi-om N, O and S, like imidazolyl, thiadiazolyl, pyridinyl, thienyl or furyl. Preferred heteroaryl groups are thienyl, furyl and pyridinyl.

The (2-5C)heteroaryl group may be attached via a carbon atom or a heteroatom, if feasible.
The term (di)(l-4C)a]kylamino as used herein means an amino group, monosubstituted or disubstituted with alkyl groi5)s, each of which contains 1-4 carbon atoms and has the same meaning as previously defined.
The term halogen means fluorine, chlorine, bromine or iodine, wherein chlorine, bromine or iodine are preferred.
The term phaxmaceutically acceptable salt represents those salts which are, within the scope of medical judgement, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the firee base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or witii an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. The acid function may be reacted with an organic or a nuneral base, like sodium hydroxide, potassium hydroxide or Uthiinn hydroxide.
One aspect of the invention relates to con5)o\mds of formula I, wherein R^ is (l-6C)alkyl. More in particular, the invention relates to con^oimds wherein R^ is
(l-4C)alkyl.
Another aspect of the invention relates to compounds according to formula I wherein R^ is halogen. More in particular, R^ is Br,
In another aspect of this invention, R^ in the compound of formula I is R^,R^^-aminosulfonyl. In particular, R^ and R^^ are independently (l-6C)alkyl,
Another aspect of this iovention relates to compounds of formula I, wherein R^ is R^^-phenyl or R^^-(2-5C)heteroaryl, the phenyl or heteroaryl group optionally being further substituted with one (l-4C)alkoxy. In particular, the invention relates to coii5)ounds wherein R^^ is H or R^^R^^-amino.

A fbrther aspect of the invention relates to compounds of fonnula I, wherein X is O,
In another aspect, the invention concerns compounds of formula I, wherein Y is CH2.
Another aspect of the invention relates to compounds wherein Z is CN.
Still another aspect of the invention concerns compounds wherein one or more of the specific definitions of the groups R^ through R^^ and X, Y and Z as defined here above are combined in the definition of the 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline compound of formula I.
Yet another aspect of the tavention concerns confounds according to Formula I which
_ft have an EC50 in the binding assay of less than 10 M (as described in example 43).
Suitable general methods for the preparation of the compoimds axe outlined below.


In some cases, the R^-groups con^rising functional groups may need additional tenporary protection depending on the type of reaction to be perfonned, which will be easily recognized by a person skilled in the art (see Protective groups in Organic Synthesis, T.W. Greene and P.G,M. Wuts, John Wiley & sons, Inc., New York, 1999).
The 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives of formula I, wherein R\ R^ R^ R\ X, Y and Z are as previously defined, may be prepared following several strategies. Method A starts from appropriately functionalised 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives of general structure H, wherein R\ R^, R\ X, Y and Z are as previously defined and FGl is a fimctional groiip, such as nitro, azido, (optionally protected) amino, (optionally protected) hydroxyl, carboxylic acid, sulfonyl chloride and the like, which may be converted to groi5)S defined for R .

For example, iV-acylation or 7V-sulfonylation of coinpounds of general formula Il-a yields compounds of general formula I-a, wherein R, R, R, X, Y and Z are as previously defined, R^ is H and R^ is an acyl or sulfonyl grojxp.
In a typicd e3q)eriment, compounds Il-a are reacted in a solvent, such as dichloromethane, ^,^-dimethylfonnamide, dimethyl sulfoxide, ethanol, tetrahydrofiiran, 1,4-dioxane, toluene, l-methyl-pyTrolidin-2-one or pyridine with an appropriately substituted acyl halide, acid anhydride or sulfonyl halide in the presence of a base such as triethylamine, JV^iV-diisopropylethylamine (DiPEA) or pyridine, to give iV-acylated or iV-sulfonylated derivatives of formula I-a, respectively. Alternatively, JV-acylated con:5)ounds of general formula I-a may be obtained by

reaction of derivatives Il-a with appropriately substituted carboxylic acids in the presence of a coiq)ling reagent such as diisoprqpyl carbodiimide (DIG), (3-dimethylaniinopropyl)-ethyl-carbodiiniide (EDCI), 0-(benzotriazol-1 'y[)-N,N,N\N'-tetramethyluronium tetrafluoroborate (TBTU) or 0-(7-azabenzotriazol-1 -yl)-iy;iV;i\r',JV'-tetrainetiiyluronium hexafluorophosphate (HATU) and a tertiary amine base (e,g, DiPEA) in a solvent such as iViiV^dimethylformamide or dichloromethane at ambient or elevated temperature.
Compounds of general formula I-b, wherein R, R, R, R, X, Y and Z are as previously defined and R is a (l-4C)alkyl groiq), may be prepared by 7V-alkylation of derivatives I-a with appropriately substituted aUcyl halides of general formula R^-Hal. This reaction is typically conducted in the presence of a base such as potassium carbonate, cesium carbonate, sodium hydroxide or sodium hydride in suitable solvents such as dichloromethane, JV^iV-dimethylformamide, ethanol, dimethyl sulfoxide, tetrahydrofiiran or 1,4-dioxane.


Alternatively, compounds of fonmda I-b may be obtained by reductive alkylation known in the art with alkyl aldehydes (e.g. acetaldehyde, (iso)butyraldehyde), acetone or butanone. Typically, con:5)ounds of general formula Il-a are treated with the appropriate carbonyl compound and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as methanol, ethanol, dichloromethane, JV^AT-dimethylfotmamide or mixtures tiiereo^ optionally in the presence of acids such as acetic acid, to give compoimds of general formula Il-b. Compounds of general formula E-b may then be iV-acylated or N-sulfonylated to give compounds of general formula I-b by the same methods described for the preparation of compounds of general formula I-a ftom Il-a.
Con^iounds of general formula Il-b may also be obtained via a 3 step sequence. First, compounds of formula Il-a may be converted to 2,4-dinitrobenzenesulfonamide derivatives II-c by ^-sulfonylation with 2,4-dinitrobenzenesulfonyl chloride (DNS-Cl).
The sulfonamide may be alkylated to give compounds of general formula Il-d by using art known Mitsunobu reactions with appropriately substituted primary or secondary alcohols of formula R -OH (R = alkyl), triphenylphosphine (optionally resin bound) and a dialkyl azodicarboxylate in appropriate solvents such as 1,4-dioxane, tetrahydrofiiran or dichloromethane at elevated or ambient temperature. Alternatively, the sulfonamide of general formula II-c may be alkylated using alkyl halides of formula R -Hal (Hal = CI, Br, I) and a suitable base such as K2CO3 in a solvent such as iV;iV-dimethylformamide, tetrahydrofuran or 1,4-dioxane. Cleavage of the N-S sulfonamide bond with a primary amine such as propylamine in a suitable solvent such as dichloromethane then gives compounds of formula E-b. Alternatively, the N-S sulfonamide bond may be cleaved using mercaptoacetic acid and a tertiary amine base in a solvent such as dichloromethane. Precedence for these types of reactions can be found in literature. For example, see: Tetrahedron Lett. 38 (1997) 5831-5834, Bioorg. Med. Chem. Lett. 10 (2000) 835-838.


Using the same methods described for the preparation of derivatives Il-b, compounds of general formula I-c are prepared, wherein R\ R^, R*, R^, X, Y and Z are as previously defined, by reacting compounds Il-a with (substituted) alkyl aldehydes or (cyclic) ketones (e.g. propionaldehyde, cyclohexanone, acetone or acetaldehyde) under reductive conditions or by alkylation of derivatives II-c with R^-OH or R^-Hal, followed by removal of the DNS-group. Confounds I-c may be reductively alkylated again using appropriately substituted aldehydes or ketones to introduce R^^, yielding confounds of general formula I-d, wherein R\ R^, R'^, R^, R^^, X, Y and Z are as previously defined In sonae cases, the reductive alkylation of Il-a may occur twice to yield coinpounds of general formiila I-d wherein R^ = R^*^ (e.g. when formaldehyde is used, R^ = R^*^ = methyl).

Con5)ounds of general formula Il-a may be obtained by the reduction of the nitro group in compounds of general formula Il-e to the corresponding amino group. Typically, con:^ounds Il-e are treated with zinc dust and acetic acid in a suitable solvent such as

THF or dioxane at ten^eratures between 0 °C and reflux temperature. Alternative methods include treatment with iron, SnCla, or hydrogen in the presence of a transition metal catalyst such palladium or platinum on charcoal, using methods and reagents well known to those skilled in the art. Alternatively, compounds of general formula Il-a may be obtained by cleavage of known ^-protecting groiq)S (= PG in formula Il-f) such as an allyloxycarbonyl (Alloc), fluoren-9-yl-methoxycarbonyl (Fmoc) or tert-butoxycarbonyl (Boc) group in compounds of general formula Il-f to give the corresponding derivatives Il-a Related protective group n^nipulations can be found in Protective groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, John Wiley & sons, Inc., New York, 1999.
Carboxylic acid derivatives of general formula Il-h, accessible by saponification of corresponding alkyl esters Il-g, may be condensed with amines of general structure R^^*^NH using a coupling reagent as desaibed before for the preparation of derivatives I-a fi-om Il-a to give conipounds of fomiula I-e, wherein R\ R^, R^, R^, R^^, X, Y and Z are as previously defined. Alternatively, compounds of general formula Il-h may be converted to tiie corresponding acid chlorides of general formula Il-i by methods known in the art: treatment of carboxylic acids of general formula Il-h with

thionyl chloride or oxalyl chloride and DMF in a suitable solvent such as dichloromethane or toluene gives the corresponding acid chlorides Il-i. Subsequent

reaction with amines of general structure R^R^*^NH, optionally in the presence of a suitable tertiary amine base, yields compounds of general formula I-e,
Con5)ounds of general formula I-:^ wherein R\ R^, R^, X, Y and Z are as previously defined and R is cyano, may be obtained by dehydration of amides of general formula I-g with trifluQToacetic anhydride and a suitable base such as triethylamine or pyridine in a suitable solvent such as dichloromethane, 1,4-dioxane or tetrahydrofiiran at 0 °C or ambient temperature. Related dehydrations of amides to give aryl nitriles can be found in literature, for example, see: Org. Prep. Proced. Int. 26 (1994) 429-438, Acta Chem. Scand. 53 (1999) 714-720, J. Org. Chem. 57 (1992) 2700-2705. Compounds of formula I-g are prepared according to the synthesis outlined for derivatives I-e.

Compounds of general fomiula II-j wherein R\ R^, R'^, X, Y and Z are as previously defined may be 0-alkylated with (substituted) alkyl halides E-Hal (E = aUcyl, fluorinated alkyl, alkoxyalkyl, hydroxyalkyl, (substituted) phenylalkyl or (substituted) heteroarylalkyl; Hal =C1, Br, I) by treatment with a base such as potassium carbonate or cesium carbonate in suitable solvents such as JV;JV-dimethylformamide, acetone, tetrahydrofiiran, 1,4-dioxane or l-methyl-pyrrolidin-2-one to give compoimds of general formula I-h, wherein R, R , R , X, Y and Z are as previously defined and E is alkyl, fluorinated alkyl, alkoxyalkyl, hydroxyalkyl, (substituted) phenylalkyl or (substituted) heteroarylalkyl. Alternatively, Mitsunobu conditions as described for the conversion of derivatives II-c to compoimds Il-d may be used to effect this conversion.


Compounds of general formula I may also be obtained by manipulation of functional groi5)S FG2 in compounds of general formula lH (method B). For example, ftmctionalization of the amino group of compounds of general fomiula Ill-a in same manner as described for the conversion of derivatives Il-a into I-a and I-b, yields con5)ounds of general formula I-k, wherein R\ R^, R^, R^^, R^^, X, Y and Z are as previously defined, A is a (substituted) phenyl or a (substituted) heteroaryl ring.

Compounds of general fijrmula I-l, wherein R\ R^, R^, R^^, X, Y and Z are as previoxisly defined, R^^ is H and A is a (substituted) phenyl or a (substituted) heteroaryl ring, may be obtained by reductive alkylation of compounds of general formxila Ill-a using the same methods described for the preparation of compounds Il-b fi-om Il-a or by the 3 step sequence described for the preparation of derivatives Il-b fi-om Il-a via 11-c and n-d. Reductive alkylation of compounds I-l with aldehydes or ketones in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride may afford

coii5)oimds of general fonnula I-m, wherein R\ R^ R^, R^"*, R^^ X, Y and Z are as previously defined and A is a (substituted) phenyl or a (substituted) heteroaryl ring.

Compounds of general fonnula Ill-a may be prepared firom compounds of general formula Dl-b or III-c in analogy to the preparation of compounds Il-a fix)m Il-e or 11-^
respectively.

Amide derivatives I-n, wherein R\ R^ R^, R^^, R^^, X, Y and Z axe as previously defined and A is a (substituted) phenyl or (substituted) heteroaryl ring, may be prepared fix)m carboxylic acids Dl-e, by the same methods (via acid chloride or by the use of coi5)ling reagents) that were described for the preparation of compounds I-e fi*om n-h.


Similarly, esters of general fonnula I-o, wherein R\ R^, R^ R^"*, X, Y and Z are as previously defined and A is a (substituted) phenyl or (substituted) heteroaiyl ring may be obtained from derivatives Ill-e and alcohols of general fonnula R^^-OH using the same methods as described for the conversion of m-e into the corresponding amides I-a
Compounds of general formula ni-e may be prepared from the corresponding aUcyl esters Ill-d by base or acid mediated ester cleavage, well known to those skilled in the art.
Derivatives of general formula I-p, wherein R\ R^, R^, R^^, X, Y and Z are as previously defined and A is a (substituted) phenyl or a (substituted) heteroaryl ring, may be prepared by alkylation of the hydroxyl group in compounds of general formula El-g with an alkyl halide of general formula R^^-Hal, in which Hal may be Br, CI or L Typically, such a reaction is carried out in an aprotic solvent such as N^N-dimethylformamide, 1,4-dioxane or tetrahydrofuran in the presence of a base, such as sodium hydride, potassium carbonate, cesium carbonate or triethyl amine at ambient or

jlevated teirperature. Alternatively, convCTsion of confounds of general fonnula Ill-g Bto aryl ethers of general formula I-p may be accomplished under Mitsunobu-type iBcylation conditions. In such a transformation, alkylation of the hydroxyl group in ^onpounds of formula Ill-g is effected with alcohols of general formula R^^-OH under the agency of (resin bound) triphenyl phosphine and diethyl azodicarboxylate or its ierivatives in a suitable ^protic solvent such as tetrahydrofuran or dichloromethane.

