Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the invention relates to compounds according to general formula (I)
• glucocorticoid receptor which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.
• Glucocorticoids exert strong anti-inflammatory, immunosuppressive and disease-modifying therapeutic effects mediated by the glucocorticoid receptor (GR). They have been widely used to treat inflammatory and immune diseases for decades and still represent the most effective therapy in those conditions. However, chronic GC treatment of inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, cystic fibrosis, osteoarthritis, polymyalgia rheumatica and giant cell arteritis is hampered by GC-associated adverse effects.
• inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, cystic fibrosis, osteoarthritis, polymyalgia rheumatica and giant cell arteritis is hampered by GC-associated adverse effects.
• prednisone which is frequently prescribed for the treatment of several inflammatory disorders
• GC cause adrenal suppression prednisolone withdrawal symptoms can be severe if the drug is discontinued abruptly when all the signs of the disease have disappeared.
• GC tapering to physiological doses is frequently part of treatment protocols to reduce the risk of relapse and other withdrawal symptoms (Liu D. et al., Allergy Asthma Clin Immunol. 2013 Aug. 15; 9(1):30). Therefore, there is high medical need for novel potent anti-inflammatory drugs with less adverse effects.
• Compounds which are active as modulators of the glucocorticoid receptor are also known e.g. from WO 2007/122165, WO 2008/076048 and WO 2008/043789, WO 2009/035067, WO 2009/142571, WO 2016/046260, and WO 2017/034006.
• novel compounds should in particular be suitable for use in the treatment and/or prophylaxis of disorders or diseases which are at least partially mediated by the glucocorticoid receptor.
• the compounds according to the invention are highly potent modulators of the glucocorticoid receptor.
• the invention relates to a compound according to general formula (I),
• the compound according to the invention is present in form of the free compound.
• “free compound” preferably means that the compound according to the invention is not present in form of a salt.
• Methods to determine whether a chemical substance is present as the free compound or as a salt are known to the skilled artisan such as 14 N or 15 N solid state NMR, x-ray diffraction, x-ray powder diffraction, IR, Raman, XPS. 1 H-NMR recorded in solution may also be used to consider the presence of protonation.
• the compound according to the invention is present in form of a physiologically acceptable salt.
• physiologically acceptable salt preferably refers to a salt obtained from a compound according to the invention and a physiologically acceptable acid or base.
• the compound according to the invention may be present in any possible form including solvates, cocrystals and polymorphs.
• solvate preferably refers to an adduct of (i) a compound according to the invention and/or a physiologically acceptable salt thereof with (ii) distinct molecular equivalents of one or more solvents.
• the compound according to the invention may be present in form of the racemate, enantiomers, diastereomers, tautomers or any mixtures thereof.
• the invention also includes isotopic isomers of a compound of the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound.
• Preferred isotopes are 2 H (deuterium), 3 H (tritium), 13 C and 14 C.
• Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art.
• the terms “—C 1-10 -alkyl”, “—C 1-8 -alkyl”, “—C 1-6 -alkyl” and “—C 1-4 -alkyl” preferably mean acyclic saturated or unsaturated aliphatic (i.e. non-aromatic) hydrocarbon residues, which can be linear (i.e. unbranched) or branched and which can be unsubstituted or mono- or polysubstituted (e.g. di- or trisubstituted), and which contain 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), 1 to 8 (i.e. 1, 2, 3, 4, 5, 6, 7 or 8), 1 to 6 (i.e.
• —C 1-10 -alkyl, —C 1-8 -alkyl, —C 1-6 -alkyl and —C 1-4 -alkyl are saturated.
• Preferred —C 1-10 -alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )—CH 3 ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexy
• Preferred —C 1 -s-alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )—CH 3 ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hex
• Preferred —C 1-6 -alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl, n-propyl, 2-propyl
• Preferred —C 1-4 -alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )—CH 3 ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl and 3-methylbut-1-ynyl.
• More preferred —C 1-4 -alkyl groups are selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
• —C 1-6 -alkylene- refers to a linear or branched, preferably linear, and preferably saturated aliphatic residues which are preferably selected from the group consisting of methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 — or —C(CH 3 ) 2 —), butylene (—CH 2 CH 2 CH 2 CH 2 —), pentylene (—CH 2 CH 2 CH 2 CH 2 CH 2 —) and hexylene (—CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —); more preferably methylene (—CH 2 —) and ethylene (—CH 2 CH 2 —) and most preferably methylene (—CH 2 —).
• —C 1-6 -alkylene- is selected from —C 1-4 -alkylene-,
• —C 3-10 -cycloalkyl and “—C 3-6 -cycloalkyl” preferably mean cyclic aliphatic hydrocarbons containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 3, 4, 5 or 6 carbon atoms, respectively, wherein the hydrocarbons in each case can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted.
• —C 3-10 -cycloalkyl and —C 3-6 -cycloalkyl are saturated.
• the —C 3-10 -cycloalkyl and —C 3-6 -cycloalkyl can be bound to the respective superordinate general structure via any desired and possible ring member of the cycloalkyl group.
• the —C 3-10 -cycloalkyl and —C 3-6 -cycloalkyl groups can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e.
• —C 3-10 -cycloalkyl and —C 3-6 -cycloalkyl can be singly or multiply bridged such as, for example, in the case of adamantyl, bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl.
• —C 3-10 -cycloalkyl and —C 3-6 -cycloalkyl are neither condensed with further ring systems nor bridged.
• —C 3-10 -cycloalkyl and —C 3-6 -cycloalkyl are neither condensed with further ring systems nor bridged and are saturated.
• Preferred —C 3-10 -cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl.
• Particularly preferred —C 3-10 -cycloalkyl groups are selected from —C 3-6 -cycloalkyl groups.
• Preferred —C 3-6 -cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.
• Particularly preferred —C 3-6 -cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, most preferably cyclopropyl.
• the terms “3 to 7-membered heterocycloalkyl” and “3 to 6-membered heterocycloalkyl” preferably mean heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members and 3 to 6, i.e.
• the 3 to 7-membered heterocycloalkyl and the 3 to 6-membered heterocycloalkyl contain only one heteroatom or heteroatom group within the ring.
• 3 to 7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl are saturated.
