WO2015091315A1 - Spiro[indolin-3,4'-piperidine] derivatives as gnrh receptor antagonists - Google Patents

Spiro[indolin-3,4'-piperidine] derivatives as gnrh receptor antagonists Download PDF

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WO2015091315A1
WO2015091315A1 PCT/EP2014/077680 EP2014077680W WO2015091315A1 WO 2015091315 A1 WO2015091315 A1 WO 2015091315A1 EP 2014077680 W EP2014077680 W EP 2014077680W WO 2015091315 A1 WO2015091315 A1 WO 2015091315A1
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alkyl
indole
sulfonyl
dihydrospiro
fluorophenyl
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PCT/EP2014/077680
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French (fr)
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Olaf Panknin
Stefan BÄURLE
Sven Ring
Wolfgang Schwede
Norbert Schmees
Katrin NOWAK-REPPEL
Gernot Langer
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the present invention refers to spiroindoline-piperidine 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.
  • GnRH gonadotropin-releasing hormone
  • Gonadotropin-releasing hormone 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).
  • LHRH luteinizing hormone-releasing hormone
  • 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.
  • GnRH plays a key role in human reproduction.
  • 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').
  • 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 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
  • 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.
  • Spiroindoline derivatives 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
  • 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 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
  • compositions containing the same are provided.
  • Ci-C6-alkyl is selected from the group consisting of hydrogen, Ci-C6-alkyl, C3-Cio-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; Ci-C 6 -alkoxy-Ci-C 6 -alkyl, C 3 -C 6 -cycloalkyl-Ci-C 3 -alkyl;
  • N(H)C(0)OR 7 is selected from the group consisting of C(0)N(R 5a )(R 5b ), N(H)C(0)R 6 , N(H)C(0)N(R 5a )(R 5b ), or N(H)C(0)OR 7 ;
  • halogen is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C 6 -alkoxy, halo-Ci-C 6 -alkoxy, C(0)OH,
  • R 5b and R 6 are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-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, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted
  • Ci-C6-alkyl is selected from the group consisting of Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl, C 2 -C6-alkenyl, C 2 -C6-alkynyl,
  • C(0)R 10 is selected from the group consisting of C(0)R 10 , C(0)OR 1 1 ,
  • C 2 -C6-alkynyl C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyi, heteroaryl or heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH , C(0)0-Ci-C 6 -alkyl, CN , N (R 5a )(R 5b ), C(0)N(R 5c )(R 5d ),
  • Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, N H 2 , halogen, C(0)OH , Ci-C 4 -alkoxy, -N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other, aryloxy or heteroaryloxy, in which said aryloxy or heteroaryloxy group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
  • Ci-Ce-haloalkoxy C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 ,
  • Ci-Ce-haloalkoxy C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 ,
  • Ci-C6-alkyl is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl, aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C 6 -haloalkyl, Ci-C 6 -alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , C(0)NH-Ci-C 6 -alkyl, C(0)N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other,
  • Ci-C6-alkyl is Ci-C6-alkyl, Cs-Cs-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl or heteroaryl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl,
  • d-Ce-alkoxy, Ci-Ce-haloalkoxy C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , C(0)NH-Ci-C 6 -alkyl, C(0)N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other, 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.
  • a particular form of the invention refers to compounds according to formula (la)
  • R 1 is selected from the group consisting of hydrogen, Ci-C6-alkyl,
  • C3-Cio-cycloalkyl C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; Ci-C 6 -alkoxy-Ci-C 6 -alkyl, C 3 -C 6 -cycloalkyl-Ci-C 3 -alkyl;
  • R 4 is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C 6 -alkoxy, halo-Ci-C 6 -alkoxy, C(0)OH,
  • 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-C2-C6-alkyl;
  • R 5c and R 5d are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-C6-alkyl;
  • spirocycloalkyl, heterospirocycloalkyl, aryl and heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci- C6-haloalkyl,
  • R 8 is selected from the group consisting of C(0)R 10 , C(0)OR 11 ,
  • C 2 -C6-alkynyl C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyl, heteroaryl or heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH , C(0)0-Ci-C 6 -alkyl, CN , N (R 5a )(R 5b ), C(0)N(R 5c )(R 5d ),
  • R 9 is hydrogen oder halogen
  • R 10 is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy
  • C 2 -C6-alkenyl or C 2 -C6-alkinyl or aryl, heteroaryl, 3- to 10-membered heterocycloalkyl-Ci-C4-alkyl, aryl-Ci-C4-alkyl or heteroaryl-Ci-C4-alkyl, in which said aryl, heteroaryl or 3- to 10-membered heterocycloalkyl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
  • Ci-Ce-haloalkoxy C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , C(0)NH-Ci-C 6 -alkyl, C(0)N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other, S(0)2-Ci-C6-alkyl, S(0)2NH2,
  • R 11 is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl,
  • aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C 6 -haloalkyl, Ci-C 6 -alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , C(0)NH-Ci-C 6 -alkyl, C(0)N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other, S(0) 2 -Ci-C 6 -alkyl, S(0) 2 NH 2 , S(0) 2 N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other;
  • R 12 is Ci-C6-alkyl, Cs-Cs-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl or heteroaryl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , C(0)NH-Ci-C 6 -alkyl, C(0)N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other, S(0)2-Ci-C6-alkyl, S(0)2NH2,
  • a further particular form of the invention refers to compounds according to formula (lb)
  • halogen is selected from the group consisting of halogen, hydroxy, CN, Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C 6 -alkoxy, halo-Ci-C 6 -alkoxy, C(0)0-Ci-C 6 -alkyl,
  • R 5d are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-C6-alkyl;
  • heteroaryl-Ci-C6-alkyl- in which said cycloalkyi, heterocycloalkyi,
  • C(0)R 10 is selected from the group consisting of C(0)R 10 , C(0)OR 11 ,
  • C 2 -C6-alkynyl C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyi, heteroaryl or
  • heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, N(R 5a )(R 5b ), C(0)N(R 5c )(R 5d ),
  • Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, NH2, halogen, C(0)OH, Ci-C 4 -alkoxy, -N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other, aryloxy or heteroaryloxy, in which said aryloxy or heteroaryloxy group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
  • Ci-Ce-haloalkoxy C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 ,
  • C3-C8-cycloalkyl or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C 4 -alkyl,
  • Ci-Ce-haloalkoxy C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 ,
  • Ci-C6-alkyl is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl, aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C 6 -haloalkyl, Ci-C 6 -alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , C(0)NH-Ci-C 6 -alkyl, C(0)N(Ci-C 6 -alkyl) 2 in which the two alkyl groups are independent from each other,
  • Compounds according to the invention are the compounds of the formula (I), (la) or (lb) and the salts, solvates and solvates of the salts thereof, the compounds which are encompassed by formula (I), (la) or (lb) 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), (la) or (lb) 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), (la) or (lb) 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.
  • hydrochloric acid hydrobromic acid
  • sulfuric acid sulfuric acid
  • phosphoric acid methanesulfonic acid
  • ethanesulfonic acid toluenesulfonic 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.
  • alkali metal salts for example sodium, lithium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines such as illust
  • 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.
  • 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,
  • the compounds of the invention may occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • halogen is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
  • 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.
  • said group has 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl”), methyl, ethyl, n-propyl- or iso-propyl.
  • 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.
  • halogen atom is F.
  • Said halo-Ci-C6-alkyl group is, in particular -CF3, -CHF2, -CH2F, -CF2CF3, -CF2CH3, or -CH 2 CF 3 .
  • 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,
  • 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.
  • said halogen atom is F.
  • Said halo-Ci-C6-alkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH 2 CF 3 .
  • 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.
  • 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.
  • said halogen atom is F.
  • Said halo-Ci-C6-alkoxy-Ci-C6-alkyl group is, for example, -CH 2 CH 2 OCF 3 , -CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 2 F, -CH 2 CH 2 OCF 2 CF 3 , or - CH 2 CH 2 OCH 2 CF 3 .
  • Alkylcarbonyl in general represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which is bonded via a carbonyl group to the rest of the molecule and is represented for example also as C(0)-Ci-C6-alkyl.
  • Non-limiting examples include acetyl, propionyl, butyryl, isobutyryl, pivaloyl.
  • Alkoxycarbonyl in general represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which is bonded via a carbonyl group to the rest of the molecule and is represented for example also as C(0)0-Ci-C6-alkyl; illustratively and preferably an alkoxycarbonyl represents methoxycarbonyl, ethoxycarbonyl,
  • propoxycarbonyl isopropoxycarbonyl, butoxycarbonyl and ie f-butoxycarbonyl.
  • Alkylsulfonyl in general represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which is bonded via a sulfonyl (-S0 2 -) group to the rest of the molecule and is represented for example also as S(0) 2 -Ci-C6-alkyl.
  • Non- limiting examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, ie f-butylsulfonyl.
  • C 2 -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 (“C 2 -C3-alkenyl”), it being
  • 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,
  • 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,
  • alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-ynyl.
  • 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.
  • 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.
  • said ring can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said ring can contain 4 or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
  • Non-limiting examples include aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, sulfolanyl, 1 ,3-dioxolanyl, 1 ,3-oxazolidinyl,
  • Cs-Cn-spirocycloalkyl or "Cs-Cn-heterospirocycloalkyl” is to be understood as a bicyclic ring system with two rings connected through just one atom.
  • the connecting atom is a quaternary carbon atom.
  • Non-limiting examples include spiro[2,2]pentane, spiro[2,3]hexane, azaspiro[2.3]hexane, spiro[3,3]heptane, azaspiro[3,3]heptane,
  • 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.
  • 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.
  • 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, tria
  • Ci-C6-alkyl Ci-C6-haloalkyl
  • Ci-C6-alkoxy Ci-C6-haloalkoxy
  • ⁇ - ⁇ - ⁇ is to be interpreted as any sub-range comprised therein, e.g. C1-C6 , C2-C5 , C3-C4 , C1-C2, C1-C3 , C1-C4 ,
  • 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.
  • 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- C 5 ; particularly C2-C3.
  • 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.
  • 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".
  • a compound according to formula (la) according to the invention is one in which R 1 is selected from the group consisting of hydrogen, Ci-C6-alkyl,
  • C3-Cio-cycloalkyl C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; C 3 -C 6 -cycloalkyl-Ci-C 3 -alkyl;
  • R 4 is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C 6 -alkoxy, halo-Ci-C 6 -alkoxy, C(0)0-Ci-C 6 -alkyl,
  • R 5a and R 5b are selected, independently from one another, from the group consisting of hydrogen, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
  • Ci-C6-haloalkoxy substituted or unsubstituted aryl, C(0)OH,
  • C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , S(0) 2 -Ci-C 6 -alkyl, S(0) 2 NH 2 , S(0) 2 NH(Ci-C 6 -alkyl), S(0) 2 N heterocyclo-Ci-C 6 -alkyl;
  • R 9 is hydrogen oder halogen
  • R 8 is selected from the group consisting of C(0)R 10 , C(0)OR 11 , C(0)N(R 5c )(R 5d ), S(0) 2 R 12 , Ci-C6-alkyl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyl, or heteroaryl-Ci-C6-alkyl in which said alkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkoxy, C(0)OH , C(0)0-Ci-C 6 -alkyl, CN, N(R 5a )(R 5b ), C(0)N(R 5c )(R 5d );
  • R 10 is d-Ce-alkyl, NH 2 , C(0)OH, Ci-C 4 -alkoxy, or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl, or aryl, heteroaryl or aryl-Ci-C4-alkyl in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, Ci-C6-alkyl, d-Ce-haloalkyl or C(0)OH, C(0)0-Ci-C 6 -alkyl, C(0)N(R 5c )(R 5d );
  • R 11 is d-Ce-alkyl, hydroxy-C 2 -C 6 -alkyl
  • R 12 is Ci-Ce-alkyl.
  • a compound according to formula (la) is one in which
  • R 1 is selected from the group consisting of hydrogen, methyl, cyclopropyl,
  • R 4 is selected from the group consisting of F, CI, CF 3 , OCF 3 , OCF 2 H, CN, OCH 3 ;
  • R 5a and R 5b are selected, independently from one another, from the group consisting of hydrogen, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl,
  • aryl-Ci-C6-alkyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , S(0) 2 -Ci-C 6 -alkyl, S(0) 2 NH 2 , S(0) 2 NH(Ci-C 6 -alkyl), S(0) 2 N heterocyclo-Ci-C 6 -alkyl;
  • R 9 is hydrogen, fluorine or clorine
  • R 8 is selected from the group consisting of hydrogen or C(0)CH3;
  • a compound of formula (lb) according to the invention is one in which
  • R 1 is aC3-Cio-cycloalkyl group, particularly a cyclopropyl group
  • R 4 is a halogen, particularly a Fluorine atom in para position
  • R 6 is selected from the group consisting of aryl, aryl-Ci-C6-alkyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C 6 -alkyl, CN, C(0)NH 2 , S(0) 2 -Ci-C 6 -alkyl, S(0) 2 NH 2 ,
  • R 8 is selected from the group consisting of C(0)CH3;
  • R 9 is a hydrogen
  • R 1 is a cyclopropyl group
  • R 4 is a Fluorine atom in para position;
  • R 6 is an aryl group optionally substituted up to two times with a halogen, CN, d-Ce-haloalkyl,
  • R 8 is selected from the group consisting of C(0)CH3;
  • R 9 is a hydrogen
  • the group R 1 comprised in formula (I), (la) or (lb) is particularly selected from the group consisting of hydrogen, Ci-C6-alkyl, C3-C10- cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- Ci-C6-alkyl;
  • compounds according to formula (I), (la) or (lb) are more in particular those in which R 1 is selected from the group consisting of Ci-C6-alkyl and C3-Cio-cycloalkyl.
  • R 2 is a substituted phenyl group.
  • compounds according to formula (I), (la) or (lb) are more in particular those in which R 3 is selected from the group consisting of C(0)N(R 5a )(R 5b ), N(H)C(0)R 6 .
  • R 4 within formula (I), (la) or (lb) as an embodiment according to the invention is a halogen, a hydroxy, a CN , a Ci-C6-alkyl, a Ci-C6-alkoxy, halo-Ci-C6-alkoxy, a C(0)0-Ci-C6-alkyl or a C(0)N H 2 group.
  • a compound according to formula (I), (la) or (lb) of the present invention comprises, according to a further particular embodiment, R 2 being a phenyl group substituted in para with R 4 being a fluorine.
  • the group R 8 according to formula (I), (la) or (lb) is selected from the group consisting of C(0)R 10 , C(0)OR 1 1 , C(0)N(R 5c )(R 5d ),
  • compounds according to formula (I), (la) or (lb) are more in particular those in which R 10 is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, Nh , halogen, C(0)OH, Ci-C4-alkoxy,or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl, or aryl, heteroaryl, aryl-Ci-C4-alkyl in which said aryl, heteroaryl group is optionally substituted up to three times with halogen, Ci-C 6 -alkyl, or C(0)OH, C(0)0-Ci-C 6 -alkyl, C(0)N(R 5c )(R 5d );
  • d-Ce-alkyl, hydroxy-C 2 -C 6 -alkyl and R 12 is Ci-C 6 -alkyl.
  • forms of enbodiments according to the present invention comprise in particular compunds according to formula (la) in which R 1 is selected from the group consisting of methyl, ethyl, cyclopropyl, ethinyl and allyl; and R 4 is a fluorine, Ci-C6-alkoxy, C1-C6- haloalkoxy or C(0)OCi-C 6 -alkyl.
  • a compound according to formula (la) is defined in accordance to a specific form of embodiment of the invention by R 4 being in the para or meta position on the phenyl radical of formula (la), in particular R 4 is a fluorine in the para position on the phenyl radical of formula (la), or as further particular alternative R 4 being Ci-C6-alkoxy or C(0)0-Ci-C6-alkyl in meta position on the phenyl radical of formula (la).
  • Another embodiment of the present invention provides compounds according to general formula (I), (la) or (lb) and related specific embodiments for use as a medicament.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • the invention provides a pharmaceutical composition comprising a compound according to the invention, together with a pharmaceutically acceptable carrier.
  • 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) or (lb) are used as a medicament.
  • 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").
  • 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).
  • endometriosis uterine fibroids
  • polycystic ovarian disease hirsutism
  • precocious puberty gonadal steroid-dependent neoplasia
  • gonadotrope pituitary adenomas sleep apnea
  • sleep apnea irritable bowel syndrome
  • premenstrual syndrome benign prostatic hypertrophy
  • infertility e.g., assisted reproductive
  • 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
  • the compounds according to general formula (I), (la) or (lb) 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.
  • 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.
  • a GnRH receptor antagonist preferably in the form of a pharmaceutical composition
  • pharmaceutical compositions are disclosed containing one or more GnRH receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.
  • 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.
  • 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) or (lb) 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.
  • 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) or (lb).
  • esters may be employed, such as methyl esters, ethyl esters, and the like.
  • the compounds of general formula (I), (la) or (lb) 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) or (lb) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of general formula (I), (la) or (lb) 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.
  • 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.
  • compositions containing one or more GnRH receptor antagonists are disclosed.
  • 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.
  • 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.
  • 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.
  • a number of factors are considered by the attending clinician, including, but not limited to: the specific GnRH mediated disorder involved; pharmacodynamic
  • the particular agent and its mode and route of administration 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.
  • compositions formulated as liquid solutions 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.
  • 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.
  • 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.
  • "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.
  • systemic administration includes oral and parenteral methods of administration. For oral
  • 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.
  • 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.