Derivatives of general formula m-g may be obtained by cleavage of the hydroxyl-protecting groiq) in compounds of general formula IQ-f Suitable protective groups, well-ki^own to those skilled in the art, are the tetrahydropyranyl (TEIP) or tert-hntyl dimethylsilyl (TBS) protective groups. Cleavage of the THP and TBS groirps is generally accon5)lished by treatment with acids, such as hydrochloric acid, trifluoromethanesulfonic acid or trifluoroacetic acid in a suitable solvent, such as tetrahydrofiiran or methanol. Alternatively, the TBS group may be removed by treatment with tetra-n-butylammonium fluoride in tetrahydrofiiran. Related protective group manipulations can be found in Protective groups in Organic Synthesis, T.W. Greene and P.G,M. Wuts, John Wiley & sons, Inc., New York, 1999.
Compounds of general formula I may also be obtained by manipulation of both functional groirps FGl and FG2 in compounds of general formula IV (method C), along the lines described for the conversions of con5)ounds of general formula 11 and in. The two functional groups can be, but do not need to be, identical. It is clear to those skilled in the art that the order in which the functional groups FGl and FG2 are

modified may be crucial for a successftil synthetic outcome. Clearly, in some cases the iise of (orthogonal) protective groups may be necessary.
For example, dinitro compounds of general formula IV-a may be reduced to the diamino compounds IV-b using the methods described for the preparation of derivatives Il-a from Il-e. Standard iV^acylation or iV-sulfonylation affords compounds of general formula I-q, wherein R\ R^, R^, X, Y and Z are as previously defined and A is a (substituted) phenyl or a (substituted) heteroaryl ring and R^^ = R^.

To allow independent variation of the substituents (e.g. R^ and R^^) , the functional groups in compounds of general formula IV need to be fimctionalized in an orthogonal manner. For example, compounds of general formula IV-c may be functionalized using the same methods described for the synthesis of derivatives I-a, I-b, I-c and I-d from coii5)Ounds Il-a to give compounds of general formula IV-d, wherein R , R , X, Y and Z are as previously defined, A is a (substituted) phenyl or a (substituted) heteroaryl ring and G is NR^R^ or NR^R^*^. These compounds may be converted to derivatives I-r, whereia R\ R^ X, Y and Z are as previously defined, A is a (substituted) phenyl or a (substituted) heteroaryl ring and G is NR'^R^ or NRV^ and K is NR^^R^^ or NR^ V^


Yet another possibility to amve at the desired compounds of general fonnula I may be the functionalization of compounds of general formula V (method D). Compounds of general formula V-a wherein X = O may be used to prepare compounds I-s, wherein R\ R^, R^ R'*, Y and Z are as previously defined and X = O, by O-aDcylation, O-acylation or 0-sulfonylation using standard conditions, well known to those skilled in the art. The substitution pattern of the (hetero)aryl ring in R"* is as previously defined. In a typical experiment, compounds V-a are reacted in a solvent, such as dichloromethane, TVi^-dimethylformamide, dimethyl sulfoxide, ethanol, tetrahydrofiiran, 1,4-dio^ane, toluene, l-methyl-pyrrolidin-2-one or pyridine with an appropriately substituted (hetero)aromatic alkyl halide of formula IX, acyl chloride of formula X, or sulfonyl chloride of formula XII in the presence of a base such as triethylamine, ^,iV^diisopropylethylamine (DiPEA), pyridine, potassium carbonate, cesium carbonate or sodium hydride, optionally in the presence of a catalytic amount of potassium iodide or tetrabutylammonium iodide, to give 0-alkylated, 0-acylated or O-sulfonylated derivatives of formula I-s, respectively.


Alternatively, O-alkylated confounds of general formula I-s in which Y = CH2 may be obtained by using art known Mitsunobu reactions with alcohols of formula Xin, triphenylphosphine (optionally resin bound) and a dialkyl azodicarboxylate (e.g. diethyl azodicarboxylate) in appropriate solvents such as 1,4-dioxane, tetrahydro&ran or dichloromethane at elevated or ambient temperature.
Additionally, 0-acylated confounds of general formula I-s, wherein Y = C(0) may be obtained by reaction of a (hetero)aromatic carboxylic acid of formula XI in the presence of a coi5)ling reagent such as diisopropyl carbodiimide (DIG), (3-dimethylaminopropyl)-eihyl-cafbodiimide (EDCI), 0-(benzotriazol-l-yl)-JV;JV;^',JV'-tetramethyluTonium tetrafluoroborate (TBTU) or 0-(7-azabenzotriazol-l-yl)-^,7^,JV^',^'-tetramethyluronium hexafluorophosphate (HATU) and a tertiary amine base {e.g, DiPEA) in a solvent such as ^,iV^dimethylformamide or dichloromethane at ambient or elevated temperature.
Likewise, compounds of general formula I-t may be prq)ared from compounds V-b by iV^aDcylation, ^-acylation or iV-sulfonylation using the same methods described for the synthesis of compounds I-s using the reagents of formula IX-Xin. Additionally, compounds of general formula I-t in which Y = CH2 may be prepared by reductive amination of (hetero)aromatic aldehydes of formula XIV with compounds V-b and a suitable reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride. Alternatively, compounds of general formula V-b may be converted to the corresponding benzimines iq)on reaction with (hetero)aromatic aldehydes XTV by methods known to those skilled in the art, followed by reduction with a reducing agent such as sodiimi borohydride to give compounds I-t in which Y = CH2.


Conq^o^^ds of general formula I-t wherein R\ R^ R^, R'^, Y and Z are as previously defined and X is NH may be iV-alkylated by the same methods as described for the preparation of derivatives I-b from I-a (if Y = C(0) or SO2) or by the same methods as described for the preparation of derivatives conrpoxmds Il-b from Il-a (if Y = CH2) to afford compounds of general formula I-u, wherein R^^ is a (MQalkyl group.
Con:5)ounds of general formula I, wherein R\ R^, R^ R*, X, Y and Z are as previously defined, may also be prepared starting from cyclohexane-l,3-diones of general formula VI, enamines of general formula Vn and benzaldehydes of general formula Vni-a-b, by the well-documented three component Hantzsch-type cyclo-condensation reaction (Method E).

Related Hantzsch-type cyclo-condensation reactions can be foimd in: Bioorg. Med. Chem. Lett. 12 (2002) 1481-1484, J. Chem. Soc, Perkm Trans. 1 (2002) 1141-1156, Synlett (2002) 89-92, Drug Dev. Res. 51 (2000) 225-232, Drug Dev. Res. 51 (2000) 233-243, J. Med. Chem. 42 (1999) 1422-1427, ibid, 5266-5271, ibid. 41 (1998) 2643-2650, WO 9408966, Arzneim.-Forsch./Dmg Res. 45 (1995) 1054-1056, J. Med. Chem. 34 (1991) 2248-2260, ibid 17 (1974) 956-65, Indian J. Chem., Sect B (1994) 526-531, Chem, Rev. 72 (1972), 1-42. The above mentioned reaction is typically conducted at elevated ten^>erature in suitable solvents such as acetic acid, (iso)propanol, ethanol, methanol or mixtures thereof.
Conpounds of general formula I-w, wherein R^ is H and R^ is R^,R^**-aminosulfonyl and R\ R^, X, Y and Z are as previously defined may be synthesized by catalytic hydrogenation of compoimds of general formula I-v, using hydrogen and a transition metal catalyst such as palladium on charcoal in suitable solvents such as ethanol, methanol, ethyl acetate or mixtures thereof


Coirpounds of general formula n are accessible from derivatives of general formula XV-a and XV-b using the same methods as described for the preparation of compounds of general formula I-s and I-t, respectively, using reagents of formula K-XIV.

Similar to the JV-aBcylations of compounds of general formula I-t to give I-u, con5)ounds of general formula E-k, wherein R\ R^, R*, Y, Z are as previously defined and X = NH, may be JV-alkylated to give con5)Ounds of general formula II-l, wherein R^^isa(l-4C)alkylgroup.


Coinpoimds of general formula n and HI may also be synthesized by the Hantzsch-type cyclo-condensation reactions by reacting compounds VI and Vn with aldehydes of formula XVI or XVn, respectively.

Confounds of general formula in are also accessible from derivatives of general formula V-a and V-b using the same methods as described for the preparation of compounds of general formula I-s and I-t, respectively, using reagents of formula
xvm-xxm.


preparation of compounds of general fonnula I-s and I-t, respectively, using reagents of formula XVm-XXm.
Compounds of general formula IV and V-a-b may also be prepared by the previously mentioned Hantzsch-type cyclo-condensation, by using substituted benzaldehydes of general fomiula XXIV or XXV, respectively.

Compounds of general formula V-c-d in which R is Br may also be obtained by ortho-bromination of phenols or anilines, which are well known to those skilled in the art. Thus, compounds of formula V-e-f — synthesized from compounds VI and Vn and aldehydes XXVI by a Hantzsch-type cyclocondensation reaction — afford compounds of formula V-c-d iq)on treatment with bromine m a suitable solvent such as acetic acid, ethanol or dichloromethane or mixtures thereof, optionally in the presence of sodium acetate. Alternatively, ^-bromosuccinimide in JV,iV-dimethylformamide or acetonitrile may be used to achieve this conversion. For example, see: J, Chem. Soc, Perkin Trans.2 6 (2000) 1113-1118, J. Org. Chem. 44 (1979), 4733-4735.


Additionally, confounds of general fonnula V-i, wherein R is a sulfamoyl group and X = O, may be obtained by reacting amines of general formula R^^*^NH with con5)oimds of general formula V-h, optionally in the presence of a tertiary amine base such as triethylamine or DiPEA. Compounds V-h are obtained by chlorosulfonylation of con^jounds of general formula V-g. For related exaniples in the literature concerning chlorosulfonylation of phenols, see: Tetrahedron 53 (1997) 4145-4158, Bioorg. Med. Chem. Lett 13 (2003) 379-382.

Con^pounds of general formula V may also be prepared from compounds of general formula XV by selective modification of FGl. For example, compounds of general formula XV-c-d, wherein R\ R^ and Z are as previously defined and FGl is NHi, may be selectively ^-acylated or iV-sulfonylated, using the same conditions described for the preparation of compounds I-a fi"om H-a, to give compoimds of general formula V-j-k, wherein R, R, R and Z are as previously defined. For examples in literature reporting similar regioselectivity in the acylation or sulfonylation of 1,2-diaminobenzene derivatives, see: J. Chem. Soc, Perldn Trans. 1 (1988) 1939-1943, J. Med. Chem. 33 (1990) 2101-2108, J. Med. Chem. 43 (2000) 4084-4097, Bioorg. Med. Chem. 10 (2002) 3997-4004. For examples describing regioselective functionalisation

of ortho'hydioxy aniline derivatives, see: J. Org. Chem. 53 (1988) 4762-4769, JP 2003026630, Phann. Chem. J. 36 (2002), 410-412.
Confounds of general fonnula XV may also be prepared by the previously mentioned Hantzsch-type cyclo-condensation, by using substituted benzaldehydes of general formula XXVn. Additionally, confounds of general formula XV wherein R^ = Br may be prepared by Hantzsch reaction with aldehydes of general formula XXVDI, followed by orthO'hronmdXion of the resulting phenols and anilines, in analogy with the preparation of compounds of fonnula V-c-d

The substituted cyclohexane-l,3-diones of general formula VI are commercially available or may be prepared by literature procedures. Relevant exaioples are found in: J. Med. Chem, 43 (2000) 4678-4693, Tetrahedron 56 (2000) 4753-4758, J. Med Chem, 35 (1992) 3429-3447, ibid. 24 (1981) 1026-1034, Org. Synt, CoU. Vol. V (1973) 400, Chem. Ber. 88 (1955) 316-327, Justus Liebig Ann. Chem. 570 (1950) 15-31.

The compound of formula VH-a is commercially available and compound Vll-b has been documented in literature, see for example: Drug Dev. Res. 51 (2000) 225-232.
Compounds of general formula DC to XIV and XVni to XXin are either commercially available, documented in hterature or readily synthesized by those skilled in the art.

Benzaldehydes of general fonnula Vni-a, wherein R^, R^, R^ and Y are as previously defined and X = O, are readily prepared fi'om benzaldehydes of general formula XXV-a using the same methods as described for the conversion of compounds of formula V-a to I-s. Likewise, compounds of general formula Vlll-b, wherein R , R , R and Y are as previously defined and X = N-R^^, are prepared from XXV-b using the same methods as described for the conversion of confounds of formula V-b to I-t. Similarly, benzaldehydes of general formula XVH-a-b are prepared fixmi aldehydes XXV-a-b, upon reaction with compounds XVin to XXm.

Following the same strategy, benzaldehydes of general formula XVI-a-b and XXIV-a-b are prepared from compounds of general formula XXVII-a-b.
Benzaldehydes of general formula XXV, XXVI, XXVn and XXVin are commercially available, documented in the literature or may be prepared by those skilled in the art. For example, see: J. Chem. Soc, Perkin Trans. 2 (2000) 1119-1124, J. Chem. Soc, Chem. Commun. 4 (1993) 419-420, Synth. Commun. 20 (1990) 2659-2666, Chem. Phaim. Bull. 34 (1986) 121-129, Indian J. Chem. Sect B 20 (1981) 1010-1013, Monatsh. Chem. 106 (1975) 1191-1201, DE 1070162, J. Org. Chem. 23 (1958) 120,

Tetrahedron Lett. 25 (1984), 2901-2904, J. Org. Chem. 25 (1960), 2053-2055, J. Chem. Soc, Perkin Trans. 2 (1992), 2235-2242.
Additionally, benzaldehydes of general formula XXV-c and XXVU-c wherein R^ is bromide and X is N-H may be obtained by bromination of compounds of general formula XXEK using the same procedures described for the conversion of compounds of general fommila V-f to V-d. Compounds of general formula XXIX are easily prepared from compoimds of general formula XXX using the same reduction methods that were described for the preparation of compounds of general formula Il-a from Il-e. Compounds of general formula XXX are commercially available, reported in literature or may be readily be prepared by those skilled in the art.