• the 3 to 7-membered heterocycloalkyl and the 3 to 6-membered heterocycloalkyl groups can also be condensed with further saturated or (partially) unsaturated cycloalkyl or heterocyclyl, aromatic or heteroaromatic ring systems.
• 3 to 7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl are not condensed with further ring systems.
• Still more preferably, 3 to 7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl are not condensed with further ring systems and are saturated.
• the 3 to 7-membered heterocycloalkyl and the 3 to 6-membered heterocycloalkyl group can be bound to the superordinate general structure via any desired and possible ring member of the heterocycloaliphatic residue if not indicated otherwise.
• 3 to 7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl are bound to the superordinate general structure via a carbon atom.
• Preferred 3 to 7-membered heterocycloalkyl groups are selected from the group consisting of tetrahydrofuranyl, azepanyl, dioxepanyl, oxazepanyl, diazepanyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl, oxiranyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl,
• Preferred 3 to 6-membered heterocycloalkyl groups are selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, oxiranyl, thiazolidinyl, tetrahydrothiophenyl, tetra-hydropyridinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyr
• More preferred 3 to 6-membered heterocycloalkyl groups are selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, and oxiranyl; still more preferably tetrahydrofuranyl.
• the term “5- to 6-membered heteroaryl” preferably means a 5 or 6-membered cyclic aromatic residue containing at least 1, if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted, if not indicated otherwise.
• the substituents can be the same or different and be in any desired and possible position of the heteroaryl.
• the binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue if not indicated otherwise.
• the 5- to 6-membered heteroaryl is bound to the suprordinate general structure via a carbon atom of the heterocycle.
• the heteroaryl can also be part of a bi- or polycyclic system having up to 14 ring members, wherein the ring system can be formed with further saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl, aromatic or heteroaromatic ring systems, which can in turn be unsubstituted or mono- or polysubstituted, if not indicated otherwise.
• the 5- to 6-membered heteroaryl is part of a bi- or polycyclic, preferably bicyclic, system.
• the 5- to 6-membered heteroaryl is not part of a bi- or polycyclic system.
• the 5- to 6-membered heteroaryl is selected from the group consisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, pyridone (pyridinone), pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 2,4,5,6-tetrahydrocyclo-penta[c]pyrazolyl, benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl
• Particularly preferred 5- to 6-membered heteroaryl are selected from the group consisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, and oxadiazolyl.
• pyridones can be regarded as pyridines that are substituted with ⁇ O, for the purpose of the specification the definition of pyridines that may optionally be substituted with ⁇ O covers pyridones.
• the 3 rd generation substituents may not be resubstituted, i.e. there are then no 4 th generation substituents. More preferably, the 2 nd generation substituents may not be resubstituted, i.e. there are no 3 rd generation substituents.
• disubstitution or trisubstitution more preferably to monosubstitution or disubstitution; of one or more hydrogen atoms each independently of one another by at least one substituent.
• a multiple substitution i.e. in case of polysubstituted residues, such as di- or trisubstituted residues, these residues may be polysubstituted either on different or on the same atoms, for example trisubstituted on the same carbon atom, as in the case of —CF 3 , —CH 2 CF 3 or disubstituted as in the case of 1,1-difluorocyclohexyl, or at various points, as in the case of —CH(OH)—CH ⁇ CH—CHCl 2 or 1-chloro-3-fluorocyclohexyl.
• the multiple substitution can be carried out using the same or using different substituents.
• substituted refers in the sense of this invention to the single substitution (monosubstitution) or multiple substitution (polysubstitution), e.g. disubstitution or trisubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent.
• the multiple substitution can be carried out using the same or using different substituents.
• —C 1-10 -alkyl, —C 1-6 -alkyl, —C 1-4 -alkyl, —C 3-10 -cycloalkyl, —C 3-6 -cycloalkyl, 3 to 7 membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl are preferably each independently from one another unsubstituted, mono-di- or trisubstituted, more preferably unsubstituted or monosubstituted or disubstituted with a substituent selected from the group consisting of —F; —Cl; —Br; —I; —CN; —C 1-6 -alkyl; —CF 3 ; —CF 2 H; —CFH 2 ; —C( ⁇ O)—NH 2 ; —C( ⁇ O)—NH(C 1-6 -alkyl); —C( ⁇ O)—N(C 1-6 -alkyl) 2
• phenyl and 5 or 6-membered heteroaryl in each case independently from one another are unsubstituted or mono- or polysubstituted; preferably unsubstituted, mono- di- or trisubstituted, still more preferably unsubstituted or monosubstituted or disubstituted; with one or more substituents selected from —F; —Cl; —Br; —I; —CN; —C 1-6 -alkyl; —CF 3 ; —CF 2 H; —CFH 2 ; —CF 2 Cl; —CFCl 2 ; —C 1-4 -alkylene-CF 3 ; C 1-4 -alkylene-CF 2 H; —C 1-4 -alkylene-CFH 2 ; —C( ⁇ O)—C 1-6 -alkyl; —C( ⁇ O)—OH; —C( ⁇ O)—OC 1-6 -alkyl;
• Preferred substituents of phenyl and 5 or 6-membered heteroaryl are selected from the group consisting of —F; —Cl; —Br; —I; —CN; —C 1-6 -alkyl; —CF 3 ; —CF 2 H; —CFH 2 ; —C 1-4 -alkylene-CF 3 ; —C 1-4 -alkylene-—CF 2 H; —C 1-4 -alkylene-CFH 2 ; —OH; —OCF 3 ; —OCF 2 H; —OCFH 2 ; —O—C 1-6 -alkyl; —O—C 3-6 -cycloalkyl and —C 3-6 -cycloalkyl; and more preferably of —F; —C 1 ; —Br; —CN; —CH 3 ; —CH 2 CH 3 ; —CF 3 ; —CF 2 H; —CFH 2 ; —CH
• phenyl and 5 or 6-membered heteroaryl are preferably each independently from one another unsubstituted, mono- di- or trisubstituted, more preferably unsubstituted or monosubstituted or disubstituted with a substituent selected from the group consisting of —F; —Cl; —Br; —I; —CN; —C 1-6 -alkyl; —CF 3 ; —CF 2 H; —CFH 2 ; —C 1-4 -alkylene-CF 3 ; —C 1-4 -alkylene-CF 2 H; —C 1-4 -alkylene-CFH 2 ; ⁇ O; —OH; —OCF 3 ; —OCF 2 H; —OCFH 2 ; —O—C 1-6 -alkyl; —O—C 3-6 -cycloalkyl and —C 3-6 -cycloalkyl.
