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WO2009013293A1 - Substituted cyclohexanecarboxamides useful as bace inhibitors - Google Patents

Substituted cyclohexanecarboxamides useful as bace inhibitors Download PDF

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Publication number
WO2009013293A1
WO2009013293A1 PCT/EP2008/059606 EP2008059606W WO2009013293A1 WO 2009013293 A1 WO2009013293 A1 WO 2009013293A1 EP 2008059606 W EP2008059606 W EP 2008059606W WO 2009013293 A1 WO2009013293 A1 WO 2009013293A1
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alkyl
alkoxy
group
amino
ring
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PCT/EP2008/059606
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French (fr)
Inventor
Stephen Hanessian
Dilip Kumar Maji
Zhihui Shao
Govindan Subramaniyan
Marina Tintelnot-Blomley
Gaoqiang Yang
Hongying Yun
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Novartis Ag
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Publication of WO2009013293A1 publication Critical patent/WO2009013293A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel amide compounds, to their preparation, to their use as medicaments and to medicaments comprising them.
  • the invention relates to a compound of the formula
  • R b is hydrogen; Ci-C 8 -alkyl; trifluoromethyl; Ci-C 8 -alkoxy; d-C 4 -alkoxy-d-C 4 - alkyl; d-C 8 -alkylthio; C 1 -C 4 -alkylthio-Ci-C 4 -alkyl; C 3 -C 8 -cycloalkyl; C 3 -C 8 -CyC- loalkyl-d-C 4 -alkyl; heterocyclyl; heterocyclyl-Ci-C 4 -alkyl; amino; d-C 8 -alkyl- amino; or dKd-Cs-alkyOamino with two identical or different d-C 8 -alkyl moieties, which two d-Cs-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted
  • R 2 and R 3 are either, independently from each other, hydrogen; Ci-C 8 -alkyl; Ci-C 4 -alkoxy-Ci-C 4 -alkyl; d-d-alkylthio-d-d-alkyl; or an aryl-d-C 4 -alkyl or heteroaryl-d-C 4 -alkyl group, which aryl-Ci-C 4 -alkyl or heteroaryl-Ci-C 4 -alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl, heteroaryl, Ci-C 6 -alkyl, hydroxy- Ci-C 4 -alkyl, Ci-C 4 -alkoxy-Ci-C 4 -alky
  • R 4 is hydrogen; hydroxy; or d-C 6 -alkoxy
  • R 5 and R 6 taken together, complete, together with the 2 carbon atoms, to which they are attached, and together with the methylene group, to which the said 2 carbon atoms are attached, a saturated ring, which ring is, in addition to the substitution by the substituents (Ri)(R 2 )(R 3 )C and R 4 and the N-substituted aminocarbonyl group depicted in the formula I, optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of d-C 8 -a!kyl, oxo, hydroxy, Ci-C 8 -alkoxy, Ci-C 4 -alkoxy- Ci-C 4 -alkyl, d-Cs-alkylthio, Ci-C 4 -alkylthio-d-C 4 -alkyl, formyl, d-Cs-alkylcarbonyl, C 1 -C 8 - alkoxycarbonyl, carbamyl, N-d-d
  • ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C ⁇ -alkyl moieties of the N,N-di- (C 1 -C 8 - alkyl)carbamyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, CrC 8 - alkylsulfonyl, d-C 8 -alkoxysulfonyl, aminosulfonyl, N-CrC 8 -alkylaminosulfonyl, N,N-di- (Ci-C B -alkyl)aminosulfonyl with two identical or different Ci-C 8 -alkyl moieties, which two Ci-Cs-alkyl
  • ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl, heteroaryl, C r C 6 -alkyl, hydroxy-d-C 4 -alkyl, Ci-C 4 -alkoxy-d-C 4 -alkyl, C r C 4 -alkyl- carbonyl-Ci-C 4 -alkyl, trifluoromethyl, hydroxy, Ci-C 6 -alkoxy, Ci-d-alkoxy-d-d-alkoxy, Ci-C 4 -alkylcarbonyl-Ci-C 4 -alkoxy, benzyloxy, phenoxy, formyloxy, d-C 4 -alkylcarbonyl- oxy, carbamyloxy, N-Ci-d
  • R 8 is hydrogen; and R 9 is hydroxy or
  • R 8 and R 9 taken together, are oxo
  • R c is a Ci-C 8 -alkyl, Ci-C 4 -alkoxy-CrC 4 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl- Ci-C 4 -alkyl group, which Ci-C 8 -alkyl, Ci-C 4 -alkoxy-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, C 1 - C 6 -alkyl, hydroxy-d-C 4 -alkyl, Ci-C 4 -alkoxy-Ci-C 4 -alkyl, oxo, hydroxy, d-C 6 -alkoxy, Ci-C 4
  • R f is hydrogen; a d-C 8 -alkyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group, which d-C 8 -al- kyl or Cs-C ⁇ -cycloalkyl-d-d-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, d-C 6 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-d -C 4 -alky I, fluoromethyl, difluoro- methyl, trifluoromethyl, oxo, hydroxy, d-C 6 -alkoxy, d-C 4 -alkoxy-d-C 4 -alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy, Ci-C 4 -alkyl
  • the C 4 -C 8 -cycloalkyl moiety which C 4 -C 8 -cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C 6 -alkoxy, CrC 4 -alkoxy-d-C 4 -alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy, d-C 4 -alkoxycarbonyloxy, d-C 4 -alkylthio, C 1 -C 4 - alkylsulfinyl, d-C 4 -alkylsulfonyl, formyl, Ci-C 4 -alkylcarbonyl, d-C 4 -alkoxycarbonyl, a d-C ⁇ -alkyl, C 3 -C
  • R h being hydrogen; a d-C ⁇ -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group, which d-C 8 -alkyl, C 3 -C 8 -cycioalkyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, d-C 6 -alkyl, hydroxy-d-C 4 -alkyl, C 1 -C 4 - alkoxy-d-C 4 -alkyl, oxo, hydroxy, d-Ce-alkoxy, d-C 4 -alkoxy-d-C 4 -alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy,
  • a corresponding compound of the formula I may exist in pure optically active form or in the form of a mixture of optical isomers, e. g. in the form of a ra- cemic mixture. All of such pure optical isomers and all of their mixtures, including the racemic mixtures, are part of the present invention.
  • a compound of the formula I may exist in free form or in salt form, e. g. a basic compound in acid addition salt form or an acidic compound in the form of a salt with a base. All of such free compounds and salts are part of the present invention.
  • a compound of the formula I may exist in tautomeric form. All of such tautomers are part of the present invention.
  • Halogen denotes fluorine, chlorine, bromine or iodine.
  • An aryl group, ring or moiety is a naphthyl or, preferably, phenyl group, ring or moiety.
  • a heteroaryl group, ring or moiety is an aromatic 5- or 6-membered structure, in which structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidyl or pyridyl, and which structure can also be anellated with a phenyl ring, such as benzothiazolyl, benzoxazolyl or quinolyl.
  • structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as furyl,
  • a heterocyclyl group, ring or moiety is a non-aromatic 5- or 6-membered cyclic structure, in which cyclic structure 1 , 2 or 3 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl or morpholinyl.
  • Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
  • carbon containing groups, moieties or molecules contain 1 to 8, preferably 1 to 6, preferably 1 to 4, preferably 1 or 2, carbon atoms.
  • the invention relates to a compound of the formula I, in free form or in salt form, in which
  • R b is hydrogen; d-C 8 -alkyl; trifluoromethyl; d-C 8 -alkoxy; C ! -C 4 -a IkOXy-C 1 -C 4 - alkyl; d-C 8 -alkylthio; C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl; C 3 -C 8 -cycloalkyl; C 3 -C 8 -cyc- loalkyl-C r C 4 -alkyl; heterocyclyl; hete TOCyCIyI-C 1 -C 4 -alky I; amino; d-C 8 -alkyl- amino; or di-(CrCs-alkyl)amino with two identical or different d-C 8 -alkyl moieties, which two d-Cs-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached
  • R b is hydrogen; Ci-C 8 -alkyl; trifluoromethyl; Ci-Cs-alkoxy; d-d-alkoxy-Ci-d- alkyl; Ci-C 8 -alkylthio; Ci-C 4 -alkylthio-C 1 -C 4 -a!kyl; C 3 -C 8 -cyc!oalkyl; C 3 -C 8 -cyc- loalkyl-C r C 4 -alkyl; heterocyclyl; heterocyclyl-Ci-d-alkyl; amino; d-C 8 -alkyl- amino; or di-(d-C 8 -alkyl)amino with two identical or different d-C 8 -alkyl moieties, which two d-C 8 -alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted
  • R b is d-C ⁇ -alkyl; d-C 8 -alkoxy; or trifluoromethyl or R a and R b , taken together, are straight-chain d-C 5 -alkylene and in which formula Id
  • R a is hydrogen
  • R 3 and R b taken together, are straight-chain CrC 5 -alkylene
  • R 2 and R 3 are either, independently from each other, hydrogen; d-C 8 -alkyl; Ci-C 4 -alkoxy-d-C 4 -alkyl; d-d-alkylthio-d-d-alkyl; or an aryl-d-C 4 -alkyl or heteroaryl-C r C 4 -alkyl group, which aryl-C r C 4 -alkyl or heteroaryl-d-d-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl, heteroaryl, d-C 6 -alky!, hydroxy- d-C 4 -alkyl, d-C 4 -alkoxy-d-C 4 -alky
  • R 4 is hydrogen; hydroxy; or Ci-C 6 -alkoxy; preferably hydrogen; or hydroxy; preferably hydrogen;
  • R 5 and R 6 taken together, complete, together with the 2 carbon atoms, to which they are attached, and together with the methylene group, to which the said 2 carbon atoms are attached, a saturated ring, which ring is, in addition to the substitution by the substituents (R 1 )(R 2 )(R 3 )C and R 4 and the N-substituted aminocarbonyl group depicted in the formula I, optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C 8 -alkyl, oxo, hydroxy, Ci-C 8 -alkoxy, Ci-C 4 -alkoxy- Ci-C 4 -alkyl, d-C ⁇ -alkylthio, d-C 4 -alkylthio-d-C 4 -alkyl, formyl, Ci-C 8 -alkylcarbonyl, C 1 -C 8 - alkoxycarbonyl, carbamyl, N-
  • R 7 is a d-C ⁇ -alkyl, C 3 -C 8 -cycloalkyl or Cs-C ⁇ -cycloalkyl-d-d-alkyl group, which C 1 -C 8 - alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-CrC 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C 3 -C 8 -cycloalkyl, heterocyclyl, Ci-C 6 -alkyl, hydroxy-Ci-C 4 -alkyl, Ci-C 4 -alkoxy-Ci-C 4 -alkyl, oxo, hydroxy, CrC ⁇ -alkoxy, Ci-C 4 -alkoxy-Ci-C 4 -alkoxy, formyloxy, d-C 4 -alkylcarbonyl- oxy,
  • R 8 is hydrogen; and R 9 is hydroxy
  • R 8 and R 9 taken together, are oxo; preferably R 8 is hydrogen; and R 9 is hydroxy;
  • R 0 is a d-C 8 -alkyl, d-C 4 -alkoxy-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl- Ci-C 4 -alkyl group, which d-C 8 -alkyl, d-C 4 -alkoxy-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, C 1 - C ⁇ -alkyl, hydroxy-d-C 4 -alkyl, d-d-alkoxy-d-Oi-alkyl, oxo, hydroxy, CrC 6 -alkoxy, d-d-
  • R f is hydrogen; a d-C 8 -alkyl or Ca-Cs-cycloalkyl-d-d-alkyl group, which Ci-C 8 -al- kyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, d-C ⁇ -aikyl, hydroxy-d-C 4 -alkyl, d-C 4 -alkoxy-Ci-C 4 -alkyl, fluoromethyl, difluoro- methyl, trifluoromethyl, oxo, hydroxy, d-C 6 -alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy, C r C 4 -alkylthio, Ci-C 4 -alkylsulfinyl, CrC ⁇ alkyl
  • the d-C ⁇ -cycloalkyl moiety which C 4 -C 8 -cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C 6 -alkoxy, d-C 4 -alkoxy-d-C 4 -alkoxy, formyloxy, d-d-alkylcarbonyloxy, d-C 4 -alkoxycarbonyloxy, d-C 4 -alkylthio, C 1 -C 4 - alkylsulfinyl, d-C 4 -alkylsulfonyl, formyl, C 1 -C 4 -alkylcarbonyl, CrC ⁇ alkoxycarbonyl, a d-C ⁇ -alkyl, C 3 -C 8 -cycl
  • R h being hydrogen; a C r C 8 -alkyl, C 3 -C 8 -cycloalkyl or Ca-C ⁇ -cycloalkyl-d-d-alkyl group, which Ci-C 8 -alkyl, C 3 -C 8 -cycloalkyl or C 3 -C 8 -cycloalkyl-d-C 4 -alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C 3 -C 8 -cycloalkyl, CrC 6 -alkyl, hydroxy-d-C 4 -alkyl, C 1 -C 4 - alkoxy-C r C 4 -alkyl, oxo, hydroxy, d-C 6 -alkoxy, d-d-alkoxy-d-d-alkoxy, formyloxy, d-C 4 -alkylcarbonyloxy, d-d-alkylthio,
  • R c is d-Cs-alkyl
  • R d and Re are, independently from each other, hydrogen; or d-C ⁇ -alkyl; and in which formula Ih k is 0;
  • R f is an aryl-Crd-alkyl group, which aryl-d -C 4 -alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C 3 -C 8 -cycloalkyl, C 3 -C8-cycloalkyl-d-C 4 -alkyl, aryl, hetero- aryl, d-C 6 -alkyl, hydroxy-d-C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, d-C 4 -alkylcarbo- nyl-d-d-alkyl, trifluoromethyl, hydroxy, CrC 6 -alkoxy, d-C 4 -alkoxy-d-d-alkoxy, d-C 4 -alkylcarbonyl-d-C 4 -alkoxy
  • R c is d-Ce-alkyl
  • R d and R e are, independently from each other, hydrogen; or d-C 8 -alkyl; and in which formula Ih k is 0; and Rf is an aryl-Ci-C 4 -alkyl group, which aryl-d-C 4 -alkyl group is optionally ring-substituted by 1 or 2 substituents independently selected from the group, consisting of
  • R c is d-Ce-alkyl
  • R d and R e are, independently from each other, hydrogen; or C r C 8 -alkyl; and in which formula Ih k is O; and
  • R f is an aryl-C r C 4 -alkyl group ring-substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C 6 -alkyl; preferably R 10 is a group of the formula (CH 2 ) k N(H)R f (Ih), in which formula Ih k is 0; and
  • R f is an aryl-CrC 4 -alkyl group ring-substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C ⁇ -alkyl.
  • the preferred embodiments (1 ) to (7) are preferred independently, collectively or in any combination or sub-combination.
  • the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
  • the invention relates to a process for the preparation of a compound of the formula I, in free form or in salt form, comprising the steps of
  • R 1 , R 2 , R 3 , R 4 , Rs and R 6 are as defined for the formula I and L 1 is a leaving group, in free form or in salt form, with a compound of the formula in which R 7 , Re, Rg and R 10 are as defined for the formula I, in free form or in salt form, or
  • a leaving group L 1 , L 2 , L 3 or L 4 is, e. g., halogen, such as F, Cl or Br, hydroxy or Ci-C 8 - alkoxy, such as methoxy, preferably Cl or hydroxy.
  • the reactions can be effected according to conventional methods, for example as described in the Examples.
  • Salts may be prepared from free compounds in known manner, and vice-versa.
  • the starting materials of the formulae II, III, IV, V, Vl and VII are known or may be prepared according to conventional procedures starting from known compounds, for example as described in the Examples.
  • Compounds of the formula I, in free form or in pharmaceutically acceptable salt form, hereinafter often referred to as "agents of the invention" exhibit valuable pharmacological properties, when tested in vitro or in vivo, and are, therefore, useful in medicaments.
  • agents of the invention are inhibitors of aspartic proteases and can be used for the treatment of a condition, disease or disorder involving processing by such enzymes.
  • agents of the invention inhibit beta-secretase and, thus, the generation of beta-amyloid and the subsequent aggregation into oligomers and fibrils.
  • the inhibiting properties of an agent of the invention towards proteases can be evaluated, e. g., in a test as described hereinafter.
  • Recombinant BACE (extracellular domain, expressed in baculovirus and purified using standard methods) at 0.1 to 10 nM concentrations is incubated with the test compound at various concentrations for 1 hour at room temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1 % CHAPS.
  • Synthetic fluorescence-quenched peptide substrate derived from the sequence of APP and containing a suitable fluorophore-quencher pair, is added to a final concentration of 1 to 5 ⁇ M, and the increase in fluorescence is recorded at a suitable excitation / emission wavelength in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals.
  • IC 5O values are calculated from percentage of inhibition of BACE-activity as a function of the test compound concentration.
  • Test 2 Inhibition of human BAC E-2
  • Recombinant BACE-2 (extracellular domain, expressed in baculovirus and purified using standard methods) at 0.1 to 10 nM concentrations is incubated with the test compound at various concentrations for 1 hour at room temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1 % CHAPS.
  • Synthetic peptide substrate derived from the sequence of APP and containing a suitable fluorophore-quencher pair, is added to a final concentration of 1 to 5 ⁇ M, and the increase in fluorescence is recorded at a suitable excitation / emission wavelength in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals.
  • IC 50 values are calculated from percentage of inhibition of BACE-2-activity as a function of the test compound concentration.
  • Test 3 Inhibition of human cathepsin D Recombinant cathepsin D (expressed as procathepsin D in baculovirus, purified using standard methods and activated by incubation in sodium formate buffer pH 3.7) is incubated with the test compound at various concentrations for 1 hour at room temperature in sodium formate or sodium acetate buffer at a suitable pH within the range of pH 3.0 to 5.0.
  • Synthetic peptide substrate Mca-Gly-Lys-Pro-lle-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-NH 2 is added to a final concentration of 1 to 5 ⁇ M, and the increase in fluorescence is recorded at excitation of 325 nm and emission at 400 nm in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals.
  • IC 5 O values are calculated from the percentage of inhibition of cathepsin D-activity as a function of the test compound concentration.
  • Test 4 Inhibition of cellular release of amyloid peptide 1-40
  • Chinese hamster ovary cells are transfected with the gene for amyloid precursor protein.
  • the cells are plated at a density of 8000 cells/well into 96-well microtiter plates and cultivated for 24 hours in DMEM cell culture medium containing 10 % FCS.
  • the test compound is added to the cells at various concentrations, and the cells are cultivated for 24 hours in the presence of the test compound.
  • the supematants are collected, and the concentration of amyloid peptide 1-40 is determined using sandwich ELISA.
  • the potency of the compound is calculated from the percentage of inhibition of amyloid peptide release as a function of the test compound concentration.
  • agents of the invention show activity at concentrations below 50 ⁇ M.
  • Example 6 shows an IC 50 value of 4.22 ⁇ M in Test 1.
  • agents of the invention are useful, e. g., in the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, such as a neurodegenerative condition, disease or disorder, e. g.
  • BACE-2 beta-site APP-cleaving enzyme 2
  • cathepsin D which are close homologues of the pepsin-type aspartyl proteases and beta-secretase
  • the appropriate dosage will vary depending on, e. g., the compound employed as active pharmaceutical ingredient, the host, the mode of administration, the nature and severity of the condition, disease or disorder or the effect desired.
  • a daily dosage of from about 0.1 to about 100, preferably from about 1 to about 50, mg/kg of animal body weight.
  • an indicated daily dosage is in the range of from about 0.5 to about 2000, preferably from about 2 to about 200, mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
  • An agent of the invention may be administered by any conventional route, in particular en- terally, preferably orally, e. g. in the form of a tablet or capsule, or parenterally, e. g. in the form of an injectable solution or suspension.
  • the invention in a further aspect, relates to an agent of the invention for use as a medicament, e. g. for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
  • the invention relates to the use of an agent of the invention as active pharmaceutical ingredient in a medicament, e. g. for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an agent of the invention as active pharmaceutical ingredient in association with at least one pharmaceutically acceptable carrier or diluent.
  • Such a composition may be manufactured in conventional manner, e. g. by mixing its components.
  • Unit dosage forms contain, e. g., from about 0.1 to about 1000, preferably from about 1 to about 500, mg of an agent of the invention.
  • An agent of the invention can be administered as sole active pharmaceutical ingredient or as a combination with at least one other active pharmaceutical ingredient effective, e. g., in the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or in the suppression of the metastasis process associated with tumor cells.
  • Such a pharmaceutical combination may be in the form of a unit dosage form, which unit dosage form comprises a predetermined quantity of each of the at least two active components in association with at least one pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical combination may be in the form of a package comprising the at least two active components separately, e. g. a pack or dispenser-device adapted for the concomitant or separate administration of the at least two active components, in which these active components are separately arranged.
  • the invention relates to such pharmaceutical combinations.
  • the invention relates to the use of an agent of the invention for the manufacture of a medicament for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
  • the invention relates to a method for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells, in a subject in need of such treatment, prevention or suppression, which method comprises administering to such subject an effective amount of an agent of the invention.
  • building block A3a (10 mg, 0.042 mmol) in DCM (1.5 ml) are added under argon at 0 0 C pyridine (34.0 ⁇ l, 0.42 mmol) and CH 2 CHCOCI (17.1 ⁇ l, 0.21 mmol). The mixture is stirred for 30 min, quenched with aqueous 1 N hydrochloric acid (0.5 ml) and extracted with DCM. The organic layer is washed with water, dried over sodium sulfate and evaporated. The purification of the residue by column chromatography yields a colorless oil.
  • a solution of building block A5a) (0.437 g, 1.44 mmol), mercuric chloride (1.57 g, 5.82 mmol) and perchloric acid (0.62 ml of a 70% aqueous solution, 4.35 mmol) in methanol (35 ml) is heated to reflux for 2 h.
  • the reaction mixture is neutralized with saturated aqueous bicarbonate solution and extracted with DCM.
  • the combined organic layers are washed with brine, dried over sodium sulfate and concentrated to yield a diastere- omeric mixture of the ester as a thick gum.
  • This product is, together with sodium methoxide in methanol (0.5 M, 5 ml), heated to reflux for 48 h.
  • reaction mixture is stirred at rt for 3 h and then quenched with aqueous ammonium chloride solution.
  • organic layer is diluted with EtOAc, washed with hydrochloric acid (1 N) and sodium bicarbonate solution, dried and concentrated.
  • the residue is purified by chromatography (EtOAc:hexanes 1 :1) to yield a colorless oil.
  • Building block A1 b) (200 mg, 0.86 mmol) is dissolved in CH 3 OH (10 ml) in a thick-walled tube. Raney-Ni (50% in water, 1.5 ml) is added, followed by a catalytic amount of H 2 PtCI 6 . The mixture is stirred under H 2 (60 psi) for 14 h (until TLC shows the full consumption of the starting material). The catalyst is filtered off, and the filtrate is evaporated to yield the crude amine, which is dissolved in DCM (3.3 ml) and water (1.6 ml). Sodium carbonate (159 mg, 1.4 mmol) is added, and the mixture is stirred for 10 min.
  • building block A6b 38 mg, 0.16 mmol
  • acetone (2 ml) and saturated sodium bicarbonate solution 0.5 ml
  • sodium bromide 4 mg, 0.04 mmol
  • TEMPO TEMPO
  • trichloroisocyanuric acid 73 mg, 0.32 mmol
  • the mixture is stirred overnight at a temperature between O 0 C and rt.
  • lsopropanol (1 ml) is added.
  • the mixture is filtered through a pad of Celite, and the filter cake is washed with EtOAc.
  • the combined filtrates are washed with 1 N aqueous hydrochloric acid (2 ml) and brine, dried over sodium sulfate and concentrated to yield the title compound.
  • a solution of building block A9b) in CH 3 OH (10 ml) is overnight subjected to reduction in the presence of Raney-Ni (20 mg) and H 2 PtCI 6 (5 mg) under a hydrogen atmosphere (60 psi).
  • the mixture is filtered, and to the filtrate is added BOC 2 O in dioxane and aqueous 1 N NaOH.
  • the mixture is stirred for 12 h, neutralized with 0.1 N aqueous hydrochloric acid and extracted with EtOAc.
  • the extract is dried over sodium sulfate and evaporated.
  • Example 1 (1 R,3S)-3-(1-Acetvlamino-1-methvl-ethyl)-cvclohexanecarboxvlic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
  • the title compound is prepared in a manner analogous to that described in Example 1 starting from building block A4 and building block B1.
  • Example 5 (1 R,3S)-3-(1 -Acetylamino-cyclopentyl)-cyclohexanecarboxy lie acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
  • the title compound is prepared in a manner analogous to that described in Example 6 starting from building block A2 and building block B2.