Furthermore, substituted betizaldehydes of general formulas Vin, XVI, XVH, XXIV, XXV, XXVI, XXVn, XXVm, XXEX, XXX may be prepared from the corresponding benzoic acids XXXI or benzoic esters of general formula XXXn by reduction methods known in the art. Additionally, oxidation of alcohols XXXIE by methods well known in the art also affords benzaldehydes. Benzyl bromides XXXIV, which may be prepared from the corresponding toluene derivatives XXXV by benzylic bromination, may be converted into benzaldehydes by art known methods as well. Furthermore, the aldehydes may be obtained by deprotection of the corresponding (cyclic) acetals of general formula XXXVI.


The coiripounds of the present invention possess at least two chiral carbon atoms and may therefore be obtained as pure enantiomers, or as a mixture of enantiomers, or as a mixture of diastereomers. Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns. For separation of diastereomers, straight phase or reversed phase columns may be used.
The compounds of the invention may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with . water, or form solvated species when concentrated in a solution with an appropriate organic solvent. The compotmds of this invention include the hydrates or solvates of the con:q)ounds listed.
The 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivatives of the invention were found to agonists of the FSH receptor. Methods to determine receptor binding, as well as in vitro and in vivo assays to determine biological activity, of gonadotropins are well known. In general, expressed receptor is contacted with the compound to be tested and binding or stimulation or inhibition of a functional response is measured.
To treasure a functional response, isolated DNA encoding the FSH receptor gene, preferably the human receptor, is expressed in sxiitable host cells. Such a cell might be the Chinese Hamster Ovary cell, but other cells are also suitable. Preferably the cells are of mammalian origin (Jia et al, MoLEndocrin., 5:759-776,1991).
Methods to construct recombinant FSH expressing ceU lines are well known in the art (Sambrook et al.. Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). Expression of receptor is attained by expression of the DNA encoding the desired protein. Techniques for site directed mutagenesis, ligation of additional sequences, PCR, and construction of suitable expression systems are all, by now, well known in the art. Portions, or all, of the DNA encoding the desired protein may be constructed synthetically using standard solid phase techniques, preferably to include restriction sites for ease of ligation. Suitable control elements for transcription and translation of the included coding sequence may be provided to the DNA coding sequences. As is well known, expression systraas are

now available which are compatible with a wide variety of hosts, including prokaryotic hosts such as bacteria and eukaryotic hosts such as yeast, plant cells, insect cells, xnatnmalian cells, avian cells and the like.
Cells e^ressing the receptor are then contacted with the test compound to observe binding, or stimulation or inhibition of a functional response.
Alternatively, isolated ceU membranes containing the expressed receptor may be used to measure binding of the test compoimd.
For measurement of binding, radioactive or fluorescent compounds may be used As reference compound human recombinant FSH can be used.
In the alternative, also competition binding assays may be performed.
Another assay involves screening for FSH receptor agonist compounds by determining stimulation of receptor mediated cAMP accumulation. Thus, such a method involves expression of the receptor on the cell surface of a host cell and exposing the cell to the test compound. The amount of cAMP is then measured. The level of cAMP will be increased, by the stimulating effect of the test conipound upon binding to the receptor.
In addition to direct measurement of e.g. cAMP levels in the exposed cell, cells lines can be used which in addition to transfection with receptor encoding DNA are also transfected with a second DNA encoding a rq)orter gene the expression of which responds to the level of cAMP. Such reporter genes might be cAMP inducible or might be constructed in such a way that they are connected to novel cAMP responsive elements. In general, reporter gene expression might be controlled by any response element reacting to changing levels of cAMP. Suitable rq)orter genes are e.g. LacZ, alkaline phosphatase, firefly luciferase and green fluorescence protein. The principles of such transactivation assays are well known in the art and are described e.g. in Stratowa, Ch., Himmler, A. and Czemilofsky, A.P., (1995) Curr. Opin. Biotechnol. 6:574.
The present invention also relates to a pharmaceutical coniposition comprising a 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroqxiinoline derivative or pharmaceutically acceptable salts thereof having the general formula I in admixture with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents. The

auxiliaries must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recq)ients thereof.
Pharmaceutical compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, local, or rectal administratibn, and the like, all in unit dosage forms for administration.
For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.
For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
Mixed with such pharmaceutically acceptable auxiliaries, e.g. as described in the standard reference, Gennaro, A.R. et al,, Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & Willdns, 2000, see especially Part 5: Pharmaceutical Manu&cturing), the active agent may be compressed into solid dosage imits, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically acceptable liquids tiie active agent can be applied as a fluid conposition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active conipoimds can be used. Suitable carriers with which the active agent of the invention can be admioistered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
The invention further includes a pharmaceutical coirtposition, as hereinbefore described, in combination with packaging material suitable for said con^osition, said

packaging material including instructions for the use of the composition for flie use as hereinbefore described.
The exact dose and regimen of administration of the active ingredient, or a pharmaceutical coic5)osition thereof, may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom tiie medicament is to be administered.
In general parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption. However, a suitable dosage for humans may be 0.05-25 mg per kg body weight. The desired dose may be presented as one dose or as multiple subdoses administered at appropriate intervals throughout the day, or, in case of female recipients, as doses to be administered at appropriate daily intervals throughout the menstrual cycle. The dosage as well as the regimen of administration may differ between a female and a male recipient
Thus, the compounds according to the invention can be used in therapy.
A fiiriher aspect of the invention resides in the use of a 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative having the general formula I for the maniifecture of a medicament to be used for the treatment of disorders responsive to FSH receptor mediated pathways, preferably for the treatment of fertility disorders. Thus, patients in need thereof can be administered with suitable amounts of the compounds according to the invention.
In yet another aspect the invention resides in the use of a 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative having the general formula I for the manufacture of a medicament to be used for the treatment of fertility disorders.
The invention is illustrated by the following examples.

EXAMPLES
General Comments:
The following abbreviations are used in the examples: DMA = iS^JV-dimethylaniline, DIPEA = i\r^-diis0propylethylamine, TFA = trifluoroacetic acid, HATU = 0-(7-azabenzotriazole-l-yl)-jy;iV^iV',iV'-tetramethyluroniiun hexafluorophosphate, Fmoc = 9-fluorenylmethoxycarbonyl, Fmoc-Cl = P-fluorenyhnethoxycarbonylchloride, DMF = iyi^-dimethylfoimamide, THF = tetrahydrofutan.
Unless stated otherwise, all final products of the examples below were lyophilized from water/1,4-dioxane inixtures, water/fe?t-butanol or water/acetonitrile mixtures. If the con5)ound was prepared as a HCl- or TFA salt, the respective acids were added in appropriate amoimts to the solvent mixture before lyophili2ation.
The names of the final products described in the examples were generated using the Beilstein Autonom program (version: 2.02.304).
The following analytical HPLC methods were used for determination of retention times:
Method 1: Column: 5 pm Luna C-18(2) 150^4.6 mm; flow: 1 ml/min; detection: 210 nm; column ten5)erature: 40 'C; solvent A: CH3CN/H2O = 1/9 (v/v); solvent B: CH3CN; solvent C: 0.1 M aqueous trifluoroacetic acid; gradient: solvent A/B/C = 65/30/5 to 10/85/5 (v/v/v) in 30.00 min, then constant for an additional 10.00 min at A/B/C = 10/85/5 (v/v/v).
Method 2: Identical to method 1, except for the gradient used: Gradient: solvent A/B/C = 75/20/5 to 15/80/5 (v/v/v) in 30.00 min, then constant for an additional 10.00 min at A/B/C =15/80/5 (v/v/v).
Method 3: Identical to method 1, except for the gradient used: Gradient: solvent A/B/C \ = 95/0/5 to 15/80/5 (v/v/v) in 30.00 min, then constant for an additional 10.00 min at A/B/C = 15/80/5 (v/v/v).
Method 4: Identical to method 1, except for the gradient used: Gradient: solvent A/B/C = 60/40/0 to 0/100/0 (v/v/v) in 20.00 min, then constant for an additional 10,00 min at A/B/C = 0/100/0 (v/v/v).
) The diastereomeric ratio was determined if baseline separation of the individual diastereomers was observed using the appropriate analytical HPLC method. Alternatively, the diastereomeric ratio was determined by ^H NMR analysis when distinct signals corresponding to the diastereomers were identified.

The following methods were used for preparative HPLC-purifications:
Method A: Cohimn = Luna C-18. Gradient: 0.1% trifluoroacetic acid in H2O/CH3CN (9/1, vA^yCHsCN = 80/20 to 0/100 (v/v) in 30-45 min, depending on the ease of separation. Detection: 210 nm.
Method B: Column = Luna C-18. Gradient: H2O/CH3CN (9/1, v/v)/CH3CN = 80/20 to 0/100 (v/v) in 30-45 mm^ depending on the ease of separation. Detection: 210 nm.
Example 1
4-r3-Bromo-4.5-bis-f3-methoxv-ben2vloxvVphenvll-2-methvl-5-oxO"7-propvl-L4,5,6,7.8-hexahvdro-quinoline-3-carbonitrile
(a). 3-Bromo-4,5-bis-r3-methoxv-benzvloxvVbenzaldehvde
A mixture of 5-bromo-3,4-dihydroxybenzaldehyde (100 mg), 3-methoxybenzyl bromide (71 ^il), potassium carbonate (140 mg) and tetrabutylammonium iodide (10 mg) in 5 ml of DMF was stirred at 60 °C for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 143 mg.
(b), 4-r3-BrDmo*4.5-bis-f3-methoxv-benzvloxv)-phenvll-2-methvl-5-oxo-7-t)ropvl-l,4.5,6.7,8-hexahvdro-quinoline-3-carbonitrile
A mixture of 3-bronM)-4,5-bis-(3-methoxy-benzyloxy)-benzaldehyde (143 mg), 3-aminocrotonitrile (28 mg), 5-propylcyclohexane-l,3-dione (52 mg) in ethanol (10 ml) was stirred at 80 °C for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/1 —>■ 2/8 (v/v) as eluent.
Yield: 122 mg, MS-ESI: [M+H]^ = 657.4/659,4; anal. HPLC Rt = 17,18 min (diastl) Rt = 17.43 min (diast.2) (method 4)
Diast ratio: 4:1

Example 2
4-r3-Bromo-4-(3-methoxv-benzvloxvV5-mlTO-phenvl1-2-methvl-5-^^ l,4,5,6,7,8-hexahvdro-qumoline-3-carbomtrile
(a). 3 -Bromo-4-hvdroxv-5-tutro-benzaldehvde
3-Bronio-4-hydroxybenzaldehyde (250 mg) was dissolved in 5 ml of acetic add Nitric acid (52 |il) was added and the mixture was stirred for 3 h during which a solid fonned. The solid was filtered off, washed with water and dried in vacuo.
Yield: 249 mg. MS-ESI: [M+H]" = 245.8/247.8
fbV 3-Bromo-4-(3-methoxv-benzvloxvV5-nitro-benzaldehvde
To a solution of 3-bromo-4-hydroxy-5-nitro-ben2aldehyde (87.4 mg) in dry dichloromethane (7.5 ml) was added 3-methoxybenzyl alcohol (35 \il), triphenylphosphine (103 mg) and diethyl azodicarboxylate (45 |il). The mixture was stirred under a nitrogen atmosphere for 17 h and then concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 9/1 —>■ 1/1 (v/v) as eluent.
Yield: 50 mg.
(c), 4-r3-Bromo-4-f3-methoxv-benzvloxv)-5-nitro-phenvn-2-methvl-5-oxo-7-propvl-L4,5,6J,8-hexahvdro-quinoline-3-carbonitrile
A mixture of 3-bromo-4-(3-methoxy-benzyloxy)-5-nitro-benzaldehyde (50 mg), 3-aminocrotonitrile (13 mg) and 5-propylcyclohexane-l,3-dione (25 mg) in 10 ml of ethanol was stirred at 80 °C for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 8/2 —> 1/1 (v/v) as eluent.
Yield: 50 mg. MS-ESI: [M+H]^ = 566.2/568.2; anal. HPLC Rt = 22.66 min (method 1)
Diast ratio: 4:1
Example 3
4-r3-AniiQO-5-bromo-4-('3-methoxv-benzvloxv)-phenvll-2-methvl-5-oxo-7-i>ropvl-1.4.5.6,7,8-hexahvdro-quinoline-3-carbonitrile

The compound described in example 2c (81 mg) was dissolved in THF (10 ml) and cooled to 0 **C. Acetic acid (123 \x[) was added, followed by addition of zinc dust (187 mg). After stirring at room temperature for 1 h, the mixture was diluted with dichloromethane and washed with sat aq. NaHCOs and brine. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method A).
Yield: 15.3 mg (as TFA salt). MS-ESI: [M+H]^ = 536.4/538.4; anal. HPLC: Rt = 18.77 min.(metiiodl)
Diast. ratio: 5:1
Example 4
4-r3-Ethoxv-4-(3-meihoxv-benzvloxv)-5-nitro-phenvl1-2-methvl-5-oxo-7-propvl-l,4,5,6J,8-hexahvdro-quinoline-3-carbonitrile
(a). 3-Ethoxv-4-(3-methoxv-benzvloxv)-5-nitro-benzaldehvde
A mixture of 5-nitro-3-ethoxy-4-hydroxybenzaldehyde (100 mg), 3-methoxybenzyl bromide (73 ^l)5 potassium carbonate (144 mg) and tetrabutylammonium iodide (10 mg) in DMF (5 ml) was stirred at 60 **C for 90 min. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 2/1 (v/v) as eluent.
Yield: 43 mg.
(b). 4-r3-Ethoxv-4-(3-methoxv-benzvloxv)-5-nitro-phenvll-2-methvl-5-oxo-7-propvl-l,4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile
A mixture of 3-ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-benzaldehyde (40 mg), 3-aminocrotonitrile (10 mg) and 5-propylcylcohexane-l53-dione (19 mg) in ethanol (2 ml) was stirred at 80 °C for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/1 (v/v) as eluent.
Yield: 50 mg. MS-ESI: [M+H]^ = 532.4; anal. HPLC: Rt = 21.17 min. (diast.1) Rt = 21.55 min. (diast 2. ) (hetero 1)