• the compound according to the invention has a stereochemistry according to general formula (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX)
• the compound according to the invention has a stereochemistry according to general formula (II), (III), (VI) or (VII), such that the residues —R 1 and —NH—R 2 on the pyrrolidone ring are oriented trans.
• the compound according to the invention has a stereochemistry according to general formula (II) or (VI).
• the compound according to the invention has a stereochemistry according to general formula (III) or (VII). The stereochemistry according to general formula (II) or (VI) is particularly preferred.
• the compound according to the invention has a stereochemistry according to general formula (IV), (V), (VIII) or (IX), such that the residues —R 1 and —NH—R 2 on the pyrrolidone ring are oriented cis.
• the compound according to the invention has a stereochemistry according to general formula (IV) or (VIII).
• the compound according to the invention has a stereochemistry according to general formula (V) or (IX).
• the compound according to the invention has a stereochemistry according to general formula (II) or (VI), more preferably (II).
• R 1 represents phenyl; —C 1-6 -alkylene-phenyl; 5 or 6-membered heteroaryl;—C 1-6 -alkylene-(5 or 6-membered heteroaryl); or —C 1-10 -alkyl.
• R 1 represents phenyl or ethyl; more preferably phenyl.
• R 1 represents phenyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —OCH 3 ; —CH 3 , —CF 3 , —CN, and cyclopropyl; more preferably —F, —OCH 3 ; and —CH 3 .
• R 1′ represents H; —C 1-10 -alkyl; or —C 3-10 -cycloalkyl.
• R 1′ represents H; methyl, ethyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; more preferably H, methyl, ethyl, cyclopropyl or cyclobutyl; still more preferably H, methyl or cyclopropyl.
• R 1′ represents H.
• R 2 represents —C( ⁇ O)—C 1-10 -alkyl; —C( ⁇ O)—C 3-10 -cycloalkyl; —C( ⁇ O)—C 1-6 -alkylene-C 3-10 -cycloalkyl; —C( ⁇ O)-(3 to 7 membered heterocycloalkyl); —C( ⁇ O)—C 1-6 -alkylene-(3 to 7 membered heterocycloalkyl); —C( ⁇ O)-phenyl; —C( ⁇ O)—C 1-6 -alkylene-phenyl; —C( ⁇ O)-(5 or 6-membered heteroaryl); —C( ⁇ O)—C 1-6 -alkylene-(5 or 6-membered heteroaryl); —S( ⁇ O) 1-2
• R 2 represents —C( ⁇ O)—C 1-10 -alkyl; —C( ⁇ O)—C 3-10 -cycloalkyl; —C( ⁇ O)—C 1-6 -alkylene-C 3-10 -cycloalkyl; —C( ⁇ O)-(3 to 7 membered heterocycloalkyl); —C( ⁇ O)-(5 or 6-membered heteroaryl); —S( ⁇ O) 2 —C 1-10 -alkyl; —S( ⁇ O) 2 —C 3-10 -cycloalkyl; —S( ⁇ O) 2 —C 1-6 -alkylene-C 3-10 -cycloalkyl; —S( ⁇ O) 2 -(3 to 7 membered heterocycloalkyl); or —S( ⁇ O) 2 -(5 or 6-membered heteroaryl).
• R 2 represents
• R 3 and R 3′ independently from one another represent H; F; Cl; —C 1-10 -alkyl; —C 3-6 -cycloalkyl; —CH 2 —C 3-6 -cycloalkyl; 3 to 7 membered heterocycloalkyl; —CH 2 -(3 to 7 membered heterocycloalkyl); —CH 2 -phenyl; or —CH 2 -(5 or 6-membered heteroaryl); or R 3 and R 3′ together with the carbon atom to which they are bound form a C 3-10 -cycloalkyl, or 3 to 7 membered heterocycloalkyl.
• R 3 and R 3′ both represent —C 1-10 -alkyl. In a particularly preferred embodiment, R 3 and R 3′ both represent —CH 3 .
• R 3 and R 3′ independently from one another represent H; F; —CH 3 ; cyclopropyl; —CH 2 -cyclopropyl; or —CH 2 -phenyl.
• R 3 and R 3′ both represent F.
• At least one of R 3 and R 3′ represents not H. In yet another preferred embodiment, one of R 3 and R 3′ represents H.
• R 3 and R 3′ together with the carbon atom to which they are bound form cyclopropyl.
• R 4 represents phenyl; —C 1-6 -alkylene-phenyl; 5 or 6-membered heteroaryl; or —C 1-6 -alkylene-(5 or 6-membered heteroaryl).
• R 4 represents phenyl or 5 or 6-membered heteroaryl.
• R 4 represents phenyl, unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, and —OCH 3 ; or 5 or 6-membered heteroaryl selected from the group consisting of pyridyl, pyrazolyl, and pyrimidinyl, wherein in each case said 5- to 6-membered heteroaryl is unsubstituted or mono- or disubstituted with substituents independently of one another selected from the group consisting of ⁇ O, —F, —Cl, —Br, —CH 3 , —CF 3 , —CN, and —OCH 3 .
• R 4 does not represent N-methylpyridinone.
• A, X, Y and Z independently from one another represent N or CH. In a preferred embodiment, A represents N.
• X represents CH.
• Y represents CH.
• Z represents CH.
• the compound according to the invention is selected from the group consisting of
• the compounds according to the invention can be synthesized by standard reactions in the field of organic chemistry known to the person skilled in the art or in a manner as described herein (cf. Reaction Schemes below) or analogously.
• the reaction conditions in the synthesis routes described herein are known to the skilled person and are for some cases also exemplified in the Examples described herein.
• Substituted indazole moieties in compounds of formula (D) and formula (F) are introduced by subjecting lactam (B) or lactam (E) in a regioselective metal catalyzed C—N coupling reaction with corresponding indazole halides (C), preferred with corresponding indazole iodides.
• Metal catalyzed C—N coupling reactions are generally known in the art ( Current Organic Synthesis, 2011, 8, 53).