  • Example 8 (1 R,3S)-3-f1-IVIethvl-1-(methvl-propionvl-amino)-ethvll-cvclohexanecar- boxylic acid [(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide
  • the title compound is prepared in a manner analogous to that described in Exampie 6 starting from building block A6 and building block B2.
  • Example 10 (1 R,3S)-3-H -Methyl-1 -(2-oxo-piperidin-1 -vD-ethyll-cvclohexanecarboxylic acid t(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide
  • Example 11 (1R.3S)-3-((S)-1-Acetvlamino-2-methvl-propyl)-cvclohexanecarboxvlic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
  • Example 12 f(S)-1-r(1 R,3R)-3-((1S.2S.4R)-1-Benzvl-4-butylcarbamovl-2-hvdroxv- pentylcarbamoyl)-1-hydroxy-cyclohexyl]-butyl ⁇ -carbamic acid tert-butyl ester (assignment of stereochemistry of amino substituent arbitrary)
  • Example 12 The title compound of Example 12 (10 mg) is treated with TMSI (15 ⁇ l) in 0.5 ml of DCM. The mixture is stirred at 0 0 C for 30 min and then evaporated. The residue is dissolved in DCM. To the solution are added solid sodium bicarbonate and acetyl chloride (10 ⁇ l, 10 eqivalents). The mixture is diluted with EtOAc, washed with aqueous sodium carbonate solution, dried over sodium sulfate and evaporated to yield the title compound.
  • HRMS (M + I) + 532.3442; calculated M + 531.3672.
  • Example 14 f(R)-1-f(1 R,3R)-3-((1S.2S.4R)-1-Benzvl-4-butvlcarbamovl-2-hvdroxy-pen- tylcarbamoyl)-1-hydroxy-cyclohexyl]-butyl ⁇ -carbamic acid tert-butyl ester (assignment of stereochemistry of amino substituent arbitrary)
  • Example 15 (1 R,3R)-3-((R)-1 -Acetylamino-butyl)-3-hydroxy-cyclohexanecarboxylic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide (assignment of stereochemistry of amino substituent arbitrary)
  • Example 14 The title compound is prepared in a manner analogous to that described in Example 13 starting from the title compound of Example 14.
  • Example 16 (1 R,3R)-3-Hydroxy-3-(1 -methy lcarbamoyl-buty l)-cyclohexanecarboxylic acid ((1 S,2S ,4R)-1 -benzyl-4-butylcarbamoyl-2-hydroxy-penty l)-amide

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Abstract

The invention relates to novel amide compounds of the formula (I) in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.

Description

Substituted cvclohexanecarboxamides useful as BACE inhibitors
The present invention relates to novel amide compounds, to their preparation, to their use as medicaments and to medicaments comprising them.
More particularly, the invention relates to a compound of the formula
Figure imgf000002_0001
in which
R1 is a group of the formula N(Ra)-C(=O)Rb (Ia); N(Ra)-S(=O)Rb (Ib); N(Ra)-S(=O)2Rb (Ic); C(=O)-N(Ra)Rb (Id); S(=O)-N(Ra)Rb (Ie); or S(=O)2-N(Ra)Rb (If), in which formulae Ia, Ib and Ic either Ra is hydrogen; Ci-C8-alkyl; d-C4-alkoxy-d-C4-alkyl; d-C4-alkylthio- Ci-C4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl; or heterocyclyl-d-d-alkyl; and
Rb is hydrogen; Ci-C8-alkyl; trifluoromethyl; Ci-C8-alkoxy; d-C4-alkoxy-d-C4- alkyl; d-C8-alkylthio; C1-C4-alkylthio-Ci-C4-alkyl; C3-C8-cycloalkyl; C3-C8-CyC- loalkyl-d-C4-alkyl; heterocyclyl; heterocyclyl-Ci-C4-alkyl; amino; d-C8-alkyl- amino; or dKd-Cs-alkyOamino with two identical or different d-C8-alkyl moieties, which two d-Cs-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, Ci-C6-alkoxy and C1- Ce-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-Cβ-alkyl moieties of the di-(d-C8-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, or Ra and Rb, taken together, complete, together with the 2 atoms, to which they are attached, a saturated or unsaturated ring, which ring is in the case of the formulae Ia and Ib monosubstituted by oxo and in the case of the formula Ic disubstituted by oxo, the said ring being optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, C1- C6-alkyl, C1-C6-SIkOXy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in the case of the formula Ia1 the nitrogen ring member depicted in the formula Ia and optionally 1 or 2 further ring members being hetero ring members and any other ring member being present being a carbon ring member and, in the case of the formulae Ib and Ic, the nitrogen and the sulfur ring members depicted in the formulae Ib and Ic and optionally 1 further ring member being hetero ring members and any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, and in which formulae Id, Ie and If either R3 is hydrogen; CrC8-alkyl; CrC^alkoxy-C^C^alkyl; d-C4-alkylthio- CrC4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-C1-C4-alkyl; heterocyclyl attached via one of its carbon ring members to the nitrogen atom depicted in the formulae Id, Ie and If; or heterocyclyl-d-d-alkyl; and Rb is hydrogen; d-C8-alkyl; d-C4-alkoxy-d-C4-alkyl; d-d-alkylthio-d-d- alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-C1-C4-alkyl; heterocyclyl; or hetero- cyclyl-Ci-C4-alkyl or Ra and Rb, taken together, complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is in the case of the formulae Id and Ie monosubstituted by oxo and in the case of the formula If disubstituted by oxo, the said ring being optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, d-Ce-alkyl, d-Ce-alkoxy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in the case of the formula Id, the nitrogen ring member depicted in the formula Id and optionally 1 or 2 further ring members being hetero ring members and any other ring member being present being a carbon ring member and, in the case of the formulae Ie and If, the nitrogen and the sulfur ring members depicted in the formulae Ie and If and optionally 1 further ring member being hetero ring members and any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, con- sisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member;
R2 and R3 are either, independently from each other, hydrogen; Ci-C8-alkyl; Ci-C4-alkoxy-Ci-C4-alkyl; d-d-alkylthio-d-d-alkyl; or an aryl-d-C4-alkyl or heteroaryl-d-C4-alkyl group, which aryl-Ci-C4-alkyl or heteroaryl-Ci-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-Ci-C4-alkyl, aryl, heteroaryl, Ci-C6-alkyl, hydroxy- Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Ci-C4-alkylcarbonyl-Ci-C4-alkyl, trifluoromethyl, hydroxy, d-C6-alkoxy, d-d-alkoxy-d-d-alkoxy, C1-C4-alkylcarbonyl-d-C4-alkoxy, benzyloxy, phenoxy, formyloxy, Ci-C4-alkyJcarbonyloxy, carbamyloxy, N-d-C4-alkyl- carbamyloxy, d-C4-alkylthio, Ci-d-alkylsulfinyl, CrC4-alkylsulfonyl, aminosulfonyl, N-Ci-d-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, C1-C4- alkylcarbonyl, Ci-C4-alkoxycarbonyl, amino, N-d-d-alkylamino, N,N-di-(C1-C4-alkyl)- amino with two identical or different Ci-C4-alkyl moieties, N-(d-C4-alkoxy-Ci-C4-alkyl)- amino, N-(Ci-C4-alkylsulfonyl)amino, N-formylamino, N^C^d-alkylcarbonylJamino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-Ci-C4-alkoxycarbonyl)amino and N-(heteroaryl- Ci-C4-alkoxycarbonyl)amino, or, taken together, complete, together with the carbon atom, to which they are attached, a C3-C8-cycloalkyl ring, in which C3-C8-cycloalkyl ring 1 or 2 of its 2 to 7 methylene ring members optionally are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member;
R4 is hydrogen; hydroxy; or d-C6-alkoxy;
R5 and R6, taken together, complete, together with the 2 carbon atoms, to which they are attached, and together with the methylene group, to which the said 2 carbon atoms are attached, a saturated ring, which ring is, in addition to the substitution by the substituents (Ri)(R2)(R3)C and R4 and the N-substituted aminocarbonyl group depicted in the formula I, optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of d-C8-a!kyl, oxo, hydroxy, Ci-C8-alkoxy, Ci-C4-alkoxy- Ci-C4-alkyl, d-Cs-alkylthio, Ci-C4-alkylthio-d-C4-alkyl, formyl, d-Cs-alkylcarbonyl, C1-C8- alkoxycarbonyl, carbamyl, N-d-C8-alkylcarbamyl, N,N-di-(Ci-C8-alkyl)carbamyl with two identical or different d-C8-alkyl moieties, which two CrC8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-Cβ-alkyl, d-C6-alkoxy and d-C6-alkylthio, - A -
and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-Cβ-alkyl moieties of the N,N-di- (C1-C8- alkyl)carbamyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, CrC8- alkylsulfonyl, d-C8-alkoxysulfonyl, aminosulfonyl, N-CrC8-alkylaminosulfonyl, N,N-di- (Ci-CB-alkyl)aminosulfonyl with two identical or different Ci-C8-alkyl moieties, which two Ci-Cs-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, Ci-C6-alkoxy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C8-alkyl moieties of the N.N-dKd-Cs-alkyOaminosulfonyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, Ci-C8-alkylsulfinyl, d-C8-alkoxysulfinyl, aminosulfi- nyl, N-d-Cβ-alkylaminosulfinyl, N,N-di-(Ci-C8-alkyl)aminosulfinyl with two identical or different Ci-C8-alkyl moieties, which two Ci-C8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, d-Cε-alkoxy and Ci-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C8-alkyl moieties of the N.N-dKd-Cβ-alkyOaminosulfi- nyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, d-C8-alkylsulfonylami- no, CrC8-alkoxysulfonylamino, aminosulfonylamino, N-Ci-Cβ-alkylaminosulfonylamino, N,N-di-(Ci-C8-alkyl)aminosulfonylamino with two identical or different d-C8-alkyl moieties, formylamino, Ci-Ce-alkylcarbonylamino, Ci-Cs-alkoxycarbonylamino, carbamylami- no, N-CrCβ-alkylcarbamylamino,
Figure imgf000005_0001
with two identical or different Ci-Cs-alkyl moieties and a heterocyclyl or heteroaryl group, the said hetero- cyclyl or heteroaryl group being optionally substituted by 1 or 2 substituents indepen- dently selected from the group, consisting of oxo, Ci-C6-alkyl, Ci-C6-alkoxy and Ci-C6- alkylthio, and which ring has 5 to 7 ring members, of which ring members 1 or 2 ring members optionally being hetero ring members and any other ring member being a carbon ring member, the said hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member; is a Ci-Cβ-alkyI, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group, which CrC8-al- kyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-CrC4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-C8-cycloalkyl, heterocyclyl, d-Ce-alkyl, hydroxy-Ci-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, oxo, hydroxy, CrC6-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, formyloxy, d-C4-alkylcarbonyl- oxy, CrC^alkylthio, CrC^alkylsulfinyl, CrC^alkylsulfonyl, carboxy, carbamyl, N-C1-C4- alkylcarbamyl, formyl, C1-C4-alkylcarbonyl, Ci-C4-a!koxycarbonyl and an aryl or hetero- aryl group, which aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, aryl, heteroaryl, Ci-C6-alkyl, hydroxy-d-C/ralkyl, Ci-C4-alkoxy-Ci-C4-alkyl, trifluoromethyl, hydroxy, CrCβ-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, C-ι-C4-alkylcar- bonyloxy, Ci-C4-alkylthio, Cn-C^alkyϊsulfinyl, Ci-C4-alkylsulfonyl, aminosulfonyl, N-Ci-C4- alkylaminosulfonyl, carboxy, carbamyl, N-CrC/t-alkylcarbamyl, formyl, CrC^alkylcarbo- nyl, Ci-C4-alkoxycarbonyl, amino, N-Ci-C4-alkylamino, N,N-di-(Ci-C4-alkyl)amino with two identical or different CrC4-a!kyl moieties, which two Ci-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, Ci-C6-alkoxy and Ci-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C4-alkyl moieties of the N,N-di- (Ci-C4-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, N-(Ci-C4-alkoxy-Ci-C4-alkyl)amino, N-(CrC4-alkylsulfonyl)amino, N-formylamino, N-(Ci-C4-alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-Ci-C4-alkoxycar- bonyl)amino and N-(heteroaryl-C1-C4-alkoxycarbonyl)amino; an aryl or heteroaryl group, which aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, aryl, heteroaryl, Ci-Cβ-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, Ci-C6-alkoxy,
Figure imgf000007_0001
benzyloxy, phenoxy, formyloxy, Ci-d-alkylcarbonyloxy, d-d-alkylthio, d-C4-alkylsulfinyl, d-d-alkylsulfo- nyl, aminosulfonyl, N-d-C4-alkylaminosulfonyl, N.N-dKd-d-alkyOaminosulfonyl with two identical or different d-d-alkyl moieties, which two Ci-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, Ci-C6-alkoxy and CrC6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C4-alkyl moieties of the N,N-di- (Ci-C4-alkyl)aminosulfonyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, Ci-C4-alkylcarbonyl, Ci-C4- alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di-(Ci-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, which two CrC4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, d-C6-alkoxy and d-Cβ-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C4-alkyl moieties of the N,N-di-(Ci-C4-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, N-(d-C4-alkoxy-d-C4- alkyl)amino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(d-C4-alkylcarbonyl)amino, N-(d-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycarbonyl)amino and N-(heteroaryl- Ci-C4-alkoxycarbonyl)amino; or an aryl group, which aryl group is optionally substituted at two of its carbon ring members, which two carbon ring members are adjacent to each other, by two substituents, which two substituents form, together with the two adjacent carbon ring members, to which they are attached, a heteroaryl ring, which heteroary! ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-Ci-C4-alkyl, aryl, heteroaryl, CrC6-alkyl, hydroxy-d-C4-alkyl, Ci-C4-alkoxy-d-C4-alkyl, CrC4-alkyl- carbonyl-Ci-C4-alkyl, trifluoromethyl, hydroxy, Ci-C6-alkoxy, Ci-d-alkoxy-d-d-alkoxy, Ci-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyl- oxy, carbamyloxy, N-Ci-d-alkylcarbamyloxy, d-C4-alkylthio, Ci-C4-alkylsulfinyl, C1-C4- alkylsulfonyl, aminosulfonyl, N-d-C4-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-al- kylcarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-C-i-C4-alkyl- amino, N,N-di-(Ci-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties,
Figure imgf000008_0001
N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(Ci-C4-alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycar- bonyl)amino and N-(heteroaryl-Ci-C4-alkoxycarbonyl)amino; either
R8 is hydrogen; and R9 is hydroxy or
R8 and R9, taken together, are oxo; and
R10 is a group of the formula CH(Rc)C(=O)N(Rd)Re (Ig); or (CH2)kN(H)Rf (Ih), in which formula Ig
Rc is a Ci-C8-alkyl, Ci-C4-alkoxy-CrC4-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl- Ci-C4-alkyl group, which Ci-C8-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, C1- C6-alkyl, hydroxy-d-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, oxo, hydroxy, d-C6-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, formyloxy, d-C4-alkylcarbonyloxy, CrC4-alkylthio, C1- C4-alkylsulfinyl, CrC4-alkylsulfonyl, formyl, CrC4-alkylcarbonyl and C1-C4- alkoxycarbonyl; and Rd and Re either are, independently from each other, hydrogen; a d-C8-alkyl, C3-C8-cycloal- kyl or C3-C8-cycloalkyl-Ci-C4-alkyl group, which Ci-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, C1- C6-alkyl, hydroxy-d-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, oxo, hydroxy, CrC6-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, Ci-C4-alkylthio, C1- C4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, d-C4-alkylcarbonyl and C1-C4- alkoxycarbonyl; or an aryl, aryl-CrC4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group, which aryl, aryl-CrC4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-CrC4- alkyl, aryl, heteroaryl, d-C6-alkyl, hydroxy-d-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, d-d-alkylcarbonyl-d-d-alkyl, trifluoromethyl, hydroxy, d-Cβ-alkoxy, C1-C4- alkoxy-Ci-C4-alkoxy, d-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyloxy, phenoxy, for- myloxy, C1-C4-alkylcarbonyloxy, carbamyloxy, N-C1-C4-alkylcarbamyloxy, Ci-C4- alkylthio, Ci-C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, aminosulfonyl, N-d-d-alkylami- nosulfonyl, carboxy, carbamyl, N-CrC4-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, Ci-C4-alkoxycarbonyl, amino, N-Ci-C4-alkylamino, N,N-di-(CrC4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, N-(d-C4-alkoxy-Ci-C4-alkyl)amino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(Ci-C4-alkylcarbonyl)amino, N-(C1-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycarbonyl)amino and N-(hete- roaryl-Ci-C4-alkoxycarbonyl)amino, or, taken together, complete, together with the nitrogen atom, to which they are attached, an azepanyl, morpholinyl, piperazinyl, piperidyl or pyrrolidyl ring, which azepanyl, morpholinyl, piperazinyl, piperidyl or pyrrolidyl ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-d-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, oxo, hydroxy, Ci-C6-alkoxy, d-d-alkoxy-Ci-d-alkoxy, formyloxy, d-C4-alkylcar- bonyloxy, CrC4-alkylthio, CrC4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, d-C4-al- kylcarbonyl and Ci-C4-alkoxycarbonyl, and in which azepanyl, morpholiny!, piperazinyl, piperidyl or pyrrolidyl ring 1 or 2 of its methylene ring members can be replaced by a hetero ring member independently selected from the group, consisting of -S(=O)- and -S(=O)2-, and in which formula Ih k is 0; 1 ; or 2; and
Rf is hydrogen; a d-C8-alkyl or C3-C8-cycloalkyl-d-C4-alkyl group, which d-C8-al- kyl or Cs-Cβ-cycloalkyl-d-d-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-C1-C4-alkyl, C1 -C4-alkoxy-d -C 4-alky I, fluoromethyl, difluoro- methyl, trifluoromethyl, oxo, hydroxy, d-C6-alkoxy, d-C4-alkoxy-d-C4-alkoxy, formyloxy, d-C4-alkylcarbonyloxy, Ci-C4-alkylthio, C1-C4-alkylsulfinyl, d-C4-alkylsul- fonyl, formyl, C1-C4-alkylcarbonyl and d-C4-alkoxycarbonyl; an aryl, aryl-d-C4-al- kyl, heteroaryl, heteroaryl-d-C4-alkyl, chroman-4-yl, isochroman-4-yl, thiochroman- 4-yl, isothiochroman-4-yl, 1 ,1-dioxo-1lambda*6*-thiochroman-4-yl, 2,2-dioxo- 2lambda*6*-isothiochroman-4-yl, 1 ,2,3,4-tetrahydro-quinol-4-yl, 1 ,2,3,4-tetrahydro- isoquinol-4-yl, 1 ,2,3,4-tetrahydro-naphth-1-yl, 1 ,1-dioxo-1 ,2,3,4-tetrahydro-1 lamb- da*6*-benzo[e][1 ,2]thiazin-4-yl, 2,2-dioxo-1 ,2,3,4-tetrahydro-2lambda*6*-benzo- [c][1 ,2]thiazin-4-yl, 1 , 1 -dioxo-3,4-dihydro-1 H-1 lambda*6*-benzo[c][1 ,2]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1 ,2]oxathiin-4-yl, 2,3,4,5-tetrahydro- benzo[b]oxepin-5-yl or 1 ,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group, which aryl, aryl-Ci-C4-alkyl, heteroaryl, heteroaryl-Ci-C4-alkyI, chroman-4-yl, isochroman-4-yl, thiochroman-4-yI, isothiochroman-4-yl, 1 ,1-dioxo-1 lambda*6*-thiochroman-4-yl, 2,2-dioxo-2lambda*6*-isothiochroman-4-yl, 1 ,2,3,4-tetrahydro-quinol-4-yl, 1 ,2,3,4- tetrahydro-isoquinol-4-yl, 1 ,2,3,4-tetrahydro-naphth-i-yl, 1 , 1 -dioxo-1 , 2,3,4- tetrahydro-1lambda*6*-benzo[e][1 ,2]thiazin-4-yl, 2,2-dioxo-1 ,2,3,4-tetrahydro- 2lambda*6*-benzo[c][1 ,2]thiazin-4-yl, 1 ,1-dioxo-3,4-dihydro-1 H-1lambda*6*-benzo- [c][1 ,2]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1 ,2]oxathiin-4- yl, 2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or 1 ,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloal- kyl-d-C4-alkyl, aryl, heteroaryl, Ci-C6-alkyl, hydroxy-Ci-C4-alkyl, d-C4-alkoxy- d-C4-alkyl, Ci-C4-alkylcarbonyl-Ci-C4-alkyl, thfluoromethyl, hydroxy, d-C6-alkoxy, C1-C4-BIkOXy-Ci-C4-BIkOXy, d^-alkylcarbonyl-d-d-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, carbamyloxy, N-d-d-alkylcarbamyloxy, C1-C4- alkylthio, CrC4-alkylsulfinyl, d-d-alkylsulfonyl, aminosulfonyl, N-CrC4-alkylami- nosulfonyl, carboxy, carbamyl, N-d-d-alkylcarbamyl, formyl, CrC4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di-(d-C4-alkyl)amino with two identical or different C,-C4-alkyl moieties, N-(d-C4-alkoxy-Ci-C4-alkyl)amino, N-(Ci-C4-alkylsulfonyl)amino, N-formylamino, N-(C1 -C4-alkylcarbonyl)amino, N- (d-C4-alkoxycarbonyl)annino, N-(aryl-d-C4-alkoxycarbonyl)amino and N-(hete- roaryl-d-d-alkoxycarbonyOamino, and in which aryl-d-C4-alkyl or heteroaryl- d-C4-alkyl group the d-C4-alkyl moiety is optionally substituted by 1 or 2 substituents independently selected from the group, consisting of fluoromethyl, difluoro- methyl and trifluoromethyl; or a C4-C8-cycloalkyl group, in which C4-C8-cycloalkyl group
(a) one of the carbon ring members of the C4-C8-cycloatkyl moiety, which carbon ring members are different from the carbon ring member of the C4-C8-cycloalkyl moiety, to which the nitrogen atom depicted in the formula Ih is attached, is optionally replaced by a hetero ring member independently selected from the group, consisting of -O-, -S-, -S(=O)-, -S(=O)2- and -N(R9)-, Rg being hydrogen; a Ci-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group, which d-C8-alkyl, C3-C8-cycloalkyl or QrCs-cycloalkyl-d-d-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-Cβ-alkyl, hydroxy-d-C4-alkyl, C1-C4- alkoxy-Ci-C4-alkyl, oxo, hydroxy, Ci-C6-alkoxy, d-C4-alkoxy-d-C4-alkoxy, formyl- oxy, Ci-C4-aIkylcarbonyloxy, CrC4-alkylthio, d-C4-alkylsulfinyl, C1-C4-alkylsulfonyl, formyl, d-d-alkylcarbonyl and d-C4-alkoxycarbonyl; or an aryl, aryl-d-C4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group, which aryl, aryl-Ci-C4-alkyl, heteroaryl or heteroaryl-CrC4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8- cycloalkyl, Ca-Cs-cycloalkyl-d-d-alkyl, aryl, heteroaryl, Ci-C6-alkyl, hyd roxy -Ci-C4- alkyl, Ci-C4-alkoxy-d-C4-alkyl, d-d-alkylcarbonyl-d-d-alkyl, trifluoromethyl, hydroxy, Ci-C6-alkoxy, CrC4-alkoxy-Ci-C4-alkoxy, d-d-alkylcarbonyl-d-d-alkoxy, benzyloxy, phenoxy, formyloxy, d-d-alkylcarbonyloxy, carbamyloxy, N-d-C4-al- kylcarbamyloxy, Ci-C4-alkylthio, Ci-C4-alkylsuIfinyl, Ci-C4-alkylsulfonyl, aminosulfo- nyl, N-d-C4-alkylaminosulfonyl, carboxy, carbamyl, N-Ci-C4-alkylcarbamyl, formyl, Ci-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di- (Ci-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, N-(C1-C4- alkoxy-Ci-C4-alkyl)amino, N^d-d-alkylsulfony^amino, N-formylamino, N-(C1-C4- alkylcarbonyl)amino, N-(d-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycarbo- nyl)amino and N-(heteroaryl-d-C4-alkoxycarbonyl)amino,
(b) the C4-C8-cycloalkyl moiety, which C4-C8-cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C6-alkoxy, CrC4-alkoxy-d-C4-alkoxy, formyloxy, d-C4-alkylcarbonyloxy, d-C4-alkoxycarbonyloxy, d-C4-alkylthio, C1-C4- alkylsulfinyl, d-C4-alkylsulfonyl, formyl, Ci-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, a d-Cβ-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group, which C1-C8- alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-d-C4-alkyl, Ci-C4-alkoxy-d-C4- alkyl, oxo, hydroxy, d-C6-alkoxy, Ci-C4-alkoxy-C!-C4-alkoxy, formyloxy, C1-C4-Bl- kylcarbonyloxy, d-C4-alkylthio, C1-C4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, d-C4-alkylcarbonyl and d-C4-alkoxycarbonyl, and an aryl, aryl-CrC4-alkyl, heteroaryl, heteroaryl-d-C4-alkyl, heterocyclyl or heterocyclyl-d-d-alkyl group, which aryl, aryl-d-C4-aIkyl, heteroaryl, heteroaryl-Ci-C4-alkyl, heterocyclyl or heterocyc- lyl-Ci-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloal- kyl, C3-C8-cycloalkyl-Ci-C4-alkyl, aryl, heteroaryl, d-C6-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy-C1-C4-alkyll d-d-alkylcarbonyl-d-d-alkyl, trifluoromethyl, hydroxy, Ci-C6-alkoxy, d-d-alkoxy-d-d-alkoxy, Ci-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyl- oxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, carbamyloxy, N-CrC4-alkylcarba- myloxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, aminosulfonyl, N-Ci-C4-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, d-d-alkylcarbonyl, d-d-alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di- (d-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, N-(C1-C4- alkoxy-d-C4-alkyl)amino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(C1-C4- alkylcarbonyl)amino, N^d-d-alkoxycarbonyOamino, N-(aryl-d-C4-alkoxycarbo- nyl)amino and N-(heteroaryl-d-C4-alkoxycarbonyl)amino, and (c) the C4-C8-cycloalkyl moiety, which C4-C8-cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted at two of its carbon ring members, which two carbon ring members are adjacent to each other, by two substituents, which two substituents form, together with the two adjacent carbon ring members, to which they are attached, a C3-C8- cycloalkyl ring, in which C3-C8-cycloalkyl ring
(i) one of the carbon ring members of the C3-C8-cycloalkyl ring thus formed, which carbon ring members are different from the said two adjacent carbon ring members of the C3-C8-cycloalkyl ring thus formed, to which the said two substituents are optionally attached, is optionally replaced by a hetero ring member independently selected from the group, consisting of -O-, -S-, -S(=O)-, -S(=O)2- and -N(Rh)-
Rh being hydrogen; a d-Cβ-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group, which d-C8-alkyl, C3-C8-cycioalkyl or C3-C8-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-d-C4-alkyl, C1-C4- alkoxy-d-C4-alkyl, oxo, hydroxy, d-Ce-alkoxy, d-C4-alkoxy-d-C4-alkoxy, formyloxy, d-C4-alkylcarbonyloxy, d-C4-alkylthio, CrC4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, CrC4-alkylcarbonyl and d-C4-alkoxycarbonyl; or an aryl, aryl-CrC4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group, which aryl, aryl-d-C4-alkyl, heteroaryl or heteroaryl-d-d-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8- cycloalkyl, C3-C8-cycloalkyl-Ci-C4-alkyl, aryl, heteroaryl, d-C6-alkyl, hyd IOXy-C1 -C4- alkyl, C1-C4-alkoxy-C1-C4-alkyl, d-d-alkylcarbonyl-d-d-alkyl, trifluoromethyl, hydroxy, Ci-C6-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, C1-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, CrC4-alkylcarbonyloxy, carbamyloxy, N-Ci-C4-al- kylcarbamyloxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl, d-C4-alkylsulfonyl, aminosulfo- nyl, N-CrC4-alkylaminosulfonyl, carboxy, carbamyl, N-CrC4-alkylcarbamyl, formyl, Ci-C4-alkylcarbonyl, Ci-C4-alkoxycarbonyl, amino, N-Ci-C4-alkylamino, N,N-di- (CrC4-alkyl)amino with two identical or different CrC4-alkyl moieties, N-(Ci-C4- alkoxy-d-C4-alkyl)amino, N-(CrC4-alkylsulfonyl)amino, N-formylamino, N-(C1-C4- alkylcarbonyl)amino, N-(d-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycarbo- nyl)amino and N-(heteroaryl-d-C4-alkoxycarbonyl)amino, and (ii) the C3-C8-cycloalkyl ring thus formed, which C3-C8-cycloalkyl ring is optionally modified as defined under (i) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C6-alkoxy, Ci -C4-a IkOXy-C1 -C4- alkoxy, formyloxy, d-C4-alkylcarbonyloxy, Ci-C4-alkoxycarbonyloxy, d-C4-alkyl- thio, d-C4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, d-C4-alkylcarbonyi, C1-C4- alkoxycarbonyl, a d-C8-alkyl, C3-C8-cycloalkyl or Cs-Cs-cycloalkyl-d-d-alkyl group, which d-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-d-C4-alkyl, Ci-C4-alkoxy-d-C4-alkyl, oxo, hydroxy, CrC6-alkoxy, d-d-alkoxy-d-d-alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, d-C4-alkylthio, d-d-alkylsulfinyl, d-C4-alkyl- sulfonyl, formyl, Ci-C4-alkylcarbonyt and Ci-C4-alkoxycarbonyl, and an aryl, aryl- Ci-C4-alkyl, heteroaryl, heteroaryl-d-C4-alkyl, heterocyclyl or heterocyclyl-d-C4- alkyl group, which aryl, aryl-d-C4-alkyl, heteroaryl, heteroaryl-d-C4-alkyl, heterocyclyl or heterocyclyl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-d-C4-alkyl, aryl, heteroaryl, d-C6-alkyl, hy- droxy-d-C4-alkyl, d-C4-alkoxy-d-C4-alkyl,
Figure imgf000013_0001
trifluoromethyl, hydroxy, d-C6-alkoxy, Ci-Cralkoxy-CrC-j-alkoxy, CrC4-alkylcarbonyl- d-C4-alkoxy, benzyloxy, phenoxy, formyloxy, CrC4-alkylcarbonyloxy, carbamyloxy, N-d-d-alkylcarbamyloxy, d-C4-alkylthio, Ci-C4-alkylsulfinyl, CrC4-alkylsul- fonyl, aminosulfonyl, N-CrC4-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkyl- carbamyl, formyl, d-C4-alkylcarbonyl, CrC^alkoxycarbonyl, amino, N-Ci-C4-alkyl- amino, N.N-di-ζCVGralkyOamino with two identical or different Ci-C4-alkyl moieties, N-(Ci-C4-alkoxy-C1-C4-alkyl)amino, N-^-C^alkylsulfonyOamino, N-formyl- amino, N-(Ci -C4-alkylcarbonyl)amino, N^CrC^alkoxycarbonyOamino, N-(aryl- C1- C4-alkoxycarbonyl)amino and N^heteroaryl-CrC^alkoxycarbonyOamino, in free form or in salt form.
