WO2015082374A1 - Spiroindoline-thiopyran-imine-oxide derivatives as gonadotropin-releasing hormone receptor antagonists and pharmaceutical compositions thereof - Google Patents

Abstract

Spiroindoline-thiopyran-imine-oxide derivatives of formula (I), process for their preparation and pharmaceutical compositions thereof, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially sex-hormone-related diseases in both men and women, in particularly those selcted from the group of endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrope pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization). The present application relates in particular to spiroindoline derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists.

Description

SPIROINDOLINE-THIOPYRAN-IMINE-OXIDE DERIVATIVES AS

GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND

PHARMACEUTICAL COMPOSITIONS THEREOF

TECHNICAL FIELD

The present invention refers to spiroindoline derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists, pharmaceutical compositions containing a spiroindoline derivative according to the invention and methods of treating disorders by administration of a spiroindoline derivative according to invention to a mammal, particularly a human, in need thereof.

BACKGROUND ART

Gonadotropin-releasing hormone (GnRH) is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu- Arg-Pro-Gly-NH2) released from the hypothalamus, also known as luteinizing hormone- releasing hormone (LHRH). GnRH acts on the pituitary gland to stimulate the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is responsible for the regulation of gonadal steroid production in both genders and late ovarian follicle development and ovulation in female mammals, FSH regulates spermatogenesis in males and early follicular development in females. Thus GnRH plays a key role in human reproduction.

As a consequence of its biological significance, synthetic antagonists and agonists to GnRH have been the center of several research activities, particularly in the field of endometriosis, uterine leiomyoma (fibroids), prostate cancer, breast cancer, ovarian cancer, prostatic hyperplasia, assisted reproductive therapy and precocious puberty. For example, peptidic GnRH agonists, such as leuprorelin (pGlu-His-Trp-Ser-Tyr-d-Leu-Leu- Arg-Pro-NHEt), are described for the use in the treatment of such conditions (The Lancet 2001 , 358, 1793 - 1803; Mol. Cell. Endo. 2000, 166, 9 - 14). Said agonists initially induce the synthesis and release of gonadotropins, by binding to the GnRH receptor on the pituitary gonadotrophic cells ('flare-up'). However, chronic administration of GnRH agonists reduces gonadotropin release from the pituitary and results in the down-regulation of the receptor, with the consequence of suppressing sex steroidal hormone production after some period of treatment.

GnRH antagonists, on the contrary, are supposed to suppress gonadotropins from the onset, offering several advantages, in particular a lack of side effects associated with the flare up seen under GnRH superagonist treatment. Several peptidic antagonists with low histamine release potential are known in the art. Said peptidic products show low oral bioavailability which limits their clinical use.

The state of the art involves a number of nonpeptidic compounds for use as GnRH receptor antagonists, for example in WO201 1/076687, WO05/007165, WO03/064429 and

WO04/067535. Although intensive research has been driven for more than 15 years aiming at non-peptidic GnRH antagonists, none of them succeeded so far to reach the market.

Nevertheless, effective small molecule GnRH receptor ligands, especially compounds which are active as antagonists as well as pharmaceutical compositions containing such GnRH receptor antagonists and methods relating to the use thereof to treat, for example, sex- hormone-related conditions, in particular for the treatment of leiomyoma are still highly required in the pharmaceutical field.

The spiroindoline derivatives according to the present invention aim to fulfill such unmet need, and provide at the same time further advantages over the known art.

Spiroindoline derivatives are known in the art as pharmaceutically active ingredients and as insecticides but their activity as GnRH receptor antagonists has been described in

WO2013/107743 for the first time.

The document WO00/66554 describes generic indolines as potential PR antagonists.

The document US2006/63791 , page 20, describes the synthesis of a nitroindoline by condensing an aldehyde and a phenylhydrazine under acidic conditions (Fischer indole synthesis) and subsequent reduction of the indolenine intermediate.

Liu et al. describes the synthesis of a spirotetrahydropyrane in a similar manner in a one-pot reaction (Tetrahedron 2010, 66, 3, 573-577). The document WO O/151737, page 224, describes the synthesis of an indolenine mixture in an analogous Fischer indole synthesis by condensing an aldehyde with a phenylhydrazine.

The document WO06/090261 , pp. 67-68, describes the synthesis of a spiropiperidine via Fischer indole synthesis and subsequent addition of a Grignard reagent to the indolenine intermediate. The document WO08/157741 , pp. 41 -42, describes the synthesis of a spiropiperidine starting from an oxindole precursor via Grignard addition and subsequent deoxygenation.

The document W093/15051 discloses a generic oxindole as potential vasopressin/oxytocin antagonists.

Further spiroindoline derivatives with pharmaceutical properties were disclosed for example in the documents W01994/29309, W01999/64002 and WO2002/47679.

DISCLOSURE OF THE INVENTION

The aim of the present invention is to provide gonadotropin-releasing hormone (GnRH) receptor antagonists, as well as the methods for their preparation and use, and

pharmaceutical compositions containing the same.

In particular, the present invention relates to compounds according to formula (I)

is selected from the group consisting of hydrogen, Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, hydroxy-Ci-C6-alkyl or Ci -Ce-a I koxy-Ci -C6-a I ky I ;

is an aryl or heteroaryl group which can be unsubstituted or substituted one to three times with a group R⁴;

is selected from the group consisting of C(0)N(R^5a)(R^5b), N(H)C(0)R⁶, N(H)C(0)N(R^5a)(R^5b) or N(H)C(0)OR⁷;

is selected from a halogen, hydroxy, CN , Ci-C6-alkyl, halo-Ci-C6-alkyl, d-Ce-alkoxy, halo-Ci-C₆-alkoxy, C(0)OH, C(0)0-Ci-C₆-alkyl, C(0)NH₂, C(0)NH-Ci-C₆-alkyl, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other; R^5b and R⁶ are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl; C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, aryl-cyclopropyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyi, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, hydroxy, d-Ce-alkyl, Ci-C₆-haloalkyl, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, CN , C(0)N H₂, S(0)₂-Ci-C₆-alkyl, S(0)₂N H₂,

S(0)2N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other;

is selected from the group consisting of Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,

Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, heteroaryl, or heteroaryl-Ci-C6-alkyl in which said cycloalkyi, aryl, heteroaryl group is optionally substituted up to three times with a halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,

d-Ce-haloalkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, CN , C(0)N H₂,

S(0)₂-Ci-C₆-alkyl, S(0)₂N H₂, S(0)₂N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

is selected from the group consisting of hydrogen, CN , C(0)R⁷, C(0)OR⁷, S(0)₂R¹⁰, C(0)N(R^5a)(R^5b), P(0)(OR¹¹ )₂, CH₂OP(OR¹¹ )₂, Ci-C₆-alkyl, C3-C7- cycloalkyl, phenyl or heteroaryl, in which said Ci-C6-alkyl, C3-C7-cycloalkyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, CN , Ci-Cs-alkyl, Ci-C₃-alkoxy, N (R^5a)(R^5b), halo-Ci-C₃-alkyl or halo-Ci-C₃-alkoxy; is hydrogen, halogen, hydroxy, CN , Ci-C6-alkyl, halo-Ci-C6-alkyl, C1-C6- alkoxy, halo-Ci-C₆-alkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, C(0)N H₂, C(0)N H-Ci- C6-alkyl, C(0)N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other;

is selected from the group consisting of Ci-C6-alkyl, Ci-C3-haloalkyl, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, Ci-C3-alkyl, Ci-C3-alkoxy, N H2, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-Ci-C3-alkyl, Ci-C3-fluoroalkoxy;

is selected from the group consisting of hydrogen, Ci-C4-alkyl or benzyl. Compounds according to the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds which are encompassed by formula (I) and are of the formulae mentioned hereinafter, and the salts, solvates and solvates of the salts thereof, and the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments, and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts.

Hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with water, such as, for example, hemi-, mono-, or dihydrates.

Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.

Solvates which are preferred for the purposes of the present invention are hydrates.

Salts for the purposes of the present invention are preferably pharmaceutically acceptable salts of the compounds according to the invention (for example, see S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19).

Pharmaceutically acceptable salts include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, maleic, fumaric, benzoic, ascorbic, succinic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, and glutamic acid.

Pharmaceutically acceptable salts also include salts of customary bases, such as for example and preferably alkali metal salts (for example sodium, lithium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines, such as illustratively and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, benzylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, dihydroabietyl- amine, arginine, lysine, and ethylenediamine. Also encompassed are salts which are themselves unsuitable for pharmaceutical uses but can be used for example for isolating or purifying the compounds of the invention. The present invention additionally encompasses prodrugs of the compounds of the invention. The term "prodrugs" encompasses compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body into compounds of the invention (for example by metabolism or hydrolysis).

The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers,

e.g. R- or S- isomers, or E- or Z-isomers, in any ratio. All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art. For example, diastereomeric mixtures can be separated into the individual isomers by chromatographic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.

If the compounds of the invention may occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Unless otherwise stated, the following definitions apply for the substituents and residues used throughout this specification and claims. The particularly named chemical groups and atoms (for example fluorine, methyl, methyloxy and so on) should be considered as particular forms of embodiment for the respective groups in compounds according to the invention.

The term "halogen", "halogen atom" or "halo" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.

The term "Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, ie f-butyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neopentyl,

1 ,1 -dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl,

2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 ,1 -dimethylbutyl,

2,3-dimethylbutyl, 1 ,3-dimethylbutyl, or 1 ,2-dimethylbutyl group, or an isomer thereof.

Particularly, said group has 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), methyl, ethyl, n-propyl- or iso-propyl. The term "halo-Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in the same way or differently, i.e. one halogen atom being independent from another.

Particularly, said halogen atom is F. Said halo-Ci-C6-alkyl group is, in particular -CF3, -CHF2, -CH2F, -CF2CF3, -CF2CH3, or -CH₂CF₃.

The term "Ci-C6-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,

ie f-butoxy, sec-butoxy, pentyloxy, isopentyloxy, or hexyloxy group, or an isomer thereof.

The term "halo-Ci-C6-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a halogen atom.

Particularly, said halogen atom is F. Said halo-Ci-C6-alkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH₂CF₃. The term "Ci-C6-alkoxy-Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a Ci-C6-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxyalkyl, isobutoxyalkyl, ie f-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, isopentyloxyalkyl, hexyloxyalkyl group, in which the term "Ci-C6-alkyl" is defined supra, or an isomer thereof.

The term "halo-Ci-C6-alkoxy-Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C6-alkoxy-Ci-C6-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a halogen atom.

Particularly, said halogen atom is F. Said halo-Ci-C6-alkoxy-Ci-C6-alkyl group is, for example, -CH₂CH₂OCF₃, -CH₂CH₂OCHF₂, -CH₂CH₂OCH₂F, -CH2CH2OCF2CF3, or -

The term "C2-C6-alkenyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5, 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.

Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l -enyl, pent-4-enyl,

(E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-l -enyl,

(Z)-pent-l -enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-l -enyl, (Z)-hex-l -enyl, isopropenyl,

2-methylprop-2-enyl, 1 -methylprop-2-enyl, 2-methylprop-1 -enyl, (E)-1 -methylprop-1 -enyl, (Z)-1 -methylprop-1 -enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1 -methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1 -methylbut-2-enyl, (Z)-1 -methylbut-2-enyl, (E)-3-methylbut-1 -enyl, (Z)-3-methylbut-1 -enyl,

(E)-2-methylbut-1 -enyl, (Z)-2-methylbut-1 -enyl, (E)-1 -methylbut-1 -enyl,

(Z)-1 -methylbut-1 -enyl, 1 ,1 -dimethylprop-2-enyl, 1-ethylprop-1 -enyl, 1 -propylvinyl,

1 -isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl,

1 -methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1 -methylpent-3-enyl,

(Z)-1 -methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,

(E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl,

(Z)-2-methylpent-2-enyl, (E)-1 -methylpent-2-enyl, (Z)-1 -methylpent-2-enyl,

(E)-4-methylpent-1 -enyl, (Z)-4-methylpent-1 -enyl, (E)-3-methylpent-1 -enyl,

(Z)-3-methylpent-1 -enyl, (E)-2-methylpent-1 -enyl, (Z)-2-methylpent-1 -enyl,

(E)-1 -methylpent-1 -enyl, (Z)-1 -methylpent-1 -enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl,

1 - ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl,

(Z)-2-ethylbut-2-enyl, (E)-1 -ethylbut-2-enyl, (Z)-1 -ethylbut-2-enyl, (E)-3-ethylbut-1 -enyl, (Z)-3-ethylbut-1 -enyl, 2-ethylbut-1 -enyl, (E)-1 -ethylbut-1 -enyl, (Z)-1 -ethylbut-1 -enyl,

2- propylprop-2-enyl, 1 -propylprop-2-enyl, 2-isopropylprop-2-enyl, 1 -isopropylprop-2-enyl, (E)-2-propylprop-1 -enyl, (Z)-2-propylprop-1 -enyl, (E)-1 -propylprop-1 -enyl,

(Z)-1 -propylprop-1 -enyl, (E)-2-isopropylprop-1 -enyl, (Z)-2-isopropylprop-1 -enyl,

(E)-1 -isopropylprop-1 -enyl, (Z)-1 -isopropylprop-1 -enyl, (E)-3,3-dimethylprop-1 -enyl,

(Z)-3,3-dimethylprop-1 -enyl, 1 -(1 ,1 -dimethylethyl)vinyl, buta-1 ,3-dienyl, penta-1 ,4-dienyl, hexa-1 ,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.