• Favorable C—N coupling reactions are palladium and copper catalyzed cross-coupling reactions ( Chem. Rev., 2016, 116, 12564 ; Chem. Soc. Rev., 2014, 43, 3525 ; Chem. Sci., 2010, 1, 13).
• Regioselective C—N couplings with arylhalides are known in the art ( Chem. Sci., 2011, 2, 27 ; J. Am. Chem. Soc., 2001, 123, 7727).
• Primary amines (A) and (G) are converted to corresponding amides and sulfonamides (acylation and sulfonamide formation) (B) and (D) using commercially available acids (activation of acids using e.g. HATU) or acid chlorides under standard amide coupling reaction conditions ( March's Advanced Organic Chemistry, 2007, 6th Edition, page 1427-1474).
• Compounds of formula (D) can be synthesized via regioselective C—N coupling of compound (O). Suitable C—N coupling reactions for N—H containing heterocycles are known in the art ( Synthesis, 2011, 829 ; Chem. Sci., 2011, 2, 27; Beilstein J. Org. Chem., 2011, 7, 59 ; J. Org. Chem., 2004, 69, 5578). Compound of formula (O) is synthesized via deprotection of compound (N) under acidic conditions.
• the compounds according to the invention can be produced in the manner described here or in an analogous manner.
• the compounds according to the invention are modulators of the glucocorticoid receptor.
• the term “selective modulator of the glucocorticoid receptor (glucocorticoid receptor modulator)” preferably means that the respective compound exhibits in a cellular target engagement assay for agonistic or antagonistic potency on the glucocorticoid receptor an EC50 or IC50 value on the glucocorticoid receptor of at most 15 ⁇ M (10 ⁇ 10 ⁇ 6 mol/L) or at most 10 ⁇ M; more preferably at most 1 ⁇ M; still more preferably at most 500 nM (10 ⁇ 9 mol/L); yet more preferably at most 300 nM; even more preferably at most 100 nM; most preferably at most 10 nM; and in particular at most 1 nM.
• the compound according to the invention exhibits in a cellular target engagement assay for agonistic or antagonistic potency on the glucocorticoid receptor an EC50 or IC50 value on the glucocorticoid receptor in the range of from 1 ⁇ M to 15 ⁇ M, more preferably from 100 nM to 1 ⁇ M, most preferably below 100 nM.
• glucocorticoid receptor modulators of this intervention can be tested for modulation of the activity of the glucocorticoid receptor using cell-based assays. These assays involve a Chinese hamster ovary (CHO) cell line which contains fragments of the glucocorticoid receptor as well as fusion proteins. The glucocorticoid receptor fragments used are capable of binding the ligand (e.g. beclomethasone) to identify molecules that compete for binding with glucocorticoid receptor ligands.
• ligand e.g. beclomethasone
• the glucocorticoid receptor ligand binding domain is fused to the DNA binding domain (DBD) of the transcriptionfactor GAL4 (GAL4 DBD-GR) and is stably integrated into a CHO cell line containing a GAL4-UAS-Luciferase reporter construct.
• DBD DNA binding domain
• GAL4 DBD-GR transcriptionfactor GAL4
• the reporter cell line is incubated with the molecules using an 8-point half-log compound dilution curve for several hours. After cell lysis the luminescence that is produced by luciferase after addition of the substrate is detected and EC50 or IC50 values can be calcuated.
• the compound according to the invention exhibits in a cellular target engagement assay for agonistic or antagonistic potency on the glucocorticoid receptor an EC50 or IC50 value on the glucocorticoid receptor of at most 1 ⁇ M (10 ⁇ 6 mol/L); still more preferably at most 500 nM (10 ⁇ 9 mol/L); yet more preferably at most 300 nM; even more preferably at most 100 nM; most preferably at most 50 nM; and in particular at most 10 nM or at most 1 nM.
• the compound according to the invention exhibits in a cellular target engagement assay for agonistic or antagonistic potency on the glucocorticoid receptor an EC50 or IC50 value on the glucocorticoid receptor in the range of from 1 ⁇ M to 15 ⁇ M, more preferably from 100 nM to 1 ⁇ M, most preferably below 100 nM.
• the compound according to the invention exhibits in a cellular target engagement assay for agonistic or antagonistic potency on the glucocorticoid receptor an EC50 or IC50 value on the glucocorticoid receptor in the range of from 0.1 nM (10 ⁇ 9 mol/L) to 1000 nM; still more preferably 1 nM to 800 nM; yet more preferably 1 nM to 500 nM; even more preferably 1 nM to 300 nM; most preferably 1 nM to 100 nM; and in particular 1 nM to 80 nM.
• Potential selective glucocorticoid receptor modulators of this intervention can be tested for their binding affinity at the glucocorticoid receptor using the binding assay described below.
• the glucocortitcoid receptor extracted from cytosol of IM9 cells is used for competitive radioligand binding assays to calculate percentage inhibition of the binding of radiolabeled ligand 3H-dexamethasone at the human glucocorticoid receptor.
• a fixed concentration of the radioligand 3H-dexamethasone and 1 ⁇ M of compound according to the present invention are mixed with the extracted glucocorticoid receptor in order to measure the percentage of inhibition of 3H-dexamethasone binding.
• the compound according to the invention exhibits in a hGR ligand-binding assay an inhibition of 3H-dexamethasone binding at 1 ⁇ M of at least 40%, more preferably at least 60%, most preferably at least 85%. In a preferred embodiment, the compound according to the invention exhibits in a hGR ligand-binding assay an inhibition of 3H-dexamethasone binding at 1 ⁇ M which is in the range from 40% to 60%, more preferably from greater than 60% to 85%, most preferably greater than 85%.
• the compounds according to the invention are useful as selective modulators of the glucocorticoid receptor.
• the compounds according to the invention are preferably useful for the in vivo treatment or prevention of diseases in which participation of the glucocorticoid receptor is implicated.
• the invention therefore further relates to a compound according to the invention for use in the modulation of glucocorticoid receptor activity.
• a further aspect of the invention relates to the use of a compound according to the invention as medicament.
• the pharmaceutical dosage form comprises a compound according to the invention and one or more pharmaceutical excipients such as physiologically acceptable carriers, additives and/or auxiliary substances; and optionally one or more further pharmacologically active ingredient.