  • GnRH receptor antagonists of this invention may be assayed by the general methods disclosed above, while the following examples disclose the synthesis of representative compounds of this invention.
  • 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 as integers, except for those cases in which
  • 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
  • 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.
  • chromatography particularly flash column chromatography
  • 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.
  • SP4 ® or Isolera Four ® Biotage autopurifier system
  • eluents such as gradients of hexane
  • 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.
  • 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.
  • 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.
  • a compound of general formula 7 may be synthesized according to the procedures depicted in Scheme 1 from a suitably functionalized amine of general formula 6 by reaction with an appropriate alkylating agent of the formula R 8 -L, where L is chloride, bromide, iodide or a sulfonate (e.g. mesylate or tosylate) or a similar leaving group in aprotic polar solvents, such as for example acetonitrile in the presence of an organic base such as diisopropylethylamine at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
  • an appropriate alkylating agent of the formula R 8 -L where L is chloride, bromide, iodide or a sulfonate (e.g. mesylate or tosylate) or a similar leaving group in aprotic polar solvents, such as for example acetonitrile in the presence of an organic base such as diisopropyle
  • a compound of formula 6 may be reacted with an aldehyde of the formula R-CHO in a suitable solvent such as for example THF or 1 ,2-dichloroethane, in the presence of a reducing agent such as for example sodium borohydride, sodium (triacetoxy)borohydride or sodium cyanoborohydride at temperatures between 0°C and the boiling point of the solvent, typically at room temperature to obtain compounds of formula 7 where R 8 is Ch -R.
  • Amines of general formula 6 are obtainable from a suitable precursor 5 by deprotection of the carbamate group. For deprotection of benzyloxycarbonyl (Cbz) groups all processes that are known to the person skilled in the art may be applied.
  • the Cbz- protected amine may be hydrogenated under an atmosphere of h at pressures between 1 bar and 100 bar, typically at 1 bar in protic polar solvents such as for example methanol or ethanol in the presence of a metal catalyst such as for example palladium on charcoal at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
  • a suitable acid such as for example hydrochloric acid or acetic acid may be necessary.
  • the Cbz group can be cleaved by reaction with a strong mineralic acid such as for example HBr or HI in protic polar solvents such as acetic acid at temperatures between -40°C and the boiling point of the solvent, typically at 0°C.
  • Amides of general formula 5 may be synthesized from aryl bromides of formula 4 by reaction with an appropriate amine HNR 5a R 5b (11 ) 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 4 can be reacted in a polar aprotic solvent such as for example dioxane with an appropriate amine in the presence of a CO source such as for example molybdenum hexacarbonyl or under a CO atmosphere 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. It might be necessary to add a ligand such as tri-tert-butylphosphonium tetrafluoroborate to the mixtur
  • a ligand such as tri-tert-butylphosphonium tetrafluoroborate
  • Scheme 1 General procedures for the preparation of compounds of general formulae 6 and 7; R 1 , R 2 , R 5a , R 5b , R 8 and R 9 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 R 3 is C(0)N(R 5a )(R 5b ).
  • amides of general formula 5 may be synthesized from suitably functionalized carboxylic acids of formula 9 by reaction with an appropriate amine HNR 5a R 5b (11 For amide formation, however, all processes that are known from peptide chemistry to the person skilled in the art may be applied.
  • the amine of general formula 6 can be reacted with an appropriate carboxylic acid in aprotic polar solvents, such as for example DMF, via an activated acid derivative, which is obtainable for example with hydroxybenzotriazole and a carbodiimide such as for example diisopropylcarbodiimide, at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature, 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.
  • aprotic polar solvents such as for example DMF
  • an activated acid derivative which is obtainable for example with hydroxybenzotriazole and a carbodiimide such as for example diisopropylcarbodiimide
  • preformed reagents such as for example 0-(7-azabenzotriazol-1 -
  • 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
  • azide which can be formed from a carboxylic acid by reaction with e.g. diphenylphosphorylazide.
  • Carboxylic acids of general formula 9 in turn may be obtained from carboxylic esters of formula 8 by saponification.
  • Carboxylic esters of general formula 8 may be synthesized from aryl bromides of formula 4 by reaction with an appropriate alcohol under palladium catalyzed carbonylation conditions.
  • Bromides of formula 4 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 bar 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.
  • a polar aprotic solvent such as for example dimethylsulfoxide
  • an appropriate alcohol such as methanol
  • a CO source such as for example molybdenum hexacarbonyl or under a CO atmosphere at pressures
  • Aryl bromides of formula 4 may be formed by the reaction of indolines 3 with a compound of formula R 2 -S(0)2-CI in an organic solvent such as dichloromethane or 1 ,2-dichloroethane in the presence of a tertiary amine base such as triethylamine or DIPEA and optionally in the presence of 4-dimethylaminopyridine at temperatures between room temperature and the boiling point of the solvent, typically at 80°C.
  • indolines of formula 4 may be reacted with electrophiles of formula R 2 -S02-CI without additional solvent in the presence of a tertiary base such as triethylamine or pyridine at room temperature to give aryl bromides of formula 4.
  • electrophiles R 2 -S02-CI are either commercially available, known compounds or may be formed from known compounds by known methods by a person skilled in the art.
  • Indolines of general formula 3 may be synthesized from suitably functionalized indolenines of general formula 2 by either reduction or addition of a nucleophile.
  • a nucleophile for reduction the indolenines 2 may be reacted in a suitable organic solvent such as for example methanol in the presence of a reducing agent such as for example sodium borohydride, sodium (triacetoxy)borohydride or sodium cyanoborohydride at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
  • a suitable organic solvent such as for example methanol
  • a reducing agent such as for example sodium borohydride, sodium (triacetoxy)borohydride or sodium cyanoborohydride at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
  • the indolenines 2 may be reacted in a suitable organic solvent such as for example THF with a nucleophile R 1 -M (where M is a metallic species; R 1 -M is for example a Grignard reagent) in the presence of a Lewis acid such as boron trifluoride diethyl etherate at temperatures between 0°C and room temperature.
  • a suitable organic solvent such as for example THF
  • R 1 -M is for example a Grignard reagent
  • Indolenines of general formula 2 may be synthesized from suitably functionalized carbonyl compound of general formula 1 by a condensation and subsequent cyclization reaction (Fischer indole synthesis) with a phenylhydrazine of general formula 10 in an organic solvent such as for example acetic acid or chloroform in the presence of a suitable acid such as for example hydrochloric acid or TFA at temperatures between 0°C and 150°C, typically at 100°C.
  • a condensation and subsequent cyclization reaction Fischer indole synthesis
  • a phenylhydrazine of general formula 10 in an organic solvent such as for example acetic acid or chloroform in the presence of a suitable acid such as for example hydrochloric acid or TFA at temperatures between 0°C and 150°C, typically at 100°C.
  • carbonyl compounds of general formula 1 and phenylhydrazines of general formula 10 are either commercially available, known compounds or may be formed from known compounds by known methods by a person skilled in the art.
  • anilines of general formula 14 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 R 3 is N(H)C(0)N(R 5a )(R 5b ).
  • a suitable organic solvent such as for example DMF
  • a tertiary amine base such as triethylamine or DIPEA
  • anilines of general formula 14 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 R 3 is N(H)C(0)OR 7 .
  • a suitable organic solvent such as for example THF
  • a tertiary amine base such as triethylamine or DIPEA
  • Anilines of general formula 14 can be obtained from nitroarenes of general formula 13 by reduction.
  • Nitroarenes 13 may be hydrogenated under an atmosphere of hydrogen at pressures between 1 bar and 100 bar in a suitable solvent such as for example ethyl acetate, methanol or ethanol or by leading hydrogen through the solution and in the presence of a metal catalyst such as for example palladium on charcoal at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
  • a suitable acid such as for example hydrochloric acid or acetic acid may be necessary.
  • Nitroarenes of general formula 13 can be synthesized from compounds of general formula 12 by regioselective nitration. For nitration, all processes that are known to the person skilled in the art may be applied. Compounds of formula 12 may be reacted with a mixture of concentrated nitric acid and sulfuric acid or with a mixture of concentrated nitric acid and acetic acid at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
  • Compounds of general formula 12 may be obtained from aryl bromides of general formula 4 by a two step protocol involving dehalogenation/deprotection and subsequent introduction of R 8 .
  • the bromides of formula 4 may be hydrogenated under an atmosphere of hydrogen at pressures between 1 bar and 100 bar in a suitable solvent such as for example ethyl acetate, tetrahydrofurane, methanol, ethanol or mixtures thereof or by leading hydrogen through the reaction mixture and in the presence of a metal catalyst such as for example palladium on charcoal at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
  • a metal catalyst such as for example palladium on charcoal at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
  • the introduction of R 8 was already described in the synthesis of 7 from 6 in Scheme 1.
  • Aryl bromides of general formula 4 are obtainable according to the procedures described in Scheme 1 .
  • anilines of general formula 14 can be obtained from carboxylic acids of general formula 15 by a two step protocol involving Curtius rearrangement followed by deprotection as shown in Scheme 3.
  • 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 16 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 14.
  • the protected aniline of general formula 16 can be obtained from carboxylic acids of general formula 15 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.
  • an organic solvent such as ie f-butanol
  • an azide source such as for example diphenylphosphoryl azide
  • an organic base such as for example triethylamine
  • indolines of general formulae 6, 7 and (I) may be chiral and may be separated into their diastereomers and/or enantiomers by chiral HPLC.
  • the synthesis of similar compounds is also described in WO 2013/107743.
  • the aryl bromide C.1 (19.4 g, 32.35 mmol) was placed in a steel autoclave under argon atmosphere and dissolved in a mixture of 680 ml methanol and 67 ml dimethyl sulfoxide. 4.63 g of trans-bis(triphenylphosphine) palladium(ll) dichloride and 10 ml triethylamine were added and the mixture was purged three times with carbon monoxide. The mixture was stirred for 30 min at 20°C under a carbon monoxide pressure of 1 1 .03 bar.
  • the autoclave was set under vacuum again, then a carbon monoxide pressure of 1 1 .08 bar was applied and the mixture heated to 100°C for -24 h, yielding a maximum pressure of 12.5 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 dissolved in dichloromethane.
  • the organic layer was dried with magnesium sulfate, concentrated in vacuo and the product purified by flash chromatography (S1O2- hexane/ethyl acetate). 17.1 g (91 %) E.1 were obtained.
  • F.2 In analogy to the preparation of F.1 from E.1, F.2 and F.3 were synthesized from H.1 and H.2. F.2:
  • G.2 was obtained in the same manner from E.3.
  • the aryl bromide C.1 (6.7 g, 1 1.1 mmol) was dissolved in a mixture of 150 ml ethanol and 50 ml tetrahydrofuran. 3.56 g palladium on charcoal (10% Pd/C; contains 50% of water) were added at rt and hydrogen gas was passed into the mixture until TLC indicated complete consumption of the starting material (2.5 h). The catalyst was filtered off and rinsed with ethanol and tetrahydrofuran. The filtrate was concentrated in vacuo and the residue partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with saturated sodium hydrogencarbonate solution and brine, dried with magnesium sulfate and concentrated in vacuo. The obtained product 1.1 (4.2 g, 98 %) was used in the next step without further purification.
  • Table 1 The following examples of table 1 were prepared in analogy to step 1 of example 1 .
  • Table 1 The following examples of table 1 were prepared in analogy to step 1 of example 1 .
  • Table 1 Table 1 :
  • Enantiomer 2 Rt in min 6.45
  • Table 2 The following examples of table 2 were prepared in analogy to example 224. Table 2:
  • Buserelin was purchased from Welding (Frankfurt/Main, Germany) or USbiological (#B8995, Swampscott, USA) for IP-One HTRF® assays and LHRH from Sigma-Aldrich® (Munich,
  • 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 [ 125 l]sodium iodide (2000 Ci/mmol; PerkinElmer Life and Analytical Sciences, USA) yielding [ 125 l]monoiodo-buserelin.
  • the radio-tracer was purified by reversed phase HPLC on a Spherisorb ODS II column (250 x 4 mm, particle size 3 ⁇ ) by elution with acetonitrile / water (34 : 66) containing 39 mM trifluoracetic acid at a flow rate of 1 mL / min.
  • HTRF time-resolved fluorescence resonance energy transfer
  • IP3 lnositol-1 ,4,5-triphosphate
  • IP1 lnositol-1 -phosphate
  • 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.
  • IP-One HTRF® assays reagents of Cisbio Bioassays (IP-One Tb Jumbo kit,
  • a cell suspension (3.33x10 6 cells/mL) containing IP1 -d2 (dilution 1 :40) was prepared and incubated at 37°C. After 1 h 3 ⁇ 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 ⁇ buserelin or LHRH (at ECso or ECso) in stimulation buffer
  • Plates were incubated for 1 h at 37°C and 5% carbon dioxide before the cells were lysed by adding 3 ⁇ 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).
  • HTRF reader e.g. a RUBYstar, PHERAstar (both BMG Labtechnologies, Offenburg, Germany) or a Viewlux (PerkinElmer LAS, Rodgau-Jijgesheim, Germany).
  • 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.

Abstract

Spiroindoline-piperidine derivatives of formula (I) as gonadotropin- releasing hormone (GnRH) receptor antagonists, 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

SPIRO[INDOLIN-3,4'-PIPERIDINE] DERIVATIVES AS GNRH RECEPTOR ANTAGONISTS
TECHNICAL FIELD
The present invention refers to spiroindoline-piperidine 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 cording to formula (I)
Figure imgf000005_0001
is selected from the group consisting of hydrogen, Ci-C6-alkyl, C3-Cio-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; Ci-C6-alkoxy-Ci-C6-alkyl, C3-C6-cycloalkyl-Ci-C3-alkyl;
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(R5a)(R5b), N(H)C(0)R6, N(H)C(0)N(R5a)(R5b), or N(H)C(0)OR7;
is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C6-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;
, R5b and R6 are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-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, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl; and R5d are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-C6-alkyl; C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, Cs-Cs-heterocycloalkyl, Cs-Cn-spirocycloalkyl, C5-Ci i-heterospirocycloalkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl, heteroaryl- Ci-C6-alkyl-, in which said cycloalkyi, heterocycloalkyi, spirocycloalkyl, heterospirocycloalkyi, aryl and heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl,
Ci-C6-alkoxy, Ci-C6-haloalkoxy substituted or unsubstituted aryl, 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)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
or are taken together with the nitrogen atom to form a cyclic group consisting of Cs-Cs-heterocycloalkyl or Cs-Cn-heterospirocycloalkyl;
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 C(0)R10, C(0)OR1 1 ,
C(0)N(R5c)(R5d), S(0)2R12, hydrogen, Ci-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyi, heteroaryl or heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH , C(0)0-Ci-C6-alkyl, CN , N (R5a)(R5b), C(0)N(R5c)(R5d),
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 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;
is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, N H2, halogen, C(0)OH , Ci-C4-alkoxy, -N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other, aryloxy or heteroaryloxy, in which said aryloxy or heteroaryloxy group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C3-C8-cycloalkyl or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl,
or C2-C6-alkenyl or C2-C6-alkinyl,
or aryl, heteroaryl, 3- to 10-membered heterocycloalkyl-Ci-C4-alkyl, aryl-Ci-C4-alkyl or heteroaryl-Ci-C4-alkyl, in which said aryl, heteroaryl or 3- to 10-membered heterocycloalkyl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl, aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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,
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 Ci-C6-alkyl, Cs-Cs-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl or heteroaryl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl,
d-Ce-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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.
A particular form of the invention refers to compounds according to formula (la)
8
Figure imgf000008_0001
(la)
in which
R1 is selected from the group consisting of hydrogen, Ci-C6-alkyl,
C3-Cio-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; Ci-C6-alkoxy-Ci-C6-alkyl, C3-C6-cycloalkyl-Ci-C3-alkyl;
R4 is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C6-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;
R5a and R5b are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-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, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
R5c and R5d are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-C6-alkyl;
C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, Cs-Cs-heterocycloalkyl, Cs-Cn-spirocycloalkyl, C5-Cii-heterospirocycloalkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl, heteroaryl-Ci-C6-alkyl-, in which said cycloalkyl, heterocycloalkyl,
spirocycloalkyl, heterospirocycloalkyl, aryl and heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci- C6-haloalkyl,
Ci-C6-alkoxy, Ci-C6-haloalkoxy substituted or unsubstituted aryl, 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)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
or are taken together with the nitrogen atom to form a cyclic group consisting of C3-C8-heterocycloalkyl or Cs-Cn-heterospirocycloalkyl;
R8 is selected from the group consisting of C(0)R10, C(0)OR11 ,
C(0)N(R5c)(R5d), S(0)2R12, hydrogen, Ci-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyl, heteroaryl or heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH , C(0)0-Ci-C6-alkyl, CN , N (R5a)(R5b), C(0)N(R5c)(R5d),
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;
R9 is hydrogen oder halogen;
R10 is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy,
N H2, halogen, C(0)OH ,
Ci-C4-alkoxy, -N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other, aryloxy or heteroaryloxy, in which said aryloxy or heteroaryloxy group is optionally substituted up to three times with halogen, hydroxy, C1-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,
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, 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,
or C3-C8-cycloalkyl or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl,
or C2-C6-alkenyl or C2-C6-alkinyl, or aryl, heteroaryl, 3- to 10-membered heterocycloalkyl-Ci-C4-alkyl, aryl-Ci-C4-alkyl or heteroaryl-Ci-C4-alkyl, in which said aryl, heteroaryl or 3- to 10-membered heterocycloalkyl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
R11 is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl,
aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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;
R12 is Ci-C6-alkyl, Cs-Cs-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl or heteroaryl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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.