Diast ratio: 4.5:1
Example 5
4-r3-Amino-5-eihoxv-4-f3-methoxv-benzvloxvVphenvl1-2-methvl-5-oxo-7-pr^^ L4,5.6J,8-hexahvdro-aiunoline-3-carbomtrile
To a solution of the confound described in example 4b (100 mg) and acetic acid (162 111) in THF (5 ml), cooled to 0 °C, was added zinc dust (246 mg) under vigorous stirring.
After stirring for 30 min., the mixture was filtered, diluted with dichloromethane and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 85 mg (as TFA salt). MS-ESI: [M+H]^ = 502.4; anal. HPLC: Rt = 15.28 min. (diastl) Rt = 16.38 min. (diast.2) (method 2)
Diast. ratio 4:1
Example 6
JV-r3-Bromo-5-r3-cvano-2-methvl-5-oxo-7-propvl-l,4,S.6.7.8-hexahvdro-Quinolin-4-vlV2-f3-methoxv-benzvloxvVphenvll-butvramide
A mixture of the compound described in example 3 (100 mg), butyryl chloride (21 \xl) and iSr,A^-diisopropylethylamine (162 |il) in dichloromethane (5 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with sat. aq. NaHCOs, The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 52 mg. MS-ESI: [M+H]^ = 606.2/608.2; anal. HPLC: Rt = 21.60 min. (diast.l) Rt = 21.99 min. (diast2) (method 1)
Diast. ratio: 4:1

Example 7
r3-Bromo-5-f3-cvano-2-methvl-5-oxo-7-i3ropvl-l,4,5,6J,8-hexahvdro-qTjdnolm 2-f3-metfaoxv-beDzvloxvVT)henvn-carbamic acid methyl ester
A mixture of the compound described in example 3 (100 mg), methyl chlorofonnate (17 \x\) and ^,iV-diisopropylethylamine (162 |il) in dry dichloromethane (5 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with sat. aq. NaHCOs, The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 35 mg. MS-ESI: [M+H]^ = 594.2/596.2; anal, HPLC: Rt - 20.33 min. (diast.l) Rt = 20.73 min. (diast.1) (method 1)
Diast. ratio: 5:1
Example 8
JV-r3-Bromo-S-r3-cvano-2-methvl-5-oxo-7-proT)vl"L4,5,6,7,8"hexahvdro-Quinolin-4-vl)-2-f3-methoxv-benzyloxv)-phenvn-2-methoxv-acetaniide
A mixture of the compound described in example 3 (100 mg), methoxy-acetyl chloride (24.3 mg) and Ar,iV-diisopropylethylamine (162 jil) in dichloromethane (5 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with sat. aq. NaHCOa. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 37 mg. MS-ESI: [M+H]^ = 608.2/610.2; anal, HPLC: Rt = 19.99 min. (diastl) Rt = 20.44 mm. (diast.2) (method 1)
Diast. ratio: 5:1
Example 9
Furan-2-carboxvhc acid r3-bTomo-5-f3-cvano-2-methvl-5-oxo-7-propvl-l,4,5.6,7.8-hexahvdro-quinolin-4-vl)-2-f3-methoxv-benzvloxv)"phenvn-amide
A mixture of the compound described in example 3 (100 mg), 2-fiiroyl chloride (28.9 mg) and iV,iV-diisqpropylethylamine (162 p.1) in dichloromethane (5 ml) was stirred for

17 h. The mixture was diluted with dichloromethane and washed with sat. aq. NaHCOs. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 92 mg. MS-ESI: [MH-H]" = 630.2/632.2; anal. HPLC: Rt = 21.27 min. (diast.l) Rt = 21.75 min. (diast2) (method 1)
Diast. ratio: 5:1
Example 10
JV-r3-Bromo-5-('3-cvano-2-methvl-5-oxo-7-propvl-l,4.5,6.7,8-hexahydro-quinolin-4" vlV2-r3-methoxy-benzvloxv)-phenvl]-metbanesulfonamide
A mixture of the compound described in example 3 (100 mg), methanesulfonyl chloride (22 |il) and pyridine (46 ^il) in dichloromethane (5 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with sat. aq. NaHCOs. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 55 mg. MS-ESI: [M+H]^ = 614.2/616.2; anal. HPLC: Rt = 18.24 min. (method
1)
Diast. ratio: 6:1
Example 11
2-Methoxv-benzoic acid 2-bromo-4-r3-cvano-2-methvl-5-oxo-7-propvl-L4,5,6.7,8-hexahvdro-auinolin-4-vlV6-nitro-phenvl ester
(a). 3-Bromo-4-hvdroxv-5-nitro-ben2aldebvde
To a cooled solution of 3"bromo-4-hydroxyben2aldehyde (5 g) in acetic acid (50 ml) was added nitric acid (1.17 ml). The mixture was allowed to reach room temperature. After stirring for 17 h, the resulting precipitate was filtered off. The solid was washed with water and dried in vacuo.
Yield: 3.7 g.

(b). 4-f3-BiDmo-4-hvdroxv-5-iiitro-phenvl)-2-me1hvl-S-oxo-7-propvl-l,4,5,6,7,8-
hexahvdro-quinoline-3-carbonitrile
A mixture of 3-bromo-4-liydroxy-5-nitro-ben2aldehyde (2 g ), 3-amiiiocrotonitrile (667 mg) and 5-propylcyclohexane-l,3-dione (1.25 g) in eihanol (75 ml) was heated to reflux for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —> 0/1 (v/v) as eluent
Yield: 1.8 g. MS-ESI: [M+H]' = 446.2/448.2
(c). 2-Methoxv-benzoic acid 2-bromo-4-f3-cvano-2-methvl-5-oxo-7-propvl-1.4.5.6,7.8-hexahvdro-quinolin-4-vlV6-nitro-phenvl ester
A naixture of 4-(3-bromo-4-hydroxy-5-nitTO-phenyl)-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (200 mg), iy;j\r-diisopropylethylamine (390 ^il) and 2-methoxy-benzoyl chloride (53 ^il) in dichloromethane (4 ml) was stirred for 4 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 -T> 0/1 (v/v) as eluent.
Yield: 90 mg. MS-ESI: [M+H]^ = 580.2/582.2; anal. HPLC: Rt = 24.32 min. (method 2)
Example 12
4-r3-Bromo-5-isopropvlaminO'4-(3-methoxv-benzvloxvVphenvn-2-methvl-S-oxo-7-
propvl-l,4,5.6,7,8-hexahvdro-quinoline-3-carbonitrile
To a mixture of the compound described in example 3 (100 mg), acetic acid (114 |il) and acetone (20 ^1) in 2 ml of dichloromethane and 2 ml of methanol was added sodium cyanoborohydride (25 mg) in 1 ml of methanol. After stirring for 17 h, the mixture was diluted with dichloromethane and washed with water. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 9/1 —> 0/1 (v/v) as eluent.
Yield: 94 mg. MS-ESI: [M+H]^ = 578,4/580.4; anal. HPLC: Rt = 23.34 min. (diast.l) Rt = 23.73 mm. (diast2) (method 1)
Diast. ratio: 5:1

Example 13
4-r3-Bromo-5-dimethvlamitin-4-(^-methoxv-beiizvloxvVphenvl1-^ propvl-l,4,S,6J.8-hexahvdro-Qiiinoliiie-3-cafbomtrile
To a mixture of the compound described in example 3 (100 mg) and acetic acid (114 [il) in 2 ml of dichloromethane and 2 ml of methanol was axided a solution of 37% formaldehyde in methanol (64 |il) and sodium cyanoborohydride (16 mg).
After stirring for 17h, dichloromethane was removed in vacuo. The remaining solution was cooled to 0 **€, during which a solid fonned. The solid was collected by filtration, washed with cold methanol, and then purified by preparative HPLC (Method B).
Yield: 90 mg, MS-ESI: [M+H]^ = 564.4/566.4; anal. HPLC: Rt = 16.18 min. (diast,l) Rt = 16.71 min. (diast2) (method 1)
Diast. ratio: 10:1
Example 14
Propane-1-sulfonic acid r5-f3-cvano-2-methvl-5-oxo-7-propvl-l,4,5,6,7,8-hexahvdro-quinolin-4-vlV3-ethoxv-2-f3-methoxv-benzvloxvVpheDvn-amide
(a). 3-Ethoxv-4-hvdroxv-5-nitro-ben2aldehvde
To a solution of 3"ethoxy-4-hydroxybenzaldehyde (5 g) in acetic acid (50 ml) was added nitric acid (1.4 ml) in 2 portions. The resulting suspension was stirred for 17 h. The solid was collected by filtration, washed with water and dried in vacuo.
Yield: 5.07 g.
(h\ 4-(3-Ethoxv-4-hvdroxv-5-nitro-phenvl)-2-methvl-5-oxo-7-t)ropvl-l,4.5,6J,8-
hexahvdro-quiaoline-3-carbQnitrile
A mixture of 3-ethoxy-4-hydroxy-5-nitro-benzaldehyde (1.5 g), 3-aminocrotonitrile (584 mg) and 5-propylcyclohexane-l,3-dione (1.09 g) in ethanol (60 ml) was heated at reflux for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —> 0/1 (v/v) as eluent.

Yield: 1.3 g. MS-ESI: [M+H]^ = 412.3
(c). 4-r3-Ethoxv-4-(3-melhoxv-benzvloxvV5-mtro-pheavll"2-methvl-5-oxo-7-proDvl-1.4,5.6J.8-hexahv(fro-quinoliDe-3-carbcmitrile
A mixture of 4-(3-ethoxy-4-hydroxy-5-mtro-phenyl)-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-qiunoline-3-carbomtrile (1.5 g), 3-methoxybenzyl bromide (2.56 ml), potassium hydroxyde (450 mg) and benzyltriethyl ammonium chloride (415 mg) in 60 ml of dichloromethane and 60 ml of water was stirred for 48 k The organic layer was separated, dried (MgS04)5 filtered, and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 7/3 —^ 4/6 (v/v) as eluent.
Yield: 1.2 g. MS-ESI: [M+H]^ = 532.3
(d). 4-r3-Amino-5-ethoxv-4-(3-methoxv-benzvloxvVphenvll-2-methvl-5-oxo-7-propvl-lA5,6,7.8-hexahvdro-quinoline-3-carbanitrile
A solution of 4-[3-ethoxy-4-(3-methoxy-ben2yloxy)-5-nitro-phenyl]-2-methyl-5-oxo-7-propyl-l,4,5,65758-hexahydro-quinoline-3-carbonitrile and acetic acid (1.3 ml) in THF (33 ml) was cooled to O^C. Zinc dust (3.02 g) was added in portions under vigorous stirring. The mixture was allowed to reach room temperature and stirred for 1 h. The mixture was then filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with sat aq. NaHCOa. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 1.1 g. MS-ESI: [M+H]^ = 502.3
(e). Propane-1 -sulfonic acid r5-f 3-cvano-2-methvl-5-oxo-7-propvl-l ,4,5,6,7.8-hexahvdro-quinolin-4-vn-3 -ethoxv-2-r3 -methoxv-benzvloxvVphenvll -amide
To a solution of 4-[3-amino-5-ethoxy-4-(3-methoxy-benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-l54,5,6,758-hexahydro-quinoline-3-carbonitrile (220 mg) and pyridine (106 |j.l) in dichloromethane (5 ml) was added propane-1-sulfonyl chloride (94 mg). After stirring for 17 h, the mixture was diluted with dichloromethane and extracted with water and sat aq, NaHCOa. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 41 mg. MS-ESI: p^+H]^ = 608.4; anal. HPLC: Rt = 20.50 min. (method 1)

Diast. ratio: 5:1
Example 15
^-r3-Bromo-5-f 3-cvano-2-inet3ivl"5-oxo-7-i>ropvl-1,4,5,6 J,8-hexahvdro-qimolin-4-vlV2-f3-me1hoxv-bCT7y1aTriiiinVphenvl1-metfaanesidfona3aiid^
(a). 4-Aniino-3-nitro-beDzaldehvde
4-Fluoro-3-mtrobenzaldehyde (3 g) was slowly added to 50 ml of cone. aq. NH4OH. After stirring for 3 h, the mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 -^ 0/1 (v/v) as eluent.
Yield: 2.1 g. MS-ESI: [M+H]"' = 167.2
(b). 4-Amino-3-bromo-5-nitro-benzaldehvde
4-AminO"3-nitro-benzaldehyde (2.1 g) was dissolved in 25 ml of dichloromethane. Bromine (2 ml) and acetic acid (1 ml) were added and the mixture was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and washed with aq. NaHSOa. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —> 0/1 (v/v) as eluent.
Yield: 2.5 g. MS-ESI: [M+H]^ = 245.0/247,0
(c). 4-f4-Ammo-3-bromo-5-nitrO"phenvl)-2-methvl-5-oxo-7-propvl-L4.5,6.7,8-
hexahvdro-quinoline-3 -carbonitrile
A mixture of 4-amino-3-bromO"5-nitro-benzaldehyde (665 mg), 3-aminocrotonitrile (223 mg), 5-propylcyclohexane-l,3-dione (418 mg) in 50 ml of ethanol was stirred at 80 °C for 4 h, then at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —>■ 0/1 (v/v) as eluent.
Yield: 680 mg. MS-ESI: [M+H]^ = 445.2/447.2