• suitable physiologically acceptable carriers, additives and/or auxiliary substances are fillers, solvents, diluents, colorings and/or binders.
• the pharmaceutical dosage form according to the invention is preferably for systemic, topical or local administration, preferably for oral administration. Therefore, the pharmaceutical dosage form can be in form of a liquid, semisolid or solid, e.g. in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, films, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and can also be administered as such.
• a liquid, semisolid or solid e.g. in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, films, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form
• the pharmaceutical dosage form according to the invention is preferably prepared with the aid of conventional means, devices, methods and processes known in the art.
• the amount of the compound according to the invention to be administered to the patient may vary and is e.g. dependent on the patient's weight or age and also on the type of administration, the indication and the severity of the disorder.
• Preferably 0.001 to 100 mg/kg, more preferably 0.05 to 75 mg/kg, most preferably 0.05 to 50 mg of a compound according to the invention are administered per kg of the patient's body weight.
• the glucocorticoid receptor is believed to have potential to modify a variety of diseases or disorders in mammals such as humans. These include in particular inflammatory diseases.
• Another aspect of the invention relates to a compound according to the invention for use in the treatment and/or prophylaxis of pain and/or inflammation; more preferably inflammatory pain.
• a further aspect of the invention relates to a method of treatment of pain and/or inflammation; more preferably inflammatory pain.
• reaction mixture was evaporated under reduced pressure, neutralized with saturated sodium bicarbonate solution, extracted with EtOAc, dried over Na 2 SO 4 and concentrated to afford ethyl 2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate (1.1 g, 40%) as off white solid.
• reaction mixture was concentrated under reduced pressure and diluted with EtOAc (100 mL), washed with water (2 ⁇ 100 mL), dried over anh. Na 2 SO 4 and concentrated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 0-3% MeOH in DCM) to afford benzyl (trans-2-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (1.8 g, 41%).
• reaction was carried out in four batches in parallel (4 g each) and the combined crude material was purified by column chromatography (silica gel, 100-200 mesh, 1.5-2.% MeOH/DCM as eluent) to afford trans-4-amino-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-5-phenylpyrrolidin-2-one (7.1 g, 56%) as an off-white solid.
• Step 1 Preparation of 3-Nitro-propionic acid methyl ester: To a stirred solution of 3-Bromo-propionic acid methyl ester (200 g, 1.19 mol) in DMSO (3 l) was added NaNO 2 (120.6 g, 1.74 mol) portion wise at 0° C. The resulting solution was stirred at room temperature for 24 h. After the reaction was judged to be complete, the mixture was was diluted with cold brine (1.5 L) and extracted with MTBE (3 ⁇ 1500 ml).
• reaction mixture was diluted with ethyl acetate (400 ml) and washed with water (100 ml ⁇ 2), followed by sat.NaHCO 3 (100 ml ⁇ 2). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated.
• the crude product was purified through column chromatography (using silica gel 100-200 mesh; 25-30% ethyl acetate in hexane as eluent) to afford rac-(3S,4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-phenylpyrrolidin-2-one (10 g, 43%) as brownish solid.
• reaction mixture was quenched with saturated NaHCO 3 solution at 0° C., stirred for 1 h, filtered over celite and washed with EtOAc-MeOH (500 ml, 2:1). The filtrate was concentrated to afford rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (3.9 g crude, considered as 100% yield) which was used without further purification.
• reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3 ⁇ 500 ml). The combined organics were washed with water (200 ml ⁇ 2) followed by brine (200 ml) and dried over Na 2 SO 4 . After removal of the solvent, the crude material was purified by column chromatography (using silica gel 100-200 mesh; 2-2.5% MeOH in DCM as eluent) to afford intermediate A8 benzyl (rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)carbamate (3.5 g, 53% in two steps).
• reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml ⁇ 2), followed by sat.NaHCO 3 (150 ml ⁇ 2).
• the organic layer was dried over anhydrous Na 2 SO 4 and concentrated to give rac-(4S,5R)-1-(4-methoxybenzyl)-3-methyl-4-nitro-5-(m-tolyl)pyrrolidin-2-one (7.1 g, 32.7%) as brown resin.
• reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate (3 ⁇ 75 ml). Combined organics were washed with water (50 ml ⁇ 2) followed by brine (50 ml ⁇ 2), dried over Na 2 SO 4 and concentrated.
• reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (150 ml ⁇ 2), followed by sat. aq. NaHCO 3 (150 ml ⁇ 2).
• the organic layer was dried over anhydrous Na 2 SO 4 and concentrated to afford rac-(4S,5R)-5-(2-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one (8.2 g, 40.3%) as brown solid.
• reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3 ⁇ 100 ml). The combined organic layers were washed with water (100 ml ⁇ 2) followed by brine (100 ml), dried over Na 2 SO 4 and concentrated.
• the crude product was mixed with another 1.5 g batch and the combined material was purified by column chromatography (using silica gel 100-200 mesh; 1-2% MeOH in DCM as eluent) to afford an mixture of isomers of intermediate A12-trans and intermediate A12-cis (3.3 g).
• the crude material was purified by column chromatography (using silica gel 100-200 mesh; 20-25% ethyl acetate/hexanes eluent) rac-(3S,4S,5R)-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-4-nitropyrrolidin-2-one (11.5 g, 45.7%) as brown solid.
• reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3 ⁇ 150 ml). The combined organics were washed with water (150 ml ⁇ 2) followed by brine (200 ml), dried over Na 2 SO 4 and concentrated.
• the crude material was purified by column chromatography (using silica gel 100-200 mesh; 1-2% MeOH in DCM as eluent) to intermediate A14 as an off-white solid. (2.5 g, 39% in two steps)
• reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (500 ml), followed by sat. aq. NaHCO 3 (300 ml ⁇ 3). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated.
• the obtained crude material was purified through column chromatography (using silica gel 100-200 mesh; 25-30% ethyl acetate/hexane eluent) to afford rac-(3S,4S,5S)-5-(5-chlorothiophen-2-yl)-1-(4-methoxybenzyl)-3-methyl-4-nitropyrrolidin-2-one (8 g, 28%) as a brown resin.
• reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3 ⁇ 90 ml). The combined organics were washed with water (90 ml) followed by brine (90 ml). The organic layer was dried over Na 2 SO 4 and concentrated.
• reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (300 ml), followed by sat. aq. NaHCO 3 (200 ml ⁇ 2). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated.
• the crude product was purified bycolumn chromatography (using silica gel 100-200 mesh; 25-30% ethyl acetate/hexane eluent) to afford rac-(3S,4S,5R)-3-benzyl-5-ethyl-1-(4-methoxybenzyl)-4-nitropyrrolidin-2-one (3.5 g, 28.3%) as brown oil.
• reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3 ⁇ 300 ml). The combined organic layers were washed with water (300 ml) followed by brine (300 ml), dried over Na 2 SO 4 and concentrated.
• the crude product was purified by column chromatography (using silica gel 100-200 mesh; 1.5-2% MeOH/DCM eluent) to afford intermediate A20 benzyl (rac-(2R,3S,4S)-4-benzyl-2-ethyl-5-oxopyrrolidin-3-yl)carbamate (2.95 g, 74.9%) as off white solid.
• benzyl N-[rac(2R,3S,4S)-4-methyl-5-oxo-2-phenyl-pyrrolidin-3-yl]carbamate 500 mg, 1.54 mmol
• 1-(4-fluorophenyl)-5-iodo-indazole 537 mg, 1.70 mmol
• K 3 PO 4 654 mg, 3.08 mmol
• CuI 58.7 mg, 0.308 mmol
• step 2 (rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate was used to obtain intermediate A15-trans benzyl (rac-(2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate.
• step 2 (rac-(2R,3S,4R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate was used to obtain intermediate A15-cis benzyl ((2R,3S,4S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(4-methoxyphenyl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate.
• step 2 ((2S,3S,4S)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate was deprotected to obtain intermediate A17-trans (3S,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpyrrolidin-2-one.
• step 2 ((2S,3S,4R)-2-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxopyrrolidin-3-yl)carbamate was deprotected to obtain intermediate A17-cis (3R,4S,5S)-4-amino-5-(5-chlorothiophen-2-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylpyrrolidin-2-one.
• 1,4-dioxane (19.1 mL) and trans-N,N-dimethyl cyclohexane-1,2-diamine (54.4 mg, 0.3826 mmol, 0.1 eq.) were added, and the reaction mixture was heated to 100° C. for 16 h. The reaction mixture was then cooled to ambient temperature, was diluted with DCM and sat. NaHCO 3 solution and was filtered through a hydrophobic frit. The organic solvent was removed, and the remains were purified via silica gel chromatography to yield 5-bromo-1-(4-fluorophenyl)-1H-indole in 35% yield.
• 6-Bromo-3-fluoro-pyridine-2-carbaldehyde (300.0 mg, 1.471 mmol, 1.0 eq.) and (4-fluorophenyl)hydrazine hydrochloride (239.1 mg, 1.471 mmol, 1.0 eq.) were dissolved in NMP (3.0 mL) and the resaction mixture was stirred for 90 minutes. Then, Cs 2 CO 3 (1437.8 mg, 4.412 mmol, 3.0 eq.) was added and the reaction mixture was heated to 115° C. for 90 minutes. The reaction mixture was then allowed to warm to ambient temperature, and was diluted with EtOAc and water.
• reaction mixture was then cooled to ambient temperature, was diluted with DCM and sat. NaHCO 3 solution and was filtered through a hydrophobic frit. The organic solvent was removed, and the remains were purified via silica gel chromatography to yield 4.0 mg (4%) of example 5.
• 5-Methylisoxazole-3-carboxylic acid (22.3 mg, 0.175 mmol, 1.5 eq.) was dissolved in DCM (1.2 mL), followed by the addition of triethylamine (0.05 mL, 0.351 mmol, 3.0 eq.). Then propylphosphonic anhydride solution (>50 wt. % in ethyl acetate, 0.14 mL, 2.0 eq.) was added, and the mixture was stirred at ambient temperature for 20 minutes. Then, intermediate A4 ent1 (50.0 mg, 0.117 mmol, 1.0 eq.), was added, and the mixture was stirred for 48 hours at ambient temperature.
• 1,4-dioxane 1.0 mL
• trans-N,N′-dimethyl cyclohexane-1,2-diamine 0.012 mL, 0.074 mmol, 0.4 eq.
• the mixture was then allowed to cool to ambient temperature and was diluted with sat. NaHCO 3 solution and DCM.
• the mixture was then filtered through a hydrophobic frit.
• Example 32 was prepared in analogy to the synthesis described for example 31, using intermediate B3 instead of intermediate B2 and requiring an additional HPLC purification. Yield: 35%
• Example 33 was prepared in analogy to the synthesis described for example 31, using intermediate B4 instead of intermediate B2. Yield: 32%
• intermediate C1-ent 1 150 mg, 0.33 mmol was dissolved in dry THF (3.3 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of LDA (1 M in THF/heptanes/ethyl benzene, 1.32 ml, 4.0 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI, 229 mg, 0.726 mmol, 2.2 eq.) dissolved in dry THF (1.7 mL) was added dropwise.
• LDA 1 M in THF/heptanes/ethyl benzene, 1.32 ml, 4.0 eq.
• the crude material was purified via flash chromatography (silica, cyclohexane/ethyl acetate gradient as eluent) and subsequent prep.-HPLC (water/acetonitrile gradient) to obtain example 95 (25.5 mg, 0.054 mmol, 16%) and example 96 (3.0 mg, 0.006 mmol, 2%) as white solids.
• N,N′-dimethylethylenediamine (0.032 g, 0.354 mmol, 0.4 eq) and CuI (0.033 g, 0.177 mmol, 0.2 eq) was added and the reaction mixture was stirred for 72 h at 90° C. in a sealed tube. After completion of the reaction, (monitored by TLC, TLC system 5% MeOH in DCM, R f -0.4), the reaction mixture was filtered through celite bed and washed 2-3 times with dioxane.
• N,N′-dimethylethylenediamine (0.034 g, 0.387 mmol, 0.4 eq) and CuI (0.037 g, 0.193 mmol, 0.2 eq) was added and the reaction mixture was stirred for 72 h at 90° C. in a sealed tube. After completion of the reaction, (monitored by TLC, TLC system 5% MeOH in DCM, R f -0.4), the reaction mixture was filtered through celite bed and washed 2-3 times with dioxane.