A further particular form of the invention refers to compounds according to formula (lb)
Figure imgf000010_0001
is selected from the group consisting of C3-Cio-cycloalkyl;
is selected from the group consisting of halogen, hydroxy, CN, Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C(0)0-Ci-C6-alkyl,
C(0)NH2;
and R5d are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-C6-alkyl;
C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, Cs-Cs-heterocycloalkyl, Cs-Cn-spirocycloalkyl, C5-Cii-heterospirocycloalkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl,
heteroaryl-Ci-C6-alkyl-, in which said cycloalkyi, heterocycloalkyi,
spirocycloalkyl, heterospirocycloalkyl, aryl and heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
or are taken together with the nitrogen atom to form a cyclic group consisting of Cs-Cs-heterocycloalkyl or Cs-Cn-heterospirocycloalkyl;
is selected from the group consisting of aryl, aryl-Ci-C6-alkyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyi, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci- C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
is selected from the group consisting of C(0)R10, C(0)OR11,
C(0)N(R5c)(R5d), S(0)2R12, hydrogen, Ci-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyi, heteroaryl or
heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, N(R5a)(R5b), C(0)N(R5c)(R5d),
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 hydrogen oder halogen; is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, NH2, halogen, C(0)OH, Ci-C4-alkoxy, -N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other, aryloxy or heteroaryloxy, in which said aryloxy or heteroaryloxy group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C3-C8-cycloalkyl or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl,
or C2-C6-alkenyl or C2-C6-alkinyl,
or aryl, heteroaryl, 3- to 10-membered heterocycloalkyl-Ci-C4-alkyl, aryl-Ci-C4-alkyl or heteroaryl-Ci-C4-alkyl, in which said aryl, heteroaryl or 3- to 10-membered heterocycloalkyl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl, aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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,
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 Ci-C6-alkyl, Cs-Cs-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl or heteroaryl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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. Compounds according to the invention are the compounds of the formula (I), (la) or (lb) and the salts, solvates and solvates of the salts thereof, the compounds which are encompassed by formula (I), (la) or (lb) 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), (la) or (lb) 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), (la) or (lb) 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 - CH2CH2OCH2CF3. Alkylcarbonyl in general represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which is bonded via a carbonyl group to the rest of the molecule and is represented for example also as C(0)-Ci-C6-alkyl. Non-limiting examples include acetyl, propionyl, butyryl, isobutyryl, pivaloyl. Alkoxycarbonyl in general represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which is bonded via a carbonyl group to the rest of the molecule and is represented for example also as C(0)0-Ci-C6-alkyl; illustratively and preferably an alkoxycarbonyl represents methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and ie f-butoxycarbonyl.
Alkylsulfonyl in general represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, which is bonded via a sulfonyl (-S02-) group to the rest of the molecule and is represented for example also as S(0)2-Ci-C6-alkyl. Non- limiting examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, ie f-butylsulfonyl.
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 "3- to 10-membered heterocycloalkyl" is to be understood as preferably meaning a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, NH, NR', wherein R' represents a d-Ce-alkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C(=0)R10, C(0)N(R5a)(R5b), -S(=0)2R12, -S(=0)2 N(R5a)(R5b) group as defined supra, it being understood that when said R' represents a C3-C6 heterocycloalkyl group, then said C3-C6 heterocycloalkyl group is present only once. Particularly, said ring can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said ring can contain 4 or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
Non-limiting examples include aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, sulfolanyl, 1 ,3-dioxolanyl, 1 ,3-oxazolidinyl,
1 ,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
1 .3- dioxanyl,1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 -dioxidothiomorpholinyl, perhydro-azepinyl, perhydro-1 ,4-diazepinyl, perhydro-1 ,4-oxazepinyl, perhydroazocinyl, octahydropyrrolo-[3,4-b]pyrrolyl, octahydroisoindolyl, octahydropyrrolo[3,4-b]pyridyl, octahydropyrrolo[1 ,2-a]pyrazinyl, decahydroisochinolinyl, 7-azabicyclo[2.2.1]heptyl,
3-azabicyclo[3.2.0]heptyl, 7-azabicyclo-[4.1.0]heptyl, 2,5-diazabicyclo[2.2.1]heptyl,
2-oxa-5-azabicyclo[2.2.1 ]heptyl, 2-azabicyclo-[2.2.2]octyl, 3-azabicyclo[3.2.1 ]octyl,
8-azabicyclo[3.2.1 ]octyl, 8-oxa-3-azabicyclo[3.2.1 ]octyl, 3-oxa-9-azabicyclo[3.3.1 ]nonyl. Particular preference is given to 5- to 7-membered monocyclic heterocycloalkyl radicals having up to 2 heteroatoms selected from the group consisting of N, O and S, such as illustratively and preferably tetrahydrofuranyl, 1 ,3-dioxolanyl, pyrrolidinyl, tetrahydropyranyl,
1 .4- dioxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, perhydro- azepinyl, perhydro-1 ,4-diazepinyl and perhydro-1 ,4-oxazepinyl. The term "Cs-Cn-spirocycloalkyl" or "Cs-Cn-heterospirocycloalkyl" is to be understood as a bicyclic ring system with two rings connected through just one atom. The rings can be different or identical and can contain 4, 5, 6, 7, 8, 9, 10 or 1 1 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, NH, NR', wherein R' represents a Ci-C6-alkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C(=0)R10,
C(0)N(R5a)(R5b), -S(=0)2R12, -S(=0)2 N(R5a)(R5b) group as defined supra. The connecting atom is a quaternary carbon atom. Non-limiting examples include spiro[2,2]pentane, spiro[2,3]hexane, azaspiro[2.3]hexane, spiro[3,3]heptane, azaspiro[3,3]heptane,
oxaazaspiro[3.3]heptane, thiaazaspiro[3,3]heptane, oxaspiro[3,3]heptane,
oxazaspiro[5,3]nonane, oxazaspiro[4,3]oktane, oxazaspiro[5,5]undekane,
diazaspiro[3,3]heptane, thiazaspiro[3,3]heptane, thiazaspiro[4,3]oktane, azaspiro[5,5]dekane, and the homologe spiro[3,4]-, spiro[4,4]-, spiro[5,5]-, spiro[6,6]-, spiro[2,4]-, spiro[2,5]-, spiro[2,6]-, spiro[3,5]-, spiro[3,6]-, spiro[4,5]-, spiro[4,6]- and spiro[5,6]-systems inclusive the heteroatom-containing group variants.
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 "C14- 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 a compound according to formula (la) according to the invention is one in which R1 is selected from the group consisting of hydrogen, Ci-C6-alkyl,
C3-Cio-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; C3-C6-cycloalkyl-Ci-C3-alkyl;
R4 is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C(0)0-Ci-C6-alkyl,
C(0)NH2;
R5a and R5b are selected, independently from one another, from the group consisting of hydrogen, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH,
C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N=heterocyclo-Ci-C6-alkyl;
R5c and R5d are selected, independently from one another, from the group consisting of hydrogen, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-dr alkyl-, heteroaryl, heteroaryl-Ci-C6-alkyl-, in which said cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyl, aryl and heteroaryl groups are optionally substituted up to three times with halogen, Ci-C6-alkyl, d-Ce-haloalkyl, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, S(0)2N=heterocyclo-Ci-C6-alkyl;or are taken together with the nitrogen atom to form a cyclic group consisting of d-Cs-heterocycloalkyl or
C5-Cii-heterospirocycloalkyl;
R9 is hydrogen oder halogen;
R8 is selected from the group consisting of C(0)R10, C(0)OR11 , C(0)N(R5c)(R5d), S(0)2R12, Ci-C6-alkyl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyl, or heteroaryl-Ci-C6-alkyl in which said alkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkoxy, C(0)OH , C(0)0-Ci-C6-alkyl, CN, N(R5a)(R5b), C(0)N(R5c)(R5d);
R10 is d-Ce-alkyl, NH2, C(0)OH, Ci-C4-alkoxy, or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl, or aryl, heteroaryl or aryl-Ci-C4-alkyl in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, Ci-C6-alkyl, d-Ce-haloalkyl or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
R11 is d-Ce-alkyl, hydroxy-C2-C6-alkyl;
R12 is Ci-Ce-alkyl.
According to a further particular form of embodiment of the invention a compound according to formula (la) is one in which
R1 is selected from the group consisting of hydrogen, methyl, cyclopropyl,
cyclobutyl, prop-1 -en-1 -yl, prop-2-en-1 -yl, 3-methylbut-2-en-1 -yl R4 is selected from the group consisting of F, CI, CF3, OCF3, OCF2H, CN, OCH3; R5a and R5b are selected, independently from one another, from the group consisting of hydrogen, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl,
aryl-Ci-C6-alkyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N=heterocyclo-Ci-C6-alkyl;
R9 is hydrogen, fluorine or clorine;
R8 is selected from the group consisting of hydrogen or C(0)CH3;
A compound of formula (lb) according to the invention is one in which
R1 is aC3-Cio-cycloalkyl group, particularly a cyclopropyl group;
R4 is a halogen, particularly a Fluorine atom in para position;
R6 is selected from the group consisting of aryl, aryl-Ci-C6-alkyl, heteroaryl, heteroaryl-Ci-C6-alkyl, in which said cycloalkyl, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2,
S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
R8 is selected from the group consisting of C(0)CH3;
R9 is a hydrogen;
A compound according to claim 1 of formula (lb) in which
R1 is a cyclopropyl group;
R4 is a Fluorine atom in para position; R6 is an aryl group optionally substituted up to two times with a halogen, CN, d-Ce-haloalkyl,
R8 is selected from the group consisting of C(0)CH3;
R9 is a hydrogen;
In a compound according to the present invention the group R1 comprised in formula (I), (la) or (lb) is particularly selected from the group consisting of hydrogen, Ci-C6-alkyl, C3-C10- cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- Ci-C6-alkyl;
C3-C6-cycloalkyl-Ci-C3-alkyl
In conjunction with the above or below definitions and embodiments, compounds according to formula (I), (la) or (lb) are more in particular those in which R1 is selected from the group consisting of Ci-C6-alkyl and C3-Cio-cycloalkyl. Furthermore, for compounds according to formula (I), (la) or (lb) as a particular embodiment according to the invention R2 is a substituted phenyl group.
In conjunction with the above or below definitions and embodiments, compounds according to formula (I), (la) or (lb) are more in particular those in which R3 is selected from the group consisting of C(0)N(R5a)(R5b), N(H)C(0)R6.
R4 within formula (I), (la) or (lb) as an embodiment according to the invention is a halogen, a hydroxy, a CN , a Ci-C6-alkyl, a Ci-C6-alkoxy, halo-Ci-C6-alkoxy, a C(0)0-Ci-C6-alkyl or a C(0)N H2 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. In a compound according to the present invention the group R8 according to formula (I), (la) or (lb) is selected from the group consisting of C(0)R10, C(0)OR1 1 , C(0)N(R5c)(R5d),
S(0)2R12, Ci-C6-alkyl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyl, heteroaryl-Ci-C6- alkyl in which said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkoxy, C(0)OH , C(0)0-Ci-C6- alkyl, CN , N (R5a)(R5b), C(0)N(R5c)(R5d; In conjunction with the above or below definitions and embodiments, compounds according to formula (I), (la) or (lb) are more in particular those in which R9 is hydrogen oder halogen.
Furthermore, in conjunction with the above or below definitions and embodiments, compounds according to formula (I), (la) or (lb) are more in particular those in which R10 is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, Nh , halogen, C(0)OH, Ci-C4-alkoxy,or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl, or aryl, heteroaryl, aryl-Ci-C4-alkyl in which said aryl, heteroaryl group is optionally substituted up to three times with halogen, Ci-C6-alkyl, or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
In conjunction with the above or below definitions and embodiments, compounds according to formula (I), (la) or (lb) are more in particular those in which R11 is
d-Ce-alkyl, hydroxy-C2-C6-alkyl and R12 is Ci-C6-alkyl.
Furthermore forms of enbodiments according to the present invention comprise in particular compunds according to formula (la) in which R1 is selected from the group consisting of methyl, ethyl, cyclopropyl, ethinyl and allyl; and R4 is a fluorine, Ci-C6-alkoxy, C1-C6- haloalkoxy or C(0)OCi-C6-alkyl.
A compound according to formula (la) is defined in accordance to a specific form of embodiment of the invention by R4 being in the para or meta position on the phenyl radical of formula (la), in particular R4 is a fluorine in the para position on the phenyl radical of formula (la), or as further particular alternative R4 being Ci-C6-alkoxy or C(0)0-Ci-C6-alkyl in meta position on the phenyl radical of formula (la).