The term "C2-C6-alkynyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl").

Said C2-Cio-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl,

3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methylpent-4-ynyl, 2-methylpent-3-ynyl, 1 -methylpent-3-ynyl, 4-methylpent-2-ynyl, 1 -methylpent-2-ynyl, 4-methylpent-1 -ynyl, 3-methylpent-1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl,

1 -propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl, 1 ,1 -dimethylbut-3-ynyl, 1 ,1 -dimethylbut-2-ynyl, or 3,3-dimethylbut-1 -ynyl group. Particularly, said alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-ynyl. The term "C3-Cio-cycloalkyl" is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, particularly 3, 4, 5, or 6 carbon atoms ("C3-C6-cycloalkyl").

Said C3-Cio-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring. Said cycloalkyl ring can optionally contain one or more double bonds e.g. cycloalkenyl, such as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated.

The term "aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C6-Ci4-aryl" group), particularly a ring having 6 carbon atoms (a "C6-aryl" group), e.g. a phenyl group, or a biphenyl group, or a ring having 9 carbon atoms (a "Cg-aryl" group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl" group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13 carbon atoms, (a "Ci3-aryl" group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "Cu- aryl" group), e.g. an anthranyl group.

The term "heteroaryl" is understood as preferably meaning a monovalent, aromatic or partially aromatic, mono- or bicyclic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5 or 6 or 9 or 10 atoms, and which can partially be saturated, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic, or tricyclic, and in addition in each case can be benzocondensed.

Preference is given to 6-membered heteroaryl radicals having up to 2 nitrogen atoms, and to 5-membered heteroaryl radicals having up to 3 heteroatoms. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, tetrazolyl and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl,; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, eic, and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, eic; or azocinyl, indolizinyl, purinyl and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl. More particularly, heteroaryl is selected from thienyl, oxazolyl, thiazolyl,

1 H-tetrazol-5-yl, pyridyl, benzothienyl, or furanyl.

The term "Ο-ι-Οβ", as used throughout this text, e.g. in the context of the definition of

"Ci-C6-alkyl", "Ci-C6-haloalkyl", "Ci-C6-alkoxy", or "Ci-C6-haloalkoxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "Ο-ι-Οβ" is to be interpreted as any sub-range comprised therein, e.g. C1-C6 , C2-C5 , C3-C4 , C1-C2, C1-C3 , C1-C4 ,

C1-C5 , C1-C6 ; particularly C1-C2, Ci-C3,Ci-C4 , C1-C5 , Ci-C6 _; more particularly C1-C4; in the case of "Ci-C6-haloalkyl" or "Ci-C6-haloalkoxy" even more particularly C1-C2.

Similarly, as used herein, the term "C2-C6", as used throughout this text, e.g. in the context of the definitions of "C2-C6-alkenyl" and "C2-C6-alkynyl", is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C2-C6" is to be interpreted as any sub-range comprised therein, e.g. C2-C6 , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2- C5 ; particularly C2-C3.

Further, as used herein, the term "C3-C10", as used throughout this text, e.g. in the context of the definition of "C3-Cio-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C10" is to be interpreted as any sub-range comprised therein, e.g. C3-C10, C4-C9 , Cs-Cs, C6-C7 ; particularly C3-C6. As used herein, the term "one or more times", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning "one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".

Throughout this document, for the sake of simplicity, the use of singular language is given preference over plural language, but is generally meant to include the plural language if not otherwise stated. E.g., the expression "A method of treating a disease in a patient, comprising administering to a patient an effective amount of a compound of formula (I)" is meant to include the simultaneous treatment of more than one disease as well as the administration of more than one compound of formula (I).

Particular forms of embodiment of compounds of the general formula (I) as described above are going to be illustrated in the following.

In particular, part of the present invention is a compound according to formula (la)

in which

R¹ is selected from the group consisting of Ci-C6-alkyl, Ci-C6-cycloalkyl, alkenyl; R³ is selected from the group consisting of C(0)N(R^5a)(R^5b), C(0)NH(R^5a), and N(H)C(0)R⁶;

R⁴ is halogen, hydroxy, CN, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy,

C(0)OH, C(0)0-Ci-C₆-alkyl, C(0)NH₂, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R^5a, R^5b and R⁶ are selected, independently from one another, from the group

consisting of aryl-Ci-C6-alkyl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy; R⁷ is selected from the group consisting of Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,

Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl, or heteroaryl-Ci-C6-alkyl- in which said cycloalkyi, aryl, heteroaryl group is optionally substituted up to three times with a halogen, hydroxy, an Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, d-Ce-haloalkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, CN , C(0)N H₂, S(0)₂-Ci-C₆-alkyl, S(0)₂NH₂, S(0)₂N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other.

R⁸ is selected from the group consisting of hydrogen, CN , C(0)R⁷, C(0)OR⁷, S(0)₂R¹⁰, C(0)N(R^5a)(R^5b), P(0)(OR¹¹ )₂, CH₂OP(OR¹¹ )₂, Ci-C₆-alkyl, C3-C7- cycloalkyl, phenyl or heteroaryl, in which said Ci-C6-alkyl, C3-C7-cycloalkyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, CN , d-Cs-alkyl, Ci-C₃-alkoxy, N (R^5a)(R^5b), halo-Ci-C₃-alkyl or halo-Ci-C₃-alkoxy;

R⁹ is hydrogen, halogen, hydroxy, CN , Ci-C6-alkyl, halo-Ci-C6-alkyl, C1-C6- alkoxy, halo-Ci-C₆-alkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, C(0)N H₂, C(0)N H-Ci-C₆-alkyl, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R¹⁰ is selected from the group consisting of Ci-C6-alkyl, Ci-C3-haloalkyl,

C3-C7-cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, Ci-C3-alkyl, Ci-C3-alkoxy, N H₂, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-Ci-C3-alkyl, Ci-C3-fluoroalkoxy;

R¹¹ is selected from the group consisting of hydrogen, Ci-C4-alkyl or benzyl.

Furthermore, it is part of the present invention a compound according to formula (lb),

R¹ is selected from the group consisting of Ci-C6-alkyl, Ci-C6-cycloalkyl, alkenyl;

R⁴ is halogen, hydroxy, CN , Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy,

C(0)OH, C(0)0-Ci-C₆-alkyl, C(0)NH₂, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R^5a and R^5b are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl;

C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, aryl-cyclopropyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyi, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, hydroxy, d-Ce-alkyl, Ci-C₆-haloalkyl, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, CN , C(0)N H₂, S(0)₂-Ci-C₆-alkyl, S(0)₂N H₂,

S(0)₂N(Ci-C6-alkyl)₂ in which the two alkyl groups are independent from each other;

R⁷ is selected from the group consisting of Ci-C6-alkyl, halo-Ci-C6-alkyl,

hydroxy-Ci-C6-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl,

Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl, or heteroaryl-Ci-C6-alkyl- in which said cycloalkyi, aryl, heteroaryl group is optionally substituted up to three times with a halogen, hydroxy, an Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,

d-Ce-haloalkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, CN , C(0)N H₂,

S(0)₂-Ci-C₆-alkyl, S(0)₂N H₂, S(0)₂N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other.

R⁸ is selected from the group consisting of hydrogen, CN , C(0)R⁷, C(0)OR⁷, S(0)₂R¹⁰, C(0)N(R^5a)(R^5b), P(0)(OR¹¹ )₂, CH₂OP(OR¹¹ )₂, Ci-C₆-alkyl,

C3-C7-cycloalkyl, phenyl or heteroaryl, in which said Ci-C6-alkyl,

C3-C7-cycloalkyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, CN,

d-Cs-alkyl, Ci-C₃-alkoxy, N(R^5a)(R^5b), halo-Ci-C₃-alkyl or halo-Ci-C₃-alkoxy; is hydrogen, halogen, hydroxy, CN , Ci-C6-alkyl, halo-Ci-C6-alkyl, d-Ce-alkoxy, halo-Ci-C₆-alkoxy, C(0)OH, C(0)0-Ci-C₆-alkyl, C(0)NH₂, C(0)NH-Ci-C₆-alkyl, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

is selected from the group consisting of Ci-C6-alkyl, Ci-C3-haloalkyl,

C3-C7-cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, Ci-C3-alkyl, Ci-C3-alkoxy, NH2, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-Ci-C3-alkyl, Ci-C3-fluoroalkoxy;

is selected from the group consisting of hydrogen, Ci-C4-alkyl or benzyl.

In conjunction with the above or below definitions and embodiments, compounds according to formula (I), (la) or (lb) are in particular those in which R¹ is a C3-C6-cycloalkyl.

Furthermore, for compounds according to formula (I), (la) or (lb) as a particular embodiment according to the invention R² is a phenyl group.

A compound according to formula (I), (la) or (lb) of the present invention comprises, according to a further particular embodiment, R² being a phenyl group substituted in para with R⁴ being a fluorine.

Furthermore, a compound according to formula (I), (la) and (lb) comprises a group R³ beeing a C(0)NH(R^5a)

Furthermore, for compounds according to formula (I), (la) or (lb) as a particular embodiment according to the invention, R⁴ is a single group in para or meta position and is selected from the group consisting of halogen, hydroxy, Ci-C4-alkyl, halo-Ci-C4-alkyl, Ci-C4-alkoxy, halo-Ci-C4-alkoxy, CN, C(0)NH2, or as particular alternative R⁴ is a single group in para or meta position selected from the group consisting of halogen, Ci-C4-alkoxy, halo-Ci-C4- alkoxy, CN, C(0)NH2; in a further particular alternative of the invention R⁴ is a single group in para position selected from the group consisting of F, CI, ,OCF2H, CN, C(0)NH2 or a single group in meta position selected from the group consisting of OCH3, OCF2H, OCF3, CN.

Furthermore, for compounds according to formula (I), (la) or (lb), R⁴ is a halogen preferably a fluorine atome ; In conjunction with the above or below definitions and embodiments, compounds according to formula (I), (la) or (lb) are in particular those in which R^5a , R^5b or R⁶ are selected, independently from one another, from the group consisting of hydrogen, aryl-Ci-C6-alkyl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, or Ci-C6-haloalkyl;

Furthermore, a compound according to formula (I), (la) or (lb) comprises in particular a group R⁸ selected from the group consisting of hydrogen, CN, C(0)R⁷ ,

-C(0)-halo-Ci-C₆-alkyl, -C(0)-Ci-C₆-alkyl;

In a compound according to formula (I), (la) or (lb) according to the present invention R⁹ is hydrogen;

In conjunction with the above or below definitions and embodiments, compounds according to formula (I), (la) or (lb) are in particular those in which

R¹ is selected from the group consisting of hydrogen and C3-C6-cycloalkyl;

R⁴ is a fluorine atom in para position;

R³ is selected from the group consisting of C(0)N(R^5a)(R^5b), C(0)NH(R^5a), and N(H)C(0)R⁶

R^5a , R^5b or R⁶ are selected, independently from one another, from the group

consisting of hydrogen, aryl-Ci-C6-alkyl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, or Ci-C6-haloalkyl;

R⁸ is selected from the group consisting of hydrogen, CN, C(0)R⁷ ,

-C(0)-halo-Ci-C₆-alkyl, -C(0)-Ci-C₆-alkyl;

R⁹ is hydrogen, or halogen;

Furthermore, in conjunction with the above or below definitions and embodiments, compounds according to formula (Ha)

in which

R⁴ is a fluorine atom in para position,

R^12a and R^12b are selected independently from one another from the group consisting of halogen, hydroxy, Ci-C4-alkyl, halo-Ci-C4-alkyl, Ci-C4-alkoxy, halo-Ci-C4-alkoxy, CN;

R⁸ is selected from the group consisting of hydrogen, CN,

-C(0)-halo-Ci-C₆-alkyl, -C(0)-Ci-C₆-alkyl;

R⁹ is a fluorine or an hydrogen atom.

Further compounds according to the invention are those of formula (lib)

in which in conjunction with the above or below definitions and embodiments R⁴ is a fluorine atom in para position

R^12a and R^12b are selected independently from one another from the group consisting of halogen, hydroxy, Ci-C4-alkyl,

halo-Ci-C₄-alkyl, Ci-C₄-alkoxy, halo-Ci-C₄-alkoxy, CN; is selected from the group consisting of halogen, hydroxy, Ci-C4-alkyl, halo-Ci-C4-alkyl, Ci-C4-alkoxy, halo-Ci-C4-alkoxy, CN.

is selected from the group consisting of hydrogen, CN,

-C(0)-halo-Ci-C₆-alkyl, -C(0)-Ci-C₆-alkyl;

is a fluorine or an hydrogen atom.