E. g. on account of one or more than one asymmetrical carbon atom, which may be present in a compound of the formula I, a corresponding compound of the formula I may exist in pure optically active form or in the form of a mixture of optical isomers, e. g. in the form of a ra- cemic mixture. All of such pure optical isomers and all of their mixtures, including the racemic mixtures, are part of the present invention.
A compound of the formula I may exist in free form or in salt form, e. g. a basic compound in acid addition salt form or an acidic compound in the form of a salt with a base. All of such free compounds and salts are part of the present invention.
A compound of the formula I may exist in tautomeric form. All of such tautomers are part of the present invention.
Halogen denotes fluorine, chlorine, bromine or iodine.
An aryl group, ring or moiety is a naphthyl or, preferably, phenyl group, ring or moiety.
A heteroaryl group, ring or moiety is an aromatic 5- or 6-membered structure, in which structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidyl or pyridyl, and which structure can also be anellated with a phenyl ring, such as benzothiazolyl, benzoxazolyl or quinolyl.
A heterocyclyl group, ring or moiety is a non-aromatic 5- or 6-membered cyclic structure, in which cyclic structure 1 , 2 or 3 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl or morpholinyl.
Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
Unless defined otherwise, carbon containing groups, moieties or molecules contain 1 to 8, preferably 1 to 6, preferably 1 to 4, preferably 1 or 2, carbon atoms.
In preferred embodiments, the invention relates to a compound of the formula I, in free form or in salt form, in which
(1) R1 is a group of the formula N(Ra)-C(=O)Rb (Ia); N(Ra)-S(=O)Rb (Ib); N(Ra)-S(=O)2Rb (Ic); C(=O)-N(Ra)Rb (Id); S(=O)-N(Ra)Rb (Ie); or S(=O)2-N(Ra)Rb (If), in which formulae Ia, Ib and Ic either Ra is hydrogen; d-C8-alkyl; d-d-alkoxy-d-d-alkyl; d-C4-alkylthio- Ci-C4-alkyl; C3-C8-cycioalkyl; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl; or heterocyclyl-d-Ct-alkyl; and
Rb is hydrogen; d-C8-alkyl; trifluoromethyl; d-C8-alkoxy; C !-C4-a IkOXy-C1 -C4- alkyl; d-C8-alkylthio; C1-C4-alkylthio-C1-C4-alkyl; C3-C8-cycloalkyl; C3-C8-cyc- loalkyl-CrC4-alkyl; heterocyclyl; hete TOCyCIyI-C1 -C4-alky I; amino; d-C8-alkyl- amino; or di-(CrCs-alkyl)amino with two identical or different d-C8-alkyl moieties, which two d-Cs-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-Cβ-alkyl, d-C6-alkoxy and C1- Cβ-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C8-alkyl moieties of the di-(d-C8-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, or Ra and Rb, taken together, complete, together with the 2 atoms, to which they are attached, a saturated or unsaturated ring, which ring is in the case of the formulae Ia and Ib monosubstituted by oxo and in the case of the formula Ic disubstituted by oxo, the said ring being optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, C1- C6-alkyl, (VCβ-alkoxy and Ci-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in the case of the formula Ia, the nitrogen ring member depicted in the formula Ia and optionally 1 or 2 further ring members being hetero ring members and any other ring member being present being a carbon ring member and, in the case of the formulae Ib and Ic, the nitrogen and the sulfur ring members depicted in the formulae Ib and Ic and optionally 1 further ring member being hetero ring members and any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, and in which formulae Id, Ie and If either R3 is hydrogen; Ci-C8-alkyl; Ci-C4-alkoxy-Ci-C4-alkyl; CrC^alkylthio- CrC4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl attached via one of its carbon ring members to the nitrogen atom depicted in the formulae Id, Ie and If; or heterocyclyl-Ci-C4-alkyl; and Rb is hydrogen; CrC8-alkyl; CrCralkoxy-CrC^alkyl; d-C^alkylthio-CrC^ alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl; or hetero- cyclyl-CrC4-alkyl or Ra and Rb, taken together, complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is in the case of the formulae Id and Ie monosubstituted by oxo and in the case of the formula If disubstituted by oxo, the said ring being optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, CVCε-alkoxy and CrC6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in the case of the formula Id, the nitrogen ring member depicted in the formula Id and optionally 1 or 2 further ring members being hetero ring members and any other ring member being present being a carbon ring member and, in the case of the formulae Ie and If, the nitrogen and the sulfur ring members depicted in the formulae Ie and If and optionally 1 further ring member being hetero ring members and any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, con- sisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member; preferably is a group of the formula N(Ra)-C(=O)Rb (Ia); or C(=O)-N(Ra)Rb (Id); in which formula Ia either R3 is hydrogen; d-Cβ-alkyl; C1-C4-alkoxy-Ci-C4-alkyl; d-C4-alkylthio- Ci-C4-alkyl; C3-C8-cycloalkyi; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl; or heterocyclyl-d-d-alkyl; and
Rb is hydrogen; Ci-C8-alkyl; trifluoromethyl; Ci-Cs-alkoxy; d-d-alkoxy-Ci-d- alkyl; Ci-C8-alkylthio; Ci-C4-alkylthio-C1-C4-a!kyl; C3-C8-cyc!oalkyl; C3-C8-cyc- loalkyl-CrC4-alkyl; heterocyclyl; heterocyclyl-Ci-d-alkyl; amino; d-C8-alkyl- amino; or di-(d-C8-alkyl)amino with two identical or different d-C8-alkyl moieties, which two d-C8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-C6-alkyl, d-C6-afkoxy and d- C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C8-alkyl moieties of the di-(d-C8-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, or Ra and Rb, taken together, complete, together with the 2 atoms, to which they are attached, a saturated or unsaturated ring, which ring is in the case of the formulae Ia and Ib monosubstituted by oxo and in the case of the formula Ic disubstituted by oxo, the said ring being optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, d- Cβ-alkyl, C1-C6-BIkOXy and d-C6-alkyIthio, and which ring has 3 to 7 ring members, of which ring members, in the case of the formula Ia, the nitrogen ring member depicted in the formula Ia and optionally 1 or 2 further ring members being hetero ring members and any other ring member being present being a carbon ring member and, in the case of the formulae Ib and Ic, the nitrogen and the sulfur ring members depicted in the formulae Ib and Ic and optionally 1 further ring member being hetero ring members and any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, and in which formula Id either R3 is hydrogen; CrC8-alkyl; Ci-C4-alkoxy-Ci-C4-alkyl; d-C^alkylthio- C1-C4-SlKyI; C3-C8-cycloalkyl; heterocyclyl attached via one of its carbon ring members to the nitrogen atom depicted in the formulae Id, Ie and If; or heterocyclyl-Ci-C4-alkyl; and Rb is hydrogen; Ci-C8-alkyl; Ci-C4-alkoxy-Ci-C4-alkyl; Ci-C4-alkylthio-CrC4- alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl; or hetero- cyclyl-CrC4-alkyl or Ra and Rb, taken together, complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is in the case of the formulae Id and Ie monosubstituted by oxo and in the case of the formula If disubstituted by oxo, the said ring being optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, CrCβ-alkyl, d-Cβ-alkoxy and d-Ce-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in the case of the formula Id, the nitrogen ring member depicted in the formula Id and optionally 1 or 2 further ring members being hetero ring members and any other ring member being present being a carbon ring member and, in the case of the formulae Ie and If, the nitrogen and the sulfur ring members depicted in the formulae Ie and If and optionally 1 further ring member being hetero ring members and any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member; preferably is a group of the formula N(Ra)-C(=O)Rb (Ia); or C(=O)-N(Ra)Rb (Id); in which formula Ia either R3 is hydrogen; or Ci-C8-alkyl; and Rb is d-Ce-alkyl; d-Cβ-alkoxy; or trifluoromethyl or R3 and Rb, taken together, are straight-chain d-Cs-alkylene and in which formula Id
R3 is hydrogen; and Rb is Ci-Cs-alkyl; preferably is a group of the formula N(Ra)-C(=O)Rb (Ia); or C(=O)-N(Ra)Rb (Id); in which formula Ia either R3 is hydrogen; or Ci-C6-alkyl; and
Rb is d-Cβ-alkyl; d-C8-alkoxy; or trifluoromethyl or Ra and Rb, taken together, are straight-chain d-C5-alkylene and in which formula Id
Ra is hydrogen; and
Rb is Ci-Ce-alkyl; preferably is a group of the formula N(Ra)-C(=O)Rb (Ia); in which formula Ia either Ra is hydrogen; or Ci-C6-alkyl; and
Rb is Ci-C6-alkyl; C1-C8-BIkOXy; or trifluoromethyl or R3 and Rb, taken together, are straight-chain d-C5-alkylene; preferably is a group of the formula N(Ra)-C(=O)Rb (Ia); in which formula Ia
R3 and Rb, taken together, are straight-chain CrC5-alkylene;
(2) R2 and R3 are either, independently from each other, hydrogen; d-C8-alkyl; Ci-C4-alkoxy-d-C4-alkyl; d-d-alkylthio-d-d-alkyl; or an aryl-d-C4-alkyl or heteroaryl-CrC4-alkyl group, which aryl-CrC4-alkyl or heteroaryl-d-d-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-Ci-C4-alkyl, aryl, heteroaryl, d-C6-alky!, hydroxy- d-C4-alkyl, d-C4-alkoxy-d-C4-alkyl, C1-C4-alkylcarbonyl-C1-C4-alkyl, trifluoromethyl, hydroxy, d-C6-alkoxy, d-C4-alkoxy-d-C4-alkoxy, C1-C4-alkylcarbonyl-C1-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, carbamyloxy, N-Ci-C4-alkyl- carbamyloxy, d-C4-alkylthio, Ci-C4-alkylsulfinyl, CrC4-alkylsulfonyl, aminosulfonyl, N-Ci-C4-alkylaminosulfonyl, carboxy, carbamyl, N-Ci-C4-alkylcarbamyl, formyl, C1-C4- alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-d-C4-alkyiamino, N,N-di-(d-C4-alkyl)- amino with two identical or different d-C4-alkyl moieties, N-(d-C4-alkoxy-Ci-C4-alkyl)- amino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(d-C4-alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, r\l-(aryl-d-C4-alkoxycarbonyl)amino and N-(heteroaryl- d-C4-alkoxycarbonyl)amino, or, taken together, complete, together with the carbon atom, to which they are attached, a C3-C8-cycloalkyl ring, in which C3-C8-cycloalkyl ring 1 or 2 of its 2 to 7 methylene ring members optionally are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member; preferably are either, independently from each other, hydrogen; or d-C8-alkyl or, taken together, complete, together with the carbon atom, to which they are attached, a C3-C8-cycloalkyl ring; preferably are either, independently from each other, hydrogen; or CrC6-alkyl or, taken together, complete, together with the carbon atom, to which they are attached, a C3-C6-cycloalkyl ring; preferably are, independently from each other, hydrogen; or d-Ce-alkyl; preferably are, independently from each other, CrC6-alkyl;
(3) R4 is hydrogen; hydroxy; or Ci-C6-alkoxy; preferably hydrogen; or hydroxy; preferably hydrogen;
(4) R5 and R6, taken together, complete, together with the 2 carbon atoms, to which they are attached, and together with the methylene group, to which the said 2 carbon atoms are attached, a saturated ring, which ring is, in addition to the substitution by the substituents (R1)(R2)(R3)C and R4 and the N-substituted aminocarbonyl group depicted in the formula I, optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C8-alkyl, oxo, hydroxy, Ci-C8-alkoxy, Ci-C4-alkoxy- Ci-C4-alkyl, d-Cβ-alkylthio, d-C4-alkylthio-d-C4-alkyl, formyl, Ci-C8-alkylcarbonyl, C1-C8- alkoxycarbonyl, carbamyl, N-d-Cs-alkylcarbamyl, N.N-dKd-Cs-alkyOcarbamyl with two identical or different d-Cs-alkyl moieties, which two d-C8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-C6-alkyl, d-C6-alkoxy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C8-a!kyl moieties of the N,N-di- (C1-C8- alkyl)carbamyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, d-C8- alkylsulfonyl, d-C8-alkoxysulfonyl, aminosulfonyl, N-d-Cβ-alkylaminosulfonyl, N,N-di- (Ci-C8-alkyl)aminosulfonyl with two identical or different d-C8-alkyl moieties, which two Ci-C8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, Ci-Ce-alkoxy and Ci-Cβ-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C8-alkyl moieties of the N.N-dKd-Cβ-alkyOaminosulfonyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, d-C8-alkylsulfinyl, d-C8-alkoxysulfinyl, aminosulfi- nyl, N-Ci-Cs-alkylaminosulfinyl, N,N-di-(Ci-C8-alkyl)aminosulfinyl with two identical or different Ci-C8-alkyl moieties, which two Ci-C8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-Cβ-alkyl, Ci-C6-alkoxy and d-Cβ-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two CrC8-alkyl moieties of the N,N-di-(d-C8-alkyl)aminosulfi- nyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, d-C8-alkylsulfonylami- no, d-Cβ-alkoxysulfonylamino, aminosulfonylamino, N-d-C8-alkylaminosulfonylamino, N,N-di-(d-Ca-alkyl)aminosulfonylamino with two identical or different d-C8-alkyl moieties, formylamino, d-Cs-alkylcarbonylamino, d-Cs-alkoxycarbonylamino, carbamylami- no, N-d-Cs-alkylcarbamylamino, N,N-di-(d-C8-alkyl)carbamylamino with two identical or different d-C8-alkyl moieties and a heterocyclyl or heteroaryl group, the said hetero- cyclyl or heteroaryl group being optionally substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, d-Cβ-alkyl, d-C6-alkoxy and Ci-C6- alkylthio, and which ring has 5 to 7 ring members, of which ring members 1 or 2 ring members optionally being hetero ring members and any other ring member being a carbon ring member, the said hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member; preferably, taken together, are straight-chain C2-C4-alkylene;
(5) R7 is a d-Cβ-alkyl, C3-C8-cycloalkyl or Cs-Cβ-cycloalkyl-d-d-alkyl group, which C1-C8- alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-CrC4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-C8-cycloalkyl, heterocyclyl, Ci-C6-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, oxo, hydroxy, CrCε-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, formyloxy, d-C4-alkylcarbonyl- oxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, carboxy, carbamyl, N-C1-C4- alkylcarbamyl, formyl, d-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl and an aryl or hetero- aryl group, which aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, aryl, heteroaryl, d-Cβ-alkyl, hydroxy-Ci-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, trifluoromethyl, hydroxy, d-C6-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcar- bonyloxy, d-C4-alkylthio, Ci-C4-alkylsulfinyl, C1-C4-alkylsulfonyl, aminosulfonyl, N-C1-C4- alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, d-C4-alkylcarbo- nyl, d-C4-alkoxycarbonyl, amino, N-Ci-C4-alkylamino, N,N-di-(d-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, which two d-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-C6-alkyl, d-C6-alkoxy and d-Ce-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C4-alkyl moieties of the N,N-di- (CrC4-alkyI)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, N-(Ci-C4-alkoxy-Ci-C4-alkyl)amino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(d-C4-alkylcarbonyl)amino, N-(Ci -C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycar- bonyl)amino and N-(heteroaryl-d-C4-alkoxycarbonyl)amino; an aryl or heteroaryl group, which aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, aryl, heteroaryl, d-Ce-alkyl, hydroxy-d-C4-alkyl, d-C4-alkoxy-CrC4-alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, d-C6-alkoxy, C1-C^aIkOXy-C1 -C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl, d-C4-alkylsulfo- nyl, aminosulfonyl, N-Ci-C4-alkylaminosulfonyl, N,N-di-(Ci-C4-alkyl)aminosulfonyl with two identical or different Ci-C4-a!kyl moieties, which two C1-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-Ce-alkyl, C1-C6-BIkOXy and CrCθ-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C4-alkyl moieties of the N,N-di- (Ci-C4-alkyl)aminosulfonyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, carboxy, carbamyl, N-Ci-C4-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, C1-C4- alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di-(d-C4-alkyl)amino with two identical or different C1 -C4-alkyl moieties, which two d-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, d-C6-alkoxy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C4-alkyl moieties of the N,N-di-(d-C4-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, N-(d-C4-alkoxy-Ci-C4- alkyl)amino, N-(Ci-C4-alkyIsulfonyl)amino, N-formylamino, N-(C1-C4-alkylcarbonyl)amino, N-(d-C4-alkoxycarbonyl)amino, N^aryl-CrC^alkoxycarbonyOamino and N-(heteroaryl- d-C4-alkoxycarbonyl)amino; or an aryl group, which aryl group is optionally substituted at two of its carbon ring members, which two carbon ring members are adjacent to each other, by two substituents, which two substituents form, together with the two adjacent carbon ring members, to which they are attached, a heteroaryl ring, which heteroaryl ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-CrC4-alkyl, aryl, heteroaryl, d-C6-alkyl, hydroxy-d-C4-alkyl, d-C4-alkoxy-Ci-C4-alkyl, Ci-C4-alkyl- carbonyl-Ci-C4-alkyl, trifluoromethyl, hydroxy, d-C6-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-alkylcarbonyl-C1-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyl- oxy, carbamyloxy, N-d-d-alkylcarbamyloxy, Ci-C4-alkylthio, d-d-alkylsulfinyl, Ci-C4- alkylsulfonyl, aminosulfonyl, N-Ci-C4-alkylaminosulfonyl, carboxy, carbamyl, N-Ci-C4-al- kylcarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-Ci-C4-alkyl- amino, N,N-di-(Ci-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, N^d-d-alkoxy-d-d-alkyOamino, N-(CrC4-alkylsulfonyl)amino, N-formylamino, N-(Ci-C4-alkylcarbonyl)amino, N-(C1-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycar- bonyl)amino and N-(heteroaryl-CrC4-alkoxycarbonyl)amino; preferably an aryl group, which aryl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, aryl, hetero- aryl, d-C6-alkyl, hydroxy-d-C4-alkyl, d-d-alkoxy-d-C4-alkyl, fluoromethyl, difluorome- thyl, trifluoromethyl, hydroxy, Ci-Ce-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, d-C4-alkylthio, d-C4-alkylsulfinyl, C1-C4- alkylsulfonyl, aminosulfonyl, N-d-C4-alkylaminosulfonyl, N,N-di-(Ci-C4-alkyl)aminosulfo- nyl with two identical or different CrC4-alkyl moieties, which two d-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-C6-alkyl, Ci-C6-alkoxy and Ci-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C4-alkyl moieties of the N,N-di- (CrC4-alkyl)aminosulfonyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, carboxy, carbamyl, N-CrC4-alkylcarbamyl, formyl, Ci-C4-alkylcarbonyl, d-d- alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di-(Ci-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, which two Ci-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, CrC6-alkoxy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two CrC4-alkyl moieties of the N^-dKd-d-alkylJamino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, N-(d-C4-alkoxy-d-C4- alkyl)amino, N-(Ci-C4-alkyisulfonyl)amino, N-formylamino, N-(Ci-C4-alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-Ci-C4-alkoxycarbonyl)amino and N-(heteroaryl- Ci-C4-alkoxycarbonyl)amino; preferably an unsubstituted aryl group; preferably unsubstituted phenyl;
(6) either
R8 is hydrogen; and R9 is hydroxy
PI
R8 and R9, taken together, are oxo; preferably R8 is hydrogen; and R9 is hydroxy;