Compounds according to the invention are:
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-benzyl-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-N-[2-(trifluoromethyl)benzyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-6-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-6-fluoro-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-4-chloro-2-cyclopropyl-N-(2,3-dichlorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-2-cyclopropyl-N-(2,3-dichlorophenyl)-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-N-(3-chloro-2-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(3-chloro-2-fluorophenyl)-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-2-cyclopropyl-N-(2,3-difluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-(2,3-difluorophenyl)-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-2-cyclopropyl-N-(2-fluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-N-(4-chloropyridin-3-yl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-N-[2-(trifluoromethyl)benzyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-4-fluoro-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
'-acetyl-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
'-acetyl-4-chloro-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(4-methylpyridin-2-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-N-(5-chloro-2-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-(2,5-dichloropyridin-3-yl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chloro-5-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-(2,5-difluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(6-methylpyridin-2-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[3-(tert-butylsulfamoyl)phenyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{3-[(5-methyl-1 ,2-oxazol-3- yl)sulfamoyl]phenyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-2-cyclopropyl-N-(2,3-dichlorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(3-chloro-2-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chloro-3-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-(2,3-difluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-(2-fluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-(3,4-dihydro-2H-chromen-4-yl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(1 ,2-oxazol-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(5-methylpyridin-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(5-chloropyridin-3-yl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(4-chloropyridin-3-yl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(1 ,3-oxazol-2-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -{[3-(difluoromethoxy)phenyl]sulfonyl}-N-[2-(trifluoromethyl)benzyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -{[3-(difluoromethoxy)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(2-hydroxybenzyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -{[3-
(difluoromethoxy)phenyl]sulfonyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-1 -[(3-cyanophenyl)sulfonyl]-2-cyclopropyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-[(3-fluoropyridin-2-yl)methyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(5-methylpyridin-3-yl)-1 '-(pyrazin-2-ylcarbonyl)- 1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{3-[(1 -methylpyrrolidin-2- ylidene)sulfamoyl]phenyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide Methyl-3-{[(1 '-acetyl-2-cyclopropyl-1 -{[3-(difluoromethoxy)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidin]-5-yl)carbonyl]amino}benzoate
1 '-acetyl-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-N-[2-(trifluoromethyl)benzyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]methyl}-1 -[(3- methoxyphenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-N-{[3-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-N-[2-(trifluoromethyl)benzyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-(2-chlorobenzoyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-(trifluoromethyl)pyridi yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyridin-2-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyridin-3-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[(2-chloropyridin-3-yl)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[(4-chloropyridin-3-yl)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
N-(5-chloropyridin-3-yl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrazin-2-ylcarbonyl)-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]
1 '-(pyrazin-2-ylcarbonyl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrazin-2-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
N-[(3-chloropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrazin-2- ylcarbonyl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrimidin-5-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[(3-chloropyridin-2-yl)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrimidin-2-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[(3-chloropyrazin-2-yl)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(1 ,3-thiazol-2-ylcarbonyl)-N-{[3- (trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dih^
carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(1 ,3-oxazol-2-ylcarbonyl)-N-{[3- (trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
N-benzyl-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide hydrobromide (1 :1 )
N-(2-cyanobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(3-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide hydrobromide (1 :1 )
N-(2-cyanobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 -[(4-fluorophenyl)sulfonyl]-2-methyl-N-[2-(trifluoromethyl)benzyl]-1 ,2-dihydrospiro[ind
3,4'-piperidine]-5-carboxamide
formic acid - N-(2-chlorobenzyl)-1 -[(4-hydroxyphenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide (1 :1 )
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -(phenylsulfonyl)-l ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-acetyl-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2-dihydrospiro[indole- 3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(4-fluorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole- 3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -{[4-(trifluoromethoxy)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(2-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole- 3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(3-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole- 3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(2-chlorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole- 3,4'-piperidine]-5-carboxamide 1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -{[2-(trifluoromethyl)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -{[3-(trifluoromethyl)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -{[4-(trifluoromethyl)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(2,4-difluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(3-chloro-4-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
methyl 3-({1 '-acetyl-5-[(2-chlorobenzyl)carbamoyl]-2-methylspiro[indole-3,4'-piperidin]-1 (2H)- yl}sulfonyl)benzoate
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -(pyridin-3-ylsulfonyl)-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-acetyl-2-methyl-1 -(pyridin-3-ylsulfonyl)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -[(1 -methyl-1 H-pyrazol-4-yl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -[(1 -methyl-1 H-imidazol-4-yl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-(methoxyacetyl)-l -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-benzoyl-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 '-(phenylacetyl)-l ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-(2,2-dimethylpropanoyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
methyl {1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-5-[(2-methylbenzyl)carbamoyl]-1 ,2-dihydro- 1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
{1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-5-[(2-methylbenzyl)carbamoyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid {5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
methyl {5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetate
{5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-3,4'- piperidin]-1 '-yl}acetic acid
1 '-benzyl-N-(2-fluorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-benzyl-N-(2-cyanobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole- 3,4'-piperidine]-5-carboxamide
methyl 1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-5-[(2-methylbenzyl)carbamoyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate
2-hydroxyethyl 5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N5-(2-methylbenzyl)-N1 '-phenyl-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
N1 '-cyclohexyl-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N5-(2-methylbenzyl)-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 '-(methylsulfonyl)-l ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(3-methylbut-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-1 -[(4-fluorophenyl)sulfonyl]-2-(3-methylbut-2-en-1 -yl)-N-{[3-(trifluoromethyl)pyridin-
2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-1 -[(4-fluorophenyl)sulfonyl]-2-(3-methylbut-2-en-1 - yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-[2-(4-fluorophenyl)propan-2-yl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[1 -(4-chlorophenyl)cyclopropyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(3-methylphenyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-[3-(methylsulfonyl)phenyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(3-sulfamoylphenyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-N-(3-chlorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chloro-4-fluorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(cyclohexylmethyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-benzyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-acetyl-1 -[(3-carbamoylphenyl)sulfonyl]-N-(2-chlorobenzyl)-2-cyclopropyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(3-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloro-5-fluoropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-[(3-methylpyridin-2-yl)methyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-ethenyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-(cyclopropylmethyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-1 -[(4-fluorophenyl)sulfonyl]-N-[(3-methylpyridin-2-yl)methyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-1 -[(4-fluorophenyl)sulfonyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(2-hydroxyethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(hydroxymethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-N-[2-(4-fluorophenyl)propan-2-yl]-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[(3-methyloxetan-3- yl)carbonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[(1 ,5-dimethyl-1 H-pyrazol-3-yl)carbonyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 -[(4-fluorophenyl)sulfonyl]-N-[(3-methylpyridin-2-yl)methyl]-1 '-(oxetan-3-yl)-2-(prop-2-en-1 - yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 -[(4-fluorophenyl)sulfonyl]-N-[(3-methylpyridin-2-yl)methyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N 2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-N1 \N1 \2-trimethyl-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 '-(pyrrolidin-1 -ylcarbonyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 '-(morpholin-4-ylcarbonyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N5-(2-chlorobenzyl)-N1 '-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
N-(4-fluorobenzyl)-2-methyl-1 -[(1 -methyl-1 H-pyrazol-5-yl)sulfonyl]-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-cyanophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-methyl-1 -[(1 -methyl-1 H-pyrazol-5-yl)sulfonyl]-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-[(1 E)-prop-1 -en-1 -yl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[2-(diethylamino)ethyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[(ethylamino)(oxo)acetyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[3-(ethylamino)-3-oxopropyl]-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 '-[2-(ethylamino)-2-oxoethyl]-1 -[(4-fluorophenyl)sulfonyl]-N-[2-
(trifluoromethyl)benzyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[2-(ethylamino)-2-oxoethyl]-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 2-cyclopropyl-1 '-[2-(ethylamino)-2-oxoethyl]-N-(2-fluorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
ethyl {5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}(oxo)acetate
ethyl {5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
N-(2-chlorobenzyl)-1 -[(4-cyanophenyl)sulfonyl]-2-cyclopropyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[2-(dimethylamino)-2-oxoethyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide methyl {5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetate
methyl (2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-5-{[2-(trifluoromethyl)benzyl]carbamoyl}-
1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl)acetate
methyl {5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
methyl {2-cyclopropyl-5-[(2-fluorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
methyl {5-[(2-chlorobenzyl)carbamoyl]-2-cyclobutyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro- 1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-[2-(trifluoromethyl)benzyl]-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-methoxyphenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-methoxyphenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide hydrobromide (1 :1 )
N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-phenyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-[(1 E)-prop-1 -en-1 -yl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-[(1 E)-prop-1 -en-1 -yl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-[(1 E)-prop-1 -en-1 -yl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide hydrobromide (1 :1 )
1 '-acetyl-N-(2-chloro-4-fluorobenzyl)-1 -[(3-cyano-4-methoxyphenyl)sulfonyl]-2-cyclopropyl-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(3-cyano-4-methoxyphenyl)sulfonyl]-2-cyclopropyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-1 -[(3-cyano-4-methoxyphenyl)sulfonyl]-2- cyclopropyl-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chloro-4-fluorobenzyl)-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N (2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(2-methoxyethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N (2-chlorobenzyl)-1 '-(cyanomethyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N (2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[2-(2-oxa-6- azaspiro[3.3]hept-6-yl)-2-oxoethyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 ' [2-(azetidin-1 -yl)-2-oxoethyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-[2-
(trifluoromethyl)benzyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
[2-(azetidin-1 -yl)-2-oxoethyl]-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
[2-(azetidin-1 -yl)-2-oxoethyl]-2-cyclopropyl-N-(2-fluorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N (2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[2-(morpholin-4-yl)-2- oxoethyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
[azetidin-1 -yl(oxo)acetyl]-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N (2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrazin-2-ylcarbonyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N (2-chloro-4-fluorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N (2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-N-{[3-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-[(3-chloropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(1 H-tetrazol-5-ylmethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 '-(2-cyanoethyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-benzyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-[2-(azetidin-1 -yl)-2-oxoethyl]-N-(2-chlorobenzyl)-2-cyclobutyl-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclobutyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-ethenyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-[(3-chloropyridin-2-yl)methyl]-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-2-(prop-2-en-1 - yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(prop-2-en-1 -yl)-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
N-[(3-chloropyridin-2-yl)methyl]-1 -[(4-fluorophenyl)sulfonyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-(but-3-en-1 -yl)-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N5-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-
3,4'-piperidine]-1 ',5-dicarboxamide
2-amino-4-{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}-4-oxobutanoic acid
1 '-(2-aminoethyl)-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}(oxo)acetic acid
5-{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}pentanoic acid 4-{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidin]-1 '-yl}butanoic acid
3-{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidin]-1 '-yl}propanoic acid
(2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-5-{[2-(trifluoromethyl)benzyl]carbamoyl}-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl)acetic acid
{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
{2-cyclopropyl-5-[(2-fluorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
{5-[(2-chlorobenzyl)carbamoyl]-2-cyclobutyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
{2-cyclobutyl-5-[(2-fluorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(2-hydroxyethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]-
5-yl}-2-chloro-5-fluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]- 5-yl}-2,6-difluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]-
5-yl}-5-fluoro-2-(trifluoromethyl)benzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]-
5-yl}-2,5-difluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]-
5-yl}-3-cyanobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]-
5-yl}-3-(trifluoromethyl)benzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]- 5-yl}-3-(difluoromethyl)benzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]-
5-yl}-3-chlorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]-
5-yl}-3-fluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]- 5-yl}-3-fluoro-2-(trifluoromethyl)benzamide N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-2-chloro-3-fluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-2-(difluoromethyl)benzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-2-chlorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-2-fluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]- 5-yl}pyridine-3-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-2-(difluoromethyl)pyridine-3-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-2-chloronicotinamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-1 ,2-thiazole-5-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-1 ,2-oxazole-3-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]- 5-yl}-5-methylnicotinamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-5-(trifluoromethyl)nicotinamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}pyrimidine-5-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-1 ,3-thiazole-5-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-1 ,2-thiazole-4-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]- 5-yl}-1 ,3-oxazole-4-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-1 ,3-thiazole-4-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4 -piperidin]-
5-yl}-1 ,3-thiazole-2-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- ,2-dihydrospiro[indole-3,4'-piperidin]
5-yl}-1 ,3-oxazole-2-carboxamide N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]-
5-yl}-1 ,2-oxazole-5-carboxamide
methyl 3-({1 '-acetyl-5-[(cyclohexylcarbonyl)amino]-2-cyclopropylspiro[indole-3,4'-piperidin]-
1 (2H)-yl}sulfonyl)benzoate
3-({1 '-acetyl-5-[(cyclohexylcarbonyl)amino]-2-cyclopropylspiro[indole-3,4'-piperidin]-1 (2H)- yl}sulfonyl)benzamide
N-{1 '-acetyl-1 -[(3-carbamoylphenyl)sulfonyl]-2-cyclopropyl-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-2,5-difluorobenzamide Another embodiment of the present invention provides compounds according to general formula (I), (la) or (lb) 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) or (lb) 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) or (lb) 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) or (lb) 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) or (lb) 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) or (lb) 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) or (lb) 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) or (lb). 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) or (lb) 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) or (lb) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of general formula (I), (la) or (lb) 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 assayed 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.
Figure imgf000044_0001
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 as integers, except for those cases in which
atropisomerism was observed. Then non integer numbers were used; signals are marked with an asterisk (*), for example (0.5H*).
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 Acquity 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
Analytical characterization of enantiomers was performed by analytical chiral HPLC. 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, R5a, R5b, R6, R7, R8, R9, R10, R11 and R12 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 7.1 1/. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).
A compound of general formula 7 may be synthesized according to the procedures depicted in Scheme 1 from a suitably functionalized amine of general formula 6 by reaction with an appropriate alkylating agent of the formula R8-L, where L is chloride, bromide, iodide or a sulfonate (e.g. mesylate or tosylate) or a similar leaving group in aprotic polar solvents, such as for example acetonitrile in the presence of an organic base such as diisopropylethylamine at temperatures between 0°C and the boiling point of the solvent, typically at room temperature. Alternatively, a compound of formula 6 may be reacted with an aldehyde of the formula R-CHO in a suitable solvent such as for example THF or 1 ,2-dichloroethane, in the presence of a reducing agent such as for example sodium borohydride, sodium (triacetoxy)borohydride or sodium cyanoborohydride at temperatures between 0°C and the boiling point of the solvent, typically at room temperature to obtain compounds of formula 7 where R8 is Ch -R. Amines of general formula 6 are obtainable from a suitable precursor 5 by deprotection of the carbamate group. For deprotection of benzyloxycarbonyl (Cbz) groups all processes that are known to the person skilled in the art may be applied. The Cbz- protected amine may be hydrogenated under an atmosphere of h at pressures between 1 bar and 100 bar, typically at 1 bar in protic polar solvents such as for example methanol or ethanol in the presence of a metal catalyst such as for example palladium on charcoal at temperatures between 0°C and the boiling point of the solvent, typically at room temperature. The addition of a suitable acid such as for example hydrochloric acid or acetic acid may be necessary. Alternatively, the Cbz group can be cleaved by reaction with a strong mineralic acid such as for example HBr or HI in protic polar solvents such as acetic acid at temperatures between -40°C and the boiling point of the solvent, typically at 0°C.
Amides of general formula 5 may be synthesized from aryl bromides of formula 4 by reaction with an appropriate amine HNR5aR5b (11 ) 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 4 can be reacted in a polar aprotic solvent such as for example dioxane with an appropriate amine in the presence of a CO source such as for example molybdenum hexacarbonyl or under a CO atmosphere 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. It might be necessary to add a ligand such as tri-tert-butylphosphonium tetrafluoroborate to the mixtur
Figure imgf000048_0001
Scheme 1 : General procedures for the preparation of compounds of general formulae 6 and 7; R1, R2, R5a, R5b, 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 C(0)N(R5a)(R5b). Alternatively, amides of general formula 5 may be synthesized from suitably functionalized carboxylic acids of formula 9 by reaction with an appropriate amine HNR5aR5b (11 For amide formation, however, all processes that are known from peptide chemistry to the person skilled in the art may be applied. The amine of general formula 6 can be reacted with an appropriate carboxylic acid in aprotic polar solvents, such as for example DMF, via an activated acid derivative, which is obtainable for example with hydroxybenzotriazole and a carbodiimide such as for example diisopropylcarbodiimide, at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature, 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), at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature, or else with activating agents such as dicyclohexylcarbodiimide / Ν,Ν-dimethylaminopyridine or N-ethyl- Ν',Ν'-dimethylaminopropylcarbodiimide / Ν,Ν-dimethylaminopyridine. The addition of a suitable base such as for example N-methylmorpholine, TEA or DIPEA may be necessary. 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 9 in turn may be obtained from carboxylic esters of formula 8 by saponification.
Carboxylic esters of general formula 8 may be synthesized from aryl bromides of formula 4 by reaction with an appropriate alcohol under palladium catalyzed carbonylation conditions. Bromides of formula 4 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 bar 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.
Aryl bromides of formula 4 may be formed by the reaction of indolines 3 with a compound of formula R2-S(0)2-CI in an organic solvent such as dichloromethane or 1 ,2-dichloroethane in the presence of a tertiary amine base such as triethylamine or DIPEA and optionally in the presence of 4-dimethylaminopyridine at temperatures between room temperature and the boiling point of the solvent, typically at 80°C. Alternatively, indolines of formula 4 may be reacted with electrophiles of formula R2-S02-CI without additional solvent in the presence of a tertiary base such as triethylamine or pyridine at room temperature to give aryl bromides of formula 4. In the above procedures, electrophiles R2-S02-CI are either commercially available, known compounds or may be formed from known compounds by known methods by a person skilled in the art.
Indolines of general formula 3 may be synthesized from suitably functionalized indolenines of general formula 2 by either reduction or addition of a nucleophile. For reduction the indolenines 2 may be reacted in a suitable organic solvent such as for example methanol in the presence of a reducing agent such as for example sodium borohydride, sodium (triacetoxy)borohydride or sodium cyanoborohydride at temperatures between 0°C and the boiling point of the solvent, typically at room temperature. In case of a nucleophilic addition the indolenines 2 may be reacted in a suitable organic solvent such as for example THF with a nucleophile R1-M (where M is a metallic species; R1-M is for example a Grignard reagent) in the presence of a Lewis acid such as boron trifluoride diethyl etherate at temperatures between 0°C and room temperature.
Indolenines of general formula 2 may be synthesized from suitably functionalized carbonyl compound of general formula 1 by a condensation and subsequent cyclization reaction (Fischer indole synthesis) with a phenylhydrazine of general formula 10 in an organic solvent such as for example acetic acid or chloroform in the presence of a suitable acid such as for example hydrochloric acid or TFA at temperatures between 0°C and 150°C, typically at 100°C.
In the above procedures carbonyl compounds of general formula 1 and phenylhydrazines of general formula 10 are either commercially available, known compounds or may be formed from known compounds by known methods by a person skilled in the art.
Figure imgf000050_0001
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(R5a)(R5b) or N(H)C(0)OR7.
Compounds of general formula (I) wherein R3 is N(H)C(0)R6, N(H)C(0)N(R5a)(R5b) or N(H)C(0)OR7 may be synthesized according to the procedures depicted in Scheme 2 from suitably functionalized anilines of general formula 14 by reaction with electrophiles. Thus, anilines of formula 14 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 5 from 9 in Scheme 1 ).
Furthermore, anilines of general formula 14 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(R5a)(R5b). Additionally, anilines of general formula 14 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.
Anilines of general formula 14 can be obtained from nitroarenes of general formula 13 by reduction. For reduction, all processes that are known to the person skilled in the art may be applied. Nitroarenes 13 may be hydrogenated under an atmosphere of hydrogen at pressures between 1 bar and 100 bar in a suitable solvent such as for example ethyl acetate, methanol or ethanol or by leading hydrogen through the solution and in the presence of a metal catalyst such as for example palladium on charcoal at temperatures between 0°C and the boiling point of the solvent, typically at room temperature. The addition of a suitable acid such as for example hydrochloric acid or acetic acid may be necessary.
Nitroarenes of general formula 13 can be synthesized from compounds of general formula 12 by regioselective nitration. For nitration, all processes that are known to the person skilled in the art may be applied. Compounds of formula 12 may be reacted with a mixture of concentrated nitric acid and sulfuric acid or with a mixture of concentrated nitric acid and acetic acid at temperatures between 0°C and the boiling point of the solvent, typically at room temperature.
Compounds of general formula 12 may be obtained from aryl bromides of general formula 4 by a two step protocol involving dehalogenation/deprotection and subsequent introduction of R8. For dehalogenation and concomitant Cbz deprotection, the bromides of formula 4 may be hydrogenated under an atmosphere of hydrogen at pressures between 1 bar and 100 bar in a suitable solvent such as for example ethyl acetate, tetrahydrofurane, methanol, ethanol or mixtures thereof or by leading hydrogen through the reaction mixture and in the presence of a metal catalyst such as for example palladium on charcoal at temperatures between 0°C and the boiling point of the solvent, typically at room temperature. The introduction of R8 was already described in the synthesis of 7 from 6 in Scheme 1.
Aryl bromides of general formula 4 are obtainable according to the procedures described in Scheme 1 .
Alternatively, anilines of general formula 14 can be obtained from carboxylic acids of general formula 15 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 16 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 14.
Figure imgf000052_0001
Scheme 3: Alternative procedures for the preparation of compounds of general formula 14 starting from carboxylic acids of general formula 15; R1, R2, R8 and R9 are as defined in the description and claims of this invention.
The protected aniline of general formula 16 can be obtained from carboxylic acids of general formula 15 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.
The obtained indolines of general formulae 6, 7 and (I) may be chiral and may be separated into their diastereomers and/or enantiomers by chiral HPLC. The synthesis of similar compounds is also described in WO 2013/107743. SYNTHESIS OF KEY INTERMEDIATES
Intermediate A.1
benzyl 5-bromo-1 'H-spiro[indol -3,4'-piperidine -1 '-carboxylate
Figure imgf000053_0001
To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (3 g, 13.4 mmol) and benzyl 4-formylpiperidine-1 -carboxylate (3.5 g, 13.4 mmol) in 75 ml chloroform trifluoroacetic acid (3.4 ml, 44 mmol) was added dropwise at rt. 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 product (5.3 g) was used in the next step without further purification.