More in particular in conjunction with the above or below definitions and embodiments, for compounds according to formula (Ha) or (lib) the groups R^12a and R^12b are selected from the group consisting of halogen, halo-Ci-C4-alkyl, or even more particularly the groups R^12a and R^12b are selected from F, CI, CF₃.

Compounds according to the invention are:

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-4-fluoro-1 -[(4- fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]- 5-carboxamide 1 '-oxide

/V-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'- hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-

1 '-[(trifluoroacetyl)imino]-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5- carboxamide 1 '-oxide

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-

1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '- oxide

2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[(trifluoroacetyl)imino]-/V-{[3- (trifluoromethyl)pyridin-2-yl]methyl}-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'- thiopyran]-5-carboxamide 1 '-oxide

2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-/V-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-

1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide 2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino- 1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide

2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-N-[2-(trifluoromethyl)benzyl]-

1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-N-{[3-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '- oxide N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-6-fluoro-1 -[(4^ fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]- 5-carboxamide 1 '-oxide

2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-(trifluoromethyl)pyridin-2- yl]methyl}-1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5- carboxamide 1 '-oxide

Another embodiment of the present invention provides compounds according to general formula (I), (la), (lb), (lla) or (Mb) and related specific embodiments for use as a medicament.

In another embodiment, the present invention provides a method of treating GnRH related disorder in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound according to the invention as defined above. In still another aspect, the invention provides use of a compound according to the invention as defined above for manufacturing a pharmaceutical composition for the treatment or prevention of GnRH related disorders.

The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as for example

endometriosis and uterine fibroids.

The term "subject" or "patient" includes organisms which are capable of suffering from a disorder or who can otherwise benefit from the administration of a compound of the invention, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from disorders, such as for example

endometriosis and uterine fibroids. The term "non-human animals" includes vertebrates, e.g., mammals, such as non-human primates, sheep, cows, dogs, cats and rodents, e.g., mice, and non-mammals, such as chickens, amphibians, reptiles, etc.

In another aspect, the invention provides a pharmaceutical composition comprising a compound according to the invention, together with a pharmaceutically acceptable carrier. In still another aspect, the invention provides a process for preparing a pharmaceutical composition. The process includes the step of combining at least one compound according to the invention as defined above with at least one pharmaceutically acceptable carrier, and bringing the resulting combination into a suitable administration form.

The compounds according to general formula (I), (la), (lb), (lla) or (Mb) are used as a medicament. In particular, said compounds are used to treat sexual hormone-related conditions in both men and women, as well as a mammal in general (also referred to herein as a "subject"). For example, such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrope pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, and infertility (e.g., assisted reproductive therapy such as in vitro fertilization).

The compounds according to general formula (I), (la), (lb), (lla) or (Mb) are further used as contraceptive.

The compounds of this invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus

erythematosus. According to a further embodiment of the present invention the compounds according to general formula (I), (la), (lb), (lla) or (Mb) are also useful and can be used in combination with androgens, estrogens, progestins, SERMs, antiestrogens and antiprogestins for the treatment of endometriosis, uterine fibroids, and in contraception, as well as in combination with an angiotensin-converting enzyme inhibitor, an angiotensin ll-receptor antagonist, or a renin inhibitor for the treatment of uterine fibroids.

A combination of compounds according to general formula (I), (la), (lb), (lla) or (Mb) with bisphosphonates and other agents for the treatment and/or prevention of disturbances of calcium, phosphate and bone metabolism, and in combination with estrogens, SERMs, progestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flushes during therapy with a GnRH antagonist is also part of the present invention.

The methods of this invention include administering an effective amount of a GnRH receptor antagonist, preferably in the form of a pharmaceutical composition, to a mammal in need thereof. Thus, in still a further embodiment, pharmaceutical compositions are disclosed containing one or more GnRH receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.

These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.

The compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts.

Thus, the term "pharmaceutically acceptable salt" of compounds of general formula (I), (la), (lb), (lla) or (Mb) is intended to encompass any and all acceptable salt forms.

In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of general formula (I), (la), (lb), (lla) or (Mb) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.

Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of general formula (I), (la), (lb), (lla) or (Mb).

Further, in the case of a carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the like.

With regard to stereoisomers, the compounds of general formula (I), (la), (lb), (lla) or (Mb) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of general formula (I), (la), (lb), (lla) or (Mb) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of general formula (I), (la), (lb), (lla) or (Mb) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention. The effectiveness of a compound as a GnRH receptor antagonist may be determined by various assay techniques. Assay techniques well known in the field include the use of cultured pituitary cells for measuring GnRH activity {Vale et al., Endocrinology 1972, 91, 562 - 572) and the measurement of radioligand binding to rat pituitary membranes (Perrin et al., Mol. Pharmacol. 1983, 23, 44 - 51 ) or to membranes from cells expressing cloned receptors as described below. Other assay techniques include (but are not limited to) measurement of the effects of GnRH receptor antagonists on the inhibition of GnRH-stimulated calcium flux, modulation of phosphoinositol hydrolysis, and the circulating concentrations of gonadotropins in the castrate animal. Descriptions of these techniques, the synthesis of radiolabeled ligand, the employment of radiolabeled ligand in radioimmunoassay, and the measurement of the effectiveness of a compound as a GnRH receptor antagonist follow.

In another embodiment of the invention, pharmaceutical compositions containing one or more GnRH receptor antagonists are disclosed. For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions.

Pharmaceutical compositions of the present invention comprise a GnRH receptor antagonist of the present invention and a pharmaceutically acceptable carrier and/or diluent. The GnRH receptor antagonist is present in the composition in an amount which is effective to treat a particular disorder that is, in an amount sufficient to achieve GnRH receptor antagonist activity, and preferably with acceptable toxicity to the patient. Typically, the pharmaceutical compositions of the present invention may include a GnRH receptor antagonist in an amount from 0.1 mg to 500 mg per day dosage depending upon the route of administration, and more typically from 0.5 mg to 150 mg per day. Appropriate concentrations and dosages can be readily determined by one skilled in the art.

Determination of a therapeutically effective amount or a prophylactically effective amount of the compounds of the invention can be readily made by the physician or veterinarian (the "attending clinician"), as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. The dosages may be varied depending upon the requirements of the patient in the judgment of the attending clinician; the severity of the condition being treated and the particular compound being employed. In determining the therapeutically effective amount or dose, and the prophylactically effective amount or dose, a number of factors are considered by the attending clinician, including, but not limited to: the specific GnRH mediated disorder involved; pharmacodynamic

characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the kind of concurrent treatment (i.e., the interaction of the compound of the invention with other coadministered therapeutics); and other relevant circumstances.

Treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a GnRH receptor antagonist, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the GnRH receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.

In another embodiment, the present invention provides a method for treating sex-hormone- related conditions as discussed above. Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition. In this context, "treat" includes prophylactic administration. Such methods include systemic administration of a GnRH receptor antagonist of this invention, preferably in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral methods of administration. For oral

administration, suitable pharmaceutical compositions of GnRH receptor antagonists include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parenteral administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the GnRH receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions. MODE(S) FOR CARRYING OUT THE INVENTION

The following examples are provided for purposes of illustration, not limitation. In summary, the GnRH receptor antagonists of this invention may be synthesized by the general methods disclosed above, while the following examples disclose the synthesis of representative compounds of this invention.

EXPERIMENTAL DETAILS AND GENERAL PROCESSES

The following table lists the abbreviations used in this paragraph and in the examples section as far as they are not explained within the text body.

Rt retention time

r.t. or rt or room temp. room temperature

s singlet

sat. saturated

t triplet

tbr broad triplet

TBAF tetrabutylammonium fluoride

TEA triethylamine

TLC thin layer chromatography

TFA trifluoroacetic acid

THF tetrahydrofuran

UPLC ultra performance liquid chromatography

UPLC-MS ultra performance liquid chromatography - mass spectrometry

NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. Chemical shifts are given in ppm; all spectra were calibrated to solvent residual peak. Integrals are given in integers.

Ultra performance liquid chromatography / liquid chromatography mass spectrometry - methods:

The terms "UPLC-MS (ESI+)" or "UPLC-MS (ESI-)" refer to the following conditions:

Instrument: Waters Acq uity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.1 % vol. formic acid (99%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 μΙ; DAD scan: 210-400 nm; ELSD; or

Instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.05% vol. formic acid (98%), eluent B: acetonitrile + 0.05% vol. formic acid (98%); gradient: 0-1 .6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min;

temperature: 60 °C; injection: 2 μΙ; DAD scan: 210-400 nm; ELSD; or

Instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; Eluent A: water + 0.2% vol. ammonia (32%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; injection: 2 μΙ; DAD scan: 210-400 nm; ELSD

Chemical names were generated according to the lUPAC rules [ACD/Name Batch ver.

12.00] or using AutoNom2000 as implemented in MDL ISIS Draw [MDL Information Systems Inc. (Elsevier MDL)]. In some cases generally accepted names of commercially available reagents were used in place of lUPAC names or AutoNom2000 generated names.

Stereodescriptors are used according to Chemical Abstracts.

Reactions employing microwave irradiation may be run with a Biotage Initiator^® microwave oven optionally equipped with a robotic unit. The reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature.

The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil^® or KP-NH^® in combination with a Biotage autopurifier system (SP4^® or Isolera Four^®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the persion skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

The following scheme and general procedures illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is obvious to the person skilled in the art that the order of transformations as exemplified in Scheme 1 can be modified in various ways. The order of transformations exemplified in Scheme 1 is therefore not intended to be limiting. In addition, interconversion of substituents, for example of residues R¹, R², R³, R⁴, R^5a, R^5b, R⁶, R⁷, R⁸ and R⁹ can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).

Compounds of general formula 8 may be synthesized according to the procedures depicted in scheme 1 from suitably functionalized carboxylic acids of formula 7 by reaction with appropriate amines HN(R^5a)(R^5b) 9. For amide formation, however, all processes that are known from peptide chemistry to the person skilled in the art may be applied. The acids of general formula 7 can be reacted with an appropriate amine in aprotic polar solvents, such as for example DMF, acetonitrile or /V-methylpyrrolid-2-one via an activated acid derivative, which is obtainable for example with hydroxybenzotriazole and a carbodiimide such as for example diisopropylcarbodiimide, or else with preformed reagents, such as for example 0-(7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (see for example Chem. Comm. 1994, 201 - 203), or else with activating agents such as dicyclohexylcarbodiimide / Λ/,/V-dimethylaminopyridine or /V-ethyl-/V',/V-dimethylaminopropyl- carbodiimide / Λ/,/V-dimethylaminopyridine. The addition of a suitable base such as for example N-methylmorpholine, TEA or DIPEA may be necessary. In certain cases, the activated acid derivative might be isolated prior to reaction with the appropriate amine. Amide formation may also be accomplished via the acid halide (which can be formed from a carboxylic acid by reaction with e.g. oxalyl chloride, thionyl chloride or sulfuryl chloride), mixed acid anhydride (which can be formed from a carboxylic acid by reaction with e.g. isobutylchloroformate), imidazolide (which can be formed from a carboxylic acid by reaction with e.g. carbonyldiimidazole) or azide (which can be formed from a carboxylic acid by reaction with e.g. diphenylphosphorylazide). Carboxylic acids of general formula 7 in turn may be obtained from carboxylic esters of formula 6 by saponification with inorganic bases such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a suitable solvent such as methanol, THF, water or mixtures thereof at temperatures between 0°C and the boiling point of the solvent(mixture), typically at room temperature. Under these conditions the trifluoroacetyl group on the sulfoximine is removed. Alternatively, carboxylic acids of general formula 7 may be directly formed from aryl bromides of general formula 5 under palladium catalyzed carbonylation conditions. Thus, bromides of formula 5 may be reacted in a suitable solvent such as for example dimethyl sulfoxide in the presence of a carbon monoxide source such as for example molybdenum hexacarbonyl or under a carbon monoxide atmosphere at pressures between 1 and 20 bar and in the presence of a palladium catalyst system such as for example palladium(ll) acetate / 1 ,1 '-bis(diphenylphosphino)ferrocene and a base such as potassium acetate at temperatures between room temperature and the boiling point of the solvent, preferably at 100°C.

Alternatively, amides of general formula 8 may be directly synthesized from aryl bromides of formula 5 by reaction with appropriate amines HN(R^5a)(R^5b) 9 under palladium catalyzed carbonylation conditions. For this carbonylation all processes that are known to the person skilled in the art may be applied. Bromides of formula 5 can be reacted in a polar aprotic solvent such as for example dioxane with an appropriate amine in the presence of a carbon monoxide source such as for example molybdenum hexacarbonyl or under a carbon monoxide atmosphere at pressures between 1 and 20 bar and in the presence of a palladium catalyst such as for example palladium(ll) acetate and a base such as sodium carbonate at temperatures between room temperature and the boiling point of the solvent, preferably at 1 10°C. It might be necessary to add a ligand such as tri-ie f-butylphosphonium tetrafluoro- borate to the mixture. Sometimes the trifluoroacetyl group is removed under these conditions.