(7) R10 is a group of the formula CH(Rc)C(=O)N(Rd)Re (Ig); or (CH2)kN(H)Rf (Ih), in which formula Ig
R0 is a d-C8-alkyl, d-C4-alkoxy-Ci-C4-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl- Ci-C4-alkyl group, which d-C8-alkyl, d-C4-alkoxy-Ci-C4-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, C1- Cβ-alkyl, hydroxy-d-C4-alkyl, d-d-alkoxy-d-Oi-alkyl, oxo, hydroxy, CrC6-alkoxy, d-d-alkoxy-d-d-alkoxy, formyloxy, d-d.-alkylcarbonyloxy, CrC4-alkylthio, Cr C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, formyl, Ci-C4-alkylcarbonyl and Ci-C4- alkoxycarbonyl; and Rd and Re either are, independently from each other, hydrogen; a d-Cs-alkyl, C3-C8-cycloal- kyl or C3-C8-cycloalkyl-d-C4-alkyl group, which d-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, C1- Ce-alkyl, hydroxy-d-C4-alkyl, Ci-C4-aikoxy-d-C4-alkyl, oxo, hydroxy, d-C6-alkoxy, d-d-alkoxy-d-d-alkoxy, formyloxy, d-C4-alkylcarbonyloxy, CrC4-alkylthio, C1- C4-alkylsulfinyl, d-d-alkylsulfonyl, formyl, d-C4-alkylcarbonyl and Ci-C4- alkoxycarbonyl; or an aryl, aryl-Ci-C4-alkyI, heteroaryl or heteroaryl-Ci-C4-alkyl group, which aryl, aryl-Ci-C4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-CrC4- alkyl, aryl, heteroaryl, Ci-C6-alkyl, hydroxy-C1-C4-alkyl, d-Cralkoxy-Ci-d-alkyl, Ci-C4-alkylcarbonyl-C1-C4-alkyl, trifluoromethyl, hydroxy, d-C6-alkoxy, C1-C4- alkoxy-d-C4-alkoxy, C1-C4-Bl kylcarbony 1-C1 -C4-alkoxy, benzyloxy, phenoxy, for- myloxy, Ci-C4-alkylcarbonyloxy, carbamyloxy, N-d-C4-alkylcarbamyloxy, C1-C4- alkylthio, d-C4-alkylsulfinyl, CrC4-alkylsulfonyl, aminosulfonyl, N-d-C4-alkylami- nosulfonyl, carboxy, carbamyl, N-d-Ci-alkylcarbamyl, formyl, CrC4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-d-Ct-alkylamino, N,N-di-(CrC4-alkyl)amino with two identical or different CrC4-alkyl moieties, N^d-d-alkoxy-d-d-alkyOamino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(d-C4-alkylcarbonyl)amino,
Figure imgf000026_0001
N-(aryl-CrC4-alkoxycarbonyl)amino and N-(hete- roaryl-d-C4-alkoxycarbonyl)amino, or, taken together, complete, together with the nitrogen atom, to which they are attached, an azepanyl, morpholinyl, piperazinyl, piperidyl or pyrrolidyl ring, which azepanyl, morpholinyl, piperazinyl, piperidyl or pyrrolidyl ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cya- no, C3-C8-cycloal ky I, d-C6-alkyl, hydroxy-CrC4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, oxo, hydroxy, d-C6-alkoxy, d-C4-alkoxy-d-C4-alkoxy, formyloxy, CrC4-alkylcar- bonyloxy, CrC4-alkylthio, d-C4-alkylsulfinyl, d-C^alkylsulfonyl, formyl, d-C4-al- kylcarbonyl and d-C4-alkoxycarbonyl, and in which azepanyl, morpholinyl, piperazinyl, piperidyl or pyrrolidyl ring 1 or 2 of its methylene ring members can be replaced by a hetero ring member independently selected from the group, consisting of -S{=0)- and -S(=0)2-, and in which formula Ih k is O; 1 ; or 2; and
Rf is hydrogen; a d-C8-alkyl or Ca-Cs-cycloalkyl-d-d-alkyl group, which Ci-C8-al- kyl or C3-C8-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-Cβ-aikyl, hydroxy-d-C4-alkyl, d-C4-alkoxy-Ci-C4-alkyl, fluoromethyl, difluoro- methyl, trifluoromethyl, oxo, hydroxy, d-C6-alkoxy,
Figure imgf000026_0002
formyloxy, d-C4-alkylcarbonyloxy, CrC4-alkylthio, Ci-C4-alkylsulfinyl, CrC^alkylsul- fonyl, formyl, d-C4-alkylcarbonyl and CrC4-alkoxycarbonyl; an aryl, aryi-d-C4-al- kyl, heteroaryl, heteroaryl-CrC4-alkyl, chroman-4-yl, isochroman-4-yl, thiochroman- 4-yl, isothiochroman-4-yl, 1 , 1-dioxo-1 lambda*6*-thiochroman-4-yl, 2,2-dioxo- 2lambda*6*-isothiochroman-4-yl, 1 ,2,3,4-tetrahydro-quinol-4-yl, 1 ,2,3,4-tetrahydro- isoquinol-4-yl, 1 ,2,3,4-tetrahydro-naphth-1 -yl, 1 , 1 -dioxo-1 ,2,3,4-tetrahydro-1 lamb- da*6*-benzo[e][1 ,2]thiazin-4-yl, 2,2-dioxo-1 ,2,3,4-tetrahydro-2lambda*6*-benzo- [c][1 ,2]thiazin-4-yl, 1 , 1 -dioxo-3,4-dihydro-1 H-1 lambda*6*-benzo[c][1 ,2]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1 ,2]oxathiin-4-yl, 2,3,4,5-tetrahydro- benzo[b]oxepin-5-yl or 1 ,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group, which aryl, aryl-Ci-C4-alkyl, heteroaryl, heteroaryl-Ci-C4-alkyl, chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1 ,1-dioxo-1 lambda*6*-thiochroman-4-yl, 2,2-dioxo-2lambda*6*-isothiochroman-4-yl, 1 ,2,3,4-tetrahydro-quinol-4-yl, 1 ,2,3,4- tetrahydro-isoquinol-4-yl, 1 ,2,3,4-tetrahydro-naphth-1-yl, 1 , 1-dioxo-1 , 2,3,4- tetrahydro-1 lambda*6*-benzo[e][1 ,2]thiazin-4-yl, 2,2-dioxo-1 ,2,3,4-tetrahydro- 2lambda*6*-benzo[c][1 ,2]thiazin-4-yl, 1 ,1-dioxo-3,4-dihydro-1 H-1lambda*6*-benzo- [c][1 ,2]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1 ,2]oxathiin-4- yl, 2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or 1 ,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloal- kyl-d-C4-a!kyl, aryl, heteroaryl, Ci-C6-alkyl, hydroxy-C1-C4-alkyl, d-d.-alkoxy- C1-C4-alkyl, d-d-alkylcarbonyl-d-C-t-alkyl, trifluoromethyl, hydroxy, Ci-C6-alkoxy, Ci-C4-alkoxy-CrC4-alkoxy, Ci-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, CrC4-alkylcarbonyloxy, carbamyloxy, N-d-C4-alkyIcarbamyloxy, CrC4- alkylthio, d-C4-alkylsulfinyl, d-C4-alkylsulfonyl, aminosulfonyl, N-d-C4-alkylami- nosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, CrC4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-CrC^alkylamino, N,N-di-(d-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, N-(Ci-C4-alkoxy-Ci-C4-alkyl)amino, N-(Ci-C4-alkylsulfonyl)amino, N-formylamino, N-(d-C4-alkylcarbonyl)amino, N- (Ci-C4-alkoxycarbonyl)amino, N-(aryl-Ci-C4-alkoxycarbonyl)amino and N-(hete- roaryl-Ci-C4-alkoxycarbonyl)amino, and in which aryl-d-CValkyl or heteroaryl- Crd-alkyl group the d-C4-alkyl moiety is optionally substituted by 1 or 2 substituents independently selected from the group, consisting of fluoromethyl, difluoro- methyl and trifluoromethyl; or a C4-C8-cycloalkyl group, in which C4-C8-cycloalkyl group
(a) one of the carbon ring members of the C4-C8-cycloalkyl moiety, which carbon ring members are different from the carbon ring member of the C4-C8-cycloalkyl moiety, to which the nitrogen atom depicted in the formula Ih is attached, is optionally replaced by a hetero ring member independently selected from the group, consisting of -O-, -S-, -S(=O)-, -S(=O)2- and -N(R9)-, Rg being hydrogen; a CrC8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-d-alkyl group, which Ci-C8-alkyl, C3-C8-cycIoalkyl or C3-C8-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-Ci-C4-alkyl, C1-C4- alkoxy-d-d-alkyl, oxo, hydroxy, CrC6-alkoxy, d-d-alkoxy-d-Ci-alkoxy, formyl- oxy, d-C4-alkylcarbonyloxy, d-C4-alkylthio, C^C^alkylsulfinyl, Ci-C4-alkylsulfonyl, formyl, C1-C4-alkylcarbonyl and C1-C4-alkoxycarbonyl; or an aryl, aryl-CT-C^alkyl, heteroaryl or heteroaryI-CrC4-alkyl group, which aryl, aryl-Ci-C4-alkyl, heteroaryl or heteroaryl-CrC4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8- cycloalkyl, Cs-Cβ-cycloalkyl-d-d-alkyl, aryl, heteroaryl, d-C6-alkyl, hyd TOXy-C1-C4- alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylcarbonyl-C1-C4-alkyl, trifluoromethyl, hydroxy, CrCβ-alkoxy, Ci-C4-alkoxy-C1-C4-alkoxy, Ci-C4-alkylcarbonyl-C1-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, carbamyloxy, N-d-C4-al- kylcarbamyloxy, d-C4-alkylthio, d-C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, aminosulfo- nyl, N-Ci-d-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di- (d-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, N-(C1-C4- alkoxy-d-d-alkyl)amino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(C1-C4- alkylcarbonyl)amino, N^d-d-alkoxycarbonyOamino, N-(aryI-C1-C4-alkoxycarbo- nyl)amino and N-(heteroaryl-C1-C4-alkoxycarbonyl)amino,
(b) the d-Cβ-cycloalkyl moiety, which C4-C8-cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C6-alkoxy, d-C4-alkoxy-d-C4-alkoxy, formyloxy, d-d-alkylcarbonyloxy, d-C4-alkoxycarbonyloxy, d-C4-alkylthio, C1-C4- alkylsulfinyl, d-C4-alkylsulfonyl, formyl, C1-C4-alkylcarbonyl, CrC^alkoxycarbonyl, a d-Cβ-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group, which C1-C8- alkyl, C3-C8-cycloalkyl or Cs-Cs-cycloalkyl-CrC^alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-C8-cycloalkyl, d-Cβ-alkyl, hydroxy-d-C4-alkyl, C1-C4-BIkOXy-Ci-C4- alkyl, oxo, hydroxy, CrC6-alkoxy, C1-C4-BIkOXy-C1-C4-BIkOXy, formyloxy, CrC4-al- kylcarbonyloxy, d-C4-alkylthio, d-C4-alkylsulfιnyl, d-C4-alkylsulfonyl, formyl, Ci-C4-alkylcarbonyl and d-d-alkoxycarbonyl, and an aryl, aryl-Ci-C4-alkyl, heteroaryl, heteroaryl-Ci-C4-alkyl, heterocyclyl or heterocyclyl-Ci-C4-alkyl group, which aryl, aryl-Ci-C4-alkyl, heteroaryl, heteroaryl-Ci-C4-alkyl, heterocyclyl or heterocyc- lyl-Ci-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloal- kyl, C3-C8-cycloalkyl-Ci-C4-alkyl, aryl, heteroaryl, d-C6-alkyl, hydroxy-Ci-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylcarbonyl-Ci-C4-alkyl, trifluoromethyl, hydroxy, d-C6-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, Ci-C4-alkylcarbonyl-C1-C4-alkoxy, benzyl- oxy, phenoxy, formyloxy,
Figure imgf000029_0001
carbamyloxy, N-C1-C4-alkylcarba- myloxy, Ci-C4-alkylthio, CrC4-alkylsulfinyl, d-C4-alkylsulfonyl, aminosulfonyl, N-Ci-C4-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-Ci-C4-alkylamino, N,N-di- (d-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, N-(C1-C4- alkoxy-d-C4-alkyl)amino, N-(C1-C4-alkylsulfonyl)amino, N-formylamino, N-(C1-C4- alkylcarbonyl)amino, N-(CrC4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycarbo- nyl)amino and N^heteroaryl-d-d-alkoxycarbonyOamino, and (c) the C4-C8-cycloalkyl moiety, which C4-C8-cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted at two of its carbon ring members, which two carbon ring members are adjacent to each other, by two substituents, which two substituents form, together with the two adjacent carbon ring members, to which they are attached, a C3-C8- cycloalkyl ring, in which C3-C8-cycloalkyl ring
(i) one of the carbon ring members of the C3-C8-cycloalkyl ring thus formed, which carbon ring members are different from the said two adjacent carbon ring members of the C3-C8-cycloalkyl ring thus formed, to which the said two substituents are optionally attached, is optionally replaced by a hetero ring member independently selected from the group, consisting of -O-, -S-, -S(=O)-, -S(=O)2- and -N(Rh)-
Rh being hydrogen; a CrC8-alkyl, C3-C8-cycloalkyl or Ca-Cβ-cycloalkyl-d-d-alkyl group, which Ci-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, CrC6-alkyl, hydroxy-d-C4-alkyl, C1-C4- alkoxy-CrC4-alkyl, oxo, hydroxy, d-C6-alkoxy, d-d-alkoxy-d-d-alkoxy, formyloxy, d-C4-alkylcarbonyloxy, d-d-alkylthio, d-d-alkylsulfinyl, CrC4-alkylsulfonyl, formyl, d-C4-alkylcarbonyl and Ci-C4-alkoxycarbonyl; or an aryl, aryl-CrC4-aIkyl, heteroaryl or heteroaryl-Ci-C4-alkyl group, which aryl, aryl-d-C4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8- cycloalkyl, C3-C8-cycloalkyl-d-C4-alkyl, aryl, heteroaryl, Ci-C6-alkyl, hydroxy-d-C4- alkyl, d-C4-alkoxy-d-C4-alkyl, C1-C4-alkylcarbonyl-Ci-C4-alkyl, trifluoromethyl, hydroxy, Ci-C6-alkoxy, d-C4-alkoxy-d-C4-alkoxy, Ci-C4-alkylcarbonyl-CrC4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, carbamyloxy, N-d-C4-al- kylcarbamyloxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl, d-C4-alkylsulfonyl, aminosulfo- nyl, N-Ci-C4-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, Ci-C4-alkylcarbonyl, Ci-C4-alkoxycarbonyl, amino, N-CrC4-alkylamino, N,N-di- (Ci-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, N-(C1-C4- alkoxy-d-C4-alkyl)amino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(C1-C4- alkylcarbonyl)amino, N-(d-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycarbo- nyl)amino and N-(heteroaryl-d-C4-alkoxycarbonyl)amino, and (ii) the C3-C8-cycloalkyl ring thus formed, which C3-C8-cycloalkyl ring is optionally modified as defined under (i) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C6-alkoxy, C1-C^aIkOXy-C1-C4- alkoxy, formyloxy, CrC4-alkylcarbonyloxy, d-C4-alkoxycarbonyloxy, d-C4-alkyl- thio, d-C4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, d-C4-alkylcarbonyl, C1-C4- alkoxycarbonyl, a CrCβ-alkyl, C3-C8-cycloalkyl or Cs-Cs-cycloalkyl-d^-alkyl group, which d-Cs-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, oxo, hydroxy, d-C6-alkoxy, C1-C4-BIkOXy-C1-C4-BIkOXy, formyloxy, d-C4-alkylcarbonyloxy, d-C4-alkylthio, d-C4-alkylsulfinyl, d-C4-alkyl- sulfonyl, formyl, CrC4-alkylcarbonyl and d-C4-alkoxycarbonyl, and an aryl, aryl- d-d-alkyl, heteroaryl, heteroaryl-d-C4-alkyl, heterocyclyl or heterocyclyl-d-C4- alkyl group, which aryl, aryl-d-C4-alkyl, heteroaryl, heteroaryl-C1-C4-alkyl, heterocyclyl or heterocyclyl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-d-C4-alkyl, aryl, heteroaryl, d-C6-alkyl, hy- droxy-CrC4-alkyl, CrC4-alkoxy-d-C4-alkyl, d-C^alkylcarbonyl-d-C-i-alkyl, trifluoromethyl, hydroxy, Ci-C6-alkoxy, Ci-C4-alkoxy-CrC4-alkoxy, CrC4-alkylcarbonyl- Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, carbamyloxy, N-d-d-alkylcarbamyloxy, d-C4-alkylthio, Ci-C4-alkylsulfinyl, Ci-C4-alkylsul- fonyl, aminosulfonyl, N-CrC^alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkyl- carbamyl, formyl, d-C4-alkylcarbonyl, d-d-alkoxycarbonyl, amino, N-Ci-C4-alkyl- amino, N,N-di-(Ci-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, N-(d-d.-alkoxy-d-d-alkyl)amino, N-(d-d-alkylsulfonyl)amino, N-formyl- amino, N-(d-d-alkylcarbonyl)amino, N-(d-C4-alkoxycarbonyl)amino, N-(aryl- C1- C4-alkoxycarbonyl)amino and N-(heteroaryl-d-C4-alkoxycarbonyl)amino; preferably R10 is a group of the formula CH(Rc)C(=O)N(Rd)Re (Ig); or (CH2)kN(H)Rf (Ih), in which formula Ig
Rc is d-Cs-alkyl; and
Rd and Re are, independently from each other, hydrogen; or d-Cβ-alkyl; and in which formula Ih k is 0; and
Rf is an aryl-Crd-alkyl group, which aryl-d -C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-d-C4-alkyl, aryl, hetero- aryl, d-C6-alkyl, hydroxy-d-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, d-C4-alkylcarbo- nyl-d-d-alkyl, trifluoromethyl, hydroxy, CrC6-alkoxy, d-C4-alkoxy-d-d-alkoxy, d-C4-alkylcarbonyl-d-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcar- bonyloxy, carbamyloxy, N-d-d-alkylcarbamyloxy, d-d-alkylthio, d-d-alkylsul- finyl, d-C4-alkylsulfonyl, aminosulfonyl, N-d-d--alkylaminosulfonyl, carboxy, car- bamyl, N-d-d-alkyicarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-d-d-alkylamino, N,N-di-(d-d--alkyl)amino with two identical or different d-C4-alkyl moieties, N-(d-C4-alkoxy-d-d-alkyl)amino, N-(d-d-alkylsulfonyl)- amino, N-formylamino, N-(d-C4-alkylcarbonyl)amino, N-(CrC4-alkoxycarbonyl)- amino, N-(aryl-d-C4-alkoxycarbonyl)amino and N-(heteroaryl-d-C4-alkoxycarbo- nyl)amino, and in which aryl-d -C4-alky I group the d-C4-alkyl moiety is optionally substituted by 1 or 2 substituents independently selected from the group, consisting of fluoromethyl, difluoromethyl and trifluoromethyl; preferably R10 is a group of the formula CH(Rc)C(=O)N(Rd)Re (Ig); or (CH2)kN(H)Rf (Ih), in which formula Ig
Rc is d-Ce-alkyl; and
Rd and Re are, independently from each other, hydrogen; or d-C8-alkyl; and in which formula Ih k is 0; and Rf is an aryl-Ci-C4-alkyl group, which aryl-d-C4-alkyl group is optionally ring-substituted by 1 or 2 substituents independently selected from the group, consisting of
Ct-Cβ-alkyl; preferably R10 is a group of the formula CH(Rc)C(=O)N(Rd)Re (Ig); or (CH2)kN(H)Rf (Ih), in which formula Ig
Rc is d-Ce-alkyl; and
Rd and Re are, independently from each other, hydrogen; or CrC8-alkyl; and in which formula Ih k is O; and
Rf is an aryl-CrC4-alkyl group ring-substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C6-alkyl; preferably R10 is a group of the formula (CH2)kN(H)Rf (Ih), in which formula Ih k is 0; and
Rf is an aryl-CrC4-alkyl group ring-substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-Cβ-alkyl.
The preferred embodiments (1 ) to (7) are preferred independently, collectively or in any combination or sub-combination.
In especially preferred embodiments, the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
In a further aspect, the invention relates to a process for the preparation of a compound of the formula I, in free form or in salt form, comprising the steps of
a) reaction of a compound of the formula
Figure imgf000032_0001
in which R1, R2, R3, R4, Rs and R6 are as defined for the formula I and L1 is a leaving group, in free form or in salt form, with a compound of the formula
Figure imgf000033_0001
in which R7, Re, Rg and R10 are as defined for the formula I, in free form or in salt form, or
b) for the preparation of a compound of the formula I, in free form or in salt form, in which R1 is a group of the formula N(Ra)-C(=O)Rb (Ia); N(Ra)-S(=O)Rb (Ib); or N(Ra)-S(=O)2Rb (Ic), in which formulae Ia, Ib and Ic R3 is hydrogen; Ci-C8-alkyl; d-d-alkoxy-d-d-alkyl; d-d-al- kylthio-Ci-C4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-CrC4-alkyl; heterocyclyl; or heterocyc- lyl-Ci-C4-alkyl; and Rb is hydrogen; d-C8-alkyl; trifluoromethyl; d-C8-alkoxy; d-d-alkoxy- Ci-C4-alkyl; Ci-C8-alkylthio; d-C4-alkylthio-d-C4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl- Crd-alkyl; heterocyclyl; heterocyclyl-d-d-alkyl; amino; d-C8-alkylamino; or di-(d-C8-al- kyl)amino with two identical or different d-C.-alkyl moieties, which two d-C8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-C6-alkyl, d-C6-alkoxy and d-C6-al- kylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C8-alkyl moieties of the di-(C1-C8-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, reaction of a compound of the formula
Figure imgf000033_0002
in which R2, R3, R4, Rs, Re, R7, R8, R9 and R10 are as defined for the formula I and R3 is hydrogen; d-Ca-alkyl; d-C4-alkoxy-d-C4-alkyl; C1-C4-alkyJthio-Ci-C4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-d-dralkyl; heterocyclyl; or heterocyclyl-d-C4-alkyl, in free form or in salt form, with a compound of the formula Rb-C(=O)-L2 (V); Rb-S(=O)-L3 (Vl); or Rb-S(=O)2-L4 (VII), in which formulae V, Vl and VII Rb is hydrogen; d-C8-alkyl; trifluoromethyl; d-C8-alko- xy; d-C4-alkoxy-d-C4-alkyl; d-C8-alkylthio; d-C4-alkylthio-d-C4-alkyt; C3-C8-cycloalkyl; C3-C8-cycloalkyl-d-C4-alkyl; heterocyclyl; heterocyclyl-d-C4-alkyl; amino; d-C8-alkylamino; or
Figure imgf000034_0001
with two identical or different d-Cs-alkyl moieties, which two Ci-C8- alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, Ci-C6- alkoxy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C8-alkyl moieties of the di- (Ci-C8-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, L2 is a leaving group, L3 is a leaving group and L4 is a leaving group, in free form or in salt form,
in each case optionally followed by reduction, oxidation or other functionalisation of the resulting compound and/or by cleavage of any protecting group(s) optionally present,
and of recovering the so obtainable compound of the formula I in free form or in salt form.
A leaving group L1, L2, L3 or L4 is, e. g., halogen, such as F, Cl or Br, hydroxy or Ci-C8- alkoxy, such as methoxy, preferably Cl or hydroxy.
The reactions can be effected according to conventional methods, for example as described in the Examples.
The working-up of the reaction mixtures and the purification of the compounds thus obtainable may be carried out in accordance with known procedures.
Salts may be prepared from free compounds in known manner, and vice-versa.
Compounds of the formula I can also be prepared by further conventional processes, which processes are further aspects of the invention, e. g. as described in the Examples.