(d), 4-f3,4-IMajriiiin-S-hTnmo-phenvlV2-me1hvl-5-oxO"7-propvl-l,4,5,6J,8"hexahv Qumoline-S-carbonitrile
4-(4-Amino-3-bromo-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-l,4^ qumoliiie-3-carbonitrile (600 mg) was dissolved in TEIF (150 ml) and cooled to 0 ^'C. Acetic acid (L3 ml) was added, followed by addition of zinc dust (2 g). The resulting slurry was stirred at 0 ^'C for 2 h, and then another 4 h at room temperature. The mixture was filtered and diluted with saturated aq. NaHCOa, followed by extraction with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 3/1 —>■ 0/1 (v/v) as eluent.
Yield: 316 mg. MS-ESI: [M+H]^ = 415.2/417.2
(e), ["2-Amino-3-broino-5-(3-cvano-2-methvl-5-oxo-7-propvl-L4,5,6.7,8-hexahvdro-quinolin-4-vlVphenvn-carbamic acid 9Jy-fluoren-9-vl methyl ester
4-(3,4-Diamino-5-bromo-phenyl)-2-methyl-5-oxo-7-propyl-l54,556,758-hexahydro-quinoline-3-carbonitrile (316 mg) and JV)7V-dimethylaniline (195 p.1) were dissolved in dichlorometiiane (40 ml) and cooled to 0 °C. A solution of 9-fluorenylmethyl chloroformate (187 mg) in dichloromethane (3 ml) was added dropwise. After stirring for 2 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —> 0/1 (v/v) as eluent.
Yield: 381 mg.
(f). r3-Bromo-5-('3-cvano-2-methvl-5-oxo-7-propvl-1.4,5,6,7,8-hexahYdTn-qniT>o1ifi-4> vl)-2-f3-methoxv-benzvlamino)-phenvn-carbamic acid 9Jy-fluoren-9-vl methvl ester
To a sohition of [2-amino-3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyH,4,5,65758" hexahydro-quinoUn-4-yl)-phenyl]-carbamic acid 9/Z-fluoren-9-yl methyl ester in methanol (5 ml) was added acetic acid (143 ^il) and m-anisaldehyde (304 |il). After stirring for 2 h, sodium cyanoborohydride (158 mg) was added. The resulting mixture was stirred for 3 h and then quenched with water, followed by extraction with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The

residue was purified by chromatography on siKcagel in heptane/ethyl acetate 1/0 —> 0/1 (v/v) as eluent
Yield: 145 mg, MS-ESI: [M+H]^ = 757.6/759.6
(g). 4-r3"AniiDO-5-bromo-4-f3-methoxv-benzvlaminoVphenvl1-2-methvl-5-oxo-7-propvl-1,4,5,6.7,8-hexahvdro-quinoline-3-carbonitrile
[3-Bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,63758-hexahydro-qiunolin-4-yl)" 2-(3-methoxy-benzylamino)-phenyl]-carbainic acid 9iy-fluoren-9-yl methyl ester (145 mg) was dissolved in 20% piperidine in DMF (5 ml) and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried QAgSOA), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield- 70 mg, MS-ESI: [M+H]^ - 535.4/537.4
(h). JV-r3-Bromo-5-r3-cvaDO-2-metfavl-5-oxo-7-proDvl-L4,5,6,7.8-hexahvdro-quinolin-4-vl)-2-r3 -methoxv-benzvlamino)-phenvll -methanesulfonamide
To a solution of 4-[3-amino-5-bromO"4-(3-methoxy-ben2ylamino)-phenyl]-2-methyl-5-oxO"7-propyl-l,4,556,758-hexahydro-quinoline-3-carbonitrile (70 mg) and pyridine (40 ^) in 1 ml of dichloromethane was added methanesulfonyl chloride (50 |il) in portions until con5)lete conversion was observed as judged by TLC (eluent: heptane/ethyl acetate 1/1, v/v). The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by prq)arative HPLC (Method A).
Yield: 18 mg (as TFA salt). MS-ESI: [M+H]^ = 613.4/615.4; anal. HPLC: Rt = 21,27 min. (method 2)
Example 16
3-Bromo-5-r3-cvano-2-methvl-5-oxo-7-propvl-L4,5,6.7,8-hexahvdro-quinoIin-4-vl)-2-r3-nitro-benzvloxv)-benzoic acid methyl ester
(a). 5-Formvl-2-hydroxv-beDzoic acid methvl ester

5-Fonnyl-2-hydroxy-benzoic acid (11.3 g) was dissolved in methaaol (35 ml) and cone, sulfuric acid (3 ml). The mixture was heated at leflux for 40 h. Diethyl ether was added, and the mixture was poured into water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was dissolved in a mixture of dioxane (80 ml) and water (50 ml) and treated with 6N hydrochloric acid (2.5 ml). After 15 min., dioxane was removed in vacuo. The mixture was extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 8.23 g. MS-ESI: [M+H]"" = 181.2
(b). 3-Bromo-5-formvl-2-hvdroxv-benzoic acid methvl ester
To a solution of 5-foTmyl-2-hydroxy-benzoic acid methyl ester (7.93 g) in acetic acid (50 ml) and dichloromethane (40 ml), cooled to 0 °C, was added bromine (2.49 ml). After stirring for 17 h, the mixture was allowed to reach room temperature. Sodium acetate (3.61 g) was added and stirring was contmued for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo.
Yield: 11.88 g. MS-ESI: [M+H]^ = 259.0/261.0
(c). 3-Bromo-5-formvl-2-f3-mtro-benzvloxvVbenzoic acid methvl ester
A mixture of 3-biomo-5-formyl-2-hydroxy-benzoic acid methyl ester (518 mg), potassium carbonate (613 mg), tetrabutylammonium iodide (68 mg) and 3-nitrobenzyl bromide (525 mg) in DMF (10 ml) was heated at 60 °C for 5 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 851 mg. MS-ESI: [M4-H]'^ = 394.0/396.0
(d). 3-Bromo-5-f3-cvano-2-methvl-5-oxo-7-propvM,4,5,6.7,8-hexahvdro-quinolin-4" vlV2-f3-mtro-benzvloxvVbenzoic acid methvl ester
A mixture of 3-bromo-5-formyl-2-(3-nitro-benzyloxy)-benzoic acid methyl ester (788 mg), 3-aminocTotonitrile (165 mg) and 5-propylcyclohexane-l,3-dione (308 mg) in ethanol (5 ml) was heated at 80 °C for 17 h. The naixture was concentrated in vacuo. The residue was purified by preparative HPLC (Method B).

Yield: 1.37 g. MS-ESI: [M+H]^ = 594.4/596.4; anal. HPLC: Rt - 24.59 min, (diast.l) Rt = 24,89 min. (diast2) (method 2)
Example 17
Propane-l-sulfonic acid (3-broiao-5"r3-cvaiio-2-methvl-5-oxo-7-propvl-h4,5.6,7,8-hexahvdro-quinoliD-4-vlV2-rfpwidin-3-vlmeihvlVamino1-phenvl}-aimde
(a). Propane-1-sulfomc acid r2"amiDO-3-bromo-S-f3-cvano-2-methvl-5"Oxo-7"propvl-
1.4,S,6J,8-hexahvdTD-quinolin-4"Vl)-phenvll-amide
The compound described in example 15d (4 g) was dissolved in 250 ml of dichloromethane. Pyridine (1.5 ml) was added, followed by dropwise addition of a solution of propanesulfonyl chloride (1.03 ml) in 50 ml of dichloromethane. The mixture was stirred for 17 h, and then washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 5.44 g, MS-ESI: [M+H]^ = 521,4/523.4
(b). Propane-1 -sulfonic acid f 3-bromo-5-f3-cvano-2-methvl-5-oxo-7-propvl-
1,4,5,6 J,8-hexahvdro-quinolin-4-yl)-2-[fpvridin-3-vhDe1hvl)-amino1-phenvl)-amide
Propane-1-sulfonic acid [2-amino-3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-qumoIin-4-yl)-phenyl]-amide (842 mg) and acetic acid (950 \iT) were dissolved in methanol (25 ml), 3-Pyridine-carboxaldehyde (1.52 ml) was added and the resulting mixture was stirred for 17 h. Sodium cyanoborohydride (1.02 g) was added and stirring was continued for 17 h. The mixture was diluted with ethyl acetate and washed with aq. citric acid and aq. NaHCOs. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method A).
Yield: 237 mg (as TFA salt), MS-ESI: [M+H]^ = 612,4/614.4; anal. HPLC: Rt = 8.79 min. (method 2)
Example 18
3-Bromo-5-(3-cvano-2-methvl-5-oxo-7-propvl-L4.5,6,7.8-hexahvdro-quinolin-4-vl)-2-r3-methoxv-benzvloxv)-JV"-propvl-ben2amide

A mixture of the compound described in example 22c (100 mg), n-propylamine (145 ^il), TBTU (75 mg) and iV,iV^diisoprqpylethylamine (31 ^1) in dichlotomethane (10 ml) was stirred for 65 h. The mixture was diluted with dichloromethane and extracted with sat aq. NaHC03. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 41 mg. MS-ESI: [M+H]^ - 605.4/607.4; anal. HPLC: Rt = 26,72 min. (diast.l) R Example 19
4"(r2-Bromo-4-f3-cvano-2-methvl-5-oxo-7--propvl-L4,5,6,7,8-hexahvdro-quinolin-4-vlV6-(t>roT>ane"l -sulfonvlamino)-phenvlaniinn]-Tnethvl} -JV-f 2-methoxv-ethvlV benzamide
(a). 4--fr2-Bromo-4-r3-cvano-2-methvl-5-oxo-7-propvM,4,5,6,7,8-hexahvdro-
quinolin"4-vl)-6-fpropane-l-sulfonvlamino)-phenvlamino1"methvU-benzoicacid
A mixture of the conipoimd described in example 17a (600 mg), benzoic acid-4-carboxaldehyde (863 mg) and acetic acid (657 [il) in methanol (5 ml) was stirred for 1 hour. Sodium cyanoborohydride (361 mg) was added and the mixture was stirred for 17 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentmted in vacuo.
Yield: 605 mg. MS-ESI: [M+H]^ = 655.4/657.4
(b). 4"ir2-Bromo-4-r3-cvano-2-methvl-5-oxo-7-propvl-1.4,5,6,7,8-hexahvdro-
quinolin-4-vl)-6-(propane-l-sulfonvlamino)-phenvlanmio1-methvU-A^-r2-methoxv-
ethvD-benzamide
A mixture of 4-{[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinolin-4-yl)-6-(propane-l-sulfonylamino)-phenylamino]-meihyl}-benzoic acid (200 mg), TBTU (300 mg), iViiV-diisopropylethylamine (536 |il) and 2-methoxyethylamine (134 ^1) in DMF (2 ml) was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and washed with aq. NaHCOs.
The organic layer was dried (MgS04)5 filtered and concentrated in vacuo.
The residue was purified by preparative HPLC (Method B).

Yield: 115 mg. MS-ESI: [M+H]^ = lUA/lUA; anal. HPLC: Rt= 17.99 min, (method 2)
Example 20
4-ir2-Bronio-4-f3-cvaDO-2-methvl"5-oxo-7-piDPvl-l,4^5,6J,8-hexahvdro-qimolm
vl)"6-fT)ropaDe-l-sdfonvlaminoVT3heaivlanunol-melhvl}-^^
ethviybenzamide
Condensation of histamine (283 mg) and the compound described in example 19a (200 mg) in the presence of TBTU (300 mg) and iy;iV-diisopropylethylamine (536 iil) was performed according to the method described in example 19b.
Yield: 123 mg (as TFA salt). MS-ESI: [M+H]^ = 748.4/750.4; anal, HPLC: Rt = 10.38 min. (method 2)
Example 21
4-r3-Bromo-4-f3-methoxv-benzvloxv)-5-('morpholme-4-carbonvl)-phenvl]-2-me1favl'5-oxo-7--propvl-1.4,5,6,7,8-hexahvdrO"quinoline-3-carbonitrile
A mixture of the compound described in example 22c (100 mg), moipholine (50 ^il), HATU (100 mg) and ^^-diisopropylethylamine (92 p,l) in dichloromethane (5 nal) was stirred for 17 h. The mixture was diluted with dichloromethane and extracted with sat. aq. NaHC03. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 54 mg. MS-ESI: [M+H]^ = 634.4/636.4; anal. HPLC: Rt = 21.32 min. (method 2)
Example 22
3-Bromo-5-(3-cvano-2-methvl-5-oxo-7-propvl-L4,5.6,7,8-hexahvdro-quiDolin-4"Vl)-2-(3 -methoxv-benzvloxv)-benzamide
(a). 3-Bromo-5-formvl-2-r3-methoxv-benzvloxvVbenzoic acidmethvl ester

A mixture of the compound described in example 16b (4.62 g), 3-methoxybenzyl bromide (3.03 ml), potassium carbonate (5.47 g) and tetrabutylammonium iodide (606 mg) in DMF (90 ml) was stirred at 60 °C for 5 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was recrystallized fix)m ethanol and diethylether (1/1, v/v).
Yield: 5.65 g.
(b). 3-Bromo-5-(3-cvano-2-meihvl-5-oxo-7-propvl-L4,5,6J,8-hexahydro-quinolin-4-vl)-2-f3-methoxV"benzvloxv)-benzoic acid methyl ester
A mixture of 3-bromo-5-formyl-2-(3-methoxy-benzyloxy)-ben2oic acid methyl ester (3,78 g), 3-aminocrotonitrile (822 mg) and 5-propylcyclohexane-l,3-dione (1535 mg) in ethanol (25 ml) was stirred at 80 °C for 17 h. The mixture was concentrated in vacuo.
Yield: 5.9 g.
(c). 3-Bromo-5-(3-cvano-2-methvl-5-oxo-7-propvl-l,4,5.6,7,8-hexahvdro-quinolin-4-vl)-2-f3-metboxv-beDzvloxvVbenzoic acid
A solution of 3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-methoxy-ben2yloxy)-benzoic acid methyl ester (5.7 g) in dioxane (135 ml) and IN NaOH (15 ml) was stirred for 17 h. The mixture was acidified with cone, acetic acid and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was dissolved in ethanol and then concentrated until a solid precipitated. The solid was collected by filtration and washed with petroleum ether.
Yield: 4.2 g. MS-ESI: [M+H]^ = 563-6/565.2
(d\ 3-Bromo-5-f3"Cvano-2-methvl-5-oxo-7-propvM,4,5,6,7.8-hexahvdro-qumolin-4-vlV2-f3-methoxv-b€aizvloxv)-ben2amide
A mixture of 3-bromo-5-(3-cyano-2-methy]-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-methoxy-ben2yloxy)-benzoic acid (57 mg), ammonium chloride (18 mg), HATU (57 mg) and iy;JV-diisopropylethylamdne (34 ^il) m DMF (0.8 ml) was stirred for 17 h. The mixture was diluted with water and extracted with ethyl acetate.