• methyl 3-cyclopropyl-2-(nitromethyl)propanoate (7.5 g, 40.06 mmol) was added to the reaction mixture followed by benzoic acid (7.34 g, 60.09 mmol) and the resulting mixture was stirred for 7-8 h at 70° C. After completion of the reaction (monitored by LCMS), the mixture was diluted with ethyl acetate (300 ml) and washed with water (200 ml), followed by sat.NaHCO 3 (100 ml ⁇ 2). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated.
• the crude product was purified by column chromatography (using silica gel 100-200 mesh; 12-15% ethyl acetate in hexanes as eluent) to afford 4 rac-(3S,4S,5R)-3-(cyclopropylmethyl)-1-(4-methoxybenzyl)-4-nitro-5-phenylpyrrolidin-2-one (7.5 g, 49.1%) as brown oil.
• rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one To a stirred solution of rac-(3S,4S,5R)-3-(cyclopropylmethyl)-4-nitro-5-phenylpyrrolidin-2-one (4 g, 15.36 mmol) in ethyl acetate-methanol (360 ml, 2:1) was added 6 N aq. HCl (118 ml) at 0° C. Zinc dust (60.29 g, 922.04 mmol) was added portionwise at the same temperature. The resulting suspension was stirred at room temperature for 16 h.
• Synthesis is of rac-(3S,4S,5R)-4-amino-3-(cyclopropylmethyl)-5-phenylpyrrolidin-2-one hydrochloride.
• intermediate C1—ent 1 150 mg, 0.33 mmol was dissolved in dry THF (3.3 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of freshly prepared LDA (1 M in THF, 0.825 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., (2-Iodoethyl)benzene (99.6 mg, 0.429 mmol, 1.3 eq.) dissolved in dry THF (1.7 mL) was added dropwise. The mixture was allowed to warm up to ⁇ 20° overnight and cooled down again to ⁇ 60° C.
• the filtrate was loaded on a strong cation exchange-cartridge (SCX, 5 g), flushed two times with ethanol (15 ml each) and eluated with 2 M NH 3 in methanol (2 ⁇ 10 mL). This procedure was repeated using the product-containing fractions two times. The clean fractions were combined, and the solvent was removed in vacuo to obtain rac-(3S,4S,5R)-4-amino-3-methyl-5-phenylpyrrolidin-2-one (296 mg, 1.56 mmol, 21%) as a colorless resin.
• SCX strong cation exchange-cartridge
• reaction control UPLC
• UPLC UPLC
• the product precipitated and was filtered off yielding N-(rac-(2R,3S,4S)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (264 mg, 1.02 mmol, 59%) as a white solid.
• the obtained material was used in the next step without further purification.
• the crude material was purified via flash chromatography (12 g silica, cyclohexane/ethyl acetate gradient as eluent) and tert-butyl rac-(3S,4S,5R)-4-(cyclopropanecarbonylamino)-3-methyl-2-oxo-5-phenyl-pyrrolidine-1-carboxylate (234 mg, 0.653 mmol, 64%) was obtained as a white solid.
• tert-butyl rac-(3S,4S,5R)-4-(cyclopropanecarbonylamino)-3-methyl-2-oxo-5-phenyl-pyrrolidine-1-carboxylate 80 mg, 0.223 mmol
• the solution was cooled down to ⁇ 78° C. and a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 0.446 ml, 0, 446 mmol, 2.0 eq) was added carefully.
• N-((2R,3R)-4-fluoro-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (27.0 mg, 0.098 mmol)
• 1-(4-fluorophenyl)-5-iodo-indazole (36.3 mg, 0.107 mmol, 1.1 eq.)
• K 3 PO 4 (41.5 mg, 0.195 mmol, 2.0 eq)
• CuI 3. mg, 0.020 mmol, 0.2 eq.
• intermediate C1—ent 1 150 mg, 0.33 mmol was dissolved in dry THF (3.3 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of freshly prepared LDA (1 M in THF, 0.825 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., 1,1-difluoro-2-iodo-ethane (82.4 mg, 0.429 mmol, 1.3 eq.) dissolved in dry THF (1.7 mL) was added dropwise. The mixture was warmed up to ⁇ 40° C. and stirred overnight at that temperature.
• 1,1-difluoro-2-iodo-ethane 82.4 mg, 0.429 mmol, 1.3 eq.
• sat. NH 4 Cl-solution was added and stirring was continued before the mixture was diluted with ethyl acetate. After the layers were separated, the organics were dried over sodium sulfate and the solvent was removed in vacuo.
• example 46 50 mg, 0.107 mmol was dissolved in dry THF (1.1 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of freshly prepared LDA (1 M in THF, 0.267 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., iodoethane (25.0 mg, 0.160 mmol, 1.5 eq.) dissolved in dry THF (0.5 mL) was added dropwise. The mixture was warmed up to ⁇ 60° C. and stirred for 90 minutes at that temperature. Then, the reaction was cooled down again to ⁇ 78° C.
• intermediate C1—ent 1 150 mg, 0.33 mmol was dissolved in dry THF (3.3 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of freshly prepared LDA (1 M in THF, 0.825 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., 1,3-Dibromopropane (93.3 mg, 0.462 mmol, 1.3 eq.) dissolved in dry THF (1.7 mL) was added dropwise. The mixture was warmed up to room temperature overnight. The mixture was cooled down again to ⁇ 20° C.
• example 106 (70 mg, 0.141 mmol) was dissolved in dry THF (1.4 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of freshly prepared LDA (1 M in THF, 0.352 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI, 66.7 mg, 0.211 mmol, 1.5 eq.) dissolved in dry THF (0.7 mL) was added dropwise. The mixture was stirred for 15 min at ⁇ 78° C. and quenched with saturated NH 4 Cl-solution.
• Example 138 was prepared in analogy to the synthesis described for example 131 using 5-(bromomethyl)-3-methyl-1,2,4-oxadiazole instead of 1,1-difluoro-2-iodo-ethane. Yield: 9%
• Examples 139a and 139b were prepared in analogy to the synthesis described for examples 131 and 132 using and 5.0 eq. of LDA and 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide instead of 1,1-difluoro-2-iodo-ethane. Yields: 7% (139a) and 6% (139b).