The starting materials of the formulae II, III, IV, V, Vl and VII are known or may be prepared according to conventional procedures starting from known compounds, for example as described in the Examples. Compounds of the formula I, in free form or in pharmaceutically acceptable salt form, hereinafter often referred to as "agents of the invention", exhibit valuable pharmacological properties, when tested in vitro or in vivo, and are, therefore, useful in medicaments.
E. g., agents of the invention are inhibitors of aspartic proteases and can be used for the treatment of a condition, disease or disorder involving processing by such enzymes. Particularly, agents of the invention inhibit beta-secretase and, thus, the generation of beta-amyloid and the subsequent aggregation into oligomers and fibrils.
The inhibiting properties of an agent of the invention towards proteases can be evaluated, e. g., in a test as described hereinafter.
Test 1: Inhibition of human BACE
Recombinant BACE (extracellular domain, expressed in baculovirus and purified using standard methods) at 0.1 to 10 nM concentrations is incubated with the test compound at various concentrations for 1 hour at room temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1 % CHAPS. Synthetic fluorescence-quenched peptide substrate, derived from the sequence of APP and containing a suitable fluorophore-quencher pair, is added to a final concentration of 1 to 5 μM, and the increase in fluorescence is recorded at a suitable excitation / emission wavelength in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals. IC5O values are calculated from percentage of inhibition of BACE-activity as a function of the test compound concentration.
Test 2: Inhibition of human BAC E-2
Recombinant BACE-2 (extracellular domain, expressed in baculovirus and purified using standard methods) at 0.1 to 10 nM concentrations is incubated with the test compound at various concentrations for 1 hour at room temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1 % CHAPS. Synthetic peptide substrate, derived from the sequence of APP and containing a suitable fluorophore-quencher pair, is added to a final concentration of 1 to 5 μM, and the increase in fluorescence is recorded at a suitable excitation / emission wavelength in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals. IC50 values are calculated from percentage of inhibition of BACE-2-activity as a function of the test compound concentration.
Test 3: Inhibition of human cathepsin D Recombinant cathepsin D (expressed as procathepsin D in baculovirus, purified using standard methods and activated by incubation in sodium formate buffer pH 3.7) is incubated with the test compound at various concentrations for 1 hour at room temperature in sodium formate or sodium acetate buffer at a suitable pH within the range of pH 3.0 to 5.0. Synthetic peptide substrate Mca-Gly-Lys-Pro-lle-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-NH2 is added to a final concentration of 1 to 5 μM, and the increase in fluorescence is recorded at excitation of 325 nm and emission at 400 nm in a microplate spectro-fluorimeter for 5 to 30 minutes in 1 -minute intervals. IC5O values are calculated from the percentage of inhibition of cathepsin D-activity as a function of the test compound concentration.
Test 4: Inhibition of cellular release of amyloid peptide 1-40
Chinese hamster ovary cells are transfected with the gene for amyloid precursor protein. The cells are plated at a density of 8000 cells/well into 96-well microtiter plates and cultivated for 24 hours in DMEM cell culture medium containing 10 % FCS. The test compound is added to the cells at various concentrations, and the cells are cultivated for 24 hours in the presence of the test compound. The supematants are collected, and the concentration of amyloid peptide 1-40 is determined using sandwich ELISA. The potency of the compound is calculated from the percentage of inhibition of amyloid peptide release as a function of the test compound concentration.
In at least one of the above-described tests, agents of the invention show activity at concentrations below 50 μM.
Specifically, the agent of the invention described in Example 6 shows an IC50 value of 4.22 μM in Test 1.
Due to their inhibiting properties towards proteases, agents of the invention are useful, e. g., in the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, such as a neurodegenerative condition, disease or disorder, e. g. Alzheimer's disease, Down's syndrome, memory impairment, cognitive impairment, dementia, amyloid neuropathies, brain inflammation, nerve trauma, brain trauma, vascular amyloidosis or cerebral haemorrhage with amyloidosis, or, based on the inhibition of BACE-2 (beta-site APP-cleaving enzyme 2) or cathepsin D, which are close homologues of the pepsin-type aspartyl proteases and beta-secretase, and the corre- lation of the BACE-2 or cathepsin D expression with a more tumorigenic or metastatic potential of tumor cells, in the suppression of the metastasis process associated with tumor cells.
For the above-mentioned indications, the appropriate dosage will vary depending on, e. g., the compound employed as active pharmaceutical ingredient, the host, the mode of administration, the nature and severity of the condition, disease or disorder or the effect desired. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 100, preferably from about 1 to about 50, mg/kg of animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range of from about 0.5 to about 2000, preferably from about 2 to about 200, mg of an agent of the invention conveniently administered, for example, in divided doses up to four times a day or in sustained release form.
An agent of the invention may be administered by any conventional route, in particular en- terally, preferably orally, e. g. in the form of a tablet or capsule, or parenterally, e. g. in the form of an injectable solution or suspension.
In accordance with the foregoing, in a further aspect, the invention relates to an agent of the invention for use as a medicament, e. g. for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
In a further aspect, the invention relates to the use of an agent of the invention as active pharmaceutical ingredient in a medicament, e. g. for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
In a further aspect, the invention relates to a pharmaceutical composition comprising an agent of the invention as active pharmaceutical ingredient in association with at least one pharmaceutically acceptable carrier or diluent. Such a composition may be manufactured in conventional manner, e. g. by mixing its components. Unit dosage forms contain, e. g., from about 0.1 to about 1000, preferably from about 1 to about 500, mg of an agent of the invention. An agent of the invention can be administered as sole active pharmaceutical ingredient or as a combination with at least one other active pharmaceutical ingredient effective, e. g., in the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or in the suppression of the metastasis process associated with tumor cells. Such a pharmaceutical combination may be in the form of a unit dosage form, which unit dosage form comprises a predetermined quantity of each of the at least two active components in association with at least one pharmaceutically acceptable carrier or diluent. Alternatively, the pharmaceutical combination may be in the form of a package comprising the at least two active components separately, e. g. a pack or dispenser-device adapted for the concomitant or separate administration of the at least two active components, in which these active components are separately arranged. In a further aspect, the invention relates to such pharmaceutical combinations.
In a further aspect, the invention relates to the use of an agent of the invention for the manufacture of a medicament for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells.
In a further aspect, the invention relates to a method for the treatment or prevention of a neurological or vascular condition, disease or disorder, in which beta-amyloid generation or aggregation plays a role, or for the suppression of the metastasis process associated with tumor cells, in a subject in need of such treatment, prevention or suppression, which method comprises administering to such subject an effective amount of an agent of the invention.
The following Examples illustrate the invention, but do not limit it.
Examples
Abbreviations
BOC tert-butoxycarbonyl
DCC dicyclohexylcarbodiimide
DCM dichloromethane
DIAD diisopropyl azodicarboxylate
DIBALH diisobutylaluminum hydride DIEA diisopropyl-ethyl-amine
DMAP 4-(N,N-dimethylamino)-pyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
DPPA diphenylphosphoryl azide
EDCI 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride
ESI electrospray ionization
EtOAc ethyl acetate
Grubbs' first generation catalyst bis(tricyclohexylphosphine)benzylideneruthenium dichloride
Grubbs' second generation benzylidene(1 ,3-dimesitylimidazolidin-2-ylidene)(tricyclohexylphosphine) catalyst ruthenium dichloride h hour(s)
HRMS high resolution mass spectrometry
IR infrared
KHMDS potassium hexamethyldisilazide
LDA lithium diisopropylamide min minute(s)
MS mass spectrometry
NMR nuclear magnetic resonance spectrometry
PyBOP (benzotriazole-i-yloxy)-tripyrrolidinophosponium-hexafluorophosphate rt room temperature
TBAF tetrabutylammonium fluoride
TBD 1 ,5,7-triazabicyclo[4.4.0]dec-5-ene
TEMPO 2,2,6,6-tetramethyl-1-piperidinooxy, free radical
THF tetrahydrofuran
TLC thin-layer chromatography
TMSCI trimethylsilylchloride
TMSI trimethylsilyliodide
Building block A1 : (1R,3S)-3-(1-Acetylamino-1-methyl-ethyl)-cyclohexanecarboxylic acid methyl ester a) 2-[(S)-3-(1-Methyl-1-nitro-ethyl)-cyclohexylidene]-[1 ,3]dithiane
To a solution of [1 ,3]dιthιan-2-yl-phosphonιc acid diethyl ester (0 768 g, 3 0 mmol) in THF (10 ml) is added at -78°C over a period of 15 mm n-butyllithium (1 4 ml, 2 24 mmol, 1 6 M in hexanes) The mixture is stirred for 1 h, and a solution of (S)-3-(1-methyl-1-nιtro-ethyl)-cyclo- hexanone (0 361 g, 1 95 mmol) in THF (5 ml) is added The mixture is stirred for further 15 mm at -78°C, allowed to warm to rt, treated with saturated aqueous ammonium chloride solution (3 ml) and extracted with EtOAc (2 x 20 ml) The organic layer is washed with brine, dried over sodium sulfate and evaporated The residue is purified by chromatography (5% EtOAc in hexanes) to yield a colorless oil IR (CHCI3) 1348, 1536 cm"1
b) (1R,3S)-3-(1-Methyl-1-nitro-ethyl)-cyclohexanecarboxylic acid methyl ester
A solution of building block A1a) (0 125 g, 0 438 mmol), mercuric chloride (0 476 g, 1 753 mmol) and perchloric acid (0 18 ml of a 70% aqueous solution, 1 31 mmol) in methanol (5 ml) is heated to reflux for 2 h After cooling and filtration, the reaction mixture is neutralized with saturated aqueous bicarbonate solution and extracted with DCM The combined organic layers are washed with brine, dried over sodium sulfate and concentrated to yield a diastere- omeπc mixture of the ester as a thick gum This product is, together with sodium methoxide in methanol (0 5 M, 5 ml), heated to reflux for 48 h The reaction mixture is cooled to rt, neutralized with Amberlite IR-120 (H+) resin and filtered The filtrate is concentrated, and the residue is purified by column chromatography (EtOAc hexanes 1 4) to yield a colorless oil IR (CHCI3) 1534, 1730 cm 1
c) (1R,3S)-3-(1-Acetylamino-1-methyl-ethyl)-cyclohexanecarboxyiic acid methyl ester
Building block A1b) (40 mg, 0 174 mmol) is dissolved in CH3OH (2 ml) in a thick-wailed tube Raney-Nι (50% in water, 0 3 ml) is added, followed by a catalytic amount of H2PtCI6 The mixture is stirred under H2 (60 psi) for 14 h The catalyst is filtered off, and the filtrate is evaporated to yield the crude amine, which is dissolved in DCM Acetic anhydride (35 μl, 0 32 mmol), triethylamine (64 μl, 0 460 mmol) and DMAP (catalytic amount) are added The reaction mixture is stirred at rt for 3 h and treated with aqueous ammonium chloride solution and EtOAc (10ml) The organic layer is washed with hydrochloric acid (1 N) and sodium bicarbonate solution, dried and evaporated The residue is purified by chromatography (EtOAc hexanes 1 1) to yield a colorless solid 1H-NMR (400 MHz, CDCI3): δ 5.4 (s, 1 H), 3.64 (s, 3H), 2.34-2.29 (m, 1 H), 2.17-2.1 1 (m, 1 H), 1.94-1.85 (m, 5H), 1.83 (m, 1 H), 1.72-1.69 (m, 1 H), 1.31-1.16 (m, 9H), 1.10 (m, 1 H).
Building block A2: (1R,3S)-3-(1-Methvl-1-propionylamino-ethyl)-cvclohexanecarboxylic acid methyl ester
To a solution of building block A1 b) (46 mg, 0.2 mmol) in CH3OH (4 ml) are added Raney-Ni (80 mg) and a catalytic amount of H2PtCI6. The mixture is stirred at rt under a hydrogen atmosphere for 14 h and filtered through Celite. The filter cake is washed with CH3OH (3 x 8 ml). The combined filtrates are evaporated to yield a colorless oil, which is dissolved in DCM (2 ml). To this solution are added pyridine (48.5 μl, 0.6 mmol), (CH3CH2CO)2O (78 mg, 0.6 mmol) and a catalytic amount of DMAP. The mixture is stirred at rt for 4 h and then quenched by adding 1 N aqueous hydrochloric acid. The organic layer is diluted with EtOAc, washed with brine and saturated sodium bicarbonate solution, dried and evaporated. The purification of the residue by column chromatography yields a colorless oil.
1H-NMR (400 MHz, CDCI3): δ 5.13 (br s, 1 H), 3.66 (s, 3H), 2.34 (m, 1H), 2.17 (q, J = 7.6 Hz, 2H), 1.93 (m, 2H), 1.85 (m, 2H), 1.71 (m, 2H), 1.34-1.29 (m, 2H), 1.28 (s, 3H), 1.26 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H), 0.98-0.88 (m, 1 H).
Building block A3: (1R.3S)-3-ri-Methvl-1-(2-oxo-2,5-dihvdro-pvrrol-1-vl)-ethvn-cvclo- hexanecarboxylic acid methyl ester
a) (1R,3S)-3-(1-Allylamino-1-methyl-ethyl)-cyclohexanecarboxylic acid methyl ester
To a solution of building block A1 b) (30 mg, 0.13 mmol) in CH3OH (2 ml) are added Raney-Ni (45 mg) and a catalytic amount of H2PtCI6. The mixture is stirred at rt under a hydrogen atmosphere for 12 h and filtered through Celite. The filter cake is washed with CH3OH (3 x 5 ml). The combined filtrates are evaporated to yield a colorless oil, which is dissolved in acetonitrile (5 ml). Sodium bicarbonate (32.9 mg, 0.39 mmol) and allyl bromide (11 μl, 0.13 mmol) are added to the solution. The mixture is stirred for 5 h and, after the addition of water (5 ml), extracted with DCM (3 x 10 ml). The combined organic layers are dried over sodium sulfate and evaporated. The purification of the residue by column chromatography yields a colorless oil.
1H-NMR (400 MHz, CDCI3): δ 5.98-5.91 (m, 1 H), 5.21 (dd, J = 1.6, 1.5 Hz, 1 H), 5.07 (dd, J = 1.6, 1.5 Hz, 1 H), 3.69 (s, 3H), 3.16 (d, J = 6.0 Hz, 2H), 2.31 (m, 1 H), 1.99-1.89 (m, 3H), 1.78- 1.75 (m, 1 H), 1.42-1.14 (m, 5H), 1.05 (s, 6H), 1.03-0.99 (m. 1 H). b) (1 R,3S)-3-[1 -(Acryloyl-allyl-amino)-i -methyl-ethylj-cyclohexanecarboxy lie acid methyl ester
To a solution of building block A3a) (10 mg, 0.042 mmol) in DCM (1.5 ml) are added under argon at 00C pyridine (34.0 μl, 0.42 mmol) and CH2CHCOCI (17.1 μl, 0.21 mmol). The mixture is stirred for 30 min, quenched with aqueous 1 N hydrochloric acid (0.5 ml) and extracted with DCM. The organic layer is washed with water, dried over sodium sulfate and evaporated. The purification of the residue by column chromatography yields a colorless oil. 1H-NMR (400 MHz, CDCI3): 5 6.47 (dd, J = 10.2, 10.1 Hz, 1 H), 6.25 (dd, J = 1.5, 1.6 Hz, 1 H), 5.87 (m, 1 H), 5.57 (dd, J = 1.5, 1.6 Hz, 1 H), 5.27 (m, 2H), 3.93 (m, 2H), 3.65 (s, 3H), 2.77 (m, 1 H), 2.34 (m, 1 H), 1.94 (m, 1 H), 1.89-1.77 (m, 2H), 1.71-1.55 (m, 2H), 1.42 (s, 6H), 1.37-1.12 (m, 3H).
c) (1R,3S)-3-[1-Methyl-1-(2-oxo-2,5-dihydro-pyrrol-1-yl)-ethyl]-cyclohexanecarboxylic acid methyl ester
To a solution of building block A3b) (10 mg, 0.034mmol) in DCM (10 ml) is added under argon at reflux temperature Grubbs' first generation catalyst (1.4 mg, 0.0017 mmol). The mixture is stirred for 3 h and then filtered through Florisil/silica. The filter cake is washed with DCM, and the combined filtrates are evaporated. The residue is purified by column chromatography to yield a colorless oil.
1H-NMR (400 MHz, CDCI3): δ 6.97 (dd, J = 1.7, 4.1 Hz, 1 H), 6.09 (dd, J = 1.7, 4.0 Hz, 1 H), 4.05 (br s, 2H), 3.64 (s, 3H), 2.65 (m, 1 H), 2.36 (m, 1 H), 1.93 (m, 1 H), 1.84-1.76 (m, 2H), 1.58-1.56 (m, 2H), 1.40 (s, 6H), 1.32-1.16 (m, 3H).
Building block A4: (1 R,3S)-3-M-Methvl-1-(2,2,2-trifluoro-acetylamino)-ethvn-cvclo- hexanecarboxylic acid methyl ester
Building block A1 b) (40 mg, 0.174 mmol) is dissolved in CH3OH (2 ml) in a thick-walled tube. Raney-Ni (50% in water, 0.3 ml) is added, followed by a catalytic amount of H2PtCI6. The mixture is stirred under H2 (60 psi) for 14 h. The catalyst is filtered off, and the filtrate is evaporated to yield the crude amine, which is dissolved in dry DCM. Trifluoroacetic anhydride (71 μl, 0.51 mmol) is added, followed by triethylamine (71 μl, 0.51 mmol) and DMAP (catalytic amount). The reaction mixture is stirred at rt for 3 h and then quenched by adding aqueous ammonium chloride solution. The organic layer is diluted with EtOAc, washed with hy- drochloric acid (1 N) and sodium bicarbonate solution, dried and concentrated. The residue is purified by chromatography (EtOAc:hexanes 1 :1) to yield a colorless oil. 1H-NMR (400 MHz, CDCI3): δ 5.92 (m, 1 H), 3.70 (s, 3H), 2.38 (m, 1 H), 2.13-1.89 (m, 4H), 1.75-1.67 (m, 2H), 1.39-1.14 (m, 9H).
Building block A5: (1 R,3S)-3-(1 -Acetylamino-cyclopenty l)-cyclohexanecarboxylic acid methyl ester
a) (S)-1-{Bis-methylsulfanyl-methylene)-3-(1-nitro-cyclopentyl)-cyclohexane
To a stirred solution of bis(methylmercapto)methyl-phosphonic acid diethyl ester (0.41 g, 1.88 mmol) in THF (10 ml) is added at -78°C over a period of 15 min n-butyllithium (1.3 ml, 2.08 mmol, 1.6 M in hexanes). The mixture is stirred for 1 h, and a solution of (S)-3-(1-nitro- cyclopentyl)-cyclohexanone (0.39 g, 2.10 mmol) in THF (5 ml) is added. The mixture is stirred for further 15 min at -78°C, allowed to warm to rt, treated after 1 h with saturated aqueous ammonium chloride solution (3 ml) and extracted with EtOAc (40 ml). The organic layer is washed with brine, dried over sodium sulfate and concentrated. The residue is purified by column chromatography (5% EtOAc in hexanes) to yield a colorless oil. IR (CHCI3): 1537, 1710 cm"1.
b) (1 R,3S)-3-(1-Nitro-cyclopentyl)-cyclohexanecarboxylic acid methyl ester
A solution of building block A5a) (0.437 g, 1.44 mmol), mercuric chloride (1.57 g, 5.82 mmol) and perchloric acid (0.62 ml of a 70% aqueous solution, 4.35 mmol) in methanol (35 ml) is heated to reflux for 2 h. After cooling and filtration, the reaction mixture is neutralized with saturated aqueous bicarbonate solution and extracted with DCM. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated to yield a diastere- omeric mixture of the ester as a thick gum. This product is, together with sodium methoxide in methanol (0.5 M, 5 ml), heated to reflux for 48 h. The reaction mixture is cooled to rt, neutralized with Amberlite IR-120 (H+) resin and filtered. The filtrate is concentrated, and the residue is purified by column chromatography (EtOAc: hexanes 1 :4) to yield a colorless oil. IR (CHCI3): 1535, 1735 Cm"1.
c) (1 R,3S)-3-(1-Acetylamino-cyclopentyl)-cyclohexanecarboxylic acid methyl ester
Building block A5b) (56 mg, 0.22 mmol) is dissolved in CH3OH (2 ml) in a thick-walled tube. Raney-Ni (50% in water, 0.3 ml) is added, followed by a catalytic amount of H2PtCI6. The mixture is stirred under H2 (60 psi) for 14 h. The catalyst is filtered off, and the filtrate is evaporated to yield the crude amine, which is dissolved in DCM (2 ml). Acetic anhydride (62 μl, 0.66 mmol) is added, followed by triethylamine (92 μl, 0.66 mmol) and DMAP (catalytic amount). The reaction mixture is stirred at rt for 3 h and then quenched with aqueous ammonium chloride solution. The organic layer is diluted with EtOAc, washed with hydrochloric acid (1 N) and sodium bicarbonate solution, dried and concentrated. The residue is purified by chromatography (EtOAc:hexanes 1 :1) to yield a colorless oil.
1H-NMR (400 MHz, CDCI3): δ 5.20 (s, 1 H), 3.60 (s, 3H), 2.36-2.22 (m, 1 H), 2.20-2.00 (m, 1 H), 1.97-1.84 (m, 8H), 1.79-1.63 (m, 8H), 1.33-1.27 (m, 3H).
Building block A6: (1R,3S)-3-ri-Methvl-1-(methvl-propionvl-amino)-ethyll-cvclohexane- carboxylic acid
a) (1 R,3S)-3-(1-Ethoxycarbonylamino-1-methyl-ethyl)-cyclohexanecarboxylic acid methyl ester
Building block A1 b) (200 mg, 0.86 mmol) is dissolved in CH3OH (10 ml) in a thick-walled tube. Raney-Ni (50% in water, 1.5 ml) is added, followed by a catalytic amount of H2PtCI6. The mixture is stirred under H2 (60 psi) for 14 h (until TLC shows the full consumption of the starting material). The catalyst is filtered off, and the filtrate is evaporated to yield the crude amine, which is dissolved in DCM (3.3 ml) and water (1.6 ml). Sodium carbonate (159 mg, 1.4 mmol) is added, and the mixture is stirred for 10 min. Ethyl chloroformate (0.1 ml, 1.05 mmol) is added dropwise. The mixture is stirred at rt for 30 min, then quenched by adding aqueous ammonium chloride solution and extracted with DCM. The combined organic extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is purified by column chromatography to yield a colorless solid. MS (ESI): 272 (M + I )+.
b) N-[1-((1S,3R)-3-Hydroxymethyl-cyclohexyl)-1-methyl-ethyl]-N-methyl-propionamide
To a solution of building block A6a) (190 mg, 0.7 mmol) in THF (5 ml) is added lithium aluminium hydride (80 mg, 2.1 mmol) portionwise at O0C during 15 min. The mixture is heated to 6O0C and stirred for 4 h. After cooling to 00C, saturated aqueous KHSO4 solution (2 ml) is added carefully, and the mixture is stirred for 30 min at a temperature between 00C and rt, diluted with DCM and water and filtered through a pad of Celite. The filtrate is washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to yield the methylamine. To a solution of this amine (28 mg, 0.15 mmol) in DCM (1 ml) and water (0.5 ml) is added sodium carbonate (35 mg, 0.31 mmol), and the mixture is stirred for 10 min. Propionyl chloride (26 μl, 0.3 mmol) is added dropwise. The mixture is stirred at rt for 40 min, then quenched by adding aqueous ammonium chloride solution and extracted with DCM. The combined organic extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is purified by column chromatography to yield the title compound. 1H-NMR (400 MHz, CDCI3): δ 3.42 (m, 5H), 2.88 (s, 3H), 2.60 (tt, J = 12.2, 3.0 Hz, 1 H), 2.33 (m, 3H), 1.80-1.47 (m, 4H), 1.35 (s, 3H), 1.32 (s, 3H), 1.29 (m, 1 H), 1.08 (t, J = 7.3 Hz, 3H), 0.94 (qd, J = 12.4, 3.5 Hz, 1 H)1 0.80 (qd, J = 12.4, 3.5 Hz, 1 H), 0.71 (q, J = 12.0 Hz, 1 H).
c) (1R,3S)-3-[1-Methyl-1-(methyl-propionyl-amino)-ethyl]-cyclohexanecarboxylic acid
To a solution of building block A6b) (38 mg, 0.16 mmol) in acetone (2 ml) and saturated sodium bicarbonate solution (0.5 ml) are added at 0°C under stirring sodium bromide (4 mg, 0.04 mmol), TEMPO (1 mg) and trichloroisocyanuric acid (73 mg, 0.32 mmol). The mixture is stirred overnight at a temperature between O0C and rt. lsopropanol (1 ml) is added. The mixture is filtered through a pad of Celite, and the filter cake is washed with EtOAc. The combined filtrates are washed with 1 N aqueous hydrochloric acid (2 ml) and brine, dried over sodium sulfate and concentrated to yield the title compound.