UPLC-MS (ESI+): [M + H]+ = 399/401 bromo pattern.
Intermediate A.2
benzyl 4-fluoro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate and benzyl 6-fluoro-1 'H- spiro[indole-3,4'- iperidine]-1 '-carboxylate
Figure imgf000053_0002
As described for intermediate A.1 (3-fluorophenyl)hydrazine hydrochloride was reacted with benzyl 4-formylpiperidine-1 -carboxylate to give a 1 :1 mixture of benzyl 4-fluoro-1 'H- spiro[indole-3,4'-piperidine]-1 '-carboxylate and benzyl 6-fluoro-1 'H-spiro[indole-3,4'- piperidine]-1 '-carboxylate. The product was used in the next step without further purification. UPLC-MS (ESI+): [M + H]+ = 339 Rt in min 1 .25 Intermediate B.1
benzyl 5-bromo-2-cyclopropyl-1 2-dihydro-1 'H-s iro[indole-3,4'-piperidine]-1 '-carboxylate
Figure imgf000054_0001
To a stirred and degassed solution of indolenine A.1 (0.5 g, 1 .25 mmol) in 4.5 ml THF boron trifluoride diethylether complex (0.15 ml, 1.25 mmol) was added dropwise at 0°C. After 5 min of stirring, cyclopropylmagnesium bromide (7.5 ml of a 0.5 M solution in THF, 7.5 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 saturated 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 (S1O2- hexane/ethyl acetate) to give 374 mg (67%) of intermediate B.1 .
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = 0.12 - 0.23 (m, 1 H), 0.34 - 0.54 (m, 2H), 0.77 - 0.92 (m, 1 H), 1.39 - 1.52 (m, 1 H), 1.57 - 1.72 (m, 1 H), 1.74 - 1.87 (m, 1 H), 1.93 - 2.05 (m, 1 H), 2.89 (d, 1 H), 3.67 - 3.83 (m, 2H), 5.10 (s, 2H), 5.80 (s, 1 H), 6.44 (s, 1 H), 7.02 - 7.07 (m, 1 H), 7.20 (mc, 1 H), 7.33 - 7.43 (m, 5H)
UPLC-MS (ESI+): [M + H]+ = 441/443. (Br isotope pattern) Rt in min 1.51 Intermediate B.2 and B.3
benzyl 2-cyclopropyl-4-fluoro-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate (B.2) and benzyl 2-cyclopropyl-6-fluoro-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate (B.3)
Figure imgf000054_0002
In analogy to the preparation of intermediate B.1 from A.2 the 4-fluoro isomer B.2 and the 6-fluoro isomer B.3 were obtained and separated by flash chromatography. B.2: benzyl 2-cyclopropyl-4-fluoro-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate 1H-NMR (300MHz, DMSO-d6): Shift [ppm] = 0.14 - 0.23 (m, 1 H), 0.32 - 0.54 (m, 3H), 0.78 - 0.93 (m, 1 H), 1.36 - 1.51 (m, 1 H), 1.57 - 1.70 (m, 1 H), 1.70 - 1.83 (m, 1 H), 1.90 - 2.04 (m, 1 H), 2.87 (d, 1 H), 3.34 - 3.49 (m, 2H), 3.63 - 3.79 (m, 2H), 5.10 (s, 2H), 5.91 (s, 1 H), 6.19 - 6.28 (m, 2H), 7.03 - 7.12 (m, 1 H), 7.30 - 7.43 (m, 5H)
UPLC-MS (ESI+): [M + H]+ = 381 Rt in min 1 .45
B.3: benzyl 2-cyclopropyl-6-fluoro-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate 1H-NMR (300MHz, DMSO-d6): Shift [ppm] = 0.14 - 0.24 (m, 1 H), 0.38 - 0.55 (m, 3H), 1.57 - 1 .74 (m, 2H), 2.06 - 2.19 (m, 2H), 3.00 (d, 1 H), 3.08 - 3.34 (m, 2H), 3.79 - 3.94 (m, 2H), 5.10 (s, 2H), 5.94 (s, 1 H), 6.18 - 6.33 (m, 2H), 6.87 - 6.96 (m, 1 H), 7.30 - 7.43 (m, 5H) UPLC-MS (ESI+): [M + H]+ = 381 Rt in min 1 .45 Intermediate C.1
benzyl 5-bromo-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-3,4'- piperidine]-1 '-carboxylate
Figure imgf000055_0001
B.1 (15 g, 34 mmol) was stirred with 4-fluorobenzenesulfonyl chloride (CAS No. [349-88-2], 9.9 g, 51 mmol) in 16 ml 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, dried and purified via flash chromatography (Si02-hexane/ethyl acetate) to give C.1 (19.4 g, 95%) 1H-NMR (300MHz, DMSO-d6): Shift [ppm] = -0.13 - 0.02 (m, 1 H), 0.33 - 0.52 (m, 2H), 0.52 - 0.66 (m, 1 H), 0.69 - 1 .04 (m, 3H), 1.93 - 2.1 1 (m, 2H), 2.90- 3.19 (m, 2H), 3.45 (d, 1 H), 3.94 - 4.07 (m, 2H), 5.06 (mc, 2H), 7.28 - 7.49 (m, 10H), 7.84 (mc, 2H)
UPLC-MS (ESI+): [M + H]+ = 599/601 (Br isotope pattern) Rt in min 1.64 Intermediate C.2
benzyl 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-3,4'- piperidine]-1 '-carboxylate
Figure imgf000056_0001
In analogy to the preparation of C.1 from B.1 C.2 was obtained from B.2.
UPLC-MS (ESI+): [M + H]+ = 539 Rt in min 1 .55
Intermediate C.3
benzyl 2-cyclopropyl-6-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-3,4'- piperidine]-1 '-carboxylate
Figure imgf000056_0002
In analogy to the preparation of C.1 from B.1 C.3 was obtained from B.3.
UPLC-MS (ESI+): [M + H]+ = 539 Rt in min 1 .55 Intermediate D.1 and D.2
benzyl 5-bromo-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidine]-1 '-carboxylate (D.1 ) and benzyl 5-bromo-2-cyclopropyl-6-fluoro- 1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate (D.2)
Figure imgf000057_0001
To a mixture of C.2 (4.49 g, 8.33 mmol) and sodium acetate (1.026 g, 12.5 mmol) in 37 ml chloroform a solution of bromine (12.5 ml ,12.5 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 was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried with magnesium sulfate and the solvents were removed in vacuo to yield 5.15 g D.1 .
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = -0.12 - 0.05 (m, 1 H), 0.37 - 0.54 (m, 2H), 0.56 - 0.68 (m, 1 H), 0.70 - 0.84 (m, 1 H), 1.00 - 1 .19 (m, 2H), 2.1 1 - 2.39 (m, 2H), 2.90 - 3.17 (m, 2H), 4.00 (d, 1 H), 4.14 (d, 1 H), 5.07 (s, 2H), 7.28 - 7.49 (m, 8H), 7.55 - 7.66 (m, 1 H), 7.81 - 7.90 (m, 2H)
UPLC-MS (ESI+): [M + H]+ = 617/619 (Br isotope pattern) Rt in min 1.64 In the same way D.2 was obtained from C.3
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = -0.13 - 0.02 (m, 1 H), 0.35 - 0.45 (m, 1 H), 0.45 - 0.53 (m, 1 H), 0.54 - 0.64 (m, 1 H), 0.69 - 0.79 (m, 1 H), 0.78 - 1.01 (m, 2H), 2.03 (s, 2H), 2.92 - 3.15 (m, 2H), 3.43 (d, 2H), 3.95 - 4.07 (m, 1 H), 5.06 (d, 2H), 7.27 - 7.47 (m, 8H), 7.58 (d, 1 H), 7.87 - 7.93 (m, 2H)
UPLC-MS (ESI+): [M + H]+ = 617/619 (Br isotope pattern) Rt in min 1.63 Intermediate E.1
1 '-benzyl 5-methyl 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole- 3,4'-piperidine]-1 ',5-dicarboxylate
Figure imgf000058_0001
The aryl bromide C.1 (19.4 g, 32.35 mmol) was placed in a steel autoclave under argon atmosphere and dissolved in a mixture of 680 ml methanol and 67 ml dimethyl sulfoxide. 4.63 g of trans-bis(triphenylphosphine) palladium(ll) dichloride and 10 ml triethylamine were added and the mixture was purged three times with carbon monoxide. The mixture was stirred for 30 min at 20°C under a carbon monoxide pressure of 1 1 .03 bar. The autoclave was set under vacuum again, then a carbon monoxide pressure of 1 1 .08 bar was applied and the mixture heated to 100°C for -24 h, yielding a maximum pressure of 12.5 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 dissolved in dichloromethane. The organic layer was dried with magnesium sulfate, concentrated in vacuo and the product purified by flash chromatography (S1O2- hexane/ethyl acetate). 17.1 g (91 %) E.1 were obtained.
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = 0.00 - 0.12 (m, 1 H), 0.33 - 0.67 (m, 3H), 0.67 - 0.81 (m, 1 H), 0.81 - 1.02 (m, 2H), 2.00 - 2.14 (m, 2H), 2.94 - 3.21 (m, 2H), 3.42 - 3.51 (m, 1 H), 3.80 (s, 3H), 3.96 - 4.12 (m, 2H), 5.07 (s, 2H), 7.28 - 7.46 (m, 7H), 7.60 (d, 1 H), 7.72 (mc, 1 H), 7.83 - 7.94 (m, 3H)
UPLC-MS (ESI+): [M + H]+ = 579 Rt in min 1 .54 Intermediate E.2 and E.3
1 '-benzyl 5-methyl 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidine]-1 ',5-dicarboxylate (E.2) and 1 '-benzyl 5-methyl 2-cyclopropyl-6- fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 ',5- dicarbox late (E.3)
Figure imgf000059_0001
In analogy to the preparation of E.1 from C.1 E.2 and E.3 were obtained from D.1 and D.2.
E.2: UPLC-MS (ESI+): [M + H]+ = 597 Rt in min 1 .52
E.3: UPLC-MS (ESI+): [M + H]+ = 597 Rt in min 1 .52
Intermediate F.1
1 '-[(benzyloxy)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole- 3,4'-piperidine]-5-carboxylic acid
Figure imgf000059_0002
A solution of the methyl ester E.1 (2.64 g, 4.56 mmol) in 26 ml THF was stirred with 1.64 g lithium hydroxide (68 mmol) and 1 1 .4 ml water overnight. The mixture was set to pH 2-3 by addition of 2 N aqueous hydrochloric acid and 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 and concentrated in vacuo.2.6 g (100 %) F.1 were obtained.
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = -0.04-0.15 (m, 1H), 0.31 -0.66 (m, 3H), 0.67
- 1.04 (m, 3H), 1.94-2.14 (m, 2H), 2.95-3.22 (m, 2H), 3.41 -3.54 (m, 1H), 3.95-4.13 (m, 2H), 5.07 (s,2H), 7.25 -7.48 (m,7H), 7.58 (d, 1H), 7.69 (mc, 1 H), 7.83 - 7.93 (m, 3H), 12.50
- 12.92 (sbr, 1H)
UPLC-MS (ESI-): [M - H]" = 563 Rt in min 1.36
Intermediate F.2 and F.3
1 '-acetyl-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxylic acid (F.2) and 1'-acetyl-2-cyclopropyl-6-fluoro-1-[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxylic acid (F.3)
Figure imgf000060_0001
In analogy to the preparation of F.1 from E.1, F.2 and F.3 were synthesized from H.1 and H.2. F.2:
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = -0.12 - -0.01 (m, 0.5H*), -0.01 - -0.10 (m, 0.5H*), 0.37-0.70 (m, 3H), 0.71 -0.86 (m, 1H), 1.01 - 1.13 (m, 1H), 1.92-2.03 (m, 3H), 2.23 - 2.34 (m, 2H), 2.66 - 2.84 (m, 1 H), 3.76 - 3.95 (m, 1 H), 4.16 (d, 0.5H*), 4.23 (d, 0.5H*), 4.37 (d, 0.5H*), 7.38 - 7.49 (m, 3H), 7.80 (t, 1H), 7.84 - 7.90 (m, 2H)
UPLC-MS (ESI-): [M - H]" = 491. Rt in min 1.09
F.3:
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = -0.13 - -0.01 (m, 0.5H*), 0.01 - -0.11 (m, 0.5H*), 0.35 - 0.66 (m, 3H), 0.69 - 0.81 (m, 1 H), 0.90 - 1.05 (m, 1 H), 1.92 (s, 1.5 H*), 2.00 (s, 1.5H*), 2.03 - 2.14 (m, 2H), 2.69 - 2.86 (m, 1 H), 3.70 - 3.87 (m, 1 H), 4.04 (d, 0.5H*), 4.11 (d, 0.5H*), 4.34 (d, 0.5H*), 7.18-7.31 (m, 1 H), 7.39 - 7.50 (m, 2H),7.52 - 7.63 (m, 1H),7.88- 7.98 (m,2H)
UPLC-MS (ESI-): [M - H]" = 491. Rt in min 1.11 Intermediate G.1 and G.2
methyl 2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxylate (G.1 ) and methyl 2-cyclopropyl-6-fluoro-1 -[(4-fluorophenyl)sulfonyl]- 1 ,2-dihyd
Figure imgf000061_0001
2.9 g (4.96 mmol) E.2 were dissolved in 81 ml hydrobromic acid (33% in acetic acid, 495 mmol) at 0°C. After 30 min the solution was poured into 50 ml diethylether and the formed precipitate was filtered off. The precipitate was slurried in dichloromethane and the pH was set to alkaline with triethylamine. The mixture was washed with water, dried with magnesium sulfate and concentrated in vacuo to give 1 .89 g (82 %) G.1 .
G.1 : UPLC-MS (ESI+): [M + H]+ = 463 Rt in min 0.95
G.2 was obtained in the same manner from E.3.
G.2: UPLC-MS (ESI+): [M + H]+ = 463 Rt in min 0.95
Intermediate H.1 and H.2 methyl 1 '-acetyl-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]- 1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxylate (H.1 ) and methyl 1 '-acetyl-2- cyclopropyl-6-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxylat
Figure imgf000061_0002
At 0°C 1.89 g G.1 (4 mmol) were dissolved in 80 ml dichloromethane and 2.8 ml
triethylamine (20.4 mmol). 1.45 ml acetylchloride (20.4 mmol) were added. After 30 min 200 ml water were added, the layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried with magnesium sulfate and concentrated in vacuo to give 2 g (100 %) H.1.
H.1 : UPLC-MS (ESI+): [M + H]+ = 505 Rt in min 1 .25 H.2 was obtained in the same manner from G.2
H.2: UPLC-MS (ESI+): [M + H]+ = 505 Rt in min 1 .26
Intermediate 1.1
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]
Figure imgf000062_0001
The aryl bromide C.1 (6.7 g, 1 1.1 mmol) was dissolved in a mixture of 150 ml ethanol and 50 ml tetrahydrofuran. 3.56 g palladium on charcoal (10% Pd/C; contains 50% of water) were added at rt and hydrogen gas was passed into the mixture until TLC indicated complete consumption of the starting material (2.5 h). The catalyst was filtered off and rinsed with ethanol and tetrahydrofuran. The filtrate was concentrated in vacuo and the residue partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with saturated sodium hydrogencarbonate solution and brine, dried with magnesium sulfate and concentrated in vacuo. The obtained product 1.1 (4.2 g, 98 %) was used in the next step without further purification.
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = -0.04 - 0.04 (m, 1 H), 0.31 - 0.47 (m, 2H), 0.53 - 0.63 (m, 1 H), 0.64 - 0.72 (m, 1 H), 0.77 (dt, 1 H), 0.88 - 0.99 (m, 1 H), 1.84 - 2.02 (m, 2H), 2.37 - 2.44 (m, 1 H), 2.64 - 2.74 (m, 1 H), 2.91 - 2.99 (m, 1 H), 3.92 (d, 1 H), 7.07 (t, 1 H), 7.16 (d, 1 H), 7.24 (t, 1 H), 7.37 (t, 2H), 7.48 (d, 1 H), 7.76 - 7.84 (m, 2H)
UPLC-MS (ESI+): [M + H]+ = 387 Rt in min 0.87 Intermediate J.1
1 -{2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '- yl}ethanone
Figure imgf000063_0001
Intermediate J.1 was prepared from 1.1 in analogy to the preparation of example 1 (Step 3). UPLC-MS (ESI+): [M + H]+ = 429 Rt in min 1 .26
Intermediate K.1 1 -{2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-5-nitro-1 ,2-dihydro-1 ' spiro[indole-3,4'-piperidin]-1 '-yl}ethanone
Figure imgf000063_0002
To a suspension of J.1 (6.1 g, 14.2 mmol) in 93 ml acetic acid concentrated nitric acid (17.7 ml, 427 mmol) was carefully added at rt. The reaction mixture was stirred for 2 h at rt and then added dropwise to a saturated sodium hydrogencarbonate solution. After the gas evolution has ceased, the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium hydrogencarbonate solution and brine, dried with magnesium sulfate and concentrated in vacuo. The obtained product (6.7 g, 100%) was used in the next step without further purification.
UPLC-MS (ESI+): [M + H]+ = 474 Rt in min 1 .25 Intermediate L.1
1 -{5-amino-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 'H-spiro[indole-3,4'- piperidin]-1 '-yl}ethanone
Figure imgf000064_0001
Intermediate K.1 (10.05 g, 21 .2 mmol) was hydrogenated with 6 g palladium on charcoal (10% Pd/C) in 415 ml ethylacetate for 5 h. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was purified by flash chromatography (Si02-hexane/ethyl acetate) to give 4.6 g L.1 (49 %).