Sulfoximines of general formula 4, 5 or 6 may be obtained from sulfoxides of general formula 2 or 3 by the procedure described in Org. Lett. 2004, 6, 1305-1307. The trifluoroacetyl group can be removed by treatment with base (potassium carbonate/methanol, 4 or 5 to give 8) or by saponification of ester 6 (excess lithium hydroxide to give 7).

Sulfoxides of general formula 3 may be directly formed from aryl bromides of general formula 2 under palladium catalyzed carbonylation conditions. Thus, bromides of formula 2 may be reacted in a suitable solvent such as for example dimethyl sulfoxide in the presence of methanol and a carbon monoxide source such as for example molybdenum hexacarbonyl or under a carbon monoxide atmosphere at pressures between 1 and 20 bar and in the presence of a palladium catalyst system such as for example palladium(ll) acetate / 1 ,1 '- bis(diphenylphosphino)ferrocene and a base such as potassium acetate at temperatures between room temperature and the boiling point of the solvent, preferably at 100°C.

Sulfoxides of formula 2 can be obtained from spirotetrahydrothiopyranes of formula 1 by oxidation in an organic solvent such as for example acetonitrile with periodic acid and a catalytic amount of iron(lll) chloride at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature. The preparation of compounds of formula 1 and 2 is described in WO 2013/107743. Sulfoxides of general formula 2 or 3 and sulfoximines of general formula 4, 5 or 6 exist as a mixture of diastereomers. These diastereomers can be separated by chromatography. They were numbered according to their retention times in the applied chromatographic procedures.

Scheme 1 : General procedures for the preparation of compounds of general formula 8;

R¹, R², R^5a, R^5b and R⁹ are as defined in the description and claims of this invention.

Carboxylic acids of general formula 7 in turn may be obtained from carboxylic esters of formula 6 by saponification.

Carboxylic esters of general formula 6 may be synthesized from aryl bromides of formula 5 by reaction with methanol under palladium catalyzed carbonylation conditions. Bromides of formula 5 can be reacted in a polar aprotic solvent such as for example dimethylsulfoxide with an appropriate alcohol such as methanol in the presence of a CO source such as for example molybdenum hexacarbonyl or under a CO atmosphere at pressures between 1 and 20 bars and in the presence of a palladium catalyst such as bis(triphenylphosphine) palladium(ll) dichloride and a base such as for example triethylamine at temperatures between room temperature and the boiling point of the solvent, preferably at 100°C.

Compounds of formula (I) in which R⁸ is not hydrogen can be synthesized from sulfoximines 8 by processes that are known to a person skilled in the art (Chemistry Letters, Vol. 33, No. 5, (2004), 482).

Scheme 2: General procedures for the preparation of compounds of general formula (I); R¹, R², R⁸ and R⁹ are as defined in the description and claims of this invention. The procedures are favorable for the synthesis of compounds of general formula (I) wherein R³ is N(H)C(0)R⁶, N(H)C(0)N(R^5a)(R^5b) or N(H)C(0)OR⁷.

Compounds of general formula (I) wherein R³ is N(H)C(0)R⁶, N(H)C(0)N(R^5a)(R^5b) or N(H)C(0)OR⁷ may be synthesized according to the procedures depicted in Scheme 2 from suitably functionalized anilines of general formula 13 by reaction with electrophiles. Thus, anilines of formula 13 may be reacted with appropriate carboxylic acids to form amides of general formula (I) wherein R³ is N(H)C(0)R⁶. For amide formation, however, all processes that are known from peptide chemistry to the person skilled in the art may be applied (see the synthesis of compounds of formula 8 in Scheme 1 ).

Furthermore, anilines of general formula 13 can be reacted with appropriate isocyanates in a suitable organic solvent such as for example DMF and optionally in the presence of a tertiary amine base such as triethylamine or DIPEA at temperatures between 0°C and the boiling point of the solvent to form ureas of general formula (I) wherein R³ is N(H)C(0)N(R^5a)(R^5b). Additionally, anilines of general formula 13 can be reacted with appropriate chloroformates or 4-nitrophenylcarbonates in a suitable organic solvent such as for example THF and in the presence of a tertiary amine base such as triethylamine or DIPEA at temperatures between 0°C and the boiling point of the solvent to form carbamates of general formula (I) wherein R³ is N(H)C(0)OR⁷.

A sequence for the preparation of similar compounds is described in WO 2013/107743.

10 can be synthesized from 5 by processes that are known to a person skilled in the art (Chemistry Letters, Vol. 33, No. 5, (2004), 482).

Alternatively, anilines of general formula 13 can be obtained from carboxylic acids of general formula 14 by a two step protocol involving Curtius rearrangement followed by deprotection as shown in Scheme 3. For deprotection of ie f-butyloxycarbonyl (Boc) groups, all processes that are known to the person skilled in the art may be applied. The protected aniline of general formula 15 may be reacted in an organic solvent such as for example dichloro- methane, diethyl ether or 1 ,4-dioxane with an acid such as trifluoroacetic acid or hydrochloric acid at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature to give 13.

Scheme 3: Alternative procedures for the preparation of compounds of general formula 13 starting from carboxylic acids of general formula 14; R¹, R², R⁸ and R⁹ are as defined in the description and claims of this invention.

The protected aniline of general formula 15 can be obtained from carboxylic acids of general formula 14 by reaction in an organic solvent such as ie f-butanol with an azide source such as for example diphenylphosphoryl azide in the presence of an organic base such as for example triethylamine at temperatures between 40°C and 150°C, preferably at 85°C. It might be necessary to add molecular sieves to the mixture.

A similar sequence is described in WO 2013/107743.

14 can be synthesized from 6 or 7 by processes that are known to a person skilled in the art. SYNTHESIS OF KEY INTERMEDIATES

Intermediate A.1

Preparation of 4-fluoro-2',3',5',6'-tetrahydrospiro[indole-3,4'-thiopyran] and

6-fluoro-2',3',5',6'-tetrahydro

To a stirred solution of (3-fluorophenyl)hydrazine (CAS No. [658-27-5], 1 .83 g, 14.5 mmol) and 4-(methoxymethylene)-3,4,5,6-tetrahydro-2/-/-thiopyran (2.09 g, 14.5 mmol) in 80 mL chloroform at rt, trifluoroacetic acid (3.7 ml_, 48 mmol) was added dropwise. The reaction mixture was heated to 50°C for 4 h and then cooled to room temperature. An aqueous solution of ammonia (25%) was carefully added to reach a pH of ~ 10. The mixture was poured into water, the phases were separated and the aqueous phase extracted twice with dichloromethane. The combined organic layers were washed twice with water, dried with magnesium sulfate and the solvents removed in vacuo. The crude product mixture (3.0 g) of regioisomers was taken to the next step without further purification.

UPLC-MS (ESI+): [M + H]⁺ = 222 Rt = 1.05/1.07 min.

Intermediate B.1

Preparation of 2-cyclopropyl-4-fluoro-1 ,2,2',3',5',6'-hexahydrospiro[indole-3,4'-thiopyran] B.1 and 2-cyclopropyl-6-flu pyran] B.2

To a stirred and degassed solution of indolenine mixture A.1 in 35 mL THF (3.0 g,

13.6 mmol) boron trifluoride diethylether complex (1.7 mL, 13.6 mmol) was added dropwise at 0°C. After 5 min of stirring cyclopropylmagnesium bromide (96 mL of a 0.5 M solution in THF, 48 mmol) was added dropwise within approximately 1 h, keeping the temperature of the mixture at 5°C. The mixture was further stirred at 0°C until TLC and/or LCMS indicated complete consumption of the starting material. Then sat. aqueous ammonium chloride solution was added and the mixture partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried with magnesium sulfate, concentrated in vacuo and purified via flash chromatography (Si02-hexane/ethyl acetate) to give 526 mg (15%) of intermediate B.1 and 810 mg (22 %) of intermediate B.2. B.1

¹H-NMR (400MHz, DMSO-d6): Shift [ppm] = 0.18 - 0.24 (m, 1 H), 0.39 - 0.48 (m, 2H), 0.51 - 0.58 (m, 1 H), 0.89 - 0.97 (m, 1 H), 1.82 - 1.96 (m, 2H), 2.29 - 2.42 (m, 2H), 2.56 - 2.62 (m, 2H), 2.76 - 2.90 (m, 2H), 2.95 (d, 1 H), 5.89 (s, 1 H), 6.24 (dd, 1 H), 6.29 (d, 1 H), 6.89 - 6.94 (m, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 264 Rt = 1.39 min.

B.2

¹H-NMR (400MHz, DMS0-d6): Shift [ppm] = 0.12 - 0.22 (m, 1 H), 0.32 - 0.46 (m, 2H), 0.47 - 0.57 (m, 1 H), 0.79 - 0.93 (m, 1 H), 1.79 - 2.03 (m, 2H), 2.08 - 2.20 (m, 1 H), 2.65 - 2.77 (m, 4H), 2.80 (d, 1 H), 5.91 (s, 1 H), 6.17 - 6.30 (m, 2H), 7.04 - 7.14 (m, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 264 Rt = 1.39 min.

Intermediate C.1

Preparation of 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2,2', 3', 5', 6'- hexahydrospiro[indole-3,4'-thiopyran]

B.1 (9.54 g, 36.2 mmol) was stirred with 4-fluorobenzenesulfonyl chloride (CAS No. [349-88- 2], 10.6 g, 54.3 mmol) and 26 mL of pyridine for 18 h. The reaction mixture was poured into ice-cooled water (2 I) and stirred for 20 min. The precipitate was filtered off, washed with water to give C.1 (14 g, 92%) which was taken to the next step without further purification.

¹H-NMR (300MHz, DMSO-d6): Shift [ppm] = 0.17 - 0.27 (m, 1 H), 0.34 - 0.50 (m, 2H), 0.56 - 0.68 (m, 1 H), 0.72 - 0.84 (m, 1 H), 0.98 - 1 .1 1 (m, 1 H), 1 .29 (dt, 1 H), 4.1 1 (d, 1 H), 6.88 (m_c, 1 H), 7.32 - 7.44 (m, 4H), 7.85 (m_c, 2H).

UPLC-MS (ESI+): [M + H]⁺ = 422 Rt = 1.53 min.

Intermediate D.1

Preparation of 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2,2', 3', 5', 6'- hexahydrospiro[indole-3,4'-thiopyran] 1 '-oxide

4 g (9.49 mmol) of C.1 were dissolved at rt in 200 mL acetonitrile, 200 mg (1 .23 mmol, 0.13 eq.) iron(lll) chloride were added and after 15 min stirring, 2.38 g (10.44 mmol, 1.1 eq.) periodic acid were added. After 60 min stirring at rt, the mixture was partitioned between ethyl acetate and half-saturated aqueous sodium hydrogencarbonate. The layers were separated and the aqueous phase (pH ~ 10) extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with sodium sulfate and the solvents removed in vacuo. The crude product 4.48 g D.1 was used in the next step without further purification. The product was obtained as a 3:2 mixture of diastereomers.

UPLC-MS (ESI+): [M + H]⁺ = 438 Rt = 1.17/1.19 min.

Intermediate E.1

Preparation of 5-bromo-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2, 2', 3', 5', 6'- hexahydrospiro[indole-3,4'-thiopyran '-oxide

To a mixture of D.1 4.58 g (9.43 mmol) and sodium acetate (1.236 g, 14.6 mmol) in 92 mL chloroform a solution of bromine (15 mL ,14.6 mmol) in acetic acid (1 M) was added at rt. The mixture was stirred at rt until TLC and/or LCMS indicated complete consumption of the starting material (3-6 h). The reaction mixture was partitioned between water and

dichloromethane. The layers were separated, the organic layer washed with sat. aqueous sodium hydrogencarbonate solution and brine, dried with magnesium sulfate and the solvents removed in vacuo. The residue was purified by preparative HPLC to yield 2.85 g E.1 (3:2 mixture of diastereomers).

¹H-NMR (300MHz, DMSO-d6): Shift [ppm] =- 0.27 - 0.12 (m, 0.6 H^*), 0.10 - 0.25 (m, 0.4 H^*), 0.77 - 0.92 (m, 1 H), 1.03 - 1 .16 (m, 1 H), 1 .33 (dt, 0.4 H^*)1.71 (dt, 0.6 H^*), 4.21 (d, 0.6 H^*), 4.26 (d, 0.4H^*), 7.29 - 7.36 (m, 1 H), 7.39 - 7.51 (m, 2.6 H^*), 7.62 (t, 1 H), 7.78 H^*).