1H-NMR (400 MHz, CDCI3): δ 8.00 (b, 1 H), 2.89 (s, 3H), 2.69 (t, J = 12.0 Hz, 1 H), 2.32 (m, 3H), 1.95 (m, 1 H), 1.80 (m, 2H), 1.57 (m, 1 H), 1.35 (s, 3H), 1.32 (s, 3H), 1.29-1.12 (m, 3H), 1.08 (t, J = 7.3 Hz, 3H), 0.94 (m, 1 H).
Building block A7: f1 R.3S)-3-ri-Methvl-1-(6-oxo-3.6-dihvdro-2H-pvridin-1-vl)-ethvn- cyclohexanecarboxylic acid methyl ester
a) (1R,3S)-3-[1-(Allyl-but-3-enoyl-amino)-1-methyl-ethyI]-cyclohexanecarboxylic acid methyl ester
To a solution of building block A3a) (14 mg, 0.059 mmol) in DCM (1 ml) are added under argon at rt but-3-enoic acid (7.5 μl, 0.088 mmol), DCC (16.9 mg, 0.082 mmol), DIEA (20.4 μl, 0.12 mmol) and DMAP (catalytic amount). The mixture is stirred for 30 min, then quenched with 1 N hydrochloric acid (0.2 ml) and extracted with DCM. The combined organic extracts are washed with water, dried over sodium sulfate and evaporated. The residue is purified by column chromatography to yield the title compound. 1H-NMR (400 MHz, CDCI3): δ 6.01-5.83 (m, 2H), 5.26-5.05 (m, 4H), 3.91 (m, 2H), 3.66 (s, 3H), 3.10 (m, 2H), 2.75-2.69 (m, 1 H), 2.34-2.31 (m, 1 H), 1.98-1.55 (m, 8H), 1.39 (s, 6H).
b) (1R,3S)-3-[1-Methyl-1-(6-oxo-3,6-dihydro-2H-pyridin-1-yl)-ethyl]-cyclohexane- carboxylic acid methyl ester
To a solution of building block A7a) (10 mg, 0.034 mmol) in DCM (6 ml) is added under argon at reflux temperature a catalytic amount of Grubbs' first generation catalyst. The mixture is heated under reflux for 3 h, filtered through a pad of Florisil/silica and evaporated. The residue is purified by column chromatography to yield the title compound. 1H-NMR (400 MHz, CDCI3): δ 5.77-5.73 (m, 1 H), 5.68-5.64 (m, 1 H), 3.94 (m, 1 H), 3.65 (s, 3H), 2.96-2.85 (m, 3H), 2.38-2.32 (m, 1 H), 1.94-1.86 (m, 1 H), 1.85-1.80 (m, 2H), 1.64-1.61 (m, 1 H), 1.41 (s, 3H), 1.40 (s, 3H).
Building block A8: (1 R,3S)-3-((S)-1 -Acetylamino-Z-methyl-propyO-cyclohexane- carboxylic acid methyl ester
a) (3R,4R)-4-Benzyloxymethoxy-5-methyl-3-vinyl-hexanoic acid methyl ester
To a suspension of copper(l)iodide (5.71 g, 30 mmol) in THF (100 ml) is added at -78°C over 20 min vinylmagnesium bromide (60 ml, 1 M in THF). The mixture is stirred for 45 min. (E)- (R)-4-Benzyloxymethoxy-5-methyl-hex-2-enoic acid methyl ester (1.39 g, 5 mmol) in THF (20 ml) and TMSCI (1 1.4 ml, 90 mmol) are added, and the mixture is stirred at -78°C for 4 h, then quenched with aqueous NH4OH/NH4CI solution (1 :1 , 100 ml) and allowed to warm to rt. The organic layer is washed with aqueous saturated ammonium chloride solution and brine, dried over sodium sulfate and evaporated. The residue is purified by column chromatography (5% EtOAc in hexanes) to yield a colorless oil. IR (CHCI3): 1740 cm"1.
b) (3R,4R)-4-Benzyloxymethoxy-5-rnethyl-3-vinyl-hexan-1 -ol
To a solution of building block A8a) (0.612 g, 2 mmol) in THF (20 ml) is added at 00C DIBALH (3 ml, 1.5 M in toluene, 4.5 mmol). The mixture is stirred for 2 h, then quenched with CH3OH (5 ml), followed by Rochelle salt (sodium potassium tartrate tetrahydrate) solution (15 ml) and EtOAc (50 ml), and stirred for further 2 h. The organic layer is washed with brine, dried over sodium sulfate and concentrated. The residue is filtered through a short pad of silica gel (the filter cake being washed with 15% EtOAC in hexanes) to yield a colorless viscous oil.
IR (CHCI3): 3416 cm"1.
c) ((3R,4R)-4-Benzyloxymethoxy-5-methyl-3-vinyl-hexyloxy)-tert-butyl-dimethyl-silane
To a solution of building block A8b) (2.2 g, 7.91 mmol) in DCM (80 ml) are added DMAP (2.89 g, 23.73 mmol) and tert-butyl-dimethylsilylchloride (1.31 g, 8.7 mmol). The mixture is stirred at rt for 30 min, diluted with DCM (100 ml), washed with 1 N hydrochloric acid and brine, dried over sodium sulfate and concentrated. The residue is filtered through a short pad of silica gel to yield a transparent oil. MS (ESI): 393.3 (M + I )+.
d) (3R,4R)-4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-hex-5-en-3-ol
Building block A8c) (1 g, 2.55 mmol) in THF (7 ml) is added at -78°C to a solution of sodium (0.704 g, 30.6 mmol) in liquid ammonia (250 ml). The mixture is stirred at -78°C for 1 h. Then, the cooling bath is removed, and the ammonia is refluxed at rt for 2 h. The mixture is quenched by careful addition of solid ammonium chloride, until it turns colorless. The excess ammonia is removed by a stream of nitrogen. The mixture is extracted with diethylether (3 x 75 ml). The combined extracts are evaporated, and the residue is purified by column chromatography (4% EtOAc in hexanes) to yield a colorless oil. IR (CHCI3): 3437 cm"1.
e) ((3R,4S)-4-Azido-5-methyl-3-vinyl-hexyloxy)-tert-butyl-dimethyl-silane
To a solution of building block A8d) (0.51 g, 1.87 mmol) in THF (19 ml) is added at 00C tri- phenyl phosphine (2.454 g, 9.37 mmol). The mixture is stirred, until a homogeneous solution is obtained. DIAD (1.85 ml, 9.37 mmol) is added with stirring over 5 min (a white precipitate is formed). DPPA (2.018 ml, 9.37 mmol) is added dropwise at 00C. The mixture is stirred at rt for 24 h and concentrated. The residue is purified by chromatography (5% EtOAc in hexanes) to yield a colorless transparent oil. IR (neat): 2099 cm"1.
f) (3R,4S)-4-Azido-5-methyl-3-vinyl-hexan-1 -ol
To a solution of building block A8e) (0.4 g, 1.35 mmol) in THF (15 ml) is added tetrabutylam- monium fluoride (1.35 ml, 1 M in THF, 1.35 mmol). The mixture is stirred at rt for 2 h and concentrated. The residue is purified by chromatography (20% EtOAc in hexanes) to yield a colorless oil.
IR (neat): 3341 , 2097 cm"1.
g) (3R,4S)-4-Azido-5-methyl-3-vinyl-hexanal
To a solution of oxalyl chloride (138 μl, 1.5 mmol) in DCM (10 ml) is added dropwise at -78°C DMSO (289 μl, 4.08 mmol). The mixture is stirred for 15 min. Building block A8f) (0.250 g, 1.36 mmol) in DCM (5 ml) is added, followed after 30 min by DIEA (945 μl, 5.44 mmol). The mixture is stirred for 30 min, then allowed to warm to rt over 30 min, quenched with water (5 ml) and extracted with DCM (50 ml). The organic extract is washed with citric acid solution and brine, dried over sodium sulphate and concentrated. The residue is purified by column chromatography (4% EtOAc in hexanes) to yield a transparent viscous oil. IR (neat): 2100, 1726 cm"1.
h) 2-((3R,4S)-4-Azido-5-methyl-3-vinyl-hexylidene)-[1,3]dithiane
To a solution of 2-phosphoryl-1 ,3-dithiane (0.371 g, 1.45 mmol) in THF (15 ml) is added at -78°C n-butyllithium (0.9 ml, 1.6 M in hexane, 1.45 mmol). The mixture is stirred for 1 h. Building block A8g) (0.24 g, 1.32 mmol) in THF (5 ml) is added. The mixture is stirred at -78°C for 15 min and after the removal of the cooling bath for further 30 min, quenched with aqueous ammonium chloride solution (5 ml) and extracted with diethylether (50 ml). The organic extract is concentrated, and the residue is purified by column chromatography (2% EtOAc in hexanes) to yield a pale yellow oil. IR (neat): 2099 cm 1.
i) (4R,5S)-5-Azido-6-methyl-4-vinyl-heptanoic acid methyl ester
Building block A8h) (0.22 g, 0.77 mmol) is dissolved in a methanolic solution of CuSO4 (30 ml, 0.2 M). The mixture is stirred at 65CC for 2.5 h, cooled to rt and concentrated. The residue is diluted with EtOAc (40 ml) and water (5 ml). The organic layer is concentrated, and the residue is purified by column chromatography (3% EtOAc in hexanes) to yield a colorless viscous oil. IR (neat): 2100, 1740 cm"1.
j) (4R,5S)-2-Allyl-5-azido-6-methyl-4-vinyl-heptanoic acid methyl ester To a solution of building block A8i) (0.15 g, 0.66 mmol) in THF (30 ml) are added at -78°C KHMDS (3.3 ml, 0.5 M in toluene, 1.65 mmol) and allyl bromide (285 μl, 3.3 mmol). The mixture is stirred for 5 min, quenched with water (7 ml) and allowed to warm to rt. The organic layer is extracted with EtOAc (50 ml), dried over sodium sulfate and concentrated. The residue is purified by column chromatography (2% EtOAc in hexanes) to yield a colorless oil. IR (neat): 2100, 1737 cm"1.
k) (1 R,5R)-5-((S)-1-Azido-2-methyl-propyl)-cyclohex-3-enecarboxylic acid methyl ester
To a solution of building block A8j) (0.029 g, 0.11 mmol) in DCM (20 ml) is added Grubbs' second generation catalyst (13 mg, 0.0153 mmol). The mixture is stirred at rt for 3 h and then concentrated. The residue is purified by chromatography (3% EtOAc in hexanes) to yield a colorless gum (mixture of epimers). This gum is taken up in a methanolic solution of NaOCH3 (0.5 M, 3 ml). The mixture is heated under reflux for 48 h, cooled to rt, neutralized with Amberlite resin, diluted with chloroform (15 ml) and filtered. The organic filtrate is concentrated, the residue is dissolved in CH3OH (5 ml), the solution is treated at O0C with an excess of diazomethane, and the mixture is allowed to warm to rt over 1 h and concentrated. The residue is filtered through a small pad of silica gel to yield the title compound. IR (CHCI3): 2099, 1737 crτϊ1.
I) (1 R,3S)-3-((S)-1-Acetylamino-2-methyl-propyl)-cyclohexanecarboxylic acid methyl ester
To a solution of building block A8k) (0.04 g, 0.168 mmol) in CH3OH (12 ml) is added Pd(OH)2/carbon (0.080 g, 20% by weight). The mixture is stirred under a hydrogen atmosphere (1 atm) for 3 h and then filtered through Celite. The organic filtrate is concentrated, and the residue is taken up in DCM (2 ml). Pyridine (41 μl, 0.504 mmol) and acetic anhydride (48 μl, 0.504 mmol) are added, and the mixture is stirred at rt for 12 h, diluted with DCM (12 ml), washed with aqueous HCI and brine, dried over sodium sulfate and evaporated. The residue is purified by chromatography (80% EtOAc in hexanes) to yield a colorless solid. 1H-NMR (400 MHz, CDCI3): δ 5.10 (d, J = 6.5 Hz, 1 H), 3.66 (s, 3H), 2.36 (tt, J = 3.5 Hz, 1 H), 2.02 (s, 3H), 1.98-1.81 (m, 2H), 1.75-1.72 (m, 2H), 1.70-1.67 (m, 3H), 1.60-1.40 (m, 1 H), 1.40-1.20 (m, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). Buildinq block A9: HR.SR^-URH-tert-ButoxvcarbonvIamino-butvO-S-hvdroxv-cvclo- hexanecarboxylic acid 2-trimethylsilanyl-ethyl ester (assignment of stereochemistry of amino substituent arbitrary)
a) (R)-3-Oxo-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester
(R)-3-Oxo-cyclohexanecarboxylic acid (184 mg, 1.29 mmol) is dissolved in DCM (12 ml). 2- Trimethylsilanyl-ethanol (0.37 ml, 2.58 mmol, 2 equivalents) and EDCI (298 mg, 1.2 equivalents) are added. The mixture is stirred at a temperature between 00C and 5°C for 24 h, quenched with aqueous ammonium chloride solution and diluted with EtOAc. The organic layer is dried over sodium sulfate and evaporated to yield a colorless oil, which is used in the next reaction step without further purification.
b) (1 R,3R)-3-Hydroxy-3-((R)-1-nitro-butyl)-cyclohexanecarboxylic acid 2-trimethylsilanyl- ethyl ester (assignment of stereochemistry of nitro substituent arbitrary)
To a solution of building block A9a) (124 mg, 0.51 mmol) in DCM (10 ml) are added at 00C 1- nitrobutane (1 ml), 4 A molecular sieve (50 mg) and TBD (53 mg). The mixture is stirred at 00C for 72 h, quenched with aqueous ammonium chloride solution and diluted with EtOAc. The organic layer is dried over sodium sulfate and evaporated to yield an oil (1 :1 mixture of epimers). Chromatography of the oil on silica gel (EtOAc : hexanes = 1 : 6) yields the title compound (less polar epimer). [α]D 20 (c = 1.0, CHCI3): + 5.0.
c) (1 R,3R)-3-((R)-1 -tert-Butoxycarbonylamino-butyl)-3-hydroxy-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester (assignment of stereochemistry of amino substituent arbitrary)
A solution of building block A9b) in CH3OH (10 ml) is overnight subjected to reduction in the presence of Raney-Ni (20 mg) and H2PtCI6 (5 mg) under a hydrogen atmosphere (60 psi). The mixture is filtered, and to the filtrate is added BOC2O in dioxane and aqueous 1 N NaOH. The mixture is stirred for 12 h, neutralized with 0.1 N aqueous hydrochloric acid and extracted with EtOAc. The extract is dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (EtOAc : hexanes = 1 : 3) to yield the title compound. [cc]D 20 (c = 0.8, CHCI3): + 3.0. Buildinq block A10: (1R,3R)-3-((S)-1-tert-Butoxvcarbonylamino-btJtvl)-3-hvdroxv-cvclo- hexanecarboxylic acid 2-trimethylsilanyl-ethyl ester (assignment of stereochemistry of amino substituent arbitrary)
a) (1R,3R)-3-Hydroxy-3-((S)-1-nitro-butyl)-cyclohexanecarboxylic acid 2-trimethylsilanyl- ethyl ester (assignment of stereochemistry of nitro substituent arbitrary)
The title compound is obtained as the more polar epimer in the final chromatography step of the synthesis of building block A9b). [α]D 20 (C = 1.7, CHCI3): - 10.4.
b) (1R,3R)-3-({S)-1-tert-Butoxycarbonylamino-butyl)-3-hydroxy-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester (assignment of stereochemistry of amino substituent arbitrary)
A solution of building block A10a) in CH3OH (10 ml) is overnight subjected to reduction in the presence of Raney-Ni (20 mg) and H2PtCI6 (5 mg) under a hydrogen atmosphere (60 psi). The mixture is filtered, and to the filtrate is added BOC2O in dioxane and aqueous 1 N NaOH. The mixture is stirred for 12 h, neutralized with 0.1 N aqueous hydrochloric acid and extracted with EtOAc. The extract is dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (EtOAc : hexanes = 1 : 3) to yield the title compound. Kb20 (c = 1.2, CHCI3): - 19.94.
Building block A11 : (1R.3R)-3-Hvdroxv-3-(1-methylcarbamovl-butvl)-cvclohexane- carboxylic acid 2-trimethylsilanyl-ethyl ester
a) (1R,3R)-3-(1-Benzyloxycarbonyl-butyl)-3-hydroxy-cyclohexanecarboxylic acid 2- trimethylsilanyl-ethyl ester
To a solution of benzyl pentanoate (480 mg, 2.5 mmol) in THF (4 ml) are added at rt LDA (2.5 mmol) and CeCI3 (3 mmol). To this mixture is added at -78°C building block A9a) (242 mg, 1 mmol) in THF (10 ml). The mixture is stirred for 5 h, quenched with aqueous ammonium chloride solution and extracted with EtOAc. The organic extract is dried over sodium sulfate and evaporated to yield the title compound (mixture of epimers).
b) (1R,3R)-3-Hydroxy-3-(1-methylcarbamoyl-butyl)-cyclohexanecarboxylic acid 2- trimethylsilanyl-ethyl ester A solution of building block A11a) (34 mg) in EtOAc is hydrogenated at rt in the presence of 10% Pd/carbon. The mixture is filtered, the filtrate is evaporated, and the residue is dissolved in DCM (10 ml). PyBOP (78 mg), DIEA (207 mg) and methylamine (27 mg) are added at 00C. The mixture is stirred for 3 h, neutralized with 0.1 N aqueous hydrochloric acid and extracted with EtOAc. The organic extract is evaporated, and the residue is purified by chromatography on silica gel (EtOAc : hexanes = 1 : 3) to yield the title compound (mixture of epimers). [cc]D 20 (c = 1 , CHCI3): + 5.2.
Example 1 : (1 R,3S)-3-(1-Acetvlamino-1-methvl-ethyl)-cvclohexanecarboxvlic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
A solution of building block A1 (25.4 mg, 0.105 mmol) and LiOH (1 N, 0.26 ml) in CH3OH (0.5 ml) is stirred at rt for 14 h, neutralized with 1 N hydrochloric acid and extracted with EtOAc (3 x 5 ml). The combined extracts are dried and concentrated to yield the crude acid, which is added to a solution of (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenyl-hexanoic acid butylamide (building block B1 , 12 mg, 0.042 mmol) in DCM/DMF (5:1 , 1 ml). At O0C PyBOP (21.8 mg, 0.042 mmol) and DIEA (14.6 μl, 0.084 mmol) are added. The mixture is stirred at 5°C for 14 h, diluted with EtOAc (5 ml), washed with 1 N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue is purified by chromatography (EtOAc/CH3OH 9:1 ) to yield a colorless solid.
1H-NMR (400 MHz, CD3OD): δ 7.28-7.14 (m, 5H), 6.18-6.15 (m, 2H), 5.20 (s, 1 H), 4.52 (s, 1 H), 4.07-4.04 (m, 1 H), 3.65 (dd, J = 13.0, 6.8 Hz, 1 H), 3.22-3.12 (m, 3H), 2.94 (m, 2H), 2.52 (dd, J = 13.0, 6.8 Hz, 1 H), 2.16-2.02 (m, 3H), 1.90-1.53 (m, 4H), 1.46-1.32 (m, 8H), 1.29-1.24 (m, 5H), 1.12-1.02 (m, 7H), 0.92 (t, J =7.2 Hz, 3H).
Example 2: (1 R,3S)-3-(1-Methyl-1-propionylamino-ethyl)-cyclohexanecarboxylic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
The title compound is prepared as a colorless solid in a manner analogous to that described in Example 1 starting from building block A2 and building block Bl
1H-NMR (400 MHz, CD3OD): δ 7.24-7.13 (m, 5H), 4.07 (m, 1 H), 3.58 (m, 1 H), 3.33 (m, 2H), 3.15 (t, J = 6.9 Hz, 2H), 2.91 (m, 1 H), 2.90-2.78 (m, 1 H), 2.58 (m, 1 H), 2.18-2.12 (m, 4H), 1.83 (m, 1 H), 175-164 (m, 3H), 1.49-126 (m, 8H), 1.22 (s, 3H), 1.20 (s, 3H), 112-101 (m, 6H), 0.98-0.93 (m, 4H). Example 3: (1 R.3S)-3-ri-Methvl-1-(2-oxo-pvrrolidin-1-vl)-ethvn-cvclohexanecarboxvlic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
To a solution of building block A3 (20 mg, 0.075 mmol) in CH3OH (5 ml) is added 10% Pd/- carbon (catalytic amount). The mixture is stirred at rt under a hydrogen atmosphere for 14 h and then filtered through Celite. The filter cake is rinsed with CH3OH (3 x 5 ml). The combined filtrates are evaporated to yield a colorless oil, which is treated with a solution of lithium hydroxide monohydrate (9.4 mg, 0.22 mmol) in CH3OH/water (2:1 , 0.66 ml). The mixture is stirred for 12 h, neutralized with aqueous 1 N hydrochloric acid and extracted with EtOAc (3 x 5 ml). The combined extracts are dried over sodium sulfate and concentrated to yield the crude acid, which is dissolved in DCM (1.5 ml). At O0C are added building block B1 (21.9 mg, 0.075 mmol), PyBOP (78.0 mg, 0.15 mmol) and DIEA (52.3 μl, 0.30 mmol). The mixture is stirred at O0C for 14 h, then diluted with EtOAc to a volume of 15 ml, washed with aqueous 1 N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried and evaporated. The residue is purified by column chromatography to yield the title compound. 1H-NMR (400 MHz, CD3OD): δ 7.26-7.24 (m, 5H), 4.10 (m, 1 H), 3.61-3.45 (m, 3H), 3.15 (t, J = 6.9 Hz, 2H), 2.92 (m, 1 H), 2.78 (m, 1 H), 2.60 (m, 1 H), 2.51 (m, 1 H), 2.34 (m, 2H), 2.16 (m, 1 H), 1.96 (m, 2H), 1.86 (m, 1 H), 1.79-1.68 (m, 2H), 1.60 (m, 1 H), 1.47-1.45 (m, 3H), 1.37- 1.29 (m, 12H), 1.11 (d, J = 7.0 Hz, 3H), 1.03 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).
Example 4:
(1R,3S)-3-[1-Methyl-1-(2,2,2-trifluoro-acetylamino)-ethyl]-cyclohexanecarboxylic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
The title compound is prepared in a manner analogous to that described in Example 1 starting from building block A4 and building block B1.
1H-NMR (400 MHz, CD3OD): δ 7.31-7.18 (m, 5H), 5.92-5.84 (m, 3H), 4.04 (dd, J = 15.9, 8.2 Hz, 1 H), 3.77-3.69 (m, 1 H), 3.29-3.16 (m, 2H), 2.95 (d, J = 7.4 Hz, 2H), 2.54 (dd, J = 12.9, 6.7 Hz, 1 H), 2.09-1.86 (m, 2H), 1.78-1.45 (m, 8H), 1.43-1.33 (m, 10H), 1.27-1.13 (m, 5H), 0.90 (t, J = 7.3 Hz, 3H).
Example 5: (1 R,3S)-3-(1 -Acetylamino-cyclopentyl)-cyclohexanecarboxy lie acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
The title compound is prepared in a manner analogous to that described in Example 1 starting from building block A5 and building block B1. 1H-NMR (400 MHz, CD3OD): δ 7.29-7.11 (m, 5H), 4.05 (m, 1 H), 3.56 (m, 1 H), 3.12 (t, J = 6.8 Hz, 2H), 2.90 (dd, J = 13.8, 5.3 Hz, 1 H), 2.73 (dd, J = 13.8, 6.9 Hz, 1 H), 2.55 (m, 1 H), 2.11 (m, 2H), 1.97 (m, 1 H), 1.88 (s, 3H), 1.86 (m, 2H), 1.74 (m, 4H), 1.69 (m, 5H), 1.51-1.12 (m, 9H), 1.08 (d, J = 6.9 Hz, 3H), 1.01 (m, 1 H), 0.92 (t, J = 7.2 Hz, 3H).
Example 6: (1R.3S)-3-(1-Acetylamino-1-methvl-ethvl)-cvclohexanecarboxylic acid [(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide
A solution of building block A1 (8.1 mg, 0.033 mmol) and lithium hydroxide monohydrate (4.2 mg, 0.099 mmol) in CH3OH/water (2:1 , 0.66 ml) is stirred for 12 h. The mixture is then carefully neutralized with 1 N hydrochloric acid and extracted with EtOAc (3 x 5 ml). The combined extracts are dried over sodium sulfate and concentrated to yield the crude acid, which is dissolved in DCM (1.5 ml). At 00C are added (2R,3S)-3-amino-1-(3-isopropyl-benzylami- no)-4-phenyi-butan-2-ol (building block B2, 14.0 mg, 0.036 mmol), PyBOP (34.3 mg, 0.066 mmol) and DIEA (34.8 μl, 0.2 mmol). The mixture is stirred at 00C for 14 h, then diluted with EtOAc to a volume of 10 ml, dried and concentrated. The residue is purified by column chromatography to yield a colorless solid.