UPLC-MS (ESI+): [M + H]+ = 444 Rt in min 0.97
COMPOUNDS ACCORDING TO THE INVENTION:
Example 1
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-pipe
Figure imgf000065_0001
Step 1
benzyl 5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro- 1 'H-spiro[indole-3,4'-piperidine -1 '-carboxylate
Figure imgf000065_0002
100 mg (0.17 mmol) intermediate E.1 and 37 mg (0.26 mmol) 1 -(2- chlorophenyl)methanamine were reacted with 101 mg (0.26 mmol) HATU in the presence of 37 μΙ (0.26 mmol) triethylamine in 3 ml DMF at rt overnight. The mixture was poured into 50 ml water. The formed precipitate was filtered off, washed with water, dissolved in dichloromethane, dried and concentrated in vacuo to give 1 18 mg (96 %) of the desired amide.
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = 0.03 - 0.18 (m, 1 H), 0.35 - 0.67 (m, 3H), 0.71 - 1 .05 (m, 3H), 1.94 - 2.19 (m, 2H), 2.97 - 3.27 (m, 2H), 3.44 - 3.55 (m, 1 H), 4.00 - 4.12 (m, 2H), 4.52 (d, 2H), 5.07 (d, 2H), 7.25 - 7.50 (m, 1 1 H), 7.57 (d, 1 H), 7.74 - 7.93 (m, 4H), 8.92 (t, 1 H)
UPLC-MS (ESI+): [M + H]+ = 688/690 (chloro isotope pattern) Rt in min 1 .26 Step 2
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[ind
piperidine]-5-carboxamide
Figure imgf000066_0001
1 14 mg (0.166 mmol) of the product of step 1 were dissolved in 2.7 ml hydrobromic acid (33% in acetic acid, 16 mmol) at 0°C. After 30 min the solution was poured into 50 ml diethylether and the formed precipitate was filtered off. The precipitate was slurried in dichloromethane and the pH was set to alkaline with triethylamine. The solution was washed with water, dried with magnesium sulfate and concentrated in vacuo to give 66 mg (72 %) of the product.
1H-NMR (300MHz, DMSO-d6): Shift [ppm] = -0.04 - 0.09 (m, 1 H), 0.32 - 0.51 (m, 2H), 0.53 - 0.74 (m, 2H), 0.75 - 0.88 (m, 1 H), 0.88 - 1 .01 (m, 1 H), 1.91 - 2.05 (m, 2H), 2.89 - 3.03 (m, 1 H), 3.99 (d, 1 H), 4.52 (d, 2H), 7.22 - 7.48 (m, 6H), 7.55 (d, 1 H), 7.70 - 7.92 (m, 4H), 8.97 (t, 1 H)
UPLC-MS (ESI+): [M + H]+ = 554/556 (CI isotope pattern) Rt in min 1.06
Step 3
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
Figure imgf000066_0002
340 mg of the product of step 2 (0.61 mmol) were dissolved at 0°C in 12 ml dichloromethane and 0.43 ml triethylamine (3 mmol). 0.22 ml acetylchloride (3 mmol) was added. After 30 min 20 ml water were added , the layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried with magnesium sulfate and concentrated in vacuo to give 380 mg (91 %) of the product.
1H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.03 (d, 0.5H*), 0.1 1 (d, 0.5H*), 0.34 - 0.62 (m, 3H), 0.65 - 0.80 (m, 2H), 0.86 - 1 .00 (m, 1 H), 1 .89 (s, 1.5H*), 1.96 (s, 1 .5H*), 2.04 - 2.55 (m, 4H), 2.73 - 2.85 (m, 1 H), 3.72 - 3.89 (m, 1 H), 4.02 (d, 0.5H*), 4.09 (d, 0.5H*), 4.48 (d, 2H), 7.23 - 7.32 (m, 3H), 7.34 - 7.44 (m, 3H), 7.54 (dd, 1 H), 7.73 (m, 1 H), 7.81 - 7.88 (m, 3H), 8.90 (t, 1 H)
UPLC-MS (ESI+): [M + H]+ = 596 / 598 (CI isotope pattern) Rt in min 1 .28
The enantiomers of the racemic material were separated by chiral preparative HPLC.
System: Dionex: Pump 680, ASI 100, Knauer: UV-Detektor K-2501
Column: Chiralpak AD-H 5μηι 150x4.6 mm; Solvent: Hexan / Ethanol 50:50; Flow: 1 .0 ml/min; Temperature: 25°C; Solution: 1 .0 mg/ml EtOH/MeOH 1 :1 ; Injection: 5.0 μΙ;
Detection: UV 220 nm
Enantiomer 1 : Rt in min 3.22
Enantiomer 2: Rt in min 3.78
The following examples of table 1 were prepared in analogy to step 1 of example 1 . Table 1 :
Figure imgf000068_0001
1H-NMR (300MHz, DMSO-d6): Shift
1'-acetyl-N-{[3- [ppm]=-0.02 (d, 0.5H*), 0.11 (d, chloro-5- 0.5H*), 0.38 -0.67 (m, 3H), 0.71 - (trifluoromethyl
y-cH3 0.82 (m, 1.5H*), 0.92 - 1.03 (m,
)pyridin-2- 1.5H*), 1.92 (s, 1.5H*), 2.00 (s, / yl]methyl}-2- 1.5H*), 2.05 - 2.12 (m, 2H), 2.75 - cyclopropyl-6- 2.86 (m, 1H), 3.74-3.86 (m, 1H), fluoro-1-[(4- 4.07 (d, 0.5H*), 4.13 (d, 0.5H*), 4.40 fluorophenyl)s
(d, 0.5H*),4.73 (d, 2H), 7.29 - 7.35
0 ulfonyl]-1,2- (m, 1 H), 7.40 - 7.50 (m, 2H), 7.54 (t, dihydrospiro[in
1H), 7.91 - 7.98 (m, 2H), 8.47 (mc, dole-3,4'- 1H), 8.68 (mc, 1H), 8.92 (mc, 1H). piperidine]-5- UPLC-MS (ESI+): [M + H]+ = 683 Rt carboxamide
in min 1.42
1H-NMR (300MHz, DMSO-d6): Shift
1 '-acetyl-4- [ppm]= -0.05 (d, 0.5H*), 0.05 (d, chloro-2- 0.5H*), 0.39 -0.58 (m, 2H), 0.60 - cyclopropyl-N- 0.73 (m, 1H), 0.76-0.90 (m,
(2,3- 1H),0.98- 1.13 (m, 1H), 1.28 (dt, dichlorophenyl 0.5H*), 1.46 (dt, 0.5H*), 1.96 (s,
)-1-[(4- 1.5H*), 2.02 (s, 1.5H*), 2.16-2.30 fluorophenyl)s (m, 1H), 2.61 - 3.26 (m, 3H), 3.88 (d, ulfonyl]-1,2- 0.5H*), 3.99 (d, 0.5H*), 4.31 (d, dihydrospiro[in 0.5H*), 4.37 (d, 0.5H*), 7.34 - 7.65
Figure imgf000069_0001
dole-3,4'- (m, 7H), 7.85 - 7.95 (m, 2H), 10.37 piperidine]-5- (s, 1H). UPLC-MS (ESI+): [M + H]+ carboxamide = 650/652 (CI isotope pattern) Rt in min 1.38
1'-acetyl-2- 1H-NMR (300MHz, DMSO-d6): Shift cyclopropyl-N- [ppm]=0.04 (d, 0.5H*), 0.14 (d,
(2,3- 0.5H*), 0.39 - 0.59 (m, 2H), 0.59 - dichlorophenyl 0.72 (m, 1H), 0.76-0.88 (m, )-4-fluoro-1- 1H),1.02- 1.19 (m, 1H), 1.96 (s, [(4- 1.5H*), 2.02 (s, 1.5H*), 3.80 - 3.97 fluorophenyl)s (m, 1H), 4.21 (d, 0.5H*), 4.28 (d, ulfonyl]-1,2- 0.5H*), 4.40 (d, 0.5H*),7.34 - 7.57 dihydrospiro[in (m, 5H), 7.62 - 7.75 (m, 2H),7.87 -
Figure imgf000069_0002
dole-3,4'- 7.98 (m, 2H), 10.04 (s, 1H). UPLC- piperidine]-5- MS (ESI+): [M + H]+ = 634/636 (CI carboxamide isotope pattern) Rt in min 1.47
1H-NMR (300MHz, DMSO-d6): Shift [ppm]= -0.06 (d, 0.5H*), 0.04 (d,
1 '-acetyl-4- 0.5H*), 0.41 -0.57 (m, 2H), 0.61 - chloro-N-(3- 0.71 (m, 1H), 0.77-0.88 (m, 1H), chloro-2- 1.00- 1.11 (m, 1H), 1.28 (dt, 0.5H*), fluorophenyl)- 1.45 (dt, 0.5H*), 2.01 (s, 1.5H*), 2.02 2-cyclopropyl- (s, 1.5H*), 2.17-2.29 (m, 1H), 2.75-
1-[(4- 2.88 (m, 1H),2.90 - 3.03 (m, 0.5H*), fluorophenyl)s 3.14-3.26 (m, 0.5H*), 3.88 (d, ulfonyl]-1,2- 0.5H*), 3.99 (d, 0.5H*), 4.31 (d, dihydrospiro[in 0.5H*), 4.37 (d, 0.5H*),7.24 (t, 1H),
Figure imgf000069_0003
dole-3,4'- 7.39 - 7.53 (m, 4H), 7.56 - 7.61 (m, piperidine]-5- 1 H), 7.72 (t, 1 H), 7.86 - 7.95 (m, 2H), carboxamide 10.48 (s, 1H). UPLC-MS (ESI+): [M
+ H]+ = 634/636 (CI isotope pattern)
Rt in min 1.36
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
soope pa ern n mn .
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
dole-3,4'- (d, 0.5H*), 7.38 - 7.40 (m, 2H), 7.60 - piperidine]-5- 7.69 (m,2H), 7.82-7.99 (m, 4H), carboxamide 8.43 (d, 1H), 8.63 (mc, 1H), 10.22 (s,
1H). UPLC-MS (ESI+): [M + H]+ = 583/585 (CI isotope pattern) Rt in min 1.17
1H-NMR (300MHz, DMSO-d6): Shift
1'-acetyl-2- [ppm]= 0.09 (d, 0.5H*), 0.21 (d, cyclopropyl-1- 0.5H*), 0.35 - 0.67 (m, 3H), 0.69 - [(4- 0.86 (m, 1.5H*), 0.89 - 1.06 (m, fluorophenyl)s 1.5H*), 1.94 (s, 1.5H*), 2.02 (s, ulfonyl]-N-(1,3- 1.5H*), 2.07- 2.18 (m, 1.5H*), 2.77-1 oxazol-2-yl)- 2.94 (m, 1H), 3.72-3.94 (m, 1H),
1,2- 4.06 (d, 0.5H*), 4.12 (d, 0.5H*), 4.37 dihydrospiro[in (d, 0.5H*), 7.17 (s, 1H), 7.35-7.52
Figure imgf000079_0001
dole-3,4'- (m, 2H), 7.60 (d, 1 H), 7.82 - 7.98 (m, piperidine]-5- 5H), 11.36 (s, 1H). UPLC-MS carboxamide (ESI+): [M + H]+ = 539 Rt in min
1.07
1H-NMR (300MHz, DMSO-d6): Shift [ppm]=0.04 (d, 0.5H*), 0.17 (d,
1'-acetyl-2- 0.5H*), 0.36 - 0.67 (m, 3H), 0.70 - cyclopropyl-1- 0.83 (m, 1.5H*), 0.91 - 1.04 (m, [(4- 1.5H*), 1.94 (s, 1.5H*), 2.02 (s, fluorophenyl)s
1.5H*), 2.06- 2.18 (m, 1.5H*), 2.77- ulfonyl]-N-{[5- 2.90 (m, 1H), 3.79 (d, 0.5H*), 3.89 (trifluoromethyl
(d, 0.5H*), 4.06 (d, 0.5H*), 4.12 (d,
)pyridin-2- 0.5H*), 4.38 (d, 0.5H*), 4.62 (d, 2H), yl]methyl}-1,2- 7.37 - 7.47 (m, 2H), 7.52 - 7.61 (m, dihydrospiropn
2H), 7.75 - 7.81 (m, 1H), 7.83 - 7.92 dole-3,4'- (m,3H), 8.12- 8.18 (m, 1H), 8.90 piperidine]-5- (mc, 1H), 9.12 (t, 1H). UPLC-MS carboxamide
(ESI+): [M + H]+ = 631 Rt in min
1.25
SystenrWaters: Alliance 2695, DAD
996, ESA: Corona;
Column:Chiralpak IC 3μηι 100x4.6 mm; Solvent:Hexan / Ethanol 70:30-1 Enantiomer 1 of Ex.42 (v/v); Flow:1.0 mL/min;
Temperature:25°C; Solution^.0 mg/mL EtOH/MeOH 1:1;
lnjection:5.0 μΙ; Detection:DAD 280 nm; Rt in min 9.39
-2 Enantiomer 2 of Ex.42 Rt in min 11.64
1'-acetyl-2- 1H-NMR (300MHz, DMSO-d6): Shift cyclopropyl-1- [ppm]=0.03 (d, 0.5H*), 0.18 (d, {[3- 0.5H*), 0.34 - 0.68 (m, 3H), 0.72 -
(difluorometho 0.86 (m, 1.5H*), 0.88- 1.07 (m, xy)phenyl]sulfo 1.5H*), 1.92 (s, 1.5H*), 2.02 (s, nyl}-N-[2- 1.5H*), 2.05- 2.19 (m, 1.5H*), 2.77- (trifluoromethyl 2.93 (m, 1H), 3.79 (d, 0.5H*), 3.89 )benzyl]-1,2- (d, 0.5H*), 4.08 (d, 0.5H*), 4.14 (d, dihydrospiro[in 0.5H*), 4.37 (d, 0.5H*), 4.64 (d, 2H), dole-3,4'- 7.34 (dt, 1H), 7.43-7.95 (m, 11H), piperidine]-5- 8.99 (t, 1H). UPLC-MS (ESI+): [M + carboxamide H]+ = 678 Rtin min 1.33
Figure imgf000080_0001
isotope pattern) Rt in min 1 .33
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
- -
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
82-2 Enantiomer 2 of Ex. 82 Rt in min 5.4
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
dole-3,4'-
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
piperidine]-5- carboxamide
N-(2- chlorobenzyl)-
2- cyclopropyl-
1 -[(4- j '"'·< fluorophenyl)s
] ulfonyl]-1 '-[(3-
UPLC-MS (ESI+): [M + H]+ = 652 Rt
143 methyloxetan- in min 1 .33
3- yl)carbonyl]-
1 ,2- dihydrospiro[in
dole-3,4'- piperidine]-5- carboxamide
N-(2- chlorobenzyl)- 2-cyclopropyl-
1 (1 ,5- dimethyl-1 H- f pyrazol-3- yl)carbonyl]-1 - UPLC-MS (ESI+): [M + H]+ = 676 Rt
144
[(4- in min 1 .37
fluorophenyl)s
Q ulfonyl]-1 ,2- dihydrospiro[in
dole-3,4'- piperidine]-5- carboxamide
1 -[(4- fluorophenyl)s
ulfonyl]-N-[(3- methylpyridin- f
2-yl)methyl]-r- (oxetan-3-yl)- UPLC-MS (ESI+): [M + H]+ = 591 Rt
145
2-(prop-2-en- in min 0.81
1 -yl)-1 ,2-
Q dihydrospiro[in
dole-3,4'- piperidine]-5- carboxamide
1 -[(4- fluorophenyl)s
j ulfonyl]-N-[(3- methylpyridin- 2-yl)methyl]-2-
UPLC-MS (ESI+): [M + H]+ = 535 Rt
146 (prop-2-en-1 - in min 0.81
yl)-1 ,2-
Q dihydrospiro[in
dole-3,4'- piperidine]-5- carboxamide
Figure imgf000109_0001
Figure imgf000110_0001
-
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Column: Chiralcel OD-H 5μηι
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
acid -
Figure imgf000128_0001
Figure imgf000129_0001
Example 224
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidin]- 5-yl}-2-chloro-5-fluorobenzamide
Figure imgf000130_0001
120 mg (0.27 mmol) intermediate L.1 and 70 mg (0.4 mmol) 2-chloro-5-fluorobenzoic acid were reacted with 154 mg (0.4 mmol) HATU in the presence of 56 μΙ (0.4 mmol) triethylamine in 2 ml DMF at rt overnight. The solution was purified by HPLC to give 80 mg (49 %) of the desired amide.
1H-NMR (300MHz, DMSO-d6): Shift [ppm]= 0.00 (d, 0.5H*), 0.14 (d, 0.5H*), 0.33 - 0.69 (m, 3.5H*), 0.71 - 0.81 (m, 1 H), 0.81 - 0.92 (m, 0.5H*), 0.94 - 1 .04 (m, 1 H), 1.64 - 1 .80 (m, 0.5H*), 1.82 - 1 .91 (m, 0.5H*), 1 .94 (s, 1.5H*), 2.01 (s, 1.5H*), 2.06 - 2.18 (m, 1 H), 2.75 - 2.96 (m, 1 H), 3.72 (d, 0.5H*), 3.84 (d, 0.5H*),3.99 (d, 0.5H*), 4.05 (d, 0.5H*), 4.30 (d, 0.5H*), 7.33 - 7.67 (m, 8H), 7.77 - 7.91 (m, 2H), 10.52 (s, 1 H)
UPLC-MS (ESI+): [M + H]+ = 600/602 (chloro isotope pattern) Rt in min 1 .27
The enantiomers of the racemic material were separated by chiral preparative HPLC.