The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 29 mg. MS-ESI: [M+H]^ = 564.4/566.4; anal. HPLC: Rt: 19.64 min. (method 2)
Example 23
JV^r2-Bromo-4-f3-cvano-2-DJiethvl-5-oxo-7-propvl-l,4.S,6J,8-hexahvdro-Qumolk-4^ vn-6-fpropane-1 ■sulfonvlaniiDo)"Phenvn-3-methoxv-benzamide
A solution of the compound described in example 17a (229 mg) and N,N' dimethylaniline (480 mg) in THF (4 ml) was treated with 75 |xl of 3-methoxybenzoyl chloride.
After stirring for 17 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
The residue was purified by preparative HPLC (Method B).
Yield: 151 mg. MS-ESI: [M+H]^ = 655.4/657,4; anal, HPLC: Rt = 20.82 min. (method 2)
Example 24
JV-r3-Bromo-5-f 3-cvano-2-methvl-5-oxo-7-propvl-1,4,5,6,7,8-hexahvdro-quipolin-4-vl)-2-(3-methanesulfonvlamino-benzvloxv)-phenvll-methanesulfonamide
TaV 3"Bromo-4-hvdroxv-5-nitro-benzaIdehvde
To a solution of 3-bromo-4-hydroxy-benzaldehyde (20 g) in acetic acid (200 nal) was added fuming nitric acid (4.18 ml). The resulting suspension was stirred for 3 h. The solid was collected by filtration. Another 420 \i\ of fimiing nitric acid was added to the filtrate. After 45 min., water was added and the resulting precipitate was collected by filtration. The combined solids were washed with water and dried in vacuo.
Yield: 18.26 g. MS-ESI: [M+H]" = 245.8/247.8
(b). 4-f3-Bromo-4-hvdroxv-5-nitro-phenvl)-2-methvl-5-oxo-7-propvl-lA5,6,7.8-
hexahvdro-quinoline-3 -carbonitrile

A mixture of 3-bromo-4-hyclroxy-5-idtro-benzaldehyde (18.26 g), 3-airdnocrotonitrile (6.09 g) and 5-prqpylcyclohexane-l,3-dione (11.45 g) in ethanol (250 ml) was stirred at 80 °C for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in dichloromethane as eluent.
Yield: 16.49 g. MS-ESI: [M+H]^ = 446.2/448.2
(c\ 4-(3-ATnmn-S-bromo-4-hvdroxv-phenvlV2--methvl-5-oxo-7-T)roT)vl-L4.5.6,7.8-hexahvdro-quinoline-3-carbonitrile
To a solution of 4-(3-bromo-4-hydroxy-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (15.8 g) and acetic acid (30 ml) in THF (300 ml), zinc dust (46 g) was added in portions, under vigorous stirring. After 2 h, the mixture was filtered and concentrated until a precipitate formed. This precipitate was collected by filtration and washed with ethanol.
Yield: 9.27 g. MS-ESI: [M+H]^ -416,2/418.2
fd). 4-|"3"Amino-5-broino-4-(3-nitro-benzvloxvVphenvlV2-methvl-5-oxo-7-propvl-L4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile
A mixture of 4-(3-amino-5-bromo-4-hydroxy-phenyl)-2-methyl"5-oxo-7-propyI-1,4,5,6,7,8-hexahydro-quinoline-3-caTbonitrile (5 g), 3-nitrobenzyl bromide (2.72 g), potassium carbonate (3.65 g) and potassium iodide (400 mg) in DMF (100 ml) was stirred for 65 h at room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —>■ 0/1 (v/v) as eluent.
Yield: 1.45 g. MS-ESI: [M+H]^ = 551,4/553.4
feV ■Ar-[3-Bromo-5-(3-cvano-2-methvl-5-oxo-7--propvl-L4,S.6,7,8-hexahvdro-quinolin-4-vlV2-r3-nitro-benzvloxvVphenvn-methanesulfonamide
'A solution of 4-[3"amino-5-bromo-4-(3-nitrO"benzyloxy)-phenyl]-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinoline-3-carbomtrile (1.15 g) and triethylamine (740 |il) in dichloromethane (20 ml) was treated with methanesulfonyl chloride (203 jil). After stirring for 18 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The

crade Ar,JV-bis-meihaiiesiilfonyl-aniline derivative was dissolved in THF (20 ml) and treated with 2N NaOH (3 ml). After 2 h, the mixture was quenched with sat. aq. NH4CI and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —► 0/1 (v/v) as eluent.
Yield: 950 mg. MS-ESI: [M+H]"' = 629.2/631.2
(f), JV-r2-(3-Amiao-ben2vloxvV3-bromo-S-(3-cvano-2-methvl-5-oxo-7-Dropvl-
l,4.5,6.7,8-hexahvdTO-quinol3n-4-vlVphenvl]-methanesulfonamide
A mixture of iV-[3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(3-nitro-ben2yloxy)-phenyl]-methanesiilfonarnide (950 mg) and sodium sulfide (350 mg) in ethanol (12 ml) and water (250 ^il) was heated at reflux for 2 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 709 mg. MS-ESI: [M+H]^ = 599.2/601.2
(gV JV-['3-Bromo-5-f3-cvano-2-methvl-5-oxo-7-propvl-l,4.5,6J.8-hexahvdro-quinolin-4-vl)-2-f3-methanesulfonvlamino-benzvloxvVphenvl1-methanesulfonamide
To a solution of iV^[2-(3-amino-benzyloxy)-3-bromo-5-(3-cyano-2-methyl-5"Oxo-7-propyl-l,4,5,657,8-hexahydro-quinolin-4-yl)-phenyl]-methanesulfonamide (709 mg) and pyridine (286 \il) in dichloromethane (20 ml) was added methanesulfonyl chloride (138 |il). After stirring for 18 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
The residue was purified by preparative HPLC (Method B).
Yield: 172 mg. MS-ESI: [M+H]^ = 677.2/679.2; anal. HPLC: Rt - 22,37 min. (method 3)
Example 25
4-r3-Bromo-5-cvano-4-f3-methoxv-benzvloxvVphenvll-2-methvl-5-oxo-7-propyl-L4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile

A solution of the compound described in example 22d (54 mg) in dichloromethane (1.2 ml) was cooled to 0 °C. Triethylamine (58 ^il) was added, followed by drqpwise addition of trifluoroacetic anhydride (25 |il). The mixture was allowed to reach room temperature. Again, triethylamme (58 |il) and trifluoroacetic anhydride (25 ^il) were added After stirring for 1 h, the mixture was extracted with water. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 26 mg. MS-ESI: [M+H]^ = 546.2/548.2; anal. HPLC: Rt = 24,86 min. (method 2)
Example 26
JV-r2-Bromo-4"f3-cvano-2-methyl-5-oxo-7-propvl-1.4,5,6,7,8-hexahvdro-quinolm-4-vl>-6-(nropane-l-sulfonvlamino)-phenvl1-JV-r3-methoxv-benzvl)-acetaniide
(a). Propane-1 -sulfonic acid [3 -bromo-5-(3 -cvano-2-methvl-5-oxo-7-propvl-
l,4,5,6.7,8-hexahvdro-quinolin-4-vl)-2-f3-methoxv-benzvlamino)-phenvl')-amide
Condensation of the compound described in example 17a (688 mg) with m-anisaldehyde (605 jil) in the presence of acetic acid (570 fil) and sodium cyanoborohydride (317 mg) in methanol (6 ml) was performed as described in example 17b.
Yield: 300 mg. MS-ESI: [M+H]^ =641.4/643.4
(b). JV"r2-Bromo-4-f3-cvaDO-2-methvl-5-oxo-7-propvl-1.4,5,6,7,8-hexahvdro-quinolin-4-vlV6-fprot)ane-l-sulfonvlamino)-phenvn-JV-f3-methoxv-benzvl)-acetamide
A solution of propane-1-sulfonic acid [3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quino]in-4-yl)-2-(3-meihoxy-benzylamino)-phenyl]-amide (120 mg) in pyridine (3 ml) was treated with acetic anhydride (153 |il). After stirring for 17 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried CMgS04)5 filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —>- 0/1 (v/v) as eluent
Yield: 27 mg. MS-ESI: [M-fH]^ = 683.2/685.2; anal. HPLC: Rt = 21.09 min. (method 2)

Example 27
Propane-1-sulfonic add l3-bTomo-5-f3-cvano-2-meihvl-5-oxo-7-propvl-L4.5,6,7,8> hexahv(ho-qiunolk-4-vlV2-rf3-methoxv-benzvlVme1hvl-amino1-^^
A mixture of the con^und described m example 26a (180 mg), 37% fonnaldehyde in water (230 |il) and acetic acid (160 ^1) in methanol (5 ml) was stirred for 2 h. Sodium cyanoborohydride (176 mg) was added and stirring was continued for 17 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo.
The residue was purified by preparative HPLC (Method B).
Yield: 17 mg. MS-ESI: [M+H]^ = 675.2/677.2; anal, HPLC: Rt = 28.11 min. (method 2)
Example 28
Propane-1-sulfonic acid r3-bromo-5-f3-cvano-2-methvl-5-oxo-7-propvH,4,5,6,7,8-hexahvdro-quinolin-4-vlV2-f3-methoxv-ben2:vlaiDinoVphenvl1-methvl-amide
A mixture of the compound described in example 26a (180 mg), methyl iodide (19 \i\) and potassium carbonate (19 mg) in DMF (1 ml) was stirred for 65 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo.
The residue was purified by preparative HPLC (Method B).
Yield: 31 mg. MS-ESI: [M+H]^ = 655.4/657.4; anal. HPLC: Rt = 25.00 min. (method 2)
Example 29
JV"-r2-Bromo-4-r3-cvano-2-methvl-5-oxo-7-propvl-L4,5.6.7,8-hexahvdro-quinolin-4-vl)-6-(propane-l-sulfonvlaminoVphenvl1-nicotinamide
) A mixture of the compound described in example 17a (100 mg), TBTU (123 mg), nicotinic acid (47 mg) and iV^j^V-diisopropylethylamine (168 ^1) in 2 ml of dichloromethane and 2 ml of THF was stirred for 65 h. The mixture was diluted with

iichloromethane and extracted with water and sat aq. NaHCOa- The organic layer was Iried (MgS04)5 filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method A).
Yield: 74 mg (as TFA salt). MS-ESI: [M+H]^ = 626.4/628.4; anal. HPLC: Rt = 12.03 min. (method 2)
Example 30
JV'-r2-(r2-Bromo-4-f3K:vano-2-methvl-5-oxo-7-propvl-l,4,5,6.7,8-hexahvdro-Quinolin-
4-vlV6-(propane-l-sulfonvlaniinoVpheyiy1aTriTin]-niethvU-phenyl)-acetainide
(a). Propane-1-sulfonic acid r3-bromo-5-f3-cvano-2-methvl-5-oxO"7-propvl-
1.4,5,6 J,8-hexahydro-quinolin-4-vl)-2-r2-mtro-benzvlamJnoVT)henvl1-amide
Condensation of the compound described in example 17a (1.05 g) with 2-nitrobenzaldehyde (1,61 g) in the presence of acetic acid (1.21 ml) and sodium cyanoborohydride (1.34 g) in methanol (25 ml) was performed as described in example 17b.
Yield: 1.21 g, MS-ESI: [M+H]^ - 676.2/678.2
(b). Propane-l-sulfonic acid r2-(2-amino-benzvlamino)-3-bromo-5-f3-cvano-2-methvl-5-oxo-7-propvl-l,4,5.6,7,8-hexahvdro-quinolin-4-vl)-phenvlVamide
Propane-l-sulfonic acid [3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6J,8" hexahydro-quinolin-4-yl)-2-(2-nitro-benzylamino)-phenyl]-amide (1.21 g) and acetic acid (1.6 ml) were dissolved in THF (150 ml). Zinc dust (2.32 g) was added under vigorous stirring. After 3 h, the mixture was filtered, diluted with ethyl acetate and washed with sat. aq. NaHCOa. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 -^ 0/1 (v/v) as eluent
Yiel± 430 mg. MS-ESI: [M+H]^ = 626.4/628.4
(c). iV"-f2-{f2-Bromo-4-r3-cvano-2-methyl-5-oxo-7-propvl-lA5,6,7,8-hexahvdro-
quinolin-4-vlV6-(prQpane-l -sulfonvlaminoVphenvlaminol-methvl} -phenvlVacetamide
A solution of propane-l-sulfonic acid [2-(2-amino-benzylamino)-3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,455,6,7,8-hexahydro-quinolin-4-yl)-phenyl]-amide (430

mg) and JV;JV-diisopropyleihylaiimie (120 |il) in 152-dichloropropane (50 ml) was cooled to 0 ^C and then treated witii acetyl chloride (49 \i\) in 1,2-dichloropropane (15 ml). After stirring for 2 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
The residue was purified by preparative HPLC (Method A),
Yield: 45 mg (as TFA salt). MS-ESI: [M+H]^ = 668,2/670.2; anal. HPLC: Rt = 18.91 min. (method 2)
Example 31
f2-l[2-Bromo-4-f3-cyano-2-methvl-5-oxo-7-propvl-L4J,6J.8-hexahydro-quinolin-4-vlV6-rpropane-l"SulfonvlaminoVphenylamino1-methvl}"phenvlVcarbaniic acid methyl ester
To a sohition of the compound described in example 30b (100 mg) in dichloromethane (5 ml) was added iVi^-diisopropylethylamine (84 jil) and methylchloroformate (12 yl). After stirring for 17 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
The residue was purified by preparative HPLC (Method A).
Yield: 19 mg (as TFA salt). MS-ESI: [M+H]^ = 684.2/686.2; anal. HPLC: Rt = 17.90 min. (method 2)
Example 32
JV-r2-Bromo-4-(3"Cvano-2-methvl-S-oxo-7-propvl-L4,5,6,7.8-hexahvdro-quinolin-4-vlV6-fpropane-l-siilfonvlamino)-phenvll-3"f2-piperazin-l-vl-acetvlaniino)-benzamide
(a), JV-[2-Bromo-4-(3-cvano-2-methvl-5-oxo-7-propvI-l,4,5,6J,8-hexahvdrO"quinolin-4-vlV6-fpropane-l-sulfonvlaminoVphenvll-3-nitro-benzamide
To a solution of the compound described in example 17a (400 mg) and N,N-dimethylaniBne (350 \i\) in THF (10 ml) was added 3-nitrobenzoyl chloride (150 jil). The mixture was stirred for 17 h, then poured into water and extracted with ethyl acetate. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo.