1H-NMR (400 MHz, CD3OD): δ 7.41-7.17 (m, 9H), 4.21 (s, 2H), 4.00 (m, 1H), 3.78 (m, 1 H), 3.10 (dd, J = 3.0, 2.9 Hz, 1 H), 2.99-2.94 (m, 2H), 2.60 (t, J = 11.4 Hz, 1 H), 2.11 (m, 1 H), 2.01 (m, 1 H), 1.89 (s, 3H), 1.80 (m, 1 H), 1.65 (m, 1 H), 1.50 (m, 1 H), 1.30 (d, J = 6.9 Hz, 6H), 1.28 (s, 6H), 1.18-1.14 (m, 6H), 0.94-0.84 (m, 2H).
Example 7: (1R.3S)-3-(1-Methyl-1-propionvlamino-ethvl)-cyclohexanecarboxvlic acid [(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide
The title compound is prepared in a manner analogous to that described in Example 6 starting from building block A2 and building block B2.
1H-NMR (400 MHz, CD3OD): δ 7.41-7.18 (m, 9H), 4.21 (s, 2H), 4.00 (m, 1H), 3.80 (m, 1 H), 3.10 (d, J = 2.9 Hz, 1 H), 2.99-2.94 (m, 2H), 2.59 (m, 1 H), 2.17-2.10 (m, 3H), 2.01 (m, 1 H), 1.85 (m, 1 H), 1.66 (d, J = 7.0 Hz, 1 H), 1.49 (d, J = 7.0 Hz, 1 H), 1.30 (s, 3H), 1.28 (s, 3H), 1.26 (m, 1 H), 1.20 (d, J = 6.1 Hz, 6H), 1.18-1.10 (m, 3H), 1.09 (t, J = 7.6 Hz, 3H), 0.97-0.80 (m, 2H).
Example 8: (1 R,3S)-3-f1-IVIethvl-1-(methvl-propionvl-amino)-ethvll-cvclohexanecar- boxylic acid [(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide The title compound is prepared in a manner analogous to that described in Exampie 6 starting from building block A6 and building block B2.
1H-NMR (CD3OD): δ 7.39-7.18 (m, 9H), 4.2 (s, 2H), 4.03 (m, 1 H), 3.75 (m, 1 H), 3.07 (m, 1 H), 2.96 (m, 2H), 2.88 (s, 3H), 2.58 (m, 2H), 2.34 (m, 2H), 1.97 (m, 1 H), 1.78 (m, 1 H), 1.49 (m, 2H), 1.37 (m, 1 H), 1.29 (s, 3H), 1.27 (s, 3H), 1.26 (d, J = 13.7 Hz, 6H), 1.22-1.10 (m, 3H), 1.05 (t, J = 7.4 Hz, 3H), 1.02-0.88 (m, 2H).
Example 9: (1R.3S)-3-f1-Methvl-1-(2-oxo-pvrrolidin-1-yl)-ethvn-cvclohexanecarboxvlic acid t(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide
To a solution of building block A3 (20 mg, 0.075 mmol) in CH3OH (5 ml) is added 10% Pd/- carbon (catalytic amount). The mixture is stirred at rt under a hydrogen atmosphere for 14 h and then filtered through Celite. The filter cake is rinsed with CH3OH (3 x 5 ml). The combined filtrates are evaporated to yield a colorless oil, which is treated with a solution of lithium hydroxide monohydrate (9.4 mg, 0.22 mmot) in CH3OH/water (2:1 , 0.66 ml). The mixture is stirred for 12 h, neutralized with aqueous 1 N hydrochloric acid and extracted with EtOAc (3 x 5 ml). The combined extracts are dried over sodium sulfate and concentrated to yield the crude acid, which is dissolved in DCM (1.5 ml). At 00C are added building block B2 (31.6 mg, 0.082 mmol), PyBOP (78.1 mg, 0.15 mmol) and DIEA (78.4 μl, 0.45 mmol). The mixture is stirred at 00C for 14 h, then diluted with EtOAc to a volume of 15 ml, washed with aqueous 1 N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue is purified by column chromatography to yield the title compound. 1H-NMR (400 MHz, CD3OD): δ 7.39-7.18 (m, 9H), 4.20 (s, 2H), 4.05 (m, 1 H), 3.76 (m, 1 H), 3.45 (m, 2H), 3.08 (m, 1 H), 2.96 (m, 2H), 2.60 (m, 1 H), 2.44 (m, 1 H)1 2.30 (m, 2H), 2.05-1.86 (m, 4H), 1.79 (m, 1 H), 1.57 (d, J = 12.6 Hz, 1 H), 1.49 (d, J = 12.6 Hz, 1 H), 1.29 (s, 3H), 1.27 (S, 3H), 1.23 (d, J = 7.9 Hz, 6H), 1.17-1.05 (m, 3H), 1.03-0.86 (m, 2H).
Example 10: (1 R,3S)-3-H -Methyl-1 -(2-oxo-piperidin-1 -vD-ethyll-cvclohexanecarboxylic acid t(1S,2R)-1-benzyl-2-hydroxy-3-(3-isopropyl-benzylamino)-propyl]-amide
To a solution of building block A7 (10 mg, 0.036 mmol) in CH3OH (2 ml) is added 10% Pd/- carbon (catalytic amount). The mixture is stirred at rt under a hydrogen atmosphere for 14 h and then filtered through Celite. The filter cake is rinsed with CH3OH (3 x 5 ml). The combined filtrates are evaporated to yield a colorless oil, which is treated with a solution of lithium hydroxide monohydrate (4.6 mg, 0.11 mmol) in THF/water (2:1 , 0.66 ml). The mixture is stirred for 1O h, carefully neutralized with aqueous 1 N hydrochloric acid and extracted with EtOAc (3 x 5 ml). The combined extracts are dried over sodium sulfate and concentrated to yield a colorless solid, which is dissolved in DCM (0.8 ml). At 00C are added building block B2 (13.9 mg, 0.036 mmol), PyBOP (31.2 mg, 0.06 mmol) and DIEA (31.3 μl, 0.18 mmol). The mixture is stirred at 00C for 7 h, then diluted with EtOAc to a volume of 10 ml, washed with aqueous 1 N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue is purified by column chromatography to yield the title compound.
1H-NMR (400 MHz, CD3OD): δ 7.39-7.16 (m, 9H), 4.20 (s, 2H), 4.05-3.99 (m, 1 H), 3.79-3.75 (m, 1 H), 3.32 (m, 2H), 3.30-3.26 (m, 2H), 3.16 (q, J = 6.7 Hz, 1 H), 3.09 (dd, J = 3.0, 2.9 Hz, 1 H), 2.98-2.92 (m, 2H), 2.64-2.55 (m, 2H), 2.29 (m, 2H), 1.99-1.94 (m, 1 H), 1.87 (m, 2H), 1.79 (m, 1 H), 1.71-1.63 (m, 4H), 1.29 (d, J = 7.0 Hz, 6H), 1.24 (s, 3H), 1.21 (s, 3H), 1.18-1.11 (m, 3H).
Example 11 : (1R.3S)-3-((S)-1-Acetvlamino-2-methvl-propyl)-cvclohexanecarboxvlic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide
The title compound is prepared in a manner analogous to that described in Example 1 starting from building block A8 and building block Bl
1H-NMR (400 MHz, CD3OD): δ 7.59 (d, J = 10.1 Hz, 1 H), 7.28-7.22 (m, 3H), 7.19-7.15 (m, 1 H), 4.09-4.04 (br s, 1 H), 3.57-3.55 (m, 1 H), 3.48-3.47 (m, 1 H), 3.33-3.32 (4H, exchangable), 3.14 (t, J = 7.1 Hz, 2H)1 2.92 (dd, J = 5.4, 5.5 Hz, 1 H), 2.74 (dd, J = 9.8, 9.8 Hz, 1 H), 2.59- 2.54 (m, 1 H), 2.20-2.18 (m, 1 H), 1.98 (s, 3H), 1.84-1.70 (m, 5H), 1.51-1.28 (m, 10H), 1.10 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 7.2 Hz, 4H), 0.91 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H).
Example 12: f(S)-1-r(1 R,3R)-3-((1S.2S.4R)-1-Benzvl-4-butylcarbamovl-2-hvdroxv- pentylcarbamoyl)-1-hydroxy-cyclohexyl]-butyl}-carbamic acid tert-butyl ester (assignment of stereochemistry of amino substituent arbitrary)
Building block A10 is treated with TBAF in 10 ml of THF. The solvent is evaporated to yield as residue the carboxylic acid. This carboxylic acid (0.033 mmol) is dissolved in DCM (1 ml). The solution is treated with building block B1 (0.040 mmol), PyBOP (22 mg), DIEA (17.6 μl) and DMF (0.25 ml). The mixture is stirred overnight at 00C, then neutralized with 0.1 N aqueous hydrochloric acid and extracted with EtOAc. The organic extract is evaporated, and the residue is purified by column chromatography (EtOAc : hexanes = 20 : 1 ) to yield a colorless solid. HRMS: (M + I)+ 590.4174; calculated M+ 589.4090. Example 13: (1 R.3R)-3-((S)-1-Acetvlamino-butvl)-3-hvdroxv-cvclohexanecarboxylic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide (assignment of stereochemistry of amino substituent arbitrary)
The title compound of Example 12 (10 mg) is treated with TMSI (15 μl) in 0.5 ml of DCM. The mixture is stirred at 00C for 30 min and then evaporated. The residue is dissolved in DCM. To the solution are added solid sodium bicarbonate and acetyl chloride (10 μl, 10 eqivalents). The mixture is diluted with EtOAc, washed with aqueous sodium carbonate solution, dried over sodium sulfate and evaporated to yield the title compound. HRMS: (M + I)+ 532.3442; calculated M+ 531.3672.
Example 14: f(R)-1-f(1 R,3R)-3-((1S.2S.4R)-1-Benzvl-4-butvlcarbamovl-2-hvdroxy-pen- tylcarbamoyl)-1-hydroxy-cyclohexyl]-butyl}-carbamic acid tert-butyl ester (assignment of stereochemistry of amino substituent arbitrary)
The title compound is prepared in a manner analogous to that described in Example 12 starting from building block A9 and building block B1. HRMS: (M + I )+ 590.4162; calculated M+ 589.4090.
Example 15: (1 R,3R)-3-((R)-1 -Acetylamino-butyl)-3-hydroxy-cyclohexanecarboxylic acid ((1S,2S,4R)-1-benzyl-4-butylcarbamoyl-2-hydroxy-pentyl)-amide (assignment of stereochemistry of amino substituent arbitrary)
The title compound is prepared in a manner analogous to that described in Example 13 starting from the title compound of Example 14.
13C-NMR (CD3OD): δ 177.96, 157.95, 139.16, 129.32, 128.3, 126.22, 78.85, 73.58, 69.84, 59.68, 54.95, 40.78, 39.02, 38.14, 37.67, 37.04, 35.09, 33.17, 31.59, 29.32, 27.84, 20.70, 20.09, 19.92, 17.61 , 13.34, 13.13.
Example 16: (1 R,3R)-3-Hydroxy-3-(1 -methy lcarbamoyl-buty l)-cyclohexanecarboxylic acid ((1 S,2S ,4R)-1 -benzyl-4-butylcarbamoyl-2-hydroxy-penty l)-amide
The title compound is prepared in a manner analogous to that described in Example 12 starting from building block A11 and building block B1. HRMS: (M + I )+ 532.10; calculated M+ 531.37.

Claims

Claims
1. A compound of the formula
Figure imgf000058_0001
in which
Ri is a group of the formula N(Ra)-C(=O)Rb (Ia); N(Ra)-S(=O)Rb (Ib); N(Ra)-S(=O)2Rb (Ic); C(=O)-N(Ra)Rb (Id); S(=O)-N(Ra)Rb (Ie); or S(=O)2-N(Ra)Rb (If), in which formulae Ia, Ib and Ic either Ra is hydrogen; CrC8-alkyl; CrC4-alkoxy-Ci-C4-alkyl; Ci-C4-alkylthio- CrC4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl; or heterocyclyl-C1-C4-alkyl; and
Rb is hydrogen; CrC8-alkyl; trifluoromethyl; Ci-C8-alkoxy; Ci-C4-alkoxy-Ci-C4- alkyl; Ci-C8-alkylthio; Ci-C4-alkylthio-CrC4-alkyl; C3-C8-cycloalkyl; C3-C8-cyc- loalkyl-CrC4-alkyl; heterocyclyl; heterocyclyl-d-C4-alkyl; amino; Ci-C8-alkyl- amino; or di-(Ci-C8-alkyl)amino with two identical or different Ci-C8-alkyl moieties, which two Ci-Cs-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, CrC6-alkoxy and C1- C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C8-alkyl moieties of the di-(Ci-C8-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, or Ra and Rb, taken together, complete, together with the 2 atoms, to which they are attached, a saturated or unsaturated ring, which ring is in the case of the formulae Ia and Ib monosubstituted by oxo and in the case of the formula Ic disubstituted by oxo, the said ring being optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, Ci- C6-alkyl, Ci-C6-alkoxy and Ci-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in the case of the formula Ia, the nitrogen ring member depicted in the formula Ia and optionally 1 or 2 further ring members being hetero ring members and any other ring member being present being a carbon ring member and, in the case of the formulae Ib and Ic, the nitrogen and the sulfur ring members depicted in the formulae Ib and Ic and optionally 1 further ring member being hetero ring members and any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, and in which formulae Id, Ie and If either Ra is hydrogen; CrC8-alkyl; d-d-alkoxy-d-C4-alkyl; CrC4-alkylthio- d-C4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl attached via one of its carbon ring members to the nitrogen atom depicted in the formulae Id, Ie and If; or heterocyclyl-Ci-C4-alkyl; and Rb is hydrogen; d-C8-alkyl; Ci-C4-alkoxy-Ci-C4-alkyl; Ci-C4-alkylthio-Ci-C4- alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl-Ci-C4-alkyl; heterocyclyl; or hetero- cyclyl-CrC4-alkyl or Ra and Rb, taken together, complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is in the case of the formulae Id and Ie monosubstituted by oxo and in the case of the formula If disubstituted by oxo, the said ring being optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, d-Ce-alkyl, d-C6-alkoxy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in the case of the formula Id, the nitrogen ring member depicted in the formula Id and optionally 1 or 2 further ring members being hetero ring members and any other ring member being present being a carbon ring member and, in the case of the formulae Ie and If, the nitrogen and the sulfur ring members depicted in the formulae Ie and If and optionally 1 further ring member being hetero ring members and any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member; R2 and R3 are either, independently from each other, hydrogen; Ci-C8-alkyl; d^-alkoxy-d-d-alkyl; Ci-C4-alkylthio-Ci-C4-alkyl; or an aryl-d-C4-alkyl or heteroaryl-Ci-C4-alkyl group, which aryl-d-C4-a!kyl or heteroaryl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C3-cycloalkyl-Ci-C4-alkyl, aryl, heteroaryl, d-C6-alkyl, hydroxy- Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, d-d-alkylcarbonyl-d^-alkyl, trifluoromethyl, hydroxy, CrC6-alkoxy, Ci-C4-alkoxy-CrC4-alkoxy, Ci-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, Ci-C4-alkylcarbonyloxy, carbamyloxy, N-d-C4-alkyl- carbamyloxy, d-C4-alkylthio, d-C4-alkylsulfinyl, d-C4-alkylsulfonyl, aminosulfonyl, N-Ci-C4-alkylaminosulfonyl, carboxy, carbamyl, N-Ci-C4-alkylcarbamyl, formyl, C1-C4- alkylcarbonyl, d-d-alkoxycarbonyl, amino, N-Ci-C4-alky!amino, N,N-di-(C1-C4-alkyl)- amino with two identical or different d-C4-alkyl moieties, N-(d-C4-alkoxy-d-C4-alkyl)- amino, N-(Ci-C4-alkylsulfonyl)amino, N-formylamino, N-(Ci-C4-alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-C1-C4-alkoxycarbonyl)amino and N-(heteroaryl- d-C4-alkoxycarbonyl)amino, or, taken together, complete, together with the carbon atom, to which they are attached, a C3-C8-cycloalkyl ring, in which C3-C8-cycloalkyl ring 1 or 2 of its 2 to 7 methylene ring members optionally are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member;
R4 is hydrogen; hydroxy; or Ci-C6-aikoxy;
R5 and R6, taken together, complete, together with the 2 carbon atoms, to which they are attached, and together with the methylene group, to which the said 2 carbon atoms are attached, a saturated ring, which ring is, in addition to the substitution by the substituents (R1)(R2)(R3)C and R4 and the N-substituted aminocarbonyl group depicted in the formula I, optionally further substituted by 1 or 2 substituents independently selected from the group, consisting of Ci-C8-alkyl, oxo, hydroxy, Ci-C8-aIkoxy, d-C4-alkoxy- CrC4-alkyl, d-C8-alkylthio, d-C4-alkylthio-Ci-C4-alkyl, formyl, d-C8-alkylcarbonyl, C1-C8- alkoxycarbonyl, carbamyl, N-d-Cs-alkylcarbamyl, N,N-di-(d-C8-alkyl)carbamyl with two identical or different d-C8-alkyl moieties, which two d-C8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-Ce-alkyl, d-C6-alkoxy and d-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two Ci-C8-alkyl moieties of the N,N-di- (C1-C8- alkyl)carbamyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, CrC8- alkylsulfonyl, d-C8-alkoxysulfonyl, aminosulfonyl, N-Ci-C8-alkylamιnosulfonyl, N,N-dι- (d-C8-alkyl)annιnosulfonyl with two identical or different CrC8-alkyl moieties, which two CrC8-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, C1-C6-SIkOXy and Ci-C6-alkylthιo, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C8-alkyl moieties of the N,N-di-(Ci-C8-alkyl)aminosulfonyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, Ci-C8-alky!su!fιnyl, Ci-C8-alkoxysulfιnyl, aminosulfi- nyl, N-Ci-Cs-alkylaminosulfinyl, N,N-dι-(Ci-C8-alkyl)amιnosulfιnyl with two identical or different d-C8-alkyl moieties, which two Ci-C8-alkyl moieties, taken together can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, CrC6-alkyl, CrC6-alkoxy and Ci-C6-alkylthιo, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C8-alkyl moieties of the N,N-dι-(Ci-C8-alkyl)amιnosulfι- nyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, d-Cs-alkylsulfonylami- no, d-Cs-alkoxysulfonylamino, aminosulfonylamino, N-Ci-Ca-alkylaminosulfonylamino, N.N-dKd-Cβ-alkyOaminosulfonylamino with two identical or different d-C8-alkyl moieties, formylamino, Ci-Cs-alkylcarbonylamino, Ci-Cs-alkoxycarbonylamino, carbamylami- no, N-d-Cs-alkylcarbamylamino, N.N-dKd-Cs-alkyOcarbamylamino with two identical or different d-C8-alkyl moieties and a heterocyclyl or heteroaryl group, the said hetero- cyclyl or heteroaryl group being optionally substituted by 1 or 2 substituents independently selected from the group, consisting of oxo, d-C6-alkyl, d-C6-alkoxy and CrC6- alkylthio, and which ring has 5 to 7 ring members of which ring members 1 or 2 ring members optionally being hetero ring members and any other ring member being a carbon ring member, the said hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member; is a d-C8-alkyl, C3-C8-cycloalkyl or Cs-Cs-cycloalkyl-d-d-alkyl group, which Ci-C8-al- kyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-C8-cycloalkyl, heterocyclyl, d-C6-alkyl, hydroxy-CrC4-alkyl, CrC4-alkoxy-d-C4-alkyl, oxo, hydroxy, CrC6-alkoxy, CrC4-alkoxy-Ci-C4-alkoxy, formyloxy, Ci-C4-alkylcarbonyl- oxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, carboxy, carbamyl, N-CrC4- alkylcarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl and an aryl or hetero- aryl group, which aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, aryl, heteroaryl, Ci-Cβ-alkyl, hydroxy-C1-C4-alkyl, CrC4-alkoxy-Ci-C4-alkyl, trifluoromethyl, hydroxy, d-Ce-alkoxy, CrC4-alkoxy-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcar- bonyloxy, Ci-C4-alkylthio, d-d-alkylsulfmyl, C1-C4-SlKyISuIfOrIyI, aminosulfonyl, N-C1-C4- alkylaminosulfonyl, carboxy, carbamyl, N-Ci-C4-alkylcarbamyl, formyl, d-C4-alkylcarbo- nyl, Ci-C4-alkoxycarbonyl, amino, N-CrC4-alkylamino, N,N-di-(Ci-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, which two d-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-C6-alkyl, d-C6-alkoxy and d-Ce-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C4-alkyl moieties of the N,N-di- (Ci-C4-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, N-(Ci-C4-alkoxy-CrC4-alkyl)amino, N-(CrC4-alkylsulfonyl)amino, N-formylamino, N-(Ci-C4-alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-Ci-C4-alkoxycar- bonyl)amino and N-(heteroaryl-C1-C4-alkoxycarbonyl)amino; an aryl or heteroaryl group, which aryl or heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, aryl, heteroaryl, d-Ce-alkyl, hydroxy-d-C4-alkyl, Ci-C4-alkoxy-CrC4-alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, Ci-Ce-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-d-alkylcarbonyloxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl, d-C4-alkylsulfo- nyl, aminosulfonyl, N-d-d-alkylaminosulfonyl, N,N-di-(Ci-C4-alkyl)aminosulfonyl with two identical or different d-C4-alkyl moieties, which two d-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, d-C6-alkyl, CrC6-alkoxy and CrC6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C4-alkyl moieties of the N,N-di- (Ci-C4-alkyl)aminosulfonyl group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, C1-C4- alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di-(Ci-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, which two Ci-C4-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, Ci-C6-alkyl, d-Cβ-alkoxy and Ci-C6-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two CrC4-alkyl moieties of the N,N-di-(C1-C4-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, N-(d-C4-alkoxy-d-C4- alkyl)amino, NKd-d-alkylsulfonyOamino, N-formylamino, N-(Ci-C4-alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-Ci-C4-alkoxycarbonyl)amino and N-(heteroaryl- d-C4-alkoxycarbonyl)amino; or an aryl group, which aryl group is optionally substituted at two of its carbon ring members, which two carbon ring members are adjacent to each other, by two substituents, which two substituents form, together with the two adjacent carbon ring members, to which they are attached, a heteroaryl ring, which heteroaryl ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloaIkyl, C3-C8-cycloalkyl-Ci-C4-alkyl, aryl, heteroaryl, Ci-C6-alkyl, hydroxy-CrC4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, CrC4-alkyl- carbonyl-d-C4-alkyl, trifluoromethyl, hydroxy, d-C6-alkoxy, d-C4-alkoxy-CrC4-alkoxy, Ci-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyl- oxy, carbamyloxy, N-d-Cralkylcarbamyloxy, Ci-C4-alkylthio, Ci-C4-alkylsulfinyl, C1-C4- alkylsulfonyl, aminosulfonyl, N-d-C4-alkylaminosulfonyl, carboxy, carbamyl, N-C1-C4-Sl- kylcarbamyl, formyl, Ci-C4-alkylcarbonyl, d-C4-aIkoxycarbonyl, amino, N-Ci-C4-alkyl- amino, N,N-di-(d-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, N^d-Cralkoxy-d-d-alkyOamino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(d-C4-alkylcarbonyl)amino, N-(Ci-C4-aIkoxycarbonyl)amino, N-(aryl-d -C4-alkoxycar- bonyl)amino and N-(heteroaryl-Ci-C4-alkoxycarbonyl)amino; either
R8 is hydrogen; and R9 is hydroxy PI
R8 and Rg, taken together, are oxo; and
R10 is a group of the formula CH(Rc)C(=O)N(Rd)Re (Ig); or (CH2)kN(H)Rf (Ih), in which formula Ig