• example 46 (71 mg, 0.152 mmol) was dissolved in dry THF (1.5 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of freshly prepared LDA (1 M in THF, 0.379 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., 1,1-difluoro-2-iodo-ethane (43.6 mg, 0.160 mmol, 1.5 eq.) dissolved in dry THF (0.75 mL) was added dropwise. The mixture was warmed up to ⁇ 50° C. and stirred for 45 minutes at that temperature.
• example 121 150 mg, 0.295 mmol was dissolved in dry THF (3 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of freshly prepared LDA (1 M in THF, 0.737 ml, 2.5 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., iodomethane (62.8 mg, 0.442 mmol, 1.5 eq.) was added dropwise. The mixture was stirred for 45 minutes at that temperature. Then, another amount of iodomethane (42 mg, 0.110 mmol, 1 eq.) was added. After stirring for 1 h at ⁇ 78° C.
• reaction was quenched with saturated NH 4 Cl-solution and diluted with dichloromethane after stirring for 5 min.
• the layers were separated by the means of a hydrophobic frit.
• the organic layer was washed with water, separated again and dried over sodium sulfate.
• Example 149 N-(rac-(2R,3S,4S)-4-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-methyl-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (14.0 mg, 0.0268 mmol, 9%) as a colorless resin.
• intermediate C1—ent 1 150 mg, 0.295 mmol was dissolved in dry THF (4.7 ml) under inert atmosphere. The solution was cooled down to ⁇ 78° C. and a solution of freshly prepared LDA (1 M in THF, 1.32 ml, 4 eq.) was added dropwise. After stirring for 15 min at ⁇ 78° C., 2-(chloromethyl)-1,3-thiazole hydrochloride (67 mg, 0.396 mmol, 1.2 eq.) was added as a solid. The mixture was for one hour at ⁇ 40° C.
• reaction progress was monitored by TLC.
• the reaction mixture was evaporated, diluted with water (50 mL) and extracted with EtOAc (2 ⁇ 100 mL). The combined organic layers were washed with brine (50 mL), dried (Na 2 SO 4 ) and evaporated.
• the crude compound was purified by flash chromatography (silica 70-90% EtOAc in petroleum ether as an eluent) to get compound benzyl (rac-(2S,3S)-2-(5-chlorothiophen-2-yl)-2-methyl-5-oxopyrrolidin-3-yl)carbamate (2.0 g, ⁇ 41%) as an off-white solid.
• reaction progress was monitored by TLC.
• the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 ⁇ 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ) and evaporated.
• the human lymphoblast cell line IM9 (ATCC, Bethesda, Md.) was cultivated in RPMI 1640 media containing 10% fetal bovine serum, penicillin (100 U/ml), streptomycin (100 ⁇ g/ml), and 2 mM L-glutamine at 370 and 7% CO2 in a humidified incubator. Cells were centrifuged for 10 minutes at 1500 g and were washed in PBS and repelleted. Cell were then resuspended in homogenization buffer consisting of: 10 mM TES, 10 mM sodium molybdate, 1 mM EDTA, pH 7.4, 20 mM 2-mercaptoethanol, and 10% glycerol.
• Disruption of the cells was performed by nitrogen cavitation using 2 ⁇ 15 minutes at 600 to 750 psi nitrogen in a N2 cavitator at 0° C.
• the amount of protein in the supernatant fraction was determined using a BCA assay kit and aliquots were snap frozen in a dry ice-acetone bath and stored at ⁇ 70° C.
• Competitive binding assays were done in duplicate in homogenization buffer with a total volume of 200 ⁇ l.
• the reporter cell line CHO-Gal4/GR consisted of a chinese hamster ovary (CHO) cell line (Leibniz Institute DSMZ—German Collection of Microorganisms and Cell Cultures GmbH: ACC-110) containing a firefly luciferase gene under the control of the GR ligand binding domain fused to the DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR) stably integrated into CHO cells.
• This cell line was established by stable transfection of CHO cells with a GAL4-UAS-Luciferase reporter construct.
• the ligand binding domain of the GR cloned into plRES2-EGFP-GAL4 containing the DNA binding domain of GAL4 from pFA-AT2 was transfected.
• This fusion construct activated firefly luciferase expression under the control of a multimerized GAL4 upstream activation sequence (UAS).
• UAS upstream activation sequence
• the signal of the emitted luminescence was recorded by the LIPR TETRA . This allowed for specific detection of ligand-induced activation of the GR and therefore for the identification of compounds with agonistic properties.
• the GAL4/UAS reporter was premixed with a vector that constitutively expressed Renilla luciferase, which served as an internal positive control for transfection efficiency.
• the complete culture medium for the assay was:
• the reporter cell line CHO-Gal4/GR consisted of a chinese hamster ovary (CHO) cell line (Leibniz Institute DSMZ—German Collection of Microorganisms and Cell Cultures GmbH: ACC-110) containing a firefly luciferase gene under the control of the GR ligand binding domain fused to the DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR) stably integrated into CHO cells.
• This cell line was established by stable transfection of CHO cells with a GAL4-UAS-Luciferase reporter construct.
• the ligand binding domain of the GR cloned into pIRES2-EGFP-GAL4 containing the DNA binding domain of GAL4 from pFA-AT2 was transfected.
• This fusion construct activated firefly luciferase expression under the control of a multimerized GAL4 upstream activation sequence (UAS).
• UAS upstream activation sequence
• the signal of the emitted luminescence was recorded by the FLIPR TETRA . This allowed for specific detection of antagonistic properties of compounds by measuring the ligand-induced inhibition of beclometasone-activated GR.
• the GAL4/UAS reporter was premixed with a vector that constitutively expressed Renilla luciferase, which served as an internal positive control for transfection efficiency.
• the complete culture medium for the assay was:
• the example compounds wherein the substituents which are connected to the central pyrrolidone have a different relative orientation, e.g. phenyl moiety and methyl moiety up (“bold bond”, ) and amide moiety down (“hashed bond”, ) or vice versa, are the “trans” diastereomer which is a racemic mixture of the two corresponding trans enantiomers.

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