UPLC-MS (ESI+): [M + H]⁺ = 516/518 (Br isotope pattern) Rt = 1.26/1.30 min. Intermediate E.2

Preparation of 5-bromo-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2, 2', 3', 5', 6'

hexahydrospiro[indole-3,4'-thiopyran '-oxide

To a solution of 5-bromo-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2, 2', 3', 5', 6'- hexahydrospiro[indole-3,4'-thiopyran] (intermediate C.1 in WO2013107743; 3.20 g,

6.63 mmol) in 160 mL acetonitrile (prepared by short ultrasonication) iron(lll) chloride (0.130 eq., 140 mg, 0.862 mmol) was added at rt. After 15 min stirring periodic acid (1.10 eq., 1.66 g, 7.30 mmol) was added and the mixture stirred at rt for 45 min. The mixture was partitioned between water and ethyl acetate. The pH of the aqueous phase was adjusted to ~ pH 9 by the addition of aqueous sat. sodium hydrogencarbonate solution. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with sodium sulfate and the solvents evaporated. The crude material was purified by flash chromatography (Si02-hexane/ethyl acetate) to yield the desired product (2.43 g, 74%) as a 3:2 mixture of diastereomers.

1H-NMR (400MHz, DMSO-d6, major isomer): Shift [ppm]= -0.19 (d, 1 H), 0.37 - 0.44 (m, 2H), 0.49 - 0.67 (m, 1 H), 0.75 - 0.85 (m, 1 H), 0.92 - 1 .01 (m, 1 H), 1.63 (dt, 1 H), 2.00 (d, 1 H), 2.30 - 2.35 (m, 1 H), 2.60 - 2.67 (m, 1 H), 2.71 - 2.78 (m, 1 H), 2.92 - 3.01 (m, 2H), 4.13 (d, 1 H) [minor isomer: 4.08 (d, 1 H)], 7.37 - 7.50 (m, 5H), 7.81 - 7.86 (m, 2H) [minor isomer: 7.88 - 7.92 (m, 2H].

UPLC-MS (ESI+): [M + H]⁺ = 498/500 (Br isotope pattern); Rt = 1.24/1.26 min.

Intermediate E.3

Preparation of /V-{5-bromo-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-oxido-1 ,2,2', 3', 5', 6'- hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-1 '-ylidene}-2,2,2-trifluoroacetamide

A suspension of intermediate E.2 (1 .29 g, 2.59 mmol), trifluoroacetamide (2.00 eq., 585 mg, 5.18 mmol), magnesium oxide (4.0 eq., 417 mg, 10.4 mmol) and rhodium(ll) acetate dimer (0.054 eq., 92 mg, 0.41 mmol) in 42 mL dichloromethane under argon was treated with iodobenzene diacetate (1 .50 eq., 1.25 g, 3.88 mmol) at rt and stirring at rt was continued for 4 hours. The reaction mixture was concentrated in vacuo and the residue subjected to flash chromatography (Si02-hexane/ethyl acetate) to yield two diastereomers (658 mg, 40%, diastereomer 1 and 544 mg, 33%, diastereomer 2). less polar diastereomer (diastereomer 1 ):

¹H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.33 - 0.46 (m, 3H), 0.54 - 0.64 (m, 1 H) , 0.78 - 0.86 (m, 1 H), 0.96 - 1 .05 (m, 1 H), 1 .59 (dt, 1 H), 2.56 - 2.57 (m, 1 H), 2.63 - 2.69 (m, 1 H), 3.43 - 3.58 (m, 2H), 3.97 - 4.14 (m, 2H), 4.41 (d, 1 H), 7.40 - 7.52 (m, 4H), 7.59 (d, 1 H), 7.84 - 7.89 (m, 2H).

UPLC-MS (ESI+): [M + H]⁺ = 609/61 1 (Br isotope pattern); Rt = 1.47 min. more polar diastereomer (diastereomer 2):

¹H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.27 - 0.33 (m, 1 H), 0.38 - 0.49 (m, 1 H), 0.56 - 0.65 (m, 1 H) , 0.85 - 0.93 (m, 1 H), 0.94 - 1.04 (m, 1 H), 1.35 (dt, 1 H), 2.37 - 2.50 (m, 1 H), 2.50 - 2.60 (m, 1 H), 3.44 - 3.57 (m, 2H), 4.03 - 4.12 (m, 2H), 4.42 (d, 1 H), 7.31 (d, 1 H), 7.41 - 7.53 (m, 4H), 7.83 - 7.87 (m, 2H).

UPLC-MS (ESI+): [M + H]⁺ = 609/61 1 (Br isotope pattern); Rt = 1.49 min. Intermediate F.1

Preparation of methyl 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2,2', 3', 5', 6'- hexahydrospiro[indole-3,4'-thiopyran]-5-carboxylate 1 '-oxide

The aryl bromide E.1 (2.8 g, 5.42 mmol) (3:2 mixture of diastereomers) was placed into a steel autoclave under argon atmosphere and dissolved in a mixture of 155 mL methanol and 15 mL dimethyl sulfoxide. 0.77 g trans-bis(triphenylphosphine) palladium(ll) dichloride and 1 .8 mL triethylamine were added and the mixture was purged 3 times with carbon monoxide. The mixture was stirred for 30 min at 20°C under a carbon monoxide pressure of 12.3 bar. The autoclave was set under vacuum again, then a carbon monoxide pressure of 15.8 bar was applied and the mixture heated to 100°C until TLC and/or LCMS indicated complete consumption of the starting material (22-24 h), yielding a maximum pressure of 17.5 bar. The reaction was cooled to rt, the pressure released and the reaction mixture concentrated in vacuo. The reaction mixture was poured into water, the precipitate was filtered off, washed with water and taken up with dichloromethane. The organic layer was dried with magnesium sulfate, concentrated in vacuo and the crude product purified by flash chromatography (S1O2- hexane/ethyl acetate). 0.72 g (25%) F.1 of the less polar diastereomer and 1 .18 g (44%) F.1 of the more polar diastereomer were obtained. less polar diastereomer (diastereomer 1 ):

¹H-NMR (400MHz, DMSO-d6): Shift [ppm] = 0.14 - 0.26 (m, 1 H), 0.38 - 0.50 (m, 1 H), 0.51 - 0.56 (m, 1 H), 0.61 - 0.74 (m, 1 H), 0.79 - 0.91 (m, 1 H), 1.03 - 1 .16 (m, 1 H), 1 .36 (dt, 1 H), 2.68 - 2.81 (m, 2H), 3.05 (dt, 1 H), 3.80 (s, 3H), 4.32 (d, 1 H), 7.40 - 7.51 (m, 3H), 7.86 (t, 1 H), 7.90 - 7.98 (m, 2H).

UPLC-MS (ESI+): [M + H]⁺ = 496 Rt = 1.17 min. more polar diastereomer (diastereomer 2):

1H-NMR (400MHz, DMSO-d6): Shift [ppm] = -0.21 - - 0.1 1 (m, 1 H), 0.39 - 0.51 (m, 3H), 0.56 - 0.68 (m, 1 H), 0.78 - 0.90 (m, 1 H), 1.02 - 1 .14 (m, 1 H), 1 .95 (dt, 1 H), 2.64 - 2.79 (m, 1 H), 2.89 - 3.16 (m, 3H), 3.81 (s, 3H), 4.27 (d, 1 H), 7.39 - 7.51 (m, 3H), 7.81 - 7.91 (m, 3H). UPLC-MS (ESI+): [M + H]⁺ = 496 Rt = 1.16 min. Intermediate F.2

Preparation of methyl 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2,2', 3', 5', 6'- hexahydrospiro[indole-3,4'-thiopy

5-bromo-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2,2',3',5',6'-hexahydrospiro[indole-3,4'- thiopyran] (intermediate C.1 in WO2013107743; 2.0 g, 4.2 mmol) was placed into a steel autoclave under argon atmosphere and dissolved in a mixture of 95 mL methanol and 9.4 mL DMSO. Trans-bis(triphenylphosphine) palladium(ll) dichloride (0.2 eq., 594 mg, 0.83 mmol) and triethylamine (2.50 eq., 1.4 mL, 10.4 mmol) were added and the mixture was purged 3 times with carbon monoxide. The mixture was stirred for 30 min at 20°C under a carbon monoxide pressure of 13.8 bar. The autoclave was set under vacuum again, then a carbon monoxide pressure of 10 bar was applied and the mixture heated to100°C (internal temperature) for 23 h to reach a pressure of 13.8 bar. The reaction was cooled to rt, the pressure released and the reaction mixture concentrated in vacuo. The concentrated mixture was poured into water, the formed precipitate filtered off and rinsed with water. The obtained solid was redissolved in dichloromethane, dried with magnesium sulfate and concentrated in vacuo. After flash chromatography (Si02-hexane/ethyl acetate) the material (888 mg) was recrystallized from ethyl acetate to give 526 mg of the desired methyl ester (26%).

1H-NMR (400MHz, DMSO-d6): Shift [ppm]= 0.30 - 0.33 (m, 1 H), 0.36 - 0.42 (m, 1 H), 0.44 - 0.50 (m, 1 H), 0.58 - 0.65 (m, 1 H), 0.73 - 0.79 (m, 1 H), 0.91 - 1.05 (m, 2H), 1.99 - 2.02 (m, 1 H), 2.10 - 2.18 (m, 1 H), 2.36 - 2.40 (m, 1 H), 2.62 - 2.67 (m, 1 H), 2.79 - 2.91 (m, 2H), 3.82 (s, 3H), 4.08 (d, 1 H), 7.37 - 7.42 (m, 2H), 7.61 (d, 1 H), 7.69 (d, 1 H), 7.88 - 7.92 (m, 3H). UPLC-MS (ESI+): [M + H]⁺ = 462; Rt = 1.47 min. Intermediate G.1

Preparation of methyl 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 '- [(trifluoroacetyl)imino]-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxylate 1 '-oxide

230 mg (0.464 mmol) of intermediate F.1 (diastereomer 1 ) were dissolved in 10 mL dichloromethane and stirred with 236 mg (0.928 mmol) trifluoroacetamide, 169 mg (1.856 mmol) magnesiumoxide, 16 mg (0.074 mmol) rhodium (ll)acetate dimer and 224 mg (0.696 mmol) iodobenzene diacetate overnight. The mixture was concentrated in vacuo and the crude product purified by flash chromatography (Si02-hexane/ethyl acetate),

diastereomer 1 :

¹H-NMR (400MHz, DMSO-d6): Shift [ppm] = 0.29 - 0.40 (m, 1 H), 0.41 - 0.57 (m, 2H), 0.59 - 0.71 (m, 1 H), 0.86 - 0.98 (m, 1 H), 1.05 - 1.19 (m, 1 H), 1.66 (dt, 1 H), 2.74 - 2.86 (m, 2H), 3.42 - 3.63 (m, 2H), 3.80 (s, 3H), 4.00 - 4.23 (m, 2H), 4.55 (d, 1 H), 7.40 - 7.53 (m, 3H), 7.82 - 7.94 (m, 3H).

UPLC-MS (ESI+): [M + H]⁺ = 607 Rt = 1.41 min.

Intermediate G.2:

In the same way diastereomer 2 was obtained from intermediate F.1 (diastereomer 2):

¹H-NMR (400MHz, DMSO-d6): Shift [ppm] = 0.37 - 0.54 (m, 3H), 0.57 - 0.69 (m, 1 H), 0.79 - 0.90 (m, 1 H), 1.08 - 1 .20 (m, 1 H), 1 .87 (dt, 1 H), 2.71 - 2.85 (m, 1 H), 2.89 - 3.03 (m, 1 H), 3.42 - 3.60 (m, 2H), 3.82 (s, 3H), 3.96 - 4.20 (m, 2H), 4.54 (d, 1 H), 7.40 - 7.52 (m, 3H), 7.84 - 7.95 (m, 3H).

UPLC-MS (ESI+): [M + H]⁺ = 607 Rt = 1.41 min.

Intermediate H.1

Preparation of 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2', 3', 5', 6'- hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxylic acid 1 '-oxide

A solution of the methyl ester G.1 (diastereomer 1 ) (723 mg, 1 .12 mmol) in 7 mL THF was stirred with 428 mg lithium hydroxide (17.8 mmol) and 3 mL water overnight. The mixture was set to pH 2-3 by addition of 2 N aqueous hydrochloric acid and the precipitate was filtered off to give the crude product which was used without further purification.

diastereomer 1 of H.1 (520 mg, 87%)

MS (ESI+): [M + H]^" = 497 Rt = 0.97 min.

Intermediate H.2

In the same way diastereomer 2 was obtained from methyl ester G.2.

MS (ESI+): [M + H]^" = 497 Rt = 0.96 min.

Intermediate H.3

Preparation of 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2,2',3',5',6'-hexahydrospiro[indole- 3,4'-thiopyran]-5-carboxylic acid

A solution of the methyl ester F.2 (1 .08 g, 2.34 mmol) in 34 mL THF was treated with an aqueous lithium hydroxide solution (58 eq., 136 mmol, 68 mL of a 2M aq. solution) and stirred at rt for 4 days. The mixture was set to pH 3 by addition of 2M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed twice with water, dried with sodium sulfate and concentrated in vacuo. The crude product (1.12 g, 66%) was used without further purification.