The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/3 (v/v) as ehient
Yield: 412 mg. MS-ESI: [M+H]^ = 670,2/672.2
(b). 3-AminorAr-f2-bromo-4-f3-cvaao-2"niethvl-5-oxo-7-T)ropvl-l,4.S.6J.8-hexahvdro-quinolin-4-vIV6-fpropane-1 ■sulfonvlaminoVphenvn-benzamide
To a solution of JV-[2-bronio-4-(3-cyano-2-methyl-5-oxo-7-propyl-l ,4,5,6,7,8-hexahydro-quinolin-4-yl)-6-(propane-1 -sulfonylamino)-phenyl]-3-nitro-baQzamide (412 mg) and acetic acid (520 ^1) in TEIF (10 ml), cooled to 0 °C, was added zinc dust (810 mg) under vigorous stirring. After stirring for 4 h, the mixture was filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 257 mg. MS-ESI: [M+H]^ - 640.4/642.4
(c). JV-r2"Bromo-4-f3-cvano-2-methvl-S-oxo-7-i)rot>vl-L4,5.6,7,8-hexahvdro-quinolin-4-vlV6-(propane-l"Sdfonvlammo)-phenvll-3--f2-chloro-acetvlamino)-benzamide
To a solution of 3-amino-iV^[2-bromo-4.(3"Cyano-2"methyl-5-oxo-7-propyH,4,5,6,7,8-hexahydro-quinolin-4-yl)-6-(propane-1 -sulfonylamino)-phenyl] -benzamide (257 mg) in THF (6 ml), jy;A^-diisoprqpylethylamine (205 \x\) and chloroacetyl chloride (50 |il) were added. The mixture was stirred for 17 h, then diluted with dichloromethane and extracted with water and sat. aq. NaHCOa. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
Yield: 287 mg. MS-ESI: [M-hH]^ = 716.2/718.2
(d). iV-[2-Bromo-4-f3-cvano-2-methvl-5-oxo-7-propvl-1.4,5,6,7,8-hexahvdro-qumolin--4-vl)-6-rpropane-1 -sulfonvlamino)-phenvl1 -3-r2-piperazin-1 -vl-acetvlamino)-benzamide
To a solution of iV-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-quinolin-4-yl)-6-(propane-1 -sulfonylamino)-phenyl]-3-(2-chloro-acetylamino)-benzamide (143 mg) in dichloromethane (4 ml) was added piperazine (172 mg). The mixture was stirred for 17 h, then diluted with dichloromethane and extracted with sat. aq. NaHCOs. The organic layer was dried (MgS04), filtered and concentrated in vacuo.

The residue was purified by preparative HPLC (Method A).
Yield: 18 mg (as TFA salt). MS-ESI: [M+H]^ = 766.4/768.4; anal. HPLC: Rt - 4.87 min. (method 2)
Example 33
4-r3-Bromo-5-(2-hvdroxv-ethoxvM-f3-inethoxv-ben2vloxvVphenvl1-2-methvl-5-oxo-7-prot>vl-lA5,6.7,8-hexahvdro-quinoline-3-carbomtrile
(a). 3-Bromo-5-hvdroxv-4-f3-Tnethoxv-beDzvloxvVbenzaldehvde
A mixture of 3-bromo-4,5-dihydroxy-benzaldehyde (1 g), lithium carbonate (314 mg), 3-methoxybenzyl chloride (742 ^1) and a catalytic amount of tetrabutylammonium iodide m DMF (5 ml) was stirred at 60 °C for 17 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04)5 filtered and concentrated in vacuo.
Yield: 1.48 g. MS-ESI: [M+H]^ =337,2/339.2
(b). 4-r3-Bromo-5-hvdroxv-4-(3-methoxv-benzvloxvVphenvn-2-methvl-5-oxo-7"
propvl-l,4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile
A mixture of 3-bromo-5-hydroxy-4-(3-methoxy-ben2yloxy)-ben2aldehyde (1.43 g), 3-aminocrotonitrile (350 mg) and 5-propylcyclohexane-l,3-dione (654 mg) in ethanol (100 ml) was heated at 80 **C for 17 h. The mixture was concentrated in vacuo and then purified by chromatography on sihcagel in heptane/etiiyl acetate 1/0 —>■ 0/1 (v/v) as ehient.
Yield: 1.31 g. MS-ESI: [M+H]^ = 537.2/539.2
(c). 4'r3-Bromo-5-f2-hvdroxv-ethQxv)-4-(3-methoxv-benzvloxvVphenvn-2-methvl-5-oxo-7-propvl-L4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile
A mixture of 4-[3-bromo-5-hydroxy"4-(3-methoxy-benzyloxy)-phenyl]-2"methyl-5-oxo-7-propyl-l54,5,6,758-hexahydro-quinoline-3-carbonitrile (100 mg), 2-bromoethanol (16 \xl), tetrabutylammonium iodide ( 5 mg) and potassium carbonate (50 mg) in DMF (2 ml) was stirred at 70 °C for 17 h. The mixture was diluted witii

ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo.
The residue was purified by preparative HPLC (Method B).
Yield: 36 mg. MS-ESI: [M+H]^ = 581.4/583.4; anal. HPLC: Rt = 20.57 min. (diast,l) Rt = 20.91 min. (diast2) (method 2)
Example 34
4-r3-Bromo-4-f3-methoxv-ben2:vloxv)-5-(2-methoxV"ethoxvVphenvll-2-methvl*5-oxo-
7-pTopvl-l,4,5,6,7,8-hexahvdro-quinoline-3-carbonitrile
Alkylation of the con:5)ound described in example 33b (100 mg) using 2-methoxybromoethane (22 |al), potassium carbonate (50 mg) and tetrabutylammonium iodide (5 mg) in DMF (2 ml) was performed according to the method described in example 33c,
Yield: 48 mg. MS-ESI: [M+H]^ = 595.2/597.2; anal. HPLC: Rt = 24.72 min. (diast.l) Rt = 25.08 min, (diast.2) (method 2)
Example 35
4-r3-Bromo-5-hvdroxy-4-(3-methoxv-benzvloxv)-phenvll-2-methvl-5-oxo-7-propvl-1,4,5,6 J,8-hexahydro-quinoline-3-carbonitrile
100 mg of the compound described in example 33b was purified by preparative HPLC (Method B).
Yield: 54 mg. MS-ESI: [M+H]^ = 537.4/539.4; anal. HPLC: Rt = 21.85 min. (method 2)
Example 36
3-Bromo-5-f3-cvano-2-methvl-5-oxo-7-propvM,4.5,6,7,8-hexabvdrn-qTiiTiolin-4-vlV ArjV-diethyl-2-fpvridin-3-vlmethoxy)-benzenesulfonamide

(a). 3-Br(Mno-5-f3-cvano-2-methvl-5-oxo-7-i3ropvl-L4.5,6J,8-hexahvdrO"qumolin-4-
vlVJVJV'-dieihvl-2-hvdroxv-betizenesdfonamide
A mixture of the compound described in example 37b (1.5 g) and diethylamine (3.1 ml) in dioxane (30 rd) was stirred for 17 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSOA), filtered and concentrated in vacuo.
Yield: 1.43 g. MS-ESI: [M-i-H]^ = 536.2/538.2
(b). 3-Bromo-5-(3-cvano-2-methvl-S-oxo-7-propvl-L4,5,6J,8-hexahydro-quiQolin-4-
vlVJ\rjV"-diethvl-2-(pyridin-3"VlmethoxvVbenzenesulfonamide
A mixture of 3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6,758-hexahydro-qiunolin-4-yl)-iV^-diethyl-2-hydroxy-benzenesulfonamide (1.43 g), 3-picolyl chloride (689 mg), potassium carbonate (774 mg) and potassium iodide (93 mg) in DMF (40 ml) was stirred at 70 °C for 2 hours and then at room temperature for 17 h. The mixture was diluted with ethyl acetate and extracted with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method A).
Yield: 991 mg (as TFA salt), MS-ESI: [M+H]^ = 627.2/629.2; anal. HPLC: Rt = 17.36 min. (method 3)
Example 37
3-Bromo-5-f3"Cvano-2-methyl-5-oxo-7-propvl-l,4,5,6J,8-hexahvdro-quinolin-4-vlV JV-methyl-2-(pvridin-3-vlmethoxvVbenzenesulfonamide
(a), 4-f3-BrQmo-4-hvdroxy-phenvlV2-methvl-5-oxo-7-propvl-l,4,5.6J.8-hexahvdro-qumoline-3-carbomtrile
A mixture of 3-bromo-4-hydroxy-benzaldehyde (13.07 g), 5-propylcyclohexane-l,3-dione (10.02 g) and 3-aminocrotonitrile (5.34 g) in ethanol (165 ml) was stirred at 80 °C for 17 L A precipitate fomied, which was collected by filtration. The filtrate was concentrated in vacuo and then triturated with ethyl acetate. The solids were combined and dried in vacuo.
Yield: 20.25 g. MS-ESI: [M+Hj^ = 401,2/403.2

(b). 3-Bromo-5"f3-cvano-2-methvl-5-oxo-7-propvl-l,4,5,6J,8-hexahv(ko-qiimol^ vlV2-hvdroxv-benzenesulfonvl chloride
To 47 ml of chlorosulfonic acid, cooled to -10 T in a pressure vessel under a nitrogen atmosphere, was slowly added 4-(3-bromo-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-l54,5,6,7,8-hexahydro-quinoline-3-cafbonitrile (20.25 g). The naixture was allowed to reach room temperature. After stirring for 17 h, the mixture was poured onto 800 ml of crushed ice and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was triturated with ethyl acetate. The solids were collected and dried in vacuo.
Yield: 23.7 g. MS-ESI: [M+H]^ = 499.0/501.0
(c). 3-Bromo-S-(3-cvano-2-methvl-5-oxo-7-propvl-1.4,5,6,7,8-hexahvdro-quinolin-4-vlV2"hvdroxv-^-methvl-benzenesulfonamide
For 30 min.5 mono-methylamine was bubbled through a solution of 3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l54,5,6,7,8-hexahydro-quitiolin-4-yl)-2-hydroxy-benzenesulfonyl chloride (240 mg) in dioxane (5 ml). The mixture was stirred for 17 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 60 mg. MS-ESI: [M+H]^ = 494.2/494.2
(d). 3-Bromo-5-(3-cvanO"2-methvl-5-oxo-7-propvl-L4,5,6,7.8-hexahvdro-quinolin-4-vlVJV-methvl-2-fpvridin"3-vhnethoxvVbenzenesulfonamide
A mixture of 3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,657,8-hexahydro-quinolin-4-yl)-2-hydroxy-^-methyl-benzenesulfonamide (52mg), 3-picolyl chloride. HCl (24mg) and potassium carbonate (88mg) in DMF (2 ml) was heated at 70 °C for 2 h, then at room temperature for 17 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method A).
Yield: 15.5mg (as TFA salt). MS-ESI: [M+H]^ = 585.2/587.2; anal. HPLC: Rt = 8.73 min. (diast.1) Rt = 9.44 min. (diast.2) (method 2)
Diast. ratio: 10:1