Rc is a CrC8-alkyl, C1-C4-alkoxy-C1-C4-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl- Ci-C4-alkyl group, which Ci-C8-alkyl, Ci-C4-alkoxy-CrC4-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, C1- Cβ-alkyl, hydroxy-Ci-C4-alkyl, Ci-C4-alkoxy-d-C4-alkyl, oxo, hydroxy, d-C6-alkoxy, C1-C4-SIkOXy-C1-C4-BIkOXy, formyloxy, d-C4-alkylcarbonyloxy, d-C4-alkylthio, C1- C4-alkylsulfinyl, d-C^alkylsulfonyl, formyl, d-C4-alkylcarbonyl and C1-C4- alkoxycarbonyl; and Rd and Re either are, independently from each other, hydrogen; a CrC8-alkyl, C3-C8-cycloal- kyl or Cs-Cβ-cycloalkyl-d-d-alkyl group, which d-C8-alkyl, C3-C8-cycloalkyl or Cs-Cβ-cycloalkyl-d-d-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, C1- C6-alkyl, hydroxy-d-C4-alkyl, d-d-alkoxy-d-d-alkyl, oxo, hydroxy, C1-C6-SIkOXy, d-dralkoxy-d-d-alkoxy, formyloxy, d-C4-alkylcarbonyloxy, d-C4-alkylthio, C1- C4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, C^C^alkylcarbonyl and C1-C4- alkoxycarbonyl; or an aryl, aryl-d-C4-alkyl, heteroaryl or heteroary!-d-C4-alkyl group, which aryl, aryl-d-C4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloalkyl-CrC4- alkyl, aryl, heteroaryl, Ci-Ce-alkyl, hydroxy-d-C4-alkyl, d-C4-alkoxy-Ci-C4-alkyl, d-d-alkylcarbonyl-d-d-alkyl, trifluoromethyl, hydroxy, CrCe-alkoxy, C1-C4- alkoxy-Ci-C4-alkoxy, C1-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyloxy, phenoxy, for- myloxy, Ci-C4-alkylcarbonyloxy, carbamyloxy, N-C1-C4-alkylcarbamyloxy, C1-C4- alkylthio, d-C4-aIkylsulfinyl, d-C4-alkylsulfonyl, aminosulfonyl, N-d-C4-alkylami- nosulfonyl, carboxy, carbamyl, N-Ci-d-aikylcarbamyl, formyl, CrC4-alkylcarbonyl, Ci-C4-alkoxycarboπyI, amino, N-d-Ci-alkylamino, N,N-di-(C1-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, N-ζCrC^alkoxy-CrC^alkylJamino, N-(d-C4-alkylsulfonyl)annino, N-formylamino, N-(C1-C4-alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-d-d-alkoxycarbonyl)amino and N-(hete- roaryl-Ci-C4-alkoxycarbonyl)amino, or, taken together, complete, together with the nitrogen atom, to which they are attached, an azepanyl, morpholinyl, piperazinyl, piperidyl or pyrrolidyl ring, which azepanyl, morpholinyl, piperazinyl, piperidyl or pyrrolidyl ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cya- no, C3-C8-cycloalkyl, CrC6-alkyl, hydroxy-CrC4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, oxo, hydroxy, Ci-C6-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, formyloxy, C1-C4-alkylcar- bonyloxy, Ci-C4-alkylthio, C1-C4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, Ci-C4-al- kylcarbonyl and d-d-alkoxycarbonyl, and in which azepanyl, morpholinyl, piperazinyl, piperidyl or pyrrolidyl ring 1 or 2 of its methylene ring members can be replaced by a hetero ring member independently selected from the group, consisting of -S(=0)- and -S(=0)2-, and in which formula Ih k is O; 1 ; or 2; and
Rf is hydrogen; a d-C8-alkyl or Ca-Cs-cycloalkyl-Crd-alkyl group, which d-C8-al- kyl or C3-C8-cycloalkyl-d-C4-alky! group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-Ce-alkyl, hydroxy-d-d-alkyl, d-d-alkoxy-d-d-alkyl, fluoromethyl, difluoro- methyl, trifluoromethyl, oxo, hydroxy, Ci-C6-alkoxy, d-C4-alkoxy-Ci-C4-alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, C1-C4-alkylthio, d-C4-alkylsulfinyl, d-C4-alkylsul- fonyl, formyl, CrC4-alkylcarbonyl and Ci-C4-alkoxycarbonyl; an aryl, aryl-Ci-C4-al- kyl, heteroaryl, heteroaryl-d-C4-alkyl, chroman-4-yl, isochroman-4-yl, thiochroman- 4-yl, isothiochroman-4-yl, 1 ,1-dioxo-1lambda*6*-thiochroman-4-yl, 2,2-dioxo- 2lambda*6*-isothiochroman-4-yl, 1 ,2,3,4-tetrahydro-quinol-4-yl, 1 ,2,3,4-tetrahydro- isoquinol-4-y I, 1 ,2,3,4-tetrahydro-naphth-1 -yl, 1 , 1 -dioxo-1 ,2,3,4-tetrahydro-1 lamb- da*6*-benzo[e][1 ,2]thiazin-4-yl, 2,2-dioxo-1 ,2,3,4-tetrahydro-2lambda*6*-benzo- [c][1 ,2]thiazin-4-yl, 1 , 1 -dioxo-3,4-dihydro-1 H-1 lambda*6*-benzo[c][1 ,2]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1 ,2]oxathiin-4-yl, 2,3,4,5-tetrahydro- benzo[b]oxepin-5-yl or 1 ,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group, which aryl, aryl-Ci-C4-alkyl, heteroaryl, heteroaryl-d-C4-alkyl, chroman-4-yl, isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl, 1 ,1-dioxo-1 lambda*6*-thiochroman-4-yl, 2,2-dioxo-2lambda*6*-isothiochroman-4-yl, 1 ,2,3,4-tetrahydro-quinol-4-yl, 1 ,2,3,4- tetrahydro-isoquϊnol-4-yl, 1 ,2,3,4-tetrahydro-naphth-i-yl, 1 , 1 -dioxo-1 , 2,3,4- tetrahydro-1 lambda*6*-benzo[e][1 ,2]thiazin-4-yl, 2,2-dioxo-1 ,2,3,4-tetrahydro- 2lambda*6*-benzo[c][1 ,2]thiazin-4-yl, 1 , 1 -dioxo-3,4-dihydro-1 H-1 Iambda*6*-benzo- [c][1 ,2]oxathiin-4-yl, 2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1 ,2]oxathiin-4- yl, 2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or 1 ,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, C3-C8-cycloal- kyl-d-C4-alkyl, aryl, heteroaryl, Ci-C6-alkyl, hydroxy-d-C4-alkyl, d-C4-alkoxy- C1-C4-SIkYl, d-d-alkylcarbonyl-d-Ct-alkyl, trifluoromethyl, hydroxy, d-C6-alkoxy, Ci-C4-alkoxy-CrC4-alkoxy, Ci-C4-alkylcarbonyl-Ci-C4-alkoxy, benzyloxy, phenoxy, formyloxy, Ci-C4-alkylcarbonyloxy, carbamyloxy,
Figure imgf000066_0001
C1-C4- alkylthio, d-C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, aminosulfonyl, N-d-C4-alkylami- nosulfonyl, carboxy, carbamyl, N-d-d-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, CrC4-alkoxycarbonyl, amino, N-Ci-C4-alkylamino, N,N-di-(C1-C4-alkyl)amino with two identical or different Ci-C4-alkyf moieties, N-(Ci-C4-alkoxy-CrC4-alkyl)amino, N-(Ci-C4-alkylsulfonyl)amino, N-formylamino, N-(d-C4-alkylcarbonyl)amino, N- (Ci-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycarbonyl)amino and N-(hete- roaryl-d-C4-alkoxycarbonyl)amino, and in which aryl-CrC^alkyl or heteroaryl- Ci-C4-alkyl group the Ci-C4-alkyl moiety is optionally substituted by 1 or 2 substituents independently selected from the group, consisting of fluoromethyl, difluoro- methyl and trifluoromethyl; or a C4-C8-cycloalkyl group, in which C4-C8-cycloalkyl group
(a) one of the carbon ring members of the C4-C8-cycloalkyl moiety, which carbon ring members are different from the carbon ring member of the C4-C8-cycloalkyl moiety, to which the nitrogen atom depicted in the formula Ih is attached, is optionally replaced by a hetero ring member independently selected from the group, consisting of -O-, -S-, -S(=O)-, -S(=O)2- and -N(R9)-, Rg being hydrogen; a d-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group, which d-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-Ci-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-d-C4-alkyl, C1-C4- alkoxy-CrC4-alkyl, oxo, hydroxy, Ci-C6-alkoxy, C1-C4-BIkOXy-C1-C4-BIkOXy, formyl- oxy, C1-C^aI kylcarbonyloxy, d-C4-alkylthio, d-C4-alkylsulfinyl, CrC4-alkylsulfonyl, formyl, d-C4-alkylcarbonyl and d-C4-alkoxycarbonyl; or an aryl, aryl-d-C4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group, which aryl, aryl-Ci-C4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8- cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, aryl, heteroaryl, d-C6-alkyl, hydroxy-d-d- alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, CrC4-alkylcarbonyl-CrC4-alkyl, trifluoromethyl, hydroxy, CrCe-alkoxy, d-d-alkoxy-d-CU-alkoxy, C1-C4-alkylcarbonyl-C1-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-C4-alkylcarbonyloxy, carbamyloxy, N-d-C4-al- kylcarbamyloxy, d-C4-alkylthio, d-C4-alkylsulfinyl, d-C4-alkylsulfonyl, aminosulfo- nyl, N-d-C4-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-d-d-alkylamino, N,N-di- (d-C4-alkyl)amino with two identical or different Ci-C4-alkyl moieties, N-(C1-C4- alkoxy-CrC4-alkyl)amino, N-(CrC4-alkylsulfonyl)amino, N-formylamino, N-(C1-C4- alkylcarbonyl)amino, N-(d-C4-alkoxycarbonyl)amino, N-(aryl-d-C4-alkoxycarbo- nyl)amino and N-(heteroaryl-d-C4-alkoxycarbonyl)amino,
(b) the C4-C8-cycloalky! moiety, which C4-C8-cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-Cβ-alkoxy, C1-C^aIkOXy-C1 -C4-alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, d-C4-alkoxycarbonyloxy, d-C4-alkylthio, C1-C4- alkylsulfinyl, Ci-C4-alkylsulfonyl, formyl, d-C4-alkylcarbonyl, Ci-C4-alkoxycarbonyl, a d-Cs-alkyl, C3-C8-cycloalkyl or Ca-Cs-cycloalkyl-d-C/ralkyl group, which C1-C8- alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-d-C4-alkyl, C ^C4 -a IkOXy-C1 -C4- alkyl, oxo, hydroxy, d-C6-alkoxy, d-C4-alkoxy-d-C4-alkoxy, formyloxy, d-C4-al- kylcarbonyloxy, C^C^alkylthio, CrC^alkylsulfinyl, d-C4-alkylsulfonyl, formyl, d-C4-alkyIcarbonyl and d-C4-alkoxycarbonyl, and an aryl, aryl-d-C4-alkyl, heteroaryl, heteroaryl-CrC^alkyl, heterocyclyl or heterocyclyl-d-d-alkyl group, which aryl, aryl-C1-C4-alkyl, heteroaryl, heteroaryl-C1-C4-alkyl, heterocyclyl or heterocyc- lyl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloal- kyl, C3-C8-cycloalkyl-d-C4-alkyl, aryl, heteroaryl, Ci-C6-alkyl, hydroxy-d-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, d-d-alkylcarbonyl-d-d-alkyl, trifluoromethyl, hydroxy, d-Cβ-alkoxy, d-C4-aIkoxy-d-C4-alkoxy, d-d-alkylcarbonyl-Ci-d-alkoxy, benzyl- oxy, phenoxy, formyloxy, C1-C4-alkylcarbonyloxy, carbamyloxy, N-d-C4-alkylcarba- myloxy, d-C4-alkylthio, d-C4-alkylsulfinyI, d-C4-alkylsulfonyl, aminosulfonyl, N-d-d-alkylaminosulfonyl, carboxy, carbamyl, N-d-C4-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-Ci-C4-alkylamino, N,N-di- (d-C4-alkyl)amino with two identical or different d-C4-alkyl moieties, N-(C1-C4- alkoxy-CrC^alkyOamino, N-(d-C4-alkylsulfonyl)amino, N-formylamino, N-(CrC4- alkylcarbonyl)amino, N-(CrC4-alkoxycarbony!)amino, N-(aryl-CrC4-alkoxycarbo- nyl)amino and N-(heteroaryl-d-C4-alkoxycarbonyl)amino, and (c) the C4-C8-cycloalkyl moiety, which C4-C8-cycloalkyl moiety is optionally modified as defined under (a) hereinbefore to contain one hetero ring member, is optionally substituted at two of its carbon ring members, which two carbon ring members are adjacent to each other, by two substituents, which two substituents form, together with the two adjacent carbon ring members, to which they are attached, a C3-C8- cycloalkyl ring, in which C3-C8-cycloa!kyl ring
(i) one of the carbon ring members of the C3-C8-cycloalkyl ring thus formed, which carbon ring members are different from the said two adjacent carbon ring members of the C3-C8-cycloalkyl ring thus formed, to which the said two substituents are optionally attached, is optionally replaced by a hetero ring member independently selected from the group, consisting of -0-, -S-, -S(=0)-, -S(=0)2- and -N(Rh)-
Rh being hydrogen; a d-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkyl-d-C4-alkyl group, which d-C8-alkyl, C3-C8-cycloalkyl or Cs-Cs-cycloalkyl-d-d-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of cyano, C3-C8-cycloalkyl, d-C6-alkyl, hydroxy-d-C4-alkyl, C1-C4- alkoxy-d-C4-alkyl, oxo, hydroxy, CrC6-alkoxy, d-d-alkoxy-d-d-alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, d-C4-alkylthio, C1-C4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, d-C4-alkylcarbonyl and d-C4-alkoxycarbonyl; or an aryl, aryl-C1-C4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group, which aryl, aryl-C1-C4-alkyl, heteroaryl or heteroaryl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8- cycloalkyl, C3-C8-cycIoalkyl-CrC4-alkyl, aryl, heteroaryl, d-C6-alkyl, hydroxy-CrC4- alkyl, d-C4-alkoxy-d-C4-alkyl, d-d-alkylcarbonyl-d-d-alkyl, trifluoromethyl, hy- droxy, d-C6-alkoxy, CrC4-alkoxy-Ci-C4-alkoxy, Ci-C4-alkylcarbonyl-C1-C4-alkoxy, benzyloxy, phenoxy, formyloxy, d-d-alkylcarbonyloxy, carbamyloxy, N-d-d-al- kylcarbamyloxy, d-C4-alkylthio, C1-C4-alkylsulfinyl, d-C4-alkylsulfonyl, aminosulfo- nyl, N-Ci-C4-alkylaminosulfonyl, carboxy, carbamyl, N-d-d-alkylcarbamyl, formyl, d-C4-alkylcarbonyl, d-C4-alkoxycarbonyl, amino, N-d-C4-alkylamino, N,N-di- (d-d-alkyl)amino with two identical or different d-C4-alkyl moieties, N-(C1-C4- alkoxy-Ci-C4-alkyl)amino, N-(CrC4-alkylsulfonyl)amino, N-formylamino, N-(C1-C4- alkylcarbonyl)amino, N-(Ci-C4-alkoxycarbonyl)amino, N-(aryl-Ci-C4-alkoxycarbo- nyl)amino and N-(heteroaryl-Ci-C4-alkoxycarbonyl)amino, and (ii) the C3-C8-cycloalkyl ring thus formed, which C3-C8-cycloalkyl ring is optionally modified as defined under (i) hereinbefore to contain one hetero ring member, is optionally substituted by 1 to 4 substituents independently selected from the group, consisting of halogen, cyano, oxo, hydroxy, d-C6-alkoxy, Ci-C4-alkoxy-d-C4- alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, d-C4-alkoxycarbonyloxy, d-C4-alkyl- thio, d-C4-alkylsulfinyl, d-C4-alkylsulfonyl, formyl, Ci-C4-alkylcarbonyl, C1-C4- alkoxycarbonyl, a d-C8-alkyl, C3-C8-cycloalkyl or C3-Cs-cycloalkyl-d-C4-alkyl group, which d-C8-alkyl, C3-C8-cycloalkyl or C3-Cs-cycloalkyl-d-C4-alkyl group is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, cyano, C3-CB-cycloalkyl, CrC6-alkyl, hydroxy-d-C4-alkyl, Crd-alkoxy-d-d-alkyl, oxo, hydroxy, d-Cβ-alkoxy, d-C4-alkoxy-d-C4-alkoxy, formyloxy, CrC4-alkylcarbonyloxy, CrC4-alkylthio, d-C4-alky!sulfinyl, Ci-C4-alkyl- sulfonyl, formyl, Ci-C4-alkylcarbonyl and d-C4-alkoxycarbonyl, and an aryl, aryl- CrC4-alkyl, heteroaryl, heteroaryl-d-C4-alkyl, heterocyclyl or heterocyclyl-d-C4- alkyl group, which aryl, aryl-d-C4-alkyl, heteroaryl, heteroaryl-d-C4-alkyl, heterocyclyl or heterocyclyl-d-C4-alkyl group is optionally ring-substituted by 1 to 3 substituents independently selected from the group, consisting of halogen, nitro, cyano, C3-C8-cycloalkyl, QrCs-cycloalkyl-d-d-alkyl, aryl, heteroaryl, d-C6-alkyl, hy- droxy-d-C4-alkyl, d-d-alkoxy-d-d-alkyl, C1-C4-alkylcarbonyl-C1-C4-alkyl, trifluo- romethyl, hydroxy, d-C6-alkoxy, d-C^alkoxy-d^-alkoxy, d-C4-alkylcarbonyl- C1-C4-BIkOXy, benzyloxy, phenoxy, formyloxy, C1-C4-alkylcarbonyloxy, carbamyloxy, N-d-d-alkylcarbamyloxy, d-C4-alkylthio, Ci-C4-alkylsulfinyl, d-C4-alkylsul- fonyl, aminosulfonyl, N-CrC^alkylaminosulfonyl, carboxy, carbamyl, N-CrC4-alkyl- carbamyl, formyl, CrC^alkylcarbonyl, CrC4-alkoxycarbonyl, amino, N-CrC4-alkyl- amino, N,N-di-(d-C4-alkyl)amino with two identical or different Ci-C4-alky! moieties, N-(Ci-C4-alkoxy-CrC4-alkyl)amino, N^d-C^alkylsulfonyOamino, N-formyl- amino, N-(Ci-C4-aIkylcarbonyl)amino, N^CrC^alkoxycarbonylJamino, N-(aryl- Cr C4-alkoxycarbonyl)amino and N-Cheteroaryl-Crd-alkoxycarbonylJamino, in free form or in salt form.
2. A process for the preparation of a compound as defined in claim 1 of the formula I, in free form or in salt form, comprising the steps of
a) reaction of a compound of the formula
Figure imgf000070_0001
in which R1 , R2, R3, R4, Rs and R6 are as defined for the formula I and L1 is a leaving group, in free form or in salt form, with a compound of the formula
Figure imgf000070_0002
in which R7, R8, R9 and R1O are as defined for the formula I, in free form or in salt form, or
b) for the preparation of a compound of the formula I, in free form or in salt form, in which R1 is a group of the formula N(Ra)-C(=O)Rb (Ia); N(Ra)-S(=O)Rb (Ib); or N(Ra)-S(=O)2Rb (Ic), in which formulae Ia, Ib and Ic R3 is hydrogen; d-Cβ-alkyl; d-d-alkoxy-Crd-alkyl; CrC4-al- kylthio-C1-C4-alkyl; C3-C8-cycloaIkyl; C3-C8-cycloalkyl-C1-C4-alkyl; heterocyclyl; or heterocyc- lyl-C1-C4-alkyl; and Rb is hydrogen; d-Cs-alkyl; trifluoromethyl; d-Cβ-alkoxy; d-C4-alkoxy- d-d-alkyl; Ci-C8-alkylthio; C1-C4-alkylthio-C1-C4-alkyl; C3-C8-cycloalkyl; C3-C8-cycloalkyl- d-d-alkyl; heterocyclyl; heterocyclyl-Ci-C4-alkyl; amino; d-C8-alkylamino; or di-(d-C8-al- kyl)amino with two identical or different d-C8-alkyl moieties, which two d-Cβ-alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, CrC6-alkyl, d-C6-alkoxy and d-Cβ-al- kylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two CrC8-alkyl moieties of the di-(C1-C8-alkyl)amino group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, reaction of a compound of the formula
Figure imgf000071_0001
in which R2, R3, R4, R5, Re, R7, Re, R9 and R10 are as defined for the formula I and Ra is hydrogen, Ci-Cβ-alkyI, d-C4-alkoxy-d-C4-alkyl, Ci-C4-alkylthιo-Ci-C4-alkyl, C3-C8-cycloalkyl, Ca-Cs-cycloalkyl-d-d-alkyl, heterocyclyl, or heterocyclyl-Ci-C4-alkyl, in free form or in salt form, with a compound of the formula Rb-C(=O)-L2 (V), Rb-S(=O)-L3 (Vl), or Rb-S(=O)2-L4 (VII), in which formulae V, Vl and VII Rb is hydrogen, Ci-Cβ-alkyI, trifluoromethyl, d-C8-alko- xy, Ci-C4-BIkOXy-C1-C4-SIkYl1 Ci-C8-alkylthιo, d-d-alkylthio-d-Ct-alkyl, C3-C8-cycloalkyl,
Figure imgf000071_0002
heterocyclyl, heterocyclyl-d-dt-alkyl, amino, d-Cs-alkylamino, or dι-(Ci-C8-alkyl)amιno with two identical or different d-C8-alkyl moieties, which two C1-C8- alkyl moieties, taken together, can complete, together with the nitrogen atom, to which they are attached, a saturated or unsaturated ring, which ring is optionally substituted by 1 to 3 substituents independently selected from the group, consisting of oxo, CrC6-alkyl, C1-C6- aikoxy and d-Cβ-alkylthio, and which ring has 3 to 7 ring members, of which ring members, in addition to the nitrogen ring member, to which the two d-C8-alkyl moieties of the dι- (d-C8-alkyl)amιno group are attached, optionally 1 or 2 further ring members are hetero ring members, any other ring member being present being a carbon ring member, the said further hetero ring member(s) being independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, L2 is a leaving group, L3 is a leaving group and L4 is a leaving group, in free form or in salt form,
in each case optionally followed by reduction, oxidation or other functionalisation of the resulting compound and/or by cleavage of any protecting group(s) optionally present,
and of recovering the so obtainable compound of the formula I in free form or in salt form
3 A compound as defined in claim 1 , in free form or in pharmaceutically acceptable salt form, for use as a medicament
4. A compound as defined in claim 1 , in free form or in pharmaceutically acceptable salt form, for use in the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation.
5. A pharmaceutical composition comprising a compound as defined in claim 1 , in free form or in pharmaceutically acceptable salt form, as active ingredient and a pharmaceutical carrier or diluent.
6. The use of a compound as defined in claim 1 , in free form or in pharmaceutically acceptable salt form, as a medicament for the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation.
7. The use of a compound as defined in claim 1 , in free form or in pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation.
8. A method for the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound as defined in claim 1 , in free form or in pharmaceutically acceptable salt form.
9. A combination comprising a therapeutically effective amount of a compound as defined in claim 1 , in free form or in pharmaceutically acceptable salt form, and a second drug substance, for simultaneous or sequential administration.
PCT/EP2008/059606 2007-07-24 2008-07-22 Substituted cyclohexanecarboxamides useful as bace inhibitors WO2009013293A1 (en)

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US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2012107153A1 (en) 2011-02-08 2012-08-16 Merck Patent Gmbh Amino statin derivativesfor the treatment of arthrosis
FR2989376A1 (en) * 2012-04-17 2013-10-18 Centre Nat Rech Scient NEW DIFUNCTIONAL COMPOUNDS OF NATURAL ORIGIN
WO2014015934A1 (en) 2012-07-24 2014-01-30 Merck Patent Gmbh Hydroxystatin derivatives for treatment of arthrosis
WO2014127881A1 (en) 2013-02-25 2014-08-28 Merck Patent Gmbh 2-amino -3,4-dihydro-quinazoline derivatives and the use thereof as cathepsin d inhibitors
WO2015018472A1 (en) 2013-08-06 2015-02-12 Merck Patent Gmbh Intraarticular application of pepstatin in the case of arthrosis

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WO2001021600A1 (en) * 1999-09-17 2001-03-29 Lg Chem Investment Ltd. Caspase inhibitor
US20040121947A1 (en) * 2000-12-28 2004-06-24 Oklahoma Medical Research Foundation Compounds which inhibit beta-secretase activity and methods of use thereof
US20030125257A1 (en) * 2001-12-20 2003-07-03 Manfred Brockhaus Assay for identifying beta secretase inhibitors

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2012107153A1 (en) 2011-02-08 2012-08-16 Merck Patent Gmbh Amino statin derivativesfor the treatment of arthrosis
FR2989376A1 (en) * 2012-04-17 2013-10-18 Centre Nat Rech Scient NEW DIFUNCTIONAL COMPOUNDS OF NATURAL ORIGIN
WO2014015934A1 (en) 2012-07-24 2014-01-30 Merck Patent Gmbh Hydroxystatin derivatives for treatment of arthrosis
WO2014127881A1 (en) 2013-02-25 2014-08-28 Merck Patent Gmbh 2-amino -3,4-dihydro-quinazoline derivatives and the use thereof as cathepsin d inhibitors
WO2015018472A1 (en) 2013-08-06 2015-02-12 Merck Patent Gmbh Intraarticular application of pepstatin in the case of arthrosis

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