¹H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.29 - 0.52 (m, 3H), 0.57 - 0.66 (m, 1 H) , 0.72 - 0.80 (m, 1 H), 0.90 - 1.05 (m, 2H), 1.98 - 2.03 (m, 1 H), 2.12 (dt, 1 H), 2.36 - 2.41 (m, 1 H), 2.62 - 2.66 (m, 1 H), 2.78 - 2.91 (m, 2H), 4.07 (d, 1 H), 7.37 - 7.43 (m, 2H), 7.59 (d, 1 H), 7.67 (d, 1 H), 7.87 - 7.92 (m, 3H), 12.86 (br.s., 1 H).

UPLC-MS (ESI-): [M - H]^" = 446; Rt = 1.26 min.

Intermediate 1.1

Preparation of 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-5-[(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3- yloxy)carbonyl]-1 ,2,2',3',5',6'-hexahydrospiro[indole-3,4'-thiopyran]

A solution of the crude carboxylic acid H.3 (2.69 g, 4.51 mmol) in 45 mL DMF was treated with HATU (1 .5 eq., 2.6 g, 6.8 mmol) and triethylamine (1 .5 eq., 0.94 mL, 6.8 mmol) and stirred at rt for 2 days. The reaction mixture was poured into 250 mL water, the precipitated material filtered off and rinsed with water. The obtained residue was taken up with

dichloromethane, washed with water, dried with magnesium sulfate and concentrated in vacuo. The crude active ester (3.0 g, 73%) was used without further purification.

UPLC-MS (ESI+): [M + H]⁺ = 566; Rt = 1.43 min. Intermediate J.1

Preparation of 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2,2',3',5',6'-hexahy -carboxamide

To a solution of the crude active ester 1.1 (1 .50 g, 1 .46 mmol) in 20 mL THF was added 1 -[3- (trifluoromethyl)pyridin-2-yl]methanamine (1.50 eq., 434 mg, 2.47 mmol) and the mixture stirred at 55°C for 3 days. Because of incomplete conversion more 1 -[3-(trifluoro- methyl)pyridin-2-yl]methanamine (1.50 eq., 434 mg, 2.47 mmol) was added and stirring at 55°C continued for 7 days. The reaction mixture was partitioned between ethyl acetate and water, the phases separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (Si02-hexane/ethyl acetate) to give the title carboxamide (376 mg, 26%).

UPLC-MS (ESI+): [M + H]⁺ = 606; Rt = 1.43 min. Intermediate K.1

2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-/V-{[3-(trifluoromethyl)pyridin-2-yl]methyl}- 1 ,2,2',3',5',6'-hexahydrospiro[in mide 1 '-oxide

To a solution of intermediate J.1 (376 mg, 0.435 mmol) in 10 mL acetonitrile iron(lll) chloride (0.13 eq., 9.2 mg, 0.056 mmol) was added at rt. After 15 min stirring periodic acid (1 .10 eq., 109 mg, 0.478 mmol) was added and the mixture stirred at rt for 90 min. The mixture was partitioned between water and ethyl acetate. The pH of the aqueous phase was adjusted to ~ pH 9 by the addition of aqueous sat. sodium hydrogencarbonate solution. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with sodium sulfate and the solvents evaporated. The crude material was purified by flash chromatography (Si02-hexane/ethyl acetate) to yield the desired product (263 mg, 97%) as a 75:25 mixture of diastereomers.

1H-NMR (400MHz, DMSO-d6, major isomer): Shift [ppm]= -0.14 (d, 1 H), 0.37 - 0.46 (m, 2H), 0.51 - 0.67 (m, 1 H), 0.78 - 0.87 (m, 1 H), 0.92 - 1 .02 (m, 1 H), 1 .68 (dt, 1 H), 2.03 - 2.06 (m, 1 H), 2.34 - 2.39 (m, 1 H), 2.75 - 2.81 (m, 2H), 2.97 - 3.01 (m, 2H), 4.20 (d, 1 H) [minor isomer: 4.13 (d, 1 H)], 4.66 - 4.79 (m, 2H), 7.39 - 7.45 (m, 2H), 7.53 (dd, 1 H), 7.58 (d, 1 H) [minor isomer: 7.59 (d, 1 H), 7.79 (d, 1 H)], 7.84 - 7.90 (m, 4H) [minor isomer: 7.91 - 7.95 (m, 2H], 8.17 (dd, 1 H), 8.78 - 8.79 (m, 1 H), 9.07 (t, 1 H) [minor isomer: 8.93 (t, 1 H)].

UPLC-MS (ESI+): [M + H]⁺ = 622; Rt = 1.17 min.

COMPOUNDS ACCORDING TO THE INVENTION: Example 1-1

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-4-fluoro-1-[(4- fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5- carboxamide 1 '-oxide

50 mg (0.1 mmol) intermediate H.1 (diastereomer 1) and 37 mg (0.15 mmol) 1-[3-chloro-5- (trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (CAS No. [175277-74-4]) were reacted with 57 mg (0.15 mmol) HATU in the presence of 42 μΙ_ (0.3 mmol) triethylamine in 1 mL DMF at rt overnight. After HPLC purification 40 mg (57%) amide were obtained.

1H-NMR (300MHz, DMSO-d6): Shift [ppm] = 0.09-0.19 (m, 1H), 0.40-0.49 (m, 1H),0.49- 0.57 (m, 1H), 0.60-0.70 (m, 1H), 0.79-0.88 (m, 1H), 1.05-1.16 (m, 1H), 1.82 (dt, 1H), 2.90-3.01 (m, 1H), 3.04 - 3.12 (m, 2H), 3.46 (s, 1H), 3.48-3.57 (m, 1H),4.39 (d, 1H), 4.72 (d,2H), 7.41 - 7.48 (m, 3H), 7.69 (t, 1 H), 7.89 - 7.96 (m, 2H), 8.47 (m_c, 1H), 8.70(m_c, 1H),

UPLC-MS (ESI+): [M + H]⁺ = 689 / 691 (CI isotope pattern) Rt = 1.26 min.

Example 1-2

Prepared in analogy to example 1-1 from intermediate H.2 (diastereomer 2).

¹H-NMR (300MHz, DMSO-d6): Shift [ppm] = 0.18 - 0.31 (m, 1H), 0.40 - 0.70 (m, 3H), 0.75 - 0.89 (m, 1H), 1.02-1.17 (m, 1H), 1.77 (dt, 1H), 2.81 -2.98 (m, 1H), 2.99-3.12 (m, 2H), 3.38 - 3.53 (m, 1 H), 3.73 (s, 1 H), 4.35 (d, 1 H), 4.73 (d, 2H), 7.37 - 7.48 (m, 3H), 7.69 (t, 1 H), 7.87 - 7.97 (m, 2H), 8.47 (m_c, 1 H), 8.69 (m_c, 1 H), 8.93 (m_c, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 689 / 691 (CI isotope pattern) Rt = 1.26 min.

Example 2-1

/V-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-f luorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'- hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide

To a solution of intermediate E.3 (diastereomer 1 ; 100 mg, 0.164 mmol) in 4 mL 1 ,4-dioxane (containing 1 % water) 1 -(2-chlorophenyl)methanamine (3.0 eq., 70 mg, 0.49 mmol), molybdenum hexacarbonyl (1.0 eq., 43 mg, 0.16 mmol), sodium carbonate (3.0 eq., 52 mg, 0.49 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.10 eq., 4.8 mg, 0.016 mmol) and palladium(ll) acetate (0.10 eq., 3.7 mg, 0.016 mmol) were added in a pressure tube. The reaction mixture was vigorously stirred at 155°C for 2 h. According to UPLC-MS the main product was the corresponding deprotected carboxylic acid. The reaction mixture was therefore filtrated over a pad of Celite, the residue washed with ethyl acetate and the combined filtrates concentrated in vacuo. The obtained crude material was taken up in 2 mL DMF, treated with 1 -(2-chlorophenyl)methanamine (3.8 eq., 89 mg, 0.63 mmol), HATU (3.8 eq., 238 mg, 0.63 mmol) and triethylamine (3.8 eq., 87 μΙ_, 0.63 mmol) and stirred at rt for 1 h. The reaction mixture was partitioned between ethyl acetate and water, the phases separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (Si02-hexane/ethyl acetate) followed by preparative HPLC to give example 2-1 (2.6 mg, 1.5%).

¹H-NMR (400MHz, DMSO-d6): Shift [ppm]= 0.24 - 0.28 (m, 1 H), 0.38 - 0.45 (m, 1 H) , 0.51 - 0.64 (m, 2H), 0.78 - 0.82 (m, 1 H), 0.96 - 1.02 (m, 1 H), 1.44 (dt, 1 H), 2.39 - 2.59 (m, 3H), 3.1 1 - 3.12 (m, 2H), 3.38 - 3.45 (m, 1 H), 3.73 (s, 1 H), 4.26 (d, 1 H), 4.53 (d, 2H), 7.27 - 7.46 (m, 6H), 7.60 (d, 1 H), 7.83 (d, 1 H), 7.89 - 7.94 (m, 3H), 9.05 (t, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 602/604 (CI isotope pattern); Rt = 1.20 min.

Example 2-2

Prepared in analogy to example 2-1 from 100 mg (0.164 mmol) diastereomer 2 of E.3 (yield: 6 mg, 4%).

¹H-NMR (400MHz, DMSO-d6): Shift [ppm]= 0.1 1 - 0.15 (m, 1 H), 0.38 - 0.45 (m, 1 H) , 0.50 - 0.57 (m, 1 H), 0.58 - 0.65 (m, 1 H), 0.79 - 0.84 (m, 1 H), 0.95 - 1.04 (m, 1 H), 1 .49 (dt, 1 H), 2.37 - 2.45 (m, 2H), 2.55 - 2.62 (m, 1 H), 3.12 - 3.14 (m, 2H), 3.47 - 3.53 (m, 2H), 4.30 (d, 1 H), 4.47 - 4.57 (m, 2H), 7.26 - 7.36 (m, 3H), 7.39 - 7.46 (m, 3H), 7.60 (d, 1 H), 7.77 (d, 1 H), 7.89 - 7.94 (m, 3H), 9.06 (t, 1 H). UPLC-MS (ESI+): [M + H]⁺ = 602/604 (CI isotope pattern); Rt = 1.23 min.

Example 3-1

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4-fluoropheny

1 '-[(trifluoroacetyl)imino]-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5- carboxamide 1 '-oxide

A solution of intermediate E.3 (diastereomer 1 ; 300 mg, 0.492 mmol) in 15 mL THF was placed into a steel autoclave under argon atmosphere. 1 -[3-chloro-5-(trifluoromethyl)pyridin- 2-yl]methanamine hydrochloride (CAS No. [175277-74-4]; 3.0 eq., 31 1 mg, 1 .48 mmol), 1 ,1 '- bis(diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (0.20 eq., 80 mg, 0.098 mmol) and triethylamine (2.35 eq., 161 μΙ_, 1 .16 mmol) were added and the mixture was purged 3 times with carbon monoxide. The mixture was stirred for 30 min at 20°C under a carbon monoxide pressure of 12 bar. The autoclave was set under vacuum again, then a carbon monoxide pressure of 12 bar was applied and the mixture heated to 100°C for 22 h, yielding a maximum pressure of 16 bar. The reaction was cooled to rt, the pressure released and the reaction mixture filtrated. The residue was washed with THF and the combined filtrates concentrated in vacuo. The obtained crude product was purified by flash chromatography (Si02-hexane/ethyl acetate) followed by preparative HPLC to give example 3-1 (68 mg, 18%).

¹H-NMR (400MHz, DMSO-d6): Shift [ppm]= 0.39 - 0.49 (m, 3H), 0.57 - 0.64 (m, 1 H) , 0.82 - 0.88 (m, 1 H), 0.99 - 1 .07 (m, 1 H), 1 .61 (dt, 1 H), 2.60 - 2.72 (m, 2H), 3.49 - 3.62 (m, 2H), 4.03 - 4.18 (m, 2H), 4.48 (d, 1 H), 4.74 (d, 2H), 7.40 - 7.44 (m, 2H), 7.59 (d, 1 H), 7.88 - 7.92 (m, 4H), 8.46 (d, 1 H), 8.90 (d, 1 H), 9.10 (t, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 767/769 (CI isotope pattern); Rt = 1.43 min.