System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak IC 3μηι 100x4.6 mm; Solvent:Hexan / Ethanol 70:30 (v/v); Flow: 1.0 ml/min; Temperature: 25°C°;
Solution: 1 .0 mg/ml EtOH/MeOH 1 :1 ; Injection: 5.0 μΙ; Detection: DAD 280 nm
Enantiomer 1 : Rt in min 5.28
Enantiomer 2: Rt in min 6.45 The following examples of table 2 were prepared in analogy to example 224. Table 2:
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
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 3: Potency in the IP-One HTRF® assay with LHRH or buserelin (at ECso) stimulation; the potency is given as I C50 [nM].
Figure imgf000145_0001
Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
25 215.5
26 317.0
27 712.8 769.0
27-1 482.8
27-2 20000.0
28 23.6
28-1 700.8
28-2 5.9
29 218.9
30 1 10.3
31 43.2
31 -1 20000.0
31 -2 20.1
32 165.7
33 42.8
33-1 20000.0
33-2 16.6
34 145.7
35 96.9
36 191 .4 41 1 .5
37 168.9
38 107.9
38-1 20000.0
38-2 53.8
39 68.0 151 .2
39-1 51.9
39-2 1244.2
40 220.0
41 228.6
42 376.3
42-1 219.7
42-2 2441.0
43 73.0 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
44 25.3
45 1 18.9
46 208.1
47 1 19.5
47-1 2655.9
47-2 16.3
48 87.5
49 149.9
49-1 10884.6
49-2 62.7
50 230.3
50-1 85.7
50-2 5777.9
51 532.0
51 -1 20000.0
51 -2 217.5
52 101 .9
53 13.3
53-1 9.6
53-2 202.7
54 247.1
54-1 65.5
54-2 12046.9
55 67.3
55-1 45.8
55-2 441 .0
56 249.8
56-1 106.9
56-2 2709.5
57 87.7
57-1 65.3
57-2 1 126.8
58 137.8 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
59 150.3
60 67.7
61 69.0
62 137.7
63 109.2
64 1 1 1 .8
64-1 20000.0
64-2 88.4
65 69.0
65-1 614.4
65-2 40.4
66 92.9
67 106.0
68 123.5
69 98.0
70 81.3
71 137.3
72 103.7
73 135.3
74 3475.6
75 1 129.2 2045.8
76 2319.2 7368.5
77 3492.8
78 961 .6 3317.6
79 235.7 2882.6
79-1 20000.0 20000.0
79-2 108.4 335.7
80 942.1
81 167.9
81 -1 1 16.1
81 -2 17551 .8
82 127.3 199.5
82-1 20000.0 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
82-2 67.5 171 .7
83 375.4 522.5
83-1 20000.0
83-2 1 19.6
84 360.3
85 235.0
85-1 121 .3
85-2 485.1
86 169.1
86-1 126.5
86-2 20000.0
87 149.2
87-1 20000.0
87-2 20.7
88 171 .2
88-1 129.0
88-2 7030.3
89 388.2
90 310.8
91 1404.6
92 264.2
93 76.8
94 477.5
95 77.0
95-1 16794.1
95-2 16.7 35.1
96 157.7 313.2
97 460.1 988.2
98 430.6
99 3256.7
100 868.9 4171.5
101 196.6
102 31 1 .5 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
103 477.4
104 694.3
105 573.1
106 350.3
107 95.6 311.7
107-1 8196.1 20000.0
107-2 45.5 137.9
108 2166.1 4483.2
109 1424.0 5198.4
110 562.5 2450.0
111 3587.4 20000.0
112 1469.6
113 124.8
113-1 1359.5
113-2 64.4
114 527.1
115 832.8
116 390.9
117 24.5
117-1 1409.2 3255.6
117-2 11.5 29.6
118 14.9 33.5
119 19.1 35.5
120 135.8
121 73.9 99.2
122 112.8 152.3
123 146.2 302.4
124 71.6 157.6
124-1 2706.9 5293.8
124-2 37.8 77.1
125 193.0
126 50.3 72.9
126-1 14861.4 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
126-2 14.1 36.0
127 122.9
128 1 14.8 457.1
129 28.6 68.9
130 174.4
131 34.2 74.0
132 55.7 128.3
133 368.1
133-1 13738.0
133-2 308.0
134 1 16.6
134-1 53.5 34.9
134-2 1 1788.4
135 172.7
135-1 20000.0
135-2 1 12.8
136 25.3 59.9
137 1 1.9 29.2
137-1 732.9 2489.7
137-2 6.1 1 1.1
138 627.6
139 227.1
140 1 164.3
141 402.8
142 83.5
143 14.3 37.5
144 15.8 26.8
145 475.4
146 1625.8
147-2 23.6
148 47.5 1 10.3
149 80.2 261 .7
150 43.7 125.9 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
151 31.1 90.4
151 -1 1 109.2
151 -2 77.1
152 9059.8
153 62.7
153-1 1 151.8
153-2 92.3
154 198.5
154-1 98.6 172.3
154-2 19283.4 20000.0
155 5933.2
156 17.5 47.1
157 149.2
158 15.3 28.1
159 31.2 77.0
160 9.8 28.9
161 16.1 48.8
162 41.4 91.9
163 40.3 107.7
164 23.8 73.6
165 33.2 61.1
166 36.2 90.7
167 62.5 220.8
168 25.5 85.1
169 20.5 46.4
170 63.3 144.0
171 31.5 74.2
172 153.6 306.4
172-1 13528.1 20000.0
172-2 40.8 98.8
173 556.2
174 340.5
174-1 283.2 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
174-2 7669.2
175 71.9
175-1 5732.3 20000.0
175-2 22.8 103.8
176 1716.5
177 10902.3
178 1 16.4
178-1 3291.1 12263.8
178-2 53.5 1 19.0
179 239.1
180 170.7
180-1 7458.2 20000.0
180-2 141 .9 315.7
181 143.1
182 79.0
183 391 .7
184 46.8 97.4
185 69.8
186 62.6 130.6
187 33.6 106.1
187-1 1 185.6 1 1748.4
187-2 27.2 67.5
188 18.3 41.5
188-1 1 190.7 2354.3
188-2 22.8 39.1
189 24.8 58.2
190 15.3 36.5
191 24.1 64.6
192 54.6 127.7
193 24.1 88.8
194 17.7 33.2
195 22.1 26.7
196 58.0 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
197 9.9 26.9
197-1 7400.2
197-2 9.1 14.2
198 39.8 96.2
198-1 20000.0
198-2 42.6
199 81.2
199-1 12339.8
199-2 22.6 51.3
200 1 1.2 26.3
201 26.2 51.3
202 479.9 1259.8
203 121 .0
203-1 39.3 1 16.7
203-2 120.1 716.9
204 26.7 68.0
205 105.8 244.7
205-1 31.1 74.5
205-2 822.6 1241.6
206 134.6
207 122.7
208 36.7 1 12.6
208-1 29.1 56.1
208-2 136.2 312.8
209 742.3
210 663.8
21 1 22.3 45.5
21 1 -1 1258.5
21 1 -2 22.1
212 50.7
213 109.3
214 10.0 1 1.7
215 52.1 153.0 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
216 24.4 70.6
217 20.7 67.6
218 20.0 36.4
219 15.1 44.0
220 41.8 102.7
221 12.8 29.5
222 46.2 122.8
223 28.9 63.3
224 56.9
224-1 18235.5
224-2 30.7
225 461 .0
226 69.2
227 67.0
227-1 7460.2
227-2 33.7
228 55.9
228-1 246.4
228-2 36.4
229 268.3
229-1 20000.0
229-2 107.6
230 37.8
231 32.0
231 -1 8513.4
231 -2 21.0
232 22.0
232-1 1543.6
232-2 12.9
233 1 17.6
233-1 20000.0
233-2 105.5
234 150.4 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
234-1 10715.7
234-2 122.1
235 59.6
236 108.1
236-1 20000.0
236-2 77.9
237 1 19.1
237-1 3359.8
237-2 72.5
238 61.2
238-1 57.2
238-2 847.8
239 317.6
240 260.7
241 415.0
241 -1 20000.0
241 -2 375.1
242 228.4
242-1 10840.2
242-2 221 .2
243 48.3
243-1 38.5
243-2 636.2
244 148.5
245 171 .8
246 247.9
246-1 252.3
246-2 15812.2
247 105.8
247-1 13624.6
247-2 74.8
248 445.8
249 31 1 .0 Example No Potency IC5o [nM]
Potency IC5o [nM]
Stimulation with Stimulation with LHRH
buserelin
249-1 19512.5
249-2 125.7
250 350.0
251 466.9
252 285.6
252-1 13010.5
252-2 133.4
253 1 10.2
254 61.1
255 152.5

Claims

1 . A compound according to Formula (I)
Figure imgf000158_0001
is selected from the group consisting of hydrogen, Ci-C6-alkyl, C3-Cio-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; Ci-C6-alkoxy-Ci-C6-alkyl, C3-C6-cycloalkyl-Ci-C3-alkyl;
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(R5a)(R5b), N(H)C(0)R6, N(H)C(0)N(R5a)(R5b), or N(H)C(0)OR7;
is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C6-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;
, R5b and R6 are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-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, heteroaryl-Ci-C6-alkyl, in which said cycloalkyi, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl; and R5d are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-C6-alkyl;
C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, Cs-Cs-heterocycloalkyl, Cs-Cn-spirocycloalkyl, C5-Cii-heterospirocycloalkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl, heteroaryl- Ci-C6-alkyl-, in which said cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyi, aryl and heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl,
Ci-C6-alkoxy, Ci-C6-haloalkoxy substituted or unsubstituted aryl, 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)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
or are taken together with the nitrogen atom to form a cyclic group consisting of C3-C8-heterocycloalkyl or Cs-Cn-heterospirocycloalkyl;
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 cycloalkyl, 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 C(0)R10, C(0)OR1 1 ,
C(0)N(R5c)(R5d), S(0)2R12, hydrogen, Ci-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyl, heteroaryl or heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH , C(0)0-Ci-C6-alkyl, CN , N (R5a)(R5b), C(0)N(R5c)(R5d),
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;
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 Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, N H2, halogen, C(0)OH , Ci-C4-alkoxy, -N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other, aryloxy or heteroaryloxy, in which said aryloxy or heteroaryloxy group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C3-C8-cycloalkyl or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl,
or C2-C6-alkenyl or C2-C6-alkinyl,
or aryl, heteroaryl, 3- to 10-membered heterocycloalkyl-Ci-C4-alkyl, aryl-Ci-C4-alkyl or heteroaryl-Ci-C4-alkyl, in which said aryl, heteroaryl or 3- to 10-membered heterocycloalkyl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl, aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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,
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 Ci-C6-alkyl, Cs-Cs-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl or heteroaryl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl,
d-Ce-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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. A compound according to claiml characterised in that
R3 is selected from the group consisting of C(0)N(R5a)(R5b), N(H)C(0)R6.
A compound according to claim 1 or 2 of formula (la)
8
R
Figure imgf000161_0001
(la)
in which
R1 is selected from the group consisting of hydrogen, Ci-C6-alkyl,
C3-Cio-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; Ci-C6-alkoxy-Ci-C6-alkyl, C3-C6-cycloalkyl-Ci-C3-alkyl;
R4 is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C6-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;
R5a and R5b are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-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,
heteroaryl-Ci-C6-alkyl, in which said cycloalkyi, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, C(0)OH, C(0)0-Ci-C6-alkyl, CN, C(0)NH2, S(0)2-Ci-C6-alkyl, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
R5c and R5d are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-C6-alkyl;
C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, Cs-Cs-heterocycloalkyl, Cs-Cn-spirocycloalkyl, C5-Cii-heterospirocycloalkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl, heteroaryl-Ci-C6-alkyl-, in which said cycloalkyl, heterocycloalkyl,
spirocycloalkyl, heterospirocycloalkyl, aryl and heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci- C6-haloalkyl,
Ci-C6-alkoxy, Ci-C6-haloalkoxy substituted or unsubstituted aryl, 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)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
or are taken together with the nitrogen atom to form a cyclic group consisting of C3-C8-heterocycloalkyl or Cs-Cn-heterospirocycloalkyl;
R8 is selected from the group consisting of C(0)R10, C(0)OR1 1 ,
C(0)N(R5c)(R5d), S(0)2R12, hydrogen, Ci-C6-alkyl, C2-C6-alkenyl,
C2-C6-alkynyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyl, heteroaryl or heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH , C(0)0-Ci-C6-alkyl, CN , N (R5a)(R5b), C(0)N(R5c)(R5d),
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;
R9 is hydrogen oder halogen;
R10 is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, N H2, halogen, C(0)OH , Ci-C4-alkoxy, -N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other, aryloxy or heteroaryloxy, in which said aryloxy or heteroaryloxy group is optionally substituted up to three times with 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,
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, 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,
or C3-C8-cycloalkyl or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl,
or C2-C6-alkenyl or C2-C6-alkinyl,
or aryl, heteroaryl, 3- to 10-membered heterocycloalkyl-Ci-C4-alkyl, aryl-Ci-C4-alkyl or heteroaryl-Ci-C4-alkyl, in which said aryl, heteroaryl or 3- to 10-membered heterocycloalkyl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
R11 is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl,
aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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;
R12 is Ci-C6-alkyl, Cs-Cs-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl or heteroaryl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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.
4. A compound according to claim 1 or 2 of formula (lb)
Figure imgf000163_0001
(lb)
in which
R1 is selected from the group consisting of C3-Cio-cycloalkyl; R4 is selected from the group consisting of halogen, hydroxy, CN , Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C(0)0-Ci-C6-alkyl, C(0)N H2;
R5c and R5d are selected, independently from one another, from the group consisting of hydrogen, Ci-C6-alkyl, halo-Ci-C6-alkyl, hydroxy-C2-C6-alkyl;
C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, Cs-Cs-heterocycloalkyl, Cs-Cn-spirocycloalkyl, C5-Ci i-heterospirocycloalkyl, aryl, aryl-Ci-C6-alkyl-, heteroaryl,
heteroaryl-Ci-C6-alkyl-, in which said cycloalkyi, heterocycloalkyi,
spirocycloalkyl, heterospirocycloalkyl, aryl and heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy substituted or unsubstituted aryl, 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 H(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
or are taken together with the nitrogen atom to form a cyclic group consisting of Cs-Cs-heterocycloalkyl or Cs-Cn-heterospirocycloalkyl;
R6 is selected from the group consisting of aryl, aryl-Ci-C6-alkyl, heteroaryl,
heteroaryl-Ci-C6-alkyl, in which said cycloalkyi, aryl, heteroaryl groups are optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci- C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, substituted or unsubstituted aryl, 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 H(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, in which the two alkyl groups are independent from each other, S(0)2N=heterocyclo-Ci-C6-alkyl;
R8 is selected from the group consisting of C(0)R10, C(0)OR11 ,
C(0)N(R5c)(R5d), S(0)2R12, hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-Cio-cycloalkyl, C3-Cio-cycloalkyl-Ci-C6-alkyl, aryl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyi, heteroaryl or
heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C(0)OH , C(0)0-Ci-C6-alkyl, CN , N (R5a)(R5b), C(0)N(R5c)(R5d),
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;
R9 is hydrogen oder halogen;
R10 is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy, N H2, halogen, C(0)OH , Ci-C4-alkoxy, -N(Ci-C6-alkyl)2 in which the two alkyl groups are independent from each other, aryloxy or heteroaryloxy, in which said aryloxy or heteroaryloxy group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C3-C8-cycloalkyl or 3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl,
or C2-C6-alkenyl or C2-C6-alkinyl,
or aryl, heteroaryl, 3- to 10-membered heterocycloalkyl-Ci-C4-alkyl, aryl-Ci-C4-alkyl or heteroaryl-Ci-C4-alkyl, in which said aryl, heteroaryl or 3- to 10-membered heterocycloalkyl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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,
or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
is Ci-C6-alkyl, hydroxy-C2-C6-alkyl, Cs-Cs-cycloalkyl, aryl, heteroaryl, aryl-Ci-C3-alkyl or heteroaryl-Ci-C3-alkyl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, d-Ce-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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,
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 Ci-C6-alkyl, Cs-Cs-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl or heteroaryl, in which said aryl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-Ce-haloalkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, 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, 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.
5. A compound according to claim 1 or 2 characterised in that
R1 is selected from the group consisting of hydrogen, Ci-C6-alkyl,
C3-Cio-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, hydroxy- d-Ce-alkyl; C3-C6-cycloalkyl-Ci-C3-alkyl
6. A compound according to claim 1 or 2 characterised in that
R4 is selected from the group consisting of halogen, hydroxy, CN, Ci-C6-alkyl, halo-d-Ce-alkyl, Ci-C6-alkoxy, halo-Ci-C6-alkoxy, C(0)0-Ci-C6-alkyl, C(0)NH2.