Example 38
4-r3-Bromo-5-hvdroxv-4-(pvridm-3-v]metfaoxvVphenvl1-2-meth l,4,S,6J,8-hexahvdro-qumoliDe-3"CarbQnitrile
(a). 3-BronK)-5-hvdrox^-4-rpvridin"3-vlmethoxvVbenzaldehvde
A mixture of 3-bromo-4,5-dihydroxy-benzaldehyde (1 g), 3-pyridinecarbinol (448 ^il), diisopropyl azodicarboxylate (DIAD) (908 ^1) and polymer siqyported triphenylphosphine (1.53 g, 3 mmol/g loading) in THF (50 ml) was stirred under a nitrogen atmosphere for 17 h. The mixture was filtered, diluted with ethyl acetate and washed with water. The organic layer was dried (MgSOA), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 —► 0/1 (v/v) as eluent.
Yield: 330 mg. MS-ESI: [M+H]^ = 308.2/310.2
(b), 4-r3-Bromo-5-hvdroxv-4-(pvridin-3-vhnethoxv)-Dhenvn-2-methvl-5-oxo-7-
propvl-l,4,5,6,7.8-hexahvdro-quinoline-3-carbonitrile
A mixture of 3-bronK>-5-hydroxy-4-(pyridin-3-ylmethoxy)-benzaldehyde (165 mg), 3-aminocrotonitrile (44 mg) and 5-propylcyclohexane-l,3-dione (83 mg) in ethanol (25 ml) was stirred at 80 °C for 17 h. The mixture was then concentrated in vacuo, and the residue was recrystallized fi'om acetonitrile.
Yield: 105 mg (as TFA salt). MS-ESI: [M+H]^ = 508.4/510.4; anal. HPLC: Rt - 7.65 min. (method 2)
Example 39
4-r3-Bromo-5-fluoromethoxv-4-(pvridin-3-vlmethoxv)-phenvll-2-methvl-5-oxo-7-propvl-L4,5,6J,8-h^ahvdro-quinoline-3-carbonitrile
A mixture of the compound described in example 38b (700 mg), bromo-fluoro-methane (1557 mg) and potassium carbonate (761 mg) in DMF (10 ml) in a pressure vessel was stirred for 20 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The

residue was purified by chroinatography on silicagel in heptane/ethyl acetate 2/8 (v/v) as eluent.
Yield: 842 mg (as TFA salt). MS-ESI: [M+H]^ = 540-2/542.2; anal. HPLC: Rt = 5.84 min. (method 1)
Diast. ratio: 7:1
Example 40
4-r3-Bromo-5-f2.2-difluoTo-ethoxvM-(pvridin-3-vlmethoxvVT)henvlV2-methvl-5-oxo-
7-propvl-1.4.S.6,7,8-hexahvdro-qu3nQline-3"Carbonitrile
A mixture of the compound described in example 38b (150 mg), 2,2-difluoro-l-bromoethane (86 mg), potassium carbonate (82 mg) and a catalytic amoimt of tetrabutylammonium iodide in DMF (5 ml) was stirred at 40 ^C for 17 h. The naixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method A).
Yield: 113 mg (as TFA salt). MS-ESI: [M+H]^ = 572.2/574.2; anal. HPLC: Rt = 10.99 min. (metiiod 2)
Example 41
3-Bromo-5-(3-cvano-2-methvl-5-oxo-7-propvl-L4,5,6.7,8-hexahvdro-qiunolin-4-vlV JV:>^-dimetiivl-2-rthiazol-4-vhnethoxv)-ben2enesulfonamide
(a). 3-Bromo-5-f 3-cvano-2-meihvl-5-oxo-7-propvl-1,4,5.6,7,8-hexahvdro-quinolin-4-vl)-2-hvdroxv-JVJ\r-dimethvl-ben2enesulfonamide
For 30 min., dimethylamine was bubbled through a solution of the compound described in example 37b (4.1 g) in dioxane (85 ml). The mixture was diluted with water and dichloromethane. In the aqueous layer, a voluminous precipitate fonned, which was collected by filtration and dried in vacuo.
I Yield: 2.19 g. MS-ESI: [M+H]^ - 508.2/510.2

(b). 3-Bromo-5-f3-cvano-2-meflivl-5-oxo-7-T)ropvl-L4,5.6J,8-hexahv(ko-qirinolin-4-vlVJV^-dimetfavl-2-riMazol-4-vlmethoxvVbeiizen^
A mixture of 3-broino-5-(3-cyano-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahydro-
qumolm-4-yl)-2-hydroxy-iV;N^dime1hyl-benzenesulfo (200 mg), potassium
carbonate (109 mg), potassium iodide (5 mg) and 4-chloromethyl-thiazole. HCl (71 mg) in DMF (4.5 ml) was heated at 60 °C for 6 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Yield: 110 mg. MS-ESI: [M+H]^ = 605.2/607.2; anal. HPLC: Rt = 19.62 min. (method 2)
Example 42
3-Bromo-5-r3"Cvano-2-methvl-5-oxo-7-propvl-l,4,5,6,7.8-hexahvdro-quinolin-4-vlV2-f2,5-dime1favl-2//-pvrazol-3-vlmethoxvVAUV^dimethvl-benzenesidfonamide
A mixture of the compound described in example 41a (153 mg), potassium carbonate (125 mg), and 5-chloromethyl-l53-dimethyl-li7-pyrazole (55 mg) in DMF (1,4 ml) was heated at 60 °C for 3 h. The mixture was diluted with IN hydrochloric acid and extracted with ethyl acetate. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B), then purified by chromatography on alimiinum oxide using ethyl acetate as eluent.
Yield: 51 mg. MS-ESI: [M+H]^ = 616.2/618.2; anal. HPLC: Rt = 18,40 min. (method 2)
Example 43
Agonistic activitv of compounds at the human FSH receptor expressed in CHO cells
Agonist activity of the compoimds at the human FSH receptor was tested in Chinese Hamster Ovary (CHO) cells stably transfected with the human FSH receptor and cotransfected with a cAMP responsive element (CRE) / promotor directing the e5q)ression of a firefly luciferase reporter gene. Binding of the compound to the Gs-coiq)led FSH receptor will result in an increase of cAMP, which in turn will induce an increased transactivation of the luciferase reporter constract The luciferase activity was quantified using a luminescence counter. The compounds were tested in the

concentration range of 0.1 nM to 10 \\M. This assay was used to determine the EC50 (concentration of test compound causing half-maximal (50 %) luciferase stimulation) and efiBcacy of the compounds compared to recombinant human FSH. For this, the software program XL^ (Excel version 2.0, built 30, ID Business Solutions Limited) was used.
The compounds described in the preceding examples all have an EC50 of less than 5.10"^. Some of the compounds, such as those of examples 2,10, 17, 19, 20, 24, 30-32, 36,37, and 39-42 showed an EC50 of less than 10"^ M.








Claims
1. A4-phenyl-5-oxo4,4,5,6,7,8-hexahydroqiiinoline derivative according to Fonnula I,

wherein
R^ is (l-6C)a]kyl, (2-6C)alkenyl or (2-6C)alkynyl;
R^ is halogen, (l-4C)alkoxy, fluorinated (l-4C)alkoxy, (l-4C)alkyl, or fluorinated (l-4C)alkyl; orR1may be H whenR1is R^jR^^-aminosulfonyl;
R^ is OH, NO2, CN, fluorinated (l-4C)alkoxy, (l-4C)a]koxy(2-4C)alkoxy, hydroxy(2-4C)alkoxy, (l-4C)a]koxycarbonyl5 (3-4C)alkenyloxycarbonyl, (l-4C)a]koxycarbonyloxy, (3-4C)alkenyloxycarbonyloxy, R,R -amino, R^,R^^-ammo, R^,R^*^-aminocarbonyl, R^,R^^-aminosulfonyl or phenyl(l-4C)alkoxy, wherein the phenyl ring is optionally substituted with one or more substituents selected ftom hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (MQalkoxy, (di)(l-4C)aIkylamino;
R'^ is R^^-phenyl or R^^-(2-5C)heteroaryl, wherein the phenyl or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluromethyl, cyano, (l-4C)alkyl, (l-4C)alkylthio, (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)a]kynyl;
R^isH,(l-4C)alkyl;
R^ is (l-4C)a]kylsulfonyl, (l-4C)alkylcarbonyl, (2-4C)alkenylcarbonyl, (3-6C)cycloalkylcarbonyl, (l-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl,

(1 -4C)alkoxy(l-4C)alkylcarbonyl, (3-4C)alkenyloxy(l-4C)a]lcylcarbonyl phenylcarbonyl, (2-5C)heteroarylcarbonyl, phenyl(l-4C)allcylcarbonyl, (2-5C)heteroaryl(l-4C)a]kylcarbonyl, wherein the phenyl ring or the heteroaromatic ring is optionally substituted with one or more substituents selected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (MQalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (MQalkoxy, (di)(MC)alkylamino;
R^ and R^^ are independently selected from H, (l-6C)alkyl, (3-6C)cycloancyl, (3-6C)cycloalkyl(l-4C)alkyl and (l-4C)alkoxy(2-4C)alkyl;
or R' and R^° may be joined in a (4-6C)heterocycloalkenyl ring or a (2-6C)heterocycloalkyl ring, optionally substituted with one or more (l-4C)alkyl substituents;
R^^ is H, (l-6C)a]koxycarbonyl, R^^,R^^-amino, (l-6C)aIkylcarbonyl, (l-6C)aI!cylsulfonyl, R^'*-oxy, R^'*,R^^-amino, R^'*,R^^-aminocaxbonyl, R^*,R'^-aminosulfonyl;
R^^isH,(l-4C)alkyl;
R^^ is (l-4C)alkylsulfonyl, (l-4C)alkylcarbonyl, (3-6C)cycloalkylcarbonyl, (l-4C)alkoxycarbonyl, (3-4C)a]kenyloxycarbonyl, (di)(l-4C)a]kylamino-(1 -4C)alkylcartjonyl, (2-6C)heterocycloalkyl(l -4C)al]cylcarbonyl, (4-6C)heterocyclo-a]kenyl(l-4C)alkylcarbonyl or (l-4C)alkoxy(l-4C)alkylcar-bonyl;
R^^ and R^^ are independently selected from H, (l-6C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(l-4C)a]lcyl, hydroxy(2-4C)alky], amino(2-4C)alkyl, (l-4C)a]koxy(2-4C)alkyl, (di)(l -4C)a]kylamino(2-4C)alkyl, (2-6C)heterocycloallcyl(2-4C)alkyl, (4-6C)heterocycloalkenyl(2-4C)alkyl, phenyl(l-4C)alkyl and (2-5C)heteroaiyl(l -4C)a]kyl;
X is O or R^^-N;
Y is CHi, C(0) or SO2;
Z is CN or NO2;

R^^ is H, (l-4C)alkyl, (l-4C)aIkylcarbonyl;
or a phannaceutically acceptable salt thereof.
The 4-phenyl-5-oxo-l54,5,657,8-hexahydroqiiinoline derivative according to
claim 1 whereinR1is (l-6C)alkyL
The 4-phenyl"5-oxo-l,4,5,6,7,8-hexahydroqiiinoline derivative according to
claims 1-2 wherein R is halogen.
The 4-phenyl-5-oxo-l54,5,6,758-hexahydroqiiinoline derivative according to
claims 1-3 whereinR1is R^R^**-aminosulfonyL
The 4-phenyl-5-oxo-l54,5,65758-hexahydroquinoline derivative according to
claim 4 whereinR1and R^^ are independently (l-6C)Blkyl
The 4-phenyl-5-oxo-l,4,5,6,758-hexahydroquinoline derivative according to
claims 1-5 wherein R*^ is R^^-phenyl or R^^-(2-5C)heteroaryl, wherein the phenyl
or heteroaryl groiip is optionally fiirther substituted with one (l-4C)alkoxy.
The 4-phenyl-5-oxo-l5455,657,8-hexahydroquinoline derivative according to
claim 6, wherein R^^ is H or R^^,R^^-amino.
The 4-phenyl-5-oxo-l54,5,6,758-hexahydroquinoline derivative according to
claims 1-7 wherem Z is CN.
The 4-phenyl-5-oxo-l5455,6,7,8-hexahydroquinoline derivative according to
claims 1-8 wherein X is O.
The 4-phenyl-5-oxo-l,455,657,8-hexahydroquinoline derivative according to
claims 1-9 wherein Y is CHa.
A 4-phenyl-5-oxo-l,4,5,6,758-hexahydroquinoline derivative according to claims
1-10 for use in ther^y.
A pharmaceutical composition comprising a 4-phenyl-5-oxo-l,4,5,6,758-
hexahydroquinoline derivative of any one of claims 1-10, and pharmaceutically
suitable auxiliaries.
Use of the 4-phenyl-5-oxo-l,4,5,6,7,8-hexahydroquinoline derivative of any one
of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof for the
manufecture of a medicament for the treatment of fertility disorders.

Documents:

4970-CHENP-2007 AMENDED PAGES OF SPECIFICATION 11-08-2014.pdf

4970-CHENP-2007 AMENDED CLAIMS 11-02-2015.pdf

4970-CHENP-2007 AMENDED CLAIMS 11-08-2014.pdf

4970-CHENP-2007 CORRESPONDENCE OTHERS 02-01-2013.pdf

4970-CHENP-2007 CORRESPONDENCE OTHERS 29-08-2013.pdf

4970-CHENP-2007 ENGLISH TRANSLATION 06-02-2012.pdf

4970-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 11-08-2014.pdf

4970-CHENP-2007 FORM-1 02-01-2013.pdf

4970-CHENP-2007 FORM-1 11-08-2014.pdf

4970-CHENP-2007 FORM-13 02-01-2013.pdf

4970-CHENP-2007 FORM-3 11-08-2014.pdf

4970-CHENP-2007 FORM-5 11-08-2014.pdf

4970-CHENP-2007 FORM-6 06-02-2012.pdf

4970-CHENP-2007 FORM-6 29-08-2013.pdf

4970-CHENP-2007 FORM-6-1 29-08-2013.pdf

4970-CHENP-2007 OTHER DOCUMENT 06-02-2012.pdf

4970-CHENP-2007 OTHERS 29-08-2013.pdf

4970-CHENP-2007 POWER OF ATTORNEY 02-01-2013.pdf

4970-CHENP-2007 POWER OF ATTORNEY 06-02-2012.pdf

4970-CHENP-2007 POWER OF ATTORNEY 11-08-2014.pdf

4970-CHENP-2007 POWER OF ATTORNEY 29-08-2013.pdf

4970-CHENP-2007 CORRESPONDENCE OTHERS 06-02-2012.pdf

4970-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 11-02-2015.pdf

4970-chenp-2007-abstract.pdf

4970-chenp-2007-claims.pdf

4970-chenp-2007-correspondnece-others.pdf

4970-chenp-2007-description(complete).pdf

4970-chenp-2007-form 1.pdf

4970-chenp-2007-form 26.pdf

4970-chenp-2007-form 3.pdf

4970-chenp-2007-form 5.pdf

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Patent Number 266130
Indian Patent Application Number 4970/CHENP/2007
PG Journal Number 15/2015
Publication Date 10-Apr-2015
Grant Date 06-Apr-2015
Date of Filing 05-Nov-2007
Name of Patentee MERCK SHARP & DOHME B.V.
Applicant Address WAARDERWEG 39, NL-2031 BN HAARLEM, NETHERLANDS.
Inventors:
# Inventor's Name Inventor's Address
1 TIMMERS, CORNELIS, MARIUS N.V ORGANON, P O BOX 20, NL-5340 BH OSS
2 GRIMA POVEDA, PEDRO, MANUEL N.V ORGANON, P O BOX 20, NL-5340 BH OSS, THE NETHERLANDS.
3 KARSTENS, WILLEM, FREDERIK, JOHAN N.V ORGANON, P O BOX 20, NL-5340 BH OSS, THE NETHERLANDS.
PCT International Classification Number C07D417/12
PCT International Application Number PCT/EP2006/061976
PCT International Filing date 2006-05-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 05103738.0 2005-05-04 EUROPEAN UNION