Example 3-2

Prepared in analogy to example 3-1 from 300 mg (0.492 mmol) diastereomer 2 of E.3 (yield: 172 mg, 42%). ¹H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.35 - 0.52 (m, 3H), 0.59 - 0.67 (m, 1 H) , 0.88 - 1 .03 (m, 2H), 1 .34 (dt, 1 H), 2.40 - 2.50 (m, 1 H), 2.61 - 2.67 (m, 1 H), 3.51 - 3.61 (m, 2H), 4.06 - 4.19 (m, 2H), 4.48 (d, 1 H), 4.66 - 4.80 (m, 2H), 7.40 - 7.46 (m, 2H), 7.58 - 7.61 (m, 2H), 7.86 - 7.91 (m, 3H), 8.45 (d, 1 H), 8.86 (s, 1 H), 9.04 (t, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 767/769 (CI isotope pattern); Rt = 1.45 min.

Example 4-1

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- 1 '-imino-1 ,2,2',3',5',6'-hexahy ]-5-carboxamide 1 '-oxide

A solution of example 3-1 (65 mg, 0.085 mmol) in 1 mL methanol was treated with solid potassium carbonate (5.0 eq., 59 mg, 0.42 mmol) and stirred at rt for 30 min. The reaction mixture was filtrated and the filtrate set aside. The obtained solid was taken up with ethyl acetate and stirred at rt for 15 min. The mixture was filtrated again, all filtrates combined and concentrated in vacuo. The obtained crude material was purified by flash chromatography (Si02-ethyl acetate/methanol) to yield example 4-1 (1 1 mg, 18%).

¹H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.19 - 0.24 (m, 1 H), 0.38 - 0.46 (m, 1 H), 0.49 - 0.65 (m, 2H), 0.75 - 0.85 (m, 1 H), 0.94 - 1.03 (m, 1 H), 1.42 (dt, 1 H), 2.38 - 2.50 (m, 2H), 2.50 - 2.59 (m, 1 H), 3.10 - 3.12 (m, 2H), 3.43 (dt, 1 H), 3.76 (s, 1 H), 4.26 (d, 1 H), 4.66 - 4.80 (m, 2H), 7.37 - 7.43 (m, 2H), 7.60 (d, 1 H), 7.84 - 7.94 (m, 4H), 8.47 (d, 1 H), 8.91 (d, 1 H), 9.15 (t, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 671/673 (CI isotope pattern); Rt = 1.24 min.

The enantiomers of the racemic material of example 4-1 were separated by chiral preparative HPLC (System: Sepiatec: Prep SFC100; Column: Chiralpak ID 5μηι 250x20 mm; Solvent: CO2 / 2-propanol 60:40; Flow: 80 mL/min; Pressure (outlet): 150 bar; Temperature: 40°C; Injection: 0.1 mL/run, 85 mg/mL CH2CI2 / CHCI₃ 2:1 ; Detection: UV 254 nm) and analytically characterized by HPLC (System: Agilent: 1260 AS, MWD, Aurora SFC-Module; Column: Chiralpak ID 5μηι 100x4.6 mm; Solvent: CO2 / 2-propanol 60:40; Flow: 4.0 mL/min; Pressure (outlet): 100 bar; Temperature: 37.5°C; Injection: 10 μί, 1.0 mg/mL ethanol / methanol 1 :1 ; Detection: DAD 254 nm): Example 4-1 -1 : Rt = 3.93 min

Example 4-1 -2: Rt = 6.02 min

Example 4-2

Prepared in analogy to example 4-1 from 1 15 mg (0.150 mmol) example 3-2 (yield: 1 1 mg, 1 1 %).

¹H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.06 - 0.1 1 (m, 1 H), 0.36 - 0.46 (m, 1 H), 0.49 - 0.66 (m, 2H), 0.78 - 0.84 (m, 1 H), 0.94 - 1.03 (m, 1 H), 1.46 (dt, 1 H), 2.36 - 2.62 (m, 3H), 3.12 - 3.14 (m, 2H), 3.47 - 3.56 (m, 2H), 4.31 (d, 1 H), 4.72 (d, 2H), 7.39 - 7.45 (m, 2H), 7.60 (d, 1 H), 7.77 (d, 1 H), 7.86 - 7.94 (m, 3H), 8.47 (d, 1 H), 8.90 (d, 1 H), 9.15 (t, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 671/673 (CI isotope pattern); Rt = 1.24 min

The enantiomers of the racemic material of example 4-2 were separated by chiral

preparative HPLC (System: Sepiatec: Prep SFC100; Column: Chiralpak ID 5μηι 250x20 mm; Solvent: CO2 / 2-propanol 60:40; Flow: 80 mL/min; Pressure (outlet): 150 bar; Temperature:

40°C; Injection: 0.1 mL/run, 85 mg/mL CH2CI2 / CHCI₃ 2:1 ; Detection: UV 254 nm) and analytically characterized by HPLC (System: Agilent: 1260 AS, MWD, Aurora SFC-Module;

Column: Chiralpak ID 5μηι 100x4.6 mm; Solvent: CO2 / 2-propanol 60:40; Flow: 4.0 mL/min;

Pressure (outlet): 100 bar; Temperature: 37.5°C; Injection: 10 μί, 1.0 mg/mL ethanol / methanol 1 :1 ; Detection: DAD 254 nm):

Example 4-2-1 : Rt = 2.26 min

Example 4-2-2: Rt = 2.72 min

Example 5

2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[(trifluoroacetyl)imino]-/V-{[3-

(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]- 5-carboxamide 1 '-oxide

A suspension of intermediate K.1 (250 mg, 0.402 mmol), magnesium oxide (4.0 eq., 65 mg, 1 .6 mmol) and rhodium(ll) acetate dimer (0.16 eq., 14 mg, 0.064 mmol) in 8 mL dichloro- methane under argon was treated with iodobenzene diacetate (1 .50 eq., 194 mg,

0.603 mmol) at rt and stirred over night. The reaction mixture was concentrated in vacuo and the residue subjected to flash chromatography (Si02-hexane/ethyl acetate) to yield the desired product (185 mg, 60%) as a 75:25 mixture of diastereomers.

1H-NMR (300MHz, DMSO-d6, major isomer): Shift [ppm]= 0.40 - 0.48 (m, 3H), 0.56 - 0.65 (m, 1 H), 0.82 - 0.89 (m, 1 H), 1.00 - 1 .08 (m, 1 H), 1 .60 (dt, 1 H), 2.59 - 2.69 (m, 2H), 3.49 - 3.63 (m, 2H), 4.09 - 4.19 (m, 2H), 4.48 (d, 1 H), 4.73 - 4.74 (m, 2H), 7.40 - 7.47 (m, 2H), 7.54 (dd, 1 H), 7.60 (d, 1 H), 7.86 - 7.92 (m, 4H), 8.17 - 8.20 (m, 1 H), 8.79 (d, 1 H) [minor isomer: 8.75 (d, 1 H)], 9.06 (t, 1 H) [minor isomer: 9.00 (t, 1 H)].

UPLC-MS (ESI+): [M + H]⁺ = 733; Rt = 1.37 min.

Example 6

2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-/V-{[3-(trifluoromethyl)pyridin-2-yl]methyl}- 1 ,2,2',3',5',6'-hexahydro-1 'H-spi boxamide 1 '-oxide

A solution of example 5 (180 mg, 0.246 mmol) in a mixture of THF and water (2 mL/0.5 mL) was treated with lithium hydroxide (5.0 eq., 29 mg, 1 .2 mmol) and stirred at rt for 75 min. The reaction mixture was partitioned between ethyl acetate and water, the phases separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give the desired product (130 mg, 81 %) as a 75:25 mixture of diastereomers.

¹H-NMR (300MHz, DMSO-d6, major isomer): Shift [ppm]= 0.19 - 0.24 (m, 1 H) [minor isomer: 0.07 - 0.1 1 (m, 1 H)], 0.39 - 0.46 (m, 1 H), 0.50 - 0.62 (m, 2H), 0.77 - 0.86 (m, 1 H), 0.97 - 1 .03 (m, 1 H), 1 .42 (dt, 1 H), 2.37 - 2.60 (m, 3H), 3.10 - 3.12 (m, 2H), 3.38 - 3.47 (m, 1 H), 3.76 (s, 1 H), 4.26 (d, 1 H) [minor isomer: 4.30 (d, 1 H)], 4.65 - 4.79 (m, 2H), 7.37 - 7.45 (m, 2H), 7.53 (d, 1 H), 7.60 (d, 1 H) [minor isomer: 7.78 (d, 1 H)], 7.84 - 7.94 (m, 4H), 8.18 (dd, 1 H), 8.79 (d, 1 H), 9.08 (t, 1 H).

UPLC-MS (ESI+): [M + H]⁺ = 637; Rt = 1.16 min. The mixture of diastereomers/enantiomers of example 6 was separated by chiral preparative HPLC (System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; Column: Chiralcel OZ-H 5μΓΠ 250x30 mm; Solvent: methanol; Flow: 40 mL/min; Temperature: rt; Injection: 0.3 mL/run, 103 mg/mL methanol; Detection: UV 280 nm) and analytically characterized by HPLC (System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralcel OZ-H 5μηι 150x4.6 mm; Solvent: methanol; Flow: 1.0 mL/min; Temperature: 25°C; Injection: 5.0 μί, 1.0 mg/mL ethanol / methanol 1 :1 ; Detection: DAD 280 nm):

Example 6-1 -1 (pure enantiomer 1 of diastereomer 1 ): Rt = 3.91 min

Example 6-1 -2 (enantiomer 2 of diastereomer 1/enantiomer 1 of diastereomer 2, 78:22): Rt = 4.48 min

Table 1 : The following examples were prepared in analogy to example 1 -1 from the corresponding intermediates H.1 or H.2 with the exception of examples 1 1 -1 and 1 1 -2 which were prepared from the 6-fluoro isomers B.1 and B.2.

BIOLOGICAL ASSAYS

1 . MATERIALS

Buserelin was purchased from Welding (Frankfurt/Main, Germany) or USbiological (#B8995, Swampscott, USA) for IP-One HTRF® assays and LHRH from Sigma-Aldrich® (Munich,

Germany). Labelled cells, Tag-Lite buffer, labelled and unlabelled GnRHR binding peptide for Tag-lite® binding assay was purchased by Cisbio Bioassays (Bagnols-sur-Ceze Cedex, France). The radio labelling was performed in the Department of Isotope Chemistry of Bayer Pharma AG (Berlin, Germany) by the iodogen method using [¹²⁵l]sodium iodide (2000 Ci/mmol; PerkinElmer Life and Analytical Sciences, USA) yielding [¹²⁵l]monoiodo-buserelin. The radio-tracer was purified by reversed phase HPLC on a Spherisorb ODS II column (250 x 4 mm, particle size 3 μηη) by elution with acetonitrile / water (34 : 66) containing 39 mM trifluoracetic acid at a flow rate of 1 mL / min.

The retention time of [¹²⁵l]monoiodo-buserelin was approximately 17 min. All other chemicals were obtained from commercial sources at the highest purity grade available.

2. METHODS

2.1 . IP-ONE HTRF® ASSAY

By using homogenous time-resolved fluorescence resonance energy transfer (HTRF), the generation of one component of the GnRH-R signalling cascade can be measured. After stimulation of CHO cells stably expressing human GnRH receptor (established by Prof.

Thomas Gudermann, currently University of Marburg, Germany; supplied as frozen cell aliquots by Cell Culture Services, Hamburg, Germany) with the ECso of the GnRH agonist buserelin, Gq protein-coupled receptor signalling cascade is activated resulting in PLC- dependent cleavage of PIP2 to lnositol-1 ,4,5-triphosphate (IP3) and Diacylglycerol. The second messenger IP3 is degraded intracellular^ to myo-inositol. Inhibition of the final degradation step from lnositol-1 -phosphate (IP1 ) to myo-inositol by addition of lithium chloride leads to accumulation of IP1 in the cells. In cell lysates, IP1 can be detected via an antibody-based HTRF detection technology, where IP1 can displace the FRET acceptor IP1 - d2 from binding by Terbium-labelled anti-IP1 antibody as donor resulting in a signal decrease. Compounds were tested for their capability of inhibiting GnRH-R activation by buserelin.

For all IP-One HTRF® assays reagents of Cisbio Bioassays (IP-One Tb Jumbo kit,

#62IPAPEJ; Cisbio Bioassays, Bagnols sur Ceze Cedex, France) were used.

For the assay, frozen cell aliquots were thawed and a cell suspension (3.33x10⁶ cells/mL) containing IP1 -d2 (dilution 1 :40) was prepared and incubated at 37°C. After 1 h 3 μΙ of the cell suspension were added to 50 nl of a 100-fold concentrated solution of the test compound in DMSO pre-dispensed in a well of a white low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). The mixture was incubated for 20 min at 22°C to allow for pre-binding of the test compound to the GnRH-R. The receptor signaling cascade was stimulated by addition of 2 μΙ buserelin or LHRH (at ECso or ECso) in stimulation buffer

(10 mM Hepes pH 7.4, 1 mM CaCI2, 0.5 mM MgCI2, 4.2 mM KCI, 146 mM NaCI, 5.5 mM a- D-Glucose, 0.05% BSA, 125 mM LiCI (final assay concentration 50 mM) in aqua dest).