7. A compound according to claim 1 or 2 characterised in that
R8 is selected from the group consisting of C(0)R10, C(0)OR11,
C(0)N(R5c)(R5d), S(0)2R12, d-Ce-alkyl, aryl-Ci-C6-alkyl, 3- to 10-membered heterocycloalkyl, heteroaryl-Ci-C6-alkyl in which said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally substituted up to three times with halogen, hydroxy, Ci-C6-alkoxy, C(0)OH, C(0)0-Ci-C6-alkyl, CN, N(R5a)(R5b), C(0)N(R5c)(R5d;
8. A compound according to any one of the previous claims characterised in that
R9 is hydrogen oder halogen.
9. A compound according to any one of the previous claims characterised in that
R10 is Ci-C6-alkyl which is optionally substituted up to three times with hydroxy,
NH2, halogen, C(0)OH, Ci-C4-alkoxy,or
3- to 10-membered heterocycloalkyl which can be unsubstituted or substituted one to three times with a hydroxy, halogen, cyano, Ci-C4-alkyl; or aryl, heteroaryl, aryl-Ci-C4-alkyl in which said aryl, heteroaryl group is optionally substituted up to three times with halogen, Ci-C6-alkyl; or C(0)OH, C(0)0-Ci-C6-alkyl, C(0)N(R5c)(R5d);
10. A compound according to any one of the previous claims characterised in that
R11 is Ci-C6-alkyl, hydroxy-C2-C6-alkyl;and
R12 is Ci-Ce-alkyl.
1 1 . A compound according to claim 1 having the following formula:
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-benzyl-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-N-[2-(trifluoromethyl)benzyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-6-fluoro-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-6-fluoro-1 -
[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-4-chloro-2-cyclopropyl-N-(2,3-dichlorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-(2,3-dichlorophenyl)-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-N-(3-chloro-2-fluorophenyl)-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-N-(3-chloro-2-fluorophenyl)-2-cyclopropyl-4-fluoro-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-4-chloro-2-cyclopropyl-N-(2,3-difluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-(2,3-difluorophenyl)-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-2-cyclopropyl-N-(2-fluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-4-chloro-N-(4-chloropyridin-3-yl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-N-[2-
(trifluoromethyl)benzyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-4-chloro-2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-4-fluoro-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-4-chloro-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -
[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-4-fluoro-1 -
[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-4-chloro-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
'-acetyl-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
'-acetyl-4-chloro-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide '-acetyl-2-cyclopropyl-4-fluoro-1 -[(4-fluorophenyl)sulfonyl]-N-{[3- (trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dih^
carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(4-methylpyridin-2-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(5-chloro-2-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-(2,5-dichloropyridin-3-yl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(2-chloro-5-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-(2,5-difluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(6-methylpyridin-2-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-[3-(tert-butylsulfamoyl)phenyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{3-[(5-methyl-1 ,2-oxazol-3- yl)sulfamoyl]phenyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-2-cyclopropyl-N-(2,3-dichlorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(3-chloro-2-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(2-chloro-3-fluorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-(2,3-difluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(2-chlorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-(2-fluorophenyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-N-(3,4-dihydro-2H-chromen-4-yl)-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(1 ,2-oxazol-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(5-methylpyridin-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-N-(5-chloropyridin-3-yl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(4-chloropyridin-3-yl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(1 ,3-oxazol-2-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[5-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -{[3-(difluoromethoxy)phenyl]sulfonyl}-N-[2-
(trifluoromethyl)benzyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-2-cyclopropyl-N-[2-(difluoromethyl)benzyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -{[3-(difluoromethoxy)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(2-hydroxybenzyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -{[3-
(difluoromethoxy)phenyl]sulfonyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-fluoro-5-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-1 -[(3-cyanophenyl)sulfonyl]-2-cyclopropyl-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-[(3-fluoropyridin-2-yl)methyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(5-methylpyridin-3-yl)-1 '-(pyrazin-2- ylcarbonyl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{3-[(1 -methylpyrrolidin-2- ylidene)sulfamoyl]phenyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide Methyl-3-{[(1 '-acetyl-2-cyclopropyl-1 -{[3-(difluoromethoxy)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidin]-5-yl)carbonyl]amino}benzoate
1 '-acetyl-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-N-[2-(trifluoromethyl)benzyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-2-cyclopropyl-N-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]methyl}-1 -[(3- methoxyphenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-N-{[3-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-N-[2-(trifluoromethyl)benzyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-(2-chlorobenzoyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyridin-2-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyridin-3-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[(2-chloropyridin-3-yl)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3- (trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[(4-chloropyridin-3-yl)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3- (trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
N-(5-chloropyridin-3-yl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrazin-2- ylcarbonyl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 '-(pyrazin-2-ylcarbonyl)-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrazin-2-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
N-[(3-chloropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrazin- 2-ylcarbonyl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrimidin-5-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[(3-chloropyridin-2-yl)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3- (trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide 2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrimidin-2-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[(3-chloropyrazin-2-yl)carbonyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3- (trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(1 ,3-thiazol-2-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(1 ,3-oxazol-2-ylcarbonyl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
N-benzyl-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide hydrobromide (1 :1 )
N-(2-cyanobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(3-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide hydrobromide (1 :1 )
N-(2-cyanobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 -[(4-fluorophenyl)sulfonyl]-2-methyl-N-[2-(trifluoromethyl)benzyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
formic acid - N-(2-chlorobenzyl)-1 -[(4-hydroxyphenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide (1 :1 )
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -(phenylsulfonyl)-l ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-acetyl-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(4-fluorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -{[4-(trifluoromethoxy)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(2-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-N-(2-chlorobenzyl)-1 -[(3-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(2-chlorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -{[2-(trifluoromethyl)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -{[3-(trifluoromethyl)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -{[4-(trifluoromethyl)phenyl]sulfonyl}-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(2,4-difluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(3-chloro-4-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
methyl 3-({1 '-acetyl-5-[(2-chlorobenzyl)carbamoyl]-2-methylspiro[indole-3,4'-piperidin]-
1 (2H)-yl}sulfonyl)benzoate
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -(pyridin-3-ylsulfonyl)-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-methyl-1 -(pyridin-3-ylsulfonyl)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -[(1 -methyl-1 H-pyrazol-4-yl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-methyl-1 -[(1 -methyl-1 H-imidazol-4-yl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
1 '-(methoxyacetyl)-l -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-benzoyl-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 '-(phenylacetyl)-l ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-(2,2-dimethylpropanoyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2- methylbenzyl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
methyl {1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-5-[(2-methylbenzyl)carbamoyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
{1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-5-[(2-methylbenzyl)carbamoyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
{5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
methyl {5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetate
{5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
1 '-benzyl-N-(2-fluorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-benzyl-N-(2-cyanobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
methyl 1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-5-[(2-methylbenzyl)carbamoyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate
2-hydroxyethyl 5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-
1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 '-carboxylate
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N5-(2-methylbenzyl)-N1 '-phenyl-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
N 1 '-cyclohexyl-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N5-(2-methylbenzyl)-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-(2-methylbenzyl)-1 '-(methylsulfonyl)-l ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(3-methylbut-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-1 -[(4-fluorophenyl)sulfonyl]-2-(3-methylbut-2-en-1 -yl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-1 -[(4-fluorophenyl)sulfonyl]-2-(3-methylbut-2- en-1 -yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-2-cyclopropyl-N-[2-(4-fluorophenyl)propan-2-yl]-1 -[(4-fluorophenyl)sulfonyl]- 1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[1 -(4-chlorophenyl)cyclopropyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]- 1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(3-methylphenyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-[3-(methylsulfonyl)phenyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-(3-sulfamoylphenyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(3-chlorophenyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(2-chloro-4-fluorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(cyclohexylmethyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-benzyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
'-acetyl-1 -[(3-carbamoylphenyl)sulfonyl]-N-(2-chlorobenzyl)-2-cyclopropyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(3-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-[(3-chloro-5-fluoropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-{[3-(trifluoromethyl)pyridin-2- yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-[(3-methylpyridin-2-yl)methyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-[(3-chloropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(2-chlorobenzyl)-2-ethenyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(2-chlorobenzyl)-2-(cyclopropylmethyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-1 -[(4-fluorophenyl)sulfonyl]-N-[(3-methylpyridin-2-yl)methyl]-2-(prop-2-en-1 - yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
'-acetyl-N-[(3-chloropyridin-2-yl)methyl]-1 -[(4-fluorophenyl)sulfonyl]-2-(prop-2-en-1 - yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(2-hydroxyethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(hydroxymethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-N-[2-(4-fluorophenyl)propan-2-yl]-1 -[(4-fluorophenyl)sulfonyl]-1 '-
(oxetan-3-yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[(3-methyloxetan-3- yl)carbonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[(1 ,5-dimethyl-1 H-pyrazol-3-yl)carbonyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 -[(4-fluorophenyl)sulfonyl]-N-[(3-methylpyridin-2-yl)methyl]-1 '-(oxetan-3-yl)-2-(prop-2- en-1 -yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 -[(4-fluorophenyl)sulfonyl]-N-[(3-methylpyridin-2-yl)methyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N 2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-N1 \N1 \2-trimethyl-1 ,2-dihydro-1 'H- spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 '-(pyrrolidin-1 -ylcarbonyl)-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 '-(morpholin-4-ylcarbonyl)-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N5-(2-chlorobenzyl)-N1 '-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
N-(4-fluorobenzyl)-2-methyl-1 -[(1 -methyl-1 H-pyrazol-5-yl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-cyanophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-methyl-1 -[(1 -methyl-1 H-pyrazol-5-yl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-[(1 E)-prop-1 -en-1 -yl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[2-(diethylamino)ethyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[(ethylamino)(oxo)acetyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[3-(ethylamino)-3-oxopropyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 2-cyclopropyl-1 '-[2-(ethylamino)-2-oxoethyl]-1 -[(4-fluorophenyl)sulfonyl]-N-[2-
(trifluoromethyl)benzyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[2-(ethylamino)-2-oxoethyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 2-cyclopropyl-1 '-[2-(ethylamino)-2-oxoethyl]-N-(2-fluorobenzyl)-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide ethyl {5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}(oxo)acetate
ethyl {5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
N-(2-chlorobenzyl)-1 -[(4-cyanophenyl)sulfonyl]-2-cyclopropyl-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 '-[2-(dimethylamino)-2-oxoethyl]-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide methyl {5-[(2-chlorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-2-methyl-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
methyl (2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-5-{[2-
(trifluoromethyl)benzyl]carbamoyl}-1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '- yl)acetate
methyl {5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
methyl {2-cyclopropyl-5-[(2-fluorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
methyl {5-[(2-chlorobenzyl)carbamoyl]-2-cyclobutyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetate
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-N-[2-(trifluoromethyl)benzyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-methyl-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-methoxyphenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-methoxyphenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide hydrobromide (1 :1 ) N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-phenyl-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-[(1 E)-prop-1 -en-1 -yl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-[(1 E)-prop-1 -en-1 -yl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-methoxyphenyl)sulfonyl]-2-[(1 E)-prop-1 -en-1 -yl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide hydrobromide (1 :1 )
1 '-acetyl-N-(2-chloro-4-fluorobenzyl)-1 -[(3-cyano-4-methoxyphenyl)sulfonyl]-2- cyclopropyl-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-1 -[(3-cyano-4-methoxyphenyl)sulfonyl]-2-cyclopropyl-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-1 -[(3-cyano-4-methoxyphenyl)sulfonyl]-2- cyclopropyl-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chloro-4-fluorobenzyl)-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-acetyl-N-[(3-chloropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(3-methoxyphenyl)sulfonyl]-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(2-methoxyethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 '-(cyanomethyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[2-(2-oxa-6- azaspiro[3.3]hept-6-yl)-2-oxoethyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
1 '-[2-(azetidin-1 -yl)-2-oxoethyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-N-[2-
(trifluoromethyl)benzyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-[2-(azetidin-1 -yl)-2-oxoethyl]-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide 1 '-[2-(azetidin-1 -yl)-2-oxoethyl]-2-cyclopropyl-N-(2-fluorobenzyl)-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-[2-(morpholin-4-yl)-2- oxoethyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
1 '-[azetidin-1 -yl(oxo)acetyl]-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(pyrazin-2-ylcarbonyl)-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chloro-4-fluorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-
1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-N-{[3-
(trifluoromethyl)pyridin-2-yl]methyl}-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5- carboxamide
N-[(3-chloropyridin-2-yl)methyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-
3-yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(1 H-tetrazol-5- ylmethyl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 '-(2-cyanoethyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-benzyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
1 '-[2-(azetidin-1 -yl)-2-oxoethyl]-N-(2-chlorobenzyl)-2-cyclobutyl-1 -[(4- fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide N-(2-chlorobenzyl)-2-cyclobutyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-
3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-2-ethenyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-[(3-chloropyridin-2-yl)methyl]-1 -[(4-fluorophenyl)sulfonyl]-1 '-(oxetan-3-yl)-2-(prop-2- en-1 -yl)-1 ,2-dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-[(3-chloropyridin-2-yl)methyl]-1 -[(4-fluorophenyl)sulfonyl]-2-(prop-2-en-1 -yl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
2-(but-3-en-1 -yl)-N-(2-chlorobenzyl)-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N5-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-1 Ή- spiro[indole-3,4'-piperidine]-1 ',5-dicarboxamide
2-amino-4-{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-
1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}-4-oxobutanoic acid 1 '-(2-aminoethyl)-N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}(oxo)acetic acid
5-{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}pentanoic acid
4-{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}butanoic acid
3-{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2- dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}propanoic acid
(2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-5-{[2-(trifluoromethyl)benzyl]carbamoyl}-
1 ,2-dihydro-1 'H-spiro[indole-3,4'-piperidin]-1 '-yl)acetic acid
{5-[(2-chlorobenzyl)carbamoyl]-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
{2-cyclopropyl-5-[(2-fluorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
{5-[(2-chlorobenzyl)carbamoyl]-2-cyclobutyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
{2-cyclobutyl-5-[(2-fluorobenzyl)carbamoyl]-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydro-
1 'H-spiro[indole-3,4'-piperidin]-1 '-yl}acetic acid
N-(2-chlorobenzyl)-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 '-(2-hydroxyethyl)-1 ,2- dihydrospiro[indole-3,4'-piperidine]-5-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-2-chloro-5-fluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-2,6-difluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-5-fluoro-2-(trifluoromethyl)benzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-2,5-difluorobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-3-cyanobenzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-3-(trifluoromethyl)benzamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-3-(difluoromethyl)benzamide -{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-3-chlorobenzamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-3-fluorobenzamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-3-fluoro-2-(trifluoromethyl)benzamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-2-chloro-3-fluorobenzamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-2-(difluoromethyl)benzamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-2-chlorobenzamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-2-fluorobenzamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}pyridine-3-carboxamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-2-(difluoromethyl)pyridine-3-carboxamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-2-chloronicotinamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-1 ,2-thiazole-5-carboxamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-1 ,2-oxazole-3-carboxamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-5-methylnicotinamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-5-(trifluoromethyl)nicotinamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}pyrimidine-5-carboxamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-1 ,3-thiazole-5-carboxamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-1 ,2-thiazole-4-carboxamide
-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4 piperidin]-5-yl}-1 ,3-oxazole-4-carboxamide N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-1 ,3-thiazole-4-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-1 ,3-thiazole-2-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-1 ,3-oxazole-2-carboxamide
N-{1 '-acetyl-2-cyclopropyl-1 -[(4-fluorophenyl)sulfonyl]-1 ,2-dihydrospiro[indole-3,4'- piperidin]-5-yl}-1 ,2-oxazole-5-carboxamide
methyl 3-({1 '-acetyl-5-[(cyclohexylcarbonyl)amino]-2-cyclopropylspiro[indole-3,4'- piperidin]-1 (2H)-yl}sulfonyl)benzoate
3-({1 '-acetyl-5-[(cyclohexylcarbonyl)amino]-2-cyclopropylspiro[indole-3,4'-piperidin]-
1 (2H)-yl}sulfonyl)benzamide
N-{1 '-acetyl-1 -[(3-carbamoylphenyl)sulfonyl]-2-cyclopropyl-1 ,2-dihydrospiro[indole-
3,4'-piperidin]-5-yl}-2,5-difluorobenzamide
A compound according to any one of the claims 1 to 1 1 for use as a medicament. A compound according to any one of the claims 1 to 1 1 for use in the treatment 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, 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.
A compound according to any one of the claims 1 to 1 1 for use as contraceptive. A pharmaceutical composition comprising a compound according to any one of the claims 1 to1 1.
PCT/EP2014/077680 2013-12-19 2014-12-15 Spiro[indolin-3,4'-piperidine] derivatives as gnrh receptor antagonists WO2015091315A1 (en)

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WO2023244657A1 (en) * 2022-06-16 2023-12-21 Lieber Institute, Inc. Non-acid inhibitors of inositol hexakisphosphate kinase (ip6k) and methods of use thereof

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WO2000004013A1 (en) * 1998-07-14 2000-01-27 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone
WO2013107743A1 (en) * 2012-01-16 2013-07-25 Bayer Intellectual Property Gmbh Spiroindoline derivatives as gonadotropin- releasing hormone receptor antagonists

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WO2000004013A1 (en) * 1998-07-14 2000-01-27 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone
WO2013107743A1 (en) * 2012-01-16 2013-07-25 Bayer Intellectual Property Gmbh Spiroindoline derivatives as gonadotropin- releasing hormone receptor antagonists

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Title
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023244657A1 (en) * 2022-06-16 2023-12-21 Lieber Institute, Inc. Non-acid inhibitors of inositol hexakisphosphate kinase (ip6k) and methods of use thereof

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