Plates were incubated for 1 h at 37°C and 5% carbon dioxide before the cells were lysed by adding 3 μΙ Terbium-labelled anti-IP1 antibody (1 :40) diluted in Conjugate & Lysis buffer as supplied with the kit. After an incubation for 1 h at 22°C to enable complete cell lysis and antibody binding to free IP1 or IP1 -d2, plates were measured in an HTRF reader, e.g. a RUBYstar, PHERAstar (both BMG Labtechnologies, Offenburg, Germany) or a Viewlux (PerkinElmer LAS, Rodgau-Jijgesheim, Germany).

From the fluorescence emissions at 665 nm (FRET) and at 620 nm (background signal of Terbium-antibody), the ratio (emission at 665 nm divided by emission at 620 nm) was calculated and the data were normalized (reaction without test compound = 0% inhibition; all other assay components except agonist = 100% inhibition). On the same microtiter plate, compounds were tested at 10 different concentrations in the range of 20 μΜ to 1 nM (20 μΜ, 6.7 μΜ, 2.2 μΜ, 0.74 μΜ, 0.25 μΜ, 82 ηΜ, 27 ηΜ, 9.2 ηΜ, 3.1 nM and 1 nM; dilution series prepared before the assay at the level of the 100-fold cone, stock solutions by serial 1 :3 dilutions in 100% DMSO) in duplicate values for each concentration. By using an in-house software, the I C50 values were calculated by a 4 parameter fit.

The data reveal that the compounds of the present invention have antagonist activities on the human GnRH receptor.

Within the meaning of the present invention the antagonist activity is reflected by the ability of a compound of the invention to antagonize human GnRH receptor stimulation in IP-One HTRF® assay at least three times the standard deviation over the background level.

Table 2 Potency in IP-One HTRF® assay with buserelin (at ECso) stimulation; the potency is given as I C50 [nM].

Claims

1 A compounds according to formula (I)

is selected from the group consisting of hydrogen, Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, hydroxy-Ci-C6-alkyl or Ci -Ce-a I koxy-Ci -C6-a I ky I ;

is an aryl or heteroaryl group which can be unsubstituted or substituted one to three times with a group R⁴;

is selected from the group consisting of C(0)N(R^5a)(R^5b), N(H)C(0)R⁶, N(H)C(0)N(R^5a)(R^5b) or N(H)C(0)OR⁷;

is selected from a halogen, hydroxy, CN , Ci-C6-alkyl, halo-Ci-C6-alkyl, d-Ce-alkoxy, halo-Ci-C₆-alkoxy, C(0)OH, C(0)0-Ci-C₆-alkyl, C(0)NH₂, C(0)NH-Ci-C₆-alkyl, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R^5b and R⁶ are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl; C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, aryl-cyclopropyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, hydroxy, d-Ce-alkyl, Ci-C₆-haloalkyl, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C(0)OH, C(0)0-Ci-C₆-alkyl, CN, C(0)NH₂, S(0)₂-Ci-C₆-alkyl, S(0)₂NH₂, S(0)2N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other;

is selected from the group consisting of Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, heteroaryl, or heteroaryl-Ci-C6-alkyl in which said cycloalkyi, aryl, heteroaryl group is optionally substituted up to three times with a halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,

d-Ce-haloalkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, CN , C(0)N H₂,

S(0)₂-Ci-C₆-alkyl, S(0)₂NH₂, S(0)₂N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R⁸ is selected from the group consisting of hydrogen, CN , C(0)R⁷, C(0)OR⁷, S(0)₂R¹⁰, C(0)N(R^5a)(R^5b), P(0)(OR¹¹ )₂, CH₂OP(OR¹¹ )₂, Ci-C₆-alkyl,

C3-C7-cycloalkyl, phenyl or heteroaryl, in which said Ci-C6-alkyl,

C3-C7-cycloalkyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, CN ,

d-Cs-alkyl, Ci-C₃-alkoxy, N (R^5a)(R^5b), halo-Ci-C₃-alkyl or halo-Ci-C₃-alkoxy;

R⁹ is hydrogen, halogen, hydroxy, CN , Ci-C6-alkyl, halo-Ci-C6-alkyl,

d-Ce-alkoxy, halo-Ci-C₆-alkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, C(0)N H₂, C(0)N H-Ci-C₆-alkyl, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R¹⁰ is selected from the group consisting of Ci-C6-alkyl, Ci-C3-haloalkyl,

C3-C7-cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, Ci-C3-alkyl, Ci-C3-alkoxy, N H₂, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-Ci-C3-alkyl, Ci-C3-fluoroalkoxy;

R¹¹ is selected from the group consisting of hydrogen, Ci-C4-alkyl or benzyl.

A compound according to claim 1 characterized in that

R² is an aryl group which can be unsubstituted or substituted one to three times with a group R⁴;

A compound according to claim 1 or 2 of formula (la)

in which

R¹ is selected from the group consisting of Ci-C6-alkyl, Ci-C6-cycloalkyl,

C2-C6-alkenyl;

R³ is selected from the group consisting of C(0)N(R^5a)(R^5b), C(0)NH(R^5a), and N(H)C(0)R⁶;

R⁴ is halogen, hydroxy, CN, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy,

C(0)OH, C(0)0-Ci-C₆-alkyl, C(0)NH₂, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R^5a, R^5b and R⁶ are selected, independently from one another, from the group

consisting of aryl-Ci-C6-alkyl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyi, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,

Ci-C6-haloalkoxy;

R⁷ is selected from the group consisting of Ci-C6-alkyl, halo-Ci-C6-alkyl,

hydroxy-Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,

Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl, or heteroaryl-Ci-C6-alkyl- in which said cycloalkyi, aryl, heteroaryl group is optionally substituted up to three times with a halogen, hydroxy, an Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,

d-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C₆-alkyl, CN, C(0)NH₂,

S(0)₂-Ci-C₆-alkyl, S(0)₂NH₂, S(0)₂N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other.

R⁸ is selected from the group consisting of hydrogen, CN, C(0)R⁷, C(0)OR⁷, S(0)₂R¹⁰, C(0)N(R^5a)(R^5b), P(0)(OR¹¹)₂, CH₂OP(OR¹¹)₂, Ci-C₆-alkyl,

C3-C7-cycloalkyl, phenyl or heteroaryl, in which said Ci-C6-alkyl,

C3-C7-cycloalkyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, CN,

Ci-Cs-alkyl, Ci-Cs-alkoxy, N(R^5a)(R^5b), halo-Ci-C₃-alkyl or halo-Ci-C₃-alkoxy;

R⁹ is hydrogen, halogen, hydroxy, CN , Ci-C6-alkyl, halo-Ci-C6-alkyl,

d-Ce-alkoxy, halo-Ci-C₆-alkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, C(0)N H₂, C(0)N H-Ci-C₆-alkyl, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R¹⁰ is selected from the group consisting of Ci-C6-alkyl, Ci-C3-haloalkyl,

C3-C7-cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, Ci-C3-alkyl, Ci-C3-alkoxy, N H2, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-Ci-C3-alkyl, Ci-C3-fluoroalkoxy;

R¹¹ is selected from the group consisting of hydrogen, Ci-C4-alkyl or benzyl.

4. A compound according to any one of the claims 1 to 5 of formula (lb)

in which

R¹ is selected from the group consisting of Ci-C6-alkyl, Ci-C6-cycloalkyl, C2-C6-alkenyl;

R⁴ is halogen, hydroxy, CN , Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy,

C(0)OH , C(0)0-Ci-C₆-alkyl, C(0)N H₂, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

R^5a and R^5b are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl; C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, aryl-cyclopropyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, hydroxy, d-Ce-alkyl, Ci-C₆-haloalkyl, Ci-C₆-alkoxy, Ci-C₆-haloalkoxy, C(0)OH, C(0)0-Ci-C₆-alkyl, CN , C(0)N H₂, S(0)₂-Ci-C₆-alkyl, S(0)₂N H₂, S(0)₂N(Ci-C6-alkyl)₂ in which the two alkyl groups are independent from each other;

is selected from the group consisting of Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl, C₂-C6-alkenyl, C₂-C6-alkynyl,

Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl, or heteroaryl-Ci-C6-alkyl- in which said cycloalkyi, aryl, heteroaryl group is optionally substituted up to three times with a halogen, hydroxy, an Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,

d-Ce-haloalkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, CN , C(0)N H₂, S(0)₂-Ci-C₆-alkyl, S(0)₂N H₂, S(0)₂N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other.

is selected from the group consisting of hydrogen, CN , C(0)R⁷, C(0)OR⁷, S(0)₂R¹⁰, C(0)N(R^5a)(R^5b), P(0)(OR¹¹ )₂, CH₂OP(OR¹¹ )₂, Ci-C₆-alkyl,

C3-C7-cycloalkyl, phenyl or heteroaryl, in which said Ci-C6-alkyl, C3-C7-cycloalkyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, CN ,

d-Cs-alkyl, Ci-C₃-alkoxy, N (R^5a)(R^5b), halo-Ci-C₃-alkyl or halo-Ci-C₃-alkoxy; is hydrogen, halogen, hydroxy, CN , Ci-C6-alkyl, halo-Ci-C6-alkyl, d-Ce-alkoxy, halo-Ci-Ce-alkoxy, C(0)OH , C(0)0-Ci-C₆-alkyl, C(0)N H₂, C(0)N H-Ci-C₆-alkyl, C(0)N(Ci-C₆-alkyl)₂ in which the two alkyl groups are independent from each other;

is selected from the group consisting of Ci-C6-alkyl, Ci-d-haloalkyl, d-d-cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, Ci-d-alkyl, Ci-d-alkoxy, N H₂, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-Ci-d-alkyl, Ci-d-fluoroalkoxy;

is selected from the group consisting of hydrogen, Ci-d-alkyl or benzyl.

5. A compound according to any one of the claims 1 to 4 characterized in that

R¹ is selected from the group consisting of hydrogen, Ci-C6-alkyl,

C3-C6-cycloalkyl;

6. A compound according to any one of the claims 1 to 5 characterized in that R^5b is a hydrogen atom;

A compound according to any one of the claims 1 to 6 characterized in that

R⁴ is a single group in para or meta position selected from the group consisting of halogen, Ci-C₄-alkoxy, halo-Ci-C₄-alkoxy, CN, C(0)NH₂.

A compound compound according to any one of the claims 1 to /characterized in that R^5a , R^5b or R⁶ are selected, independently from one another, from the group

consisting of hydrogen, aryl-Ci-C6-alkyl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with a halogen, or Ci-C6-haloalkyl;

A compound compound according to any one of the claims 1 to 8 characterized in that

R⁸ is selected from the group consisting of hydrogen, CN, C(0)R⁷ ,

-C(0)-halo-Ci-C₆-alkyl, -C(0)-Ci-C₆-alkyl;

A compound compound according to any one of the claims 1 to 9 characterized in that

R⁹ is hydrogen, halogen;

A compound according to claim 1 with the following formula:

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-4-fluoro-1 -[(4- fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'- thiopyran]-5-carboxamide 1 '-oxide

/V-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'- hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 '-[(trifluoroacetyl)imino]-1 ,2,2',3',5',6'-hexahydro-1 Ή- spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide

/V-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'- thiopyran]-5-carboxamide 1 '-oxide

2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[(trifluoroacetyl)imino]-/V-{[3-

(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'- thiopyran]-5-carboxamide 1 '-oxide 2-cyclopropyl-1 -[(4-fluorophenyl)sulfo

yl]methyl}-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide

2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 '- imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '- oxide

2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-N-[2-

(trifluoromethyl)benzyl]-1 _!2_!2\3\5\6'-hexahydro-1 'H-spiro[indole-3,4'-thiopyran]-5- carboxamide 1 '-oxide

2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 '-imino-N-{[3-

(trifluoromethyl)pyridin-2-yl]methyl}-1 _!2_!2'_!3'_!5'_!6'-hexahydro-1 'H-spiro[indole-3,4'- thiopyran]-5-carboxamide 1 '-oxide

N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-6-fluoro-1 -[(4- fluorophenyl)sulfonyl]-1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 'H-spiro[indole-3,4'- thiopyran]-5-carboxamide 1 '-oxide

2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-

(trifluoromethyl)pyridin-2-yl]methyl}-1 '-imino-1 ,2,2',3',5',6'-hexahydro-1 Ή- spiro[indole-3,4'-thiopyran]-5-carboxamide 1 '-oxide

12. A compound according to any one of the claims 1 to 15 for use as a medicament.

13. A compound according to any one of the claims 1 to 15 for use in the treatment of endometriosis, uterine leiomyoma (fibroids), polycystic ovarian disease, menorrhagia, dysmenorrhea, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrope pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception, infertility, assisted reproductive therapy such as in vitro fertilization, in the treatment of growth hormone deficiency and short stature, and in the treatment of systemic lupus erythematosus.

14. A compound according to any one of the claims 1 to 15 for use as contraceptive.

15. A pharmaceutical composition comprising a compound according to any one of the claims 1 to 15